From a0e050b8065e358d2c66deb8dfbc38e9ae2d2513 Mon Sep 17 00:00:00 2001 From: Xiang Li Date: Tue, 31 Dec 2024 10:34:25 -0500 Subject: [PATCH] Add version to OncoKB data --- data/Makefile | 12 +- .../isoform_overrides_oncokb_grch37.txt | 1631 ++-- .../isoform_overrides_oncokb_grch38.txt | 1631 ++-- .../common_input/oncokb_cancer_genes_list.txt | 167 +- .../oncokb_cancer_genes_list_from_API.json | 7747 +++++++++-------- .../export/annotation_version.txt | 3 +- .../export/annotation_version.txt | 1 + .../export/annotation_version.txt | 1 + scripts/download_oncokb_isoform_overrides.py | 7 +- 9 files changed, 6262 insertions(+), 4938 deletions(-) diff --git a/data/Makefile b/data/Makefile index 2c0e7fd..7db94d5 100644 --- a/data/Makefile +++ b/data/Makefile @@ -40,6 +40,10 @@ QSIZE=1000 # Genome build(grch37 or grch38). Use in Uniprot mapping GENOME_BUILD=$(firstword $(subst _, ,$(VERSION))) +# OncoKB version. Used for downloading OncoKB cancer gene list and generating isoform overrides table. +# Check OncoKB website for the latest version number. +ONCOKB_VERSION=v4.24 + ifeq ($(GENOME_BUILD), grch38) MSKCC_ISOFORM_OVERRIDES_FILE_NAME=isoform_overrides_at_mskcc_grch38.txt ONCOKB_ISOFORM_OVERRIDES_FILE_NAME=isoform_overrides_oncokb_grch38.txt @@ -203,16 +207,16 @@ $(VERSION)/input/ensembl_biomart_ccds.txt $(VERSION)/input/ensembl_biomart_genei # download OncoKB cancer genes list # need to set ONCOKB_TOKEN first by "export ONCOKB_TOKEN=" common_input/oncokb_cancer_genes_list_from_API.json: - curl -X 'GET' "https://www.oncokb.org/api/v1/utils/cancerGeneList" -H "accept: application/json" -H "Authorization: Bearer $(ONCOKB_TOKEN)" | python -m json.tool > $@ + curl -X 'GET' "https://www.oncokb.org/api/v1/utils/cancerGeneList?version=$(ONCOKB_VERSION)" -H "accept: application/json" -H "Authorization: Bearer $(ONCOKB_TOKEN)" | python -m json.tool > $@ common_input/oncokb_cancer_genes_list.txt: - curl -X 'GET' "https://www.oncokb.org/api/v1/utils/cancerGeneList.txt" -H "accept: text/plain" -H "Authorization: Bearer $(ONCOKB_TOKEN)" > $@ + curl -X 'GET' "https://www.oncokb.org/api/v1/utils/cancerGeneList.txt?version=$(ONCOKB_VERSION)" -H "accept: text/plain" -H "Authorization: Bearer $(ONCOKB_TOKEN)" > $@ common_input/isoform_overrides_oncokb_grch37.txt: - python ../scripts/download_oncokb_isoform_overrides.py grch37 > $@ + python ../scripts/download_oncokb_isoform_overrides.py grch37 $(ONCOKB_VERSION)> $@ common_input/isoform_overrides_oncokb_grch38.txt: - python ../scripts/download_oncokb_isoform_overrides.py grch38 > $@ + python ../scripts/download_oncokb_isoform_overrides.py grch38 $(ONCOKB_VERSION)> $@ # ClinVar version # The latest version date number can be found on https://ftp.ncbi.nlm.nih.gov/pub/clinvar/vcf_GRCh37/ and https://ftp.ncbi.nlm.nih.gov/pub/clinvar/vcf_GRCh38/ diff --git a/data/common_input/isoform_overrides_oncokb_grch37.txt b/data/common_input/isoform_overrides_oncokb_grch37.txt index dd08426..af2b785 100644 --- a/data/common_input/isoform_overrides_oncokb_grch37.txt +++ b/data/common_input/isoform_overrides_oncokb_grch37.txt @@ -1,726 +1,905 @@ -enst_id ref_seq entrez_gene_id hugo_symbol oncogene highest_sensitive_level highest_resistance_level summary background tsg highest_resistanc_level -ENST00000318560 NM_005157.4 25 ABL1 True 1 R1 False R1 -ENST00000502732 NM_007314.3 27 ABL2 True False -ENST00000321945 NM_139076.2 84142 ABRAXAS1 False True -ENST00000331925 NM_001199954.1 71 ACTG1 False True -ENST00000263640 NM_001111067.2 90 ACVR1 True False -ENST00000396623 NM_144650 137872 ADHFE1 True False -ENST00000265343 NM_014423 27125 AFF4 True False -ENST00000373204 NM_012199.2 26523 AGO1 True False -ENST00000220592 NM_012154.3 27161 AGO2 False False -ENST00000262713 NM_032876.5 84962 AJUBA False True -ENST00000349310 NM_001014431.1 207 AKT1 True 3A False -ENST00000392038 NM_001626.4 208 AKT2 True False -ENST00000263826 NM_005465.4 10000 AKT3 True False -ENST00000295897 NM_000477.5 213 ALB False False -ENST00000261733 NM_000690 217 ALDH2 False True -ENST00000389048 NM_004304.4 238 ALK True 1 R2 False R2 -ENST00000319144 NM_001139.2 242 ALOX12B True True -ENST00000330258 NM_152424.3 139285 AMER1 False True -ENST00000301030 NM_013275.5 29123 ANKRD11 False True -ENST00000257430 NM_000038.5 324 APC False True -ENST00000257254 NM_005161.4 187 APLNR True True -ENST00000374690 NM_000044.3 367 AR True False -ENST00000377045 NM_001654.4 369 ARAF True 2 False -ENST00000404338 NM_004491.4 2909 ARHGAP35 True True -ENST00000426542 NM_001177693.1 64283 ARHGEF28 True False -ENST00000324856 NM_006015.4 8289 ARID1A False 4 True -ENST00000346085 NM_020732.3 57492 ARID1B False True -ENST00000334344 NM_152641.2 196528 ARID2 False True -ENST00000263620 NM_005224.2 1820 ARID3A False True -ENST00000346246 NM_001307939.1 10620 ARID3B True False -ENST00000378909 NM_001017363.1 138715 ARID3C False False -ENST00000355431 NM_002892.3 5926 ARID4A False True -ENST00000264183 NM_001206794.1 51742 ARID4B False True -ENST00000357485 NM_212481.1 10865 ARID5A False False -ENST00000279873 NM_032199.2 84159 ARID5B False True -ENST00000375687 NM_015338.5 171023 ASXL1 False True -ENST00000435504 NM_018263.4 55252 ASXL2 False True -ENST00000262053 NM_005171.4 466 ATF1 True False -ENST00000278616 NM_000051.3 472 ATM False 1 True -ENST00000295598 NM_000701 476 ATP1A1 True True -ENST00000369762 NM_001183.5 537 ATP6AP1 False False -ENST00000276390 NM_001693.3 526 ATP6V1B2 False True -ENST00000350721 NM_001184.3 545 ATR False True -ENST00000320211 NM_130384 84126 ATRIP False True -ENST00000373344 NM_000489.3 546 ATRX False True -ENST00000377617 NM_002973.3 6311 ATXN2 False True -ENST00000295900 NM_000333.3 6314 ATXN7 True False -ENST00000312783 NM_003600.2 6790 AURKA True False -ENST00000585124 NM_004217.3 9212 AURKB True False -ENST00000262320 NM_003502.3 8312 AXIN1 False True -ENST00000307078 NM_004655.3 8313 AXIN2 False True -ENST00000301178 NM_021913.4 558 AXL True False -ENST00000558401 NM_004048.2 567 B2M False True -ENST00000297574 79870 BAALC True False -ENST00000359435 NM_001033549.1 29086 BABAM1 False False -ENST00000257749 NM_001170794.1 60468 BACH2 False True -ENST00000460680 NM_004656.3 8314 BAP1 False True -ENST00000260947 NM_000465.2 580 BARD1 False 1 True -ENST00000449228 NM_001127240.2 27113 BBC3 False True -ENST00000370580 NM_003921.4 8915 BCL10 False True -ENST00000357195 NM_138576.3 64919 BCL11B False True -ENST00000333681 NM_000633.2 596 BCL2 True False -ENST00000307677 NM_138578.1 598 BCL2L1 False False -ENST00000393256 NM_138621.4 10018 BCL2L11 False True -ENST00000164227 NM_005178 602 BCL3 True False -ENST00000232014 NM_001706.4 604 BCL6 True False -ENST00000234739 NM_004326.3 607 BCL9 True False -ENST00000378444 NM_001123385.1 54880 BCOR False True -ENST00000218147 63035 BCORL1 False True -ENST00000305877 NM_004327.3 613 BCR True False -ENST00000263464 NM_182962.2 330 BIRC3 False False -ENST00000355112 NM_000057.2 641 BLM False True -ENST00000372037 NM_004329.2 657 BMPR1A False True -ENST00000288602 NM_004333.4 673 BRAF True 1 False -ENST00000357654 NM_007294.3 672 BRCA1 False 1 True -ENST00000380152 NM_000059.3 675 BRCA2 False 1 True -ENST00000303407 NM_007371 8019 BRD3 True False -ENST00000263377 NM_058243.2 23476 BRD4 True False -ENST00000259008 NM_032043.2 83990 BRIP1 False 1 True -ENST00000309383 NM_032430 84446 BRSK1 False True -ENST00000256015 NM_001731.2 694 BTG1 False True -ENST00000290551 NM_006763 7832 BTG2 False True -ENST00000308731 NM_000061.2 695 BTK True R1 False R1 -ENST00000316448 NM_004343.3 811 CALR True False -ENST00000396946 NM_032415.4 84433 CARD11 True False -ENST00000327064 NM_199141.1 10498 CARM1 False False -ENST00000358485 NM_001080125.1 841 CASP8 False True -ENST00000412916 NM_022845.2 865 CBFB False True -ENST00000264033 NM_005188.3 867 CBL False True -ENST00000276014 NM_033031.2 85417 CCNB3 True False -ENST00000227507 NM_053056.2 595 CCND1 True False -ENST00000261254 NM_001759.3 894 CCND2 True False -ENST00000372991 NM_001760.3 896 CCND3 True False -ENST00000262643 NM_001238.2 898 CCNE1 True 4 False -ENST00000576892 NM_152274.4 92002 CCNQ False True -ENST00000381577 NM_014143.3 29126 CD274 True False -ENST00000318443 NM_001024736.1 80381 CD276 True False -ENST00000324106 NM_006139.3 940 CD28 True False -ENST00000369489 NM_001779.2 965 CD58 False True -ENST00000221972 NM_001783.3 973 CD79A True False -ENST00000392795 NM_001039933.1 974 CD79B True False -ENST00000344548 NM_001791.3 998 CDC42 True False -ENST00000367435 NM_024529.4 79577 CDC73 False True -ENST00000261769 NM_004360.3 999 CDH1 False True -ENST00000447079 NM_016507.2 51755 CDK12 False 1 True -ENST00000257904 NM_000075.3 1019 CDK4 True 4 False -ENST00000265734 NM_001145306.1 1021 CDK6 True False -ENST00000381527 NM_001260.1 1024 CDK8 True False -ENST00000244741 NM_078467.2 1026 CDKN1A False True -ENST00000228872 NM_004064.3 1027 CDKN1B False True -ENST00000304494 NM_000077.4 1029 CDKN2A False 4 True -ENST00000276925 NM_004936.3 1030 CDKN2B False True -ENST00000262662 NM_078626.2 1031 CDKN2C False True -ENST00000498907 NM_004364.3 1050 CEBPA False True -ENST00000335756 NM_001809.3 1058 CENPA False False -ENST00000428830 NM_001274.5 1111 CHEK1 False 1 True -ENST00000328354 NM_007194.3 11200 CHEK2 False 1 True -ENST00000398235 NM_001039690 54921 CHTF8 False True -ENST00000575354 NM_015125.3 23152 CIC False True -ENST00000324288 NM_001286402 4261 CIITA False True -ENST00000338099 NM_001099642.1 55783 CMTR2 False True -ENST00000367669 NM_022457.5 64326 COP1 True False -ENST00000231948 NM_016302.3 51185 CRBN False True -ENST00000432329 NM_134442.3 1385 CREB1 True False -ENST00000262367 NM_004380.2 1387 CREBBP False True -ENST00000354336 NM_005207.3 1399 CRKL True False -ENST00000381566 NM_022148.2 64109 CRLF2 True False -ENST00000438362 NM_001242891.1 7812 CSDE1 False False -ENST00000286301 NM_005211.3 1436 CSF1R False False -ENST00000361632 NM_000760.3 1441 CSF3R True False -ENST00000264010 NM_006565.3 10664 CTCF False True -ENST00000302823 NM_005214.4 1493 CTLA4 True False -ENST00000349496 NM_001904.3 1499 CTNNB1 True False -ENST00000361367 NM_014633.4 9646 CTR9 False True -ENST00000264414 NM_003590.4 8452 CUL3 False True -ENST00000292535 NM_181552.3 1523 CUX1 False True -ENST00000241393 NM_003467.2 7852 CXCR4 True False -ENST00000398568 NM_001042355.1 1540 CYLD False True -ENST00000260433 NM_000103.3 1588 CYP19A1 True False -ENST00000282018 NM_020377.2 57105 CYSLTR2 True False -ENST00000374542 NM_001141970.1 1616 DAXX False True -ENST00000233078 NM_018959.3 26528 DAZAP1 False False -ENST00000292782 NM_020640.2 54165 DCUN1D1 True False -ENST00000346473 NM_001195057.1 1649 DDIT3 False False -ENST00000367921 NM_006182.2 4921 DDR2 True False -ENST00000399959 NM_001356.4 1654 DDX3X False True -ENST00000505374 NM_024415.2 54514 DDX4 True False -ENST00000507955 NM_016222.2 51428 DDX41 False True -ENST00000397239 NM_003472.3 7913 DEK True False -ENST00000393063 NM_177438.2 23405 DICER1 False True -ENST00000377767 NM_014953.3 22894 DIS3 False True -ENST00000373970 NM_012242.2 22943 DKK1 False False -ENST00000285311 NM_014421.2 27123 DKK2 False False -ENST00000326932 NM_001018057.1 27122 DKK3 False False -ENST00000220812 NM_014420.2 27121 DKK4 False False -ENST00000254322 NM_006145.1 3337 DNAJB1 False False -ENST00000340748 NM_001379.2 1786 DNMT1 True False -ENST00000264709 NM_022552.4 1788 DNMT3A False True -ENST00000328111 NM_006892.3 1789 DNMT3B False True -ENST00000398665 NM_032482.2 84444 DOT1L True False -ENST00000344624 NM_013235.4 29102 DROSHA False False -ENST00000257600 NM_004416.2 1840 DTX1 False True -ENST00000344450 NM_020185.4 56940 DUSP22 False True -ENST00000240100 NM_001394.6 1846 DUSP4 False True -ENST00000346618 NM_001949.4 1871 E2F3 True False -ENST00000367682 NM_001077706.2 345930 ECT2L False True -ENST00000263360 NM_003797.3 8726 EED False True -ENST00000308874 NM_201446.2 51162 EGFL7 True False -ENST00000275493 NM_005228.3 1956 EGFR True 1 R2 False R2 -ENST00000239938 NM_001964.2 1958 EGR1 False True -ENST00000379607 NM_001412.3 1964 EIF1AX False False -ENST00000424014 NM_001414 1967 EIF2B1 False True -ENST00000323963 NM_001967.3 1974 EIF4A2 True False -ENST00000280892 NM_001130678.1 1977 EIF4E True False -ENST00000359651 NM_004433.4 1999 ELF3 True True -ENST00000284811 NM_005648.3 6921 ELOC False False -ENST00000263253 NM_001429.3 2033 EP300 False True -ENST00000389561 NM_015409.3 57634 EP400 False True -ENST00000263734 NM_001430.4 2034 EPAS1 False False -ENST00000263735 NM_002354.2 4072 EPCAM False True -ENST00000336596 NM_005233.5 2042 EPHA3 False True -ENST00000273854 NM_004439.5 2044 EPHA5 False False -ENST00000369303 NM_004440.3 2045 EPHA7 True True -ENST00000398015 NM_004441.4 2047 EPHB1 False True -ENST00000222139 NM_000121.3 2057 EPOR True False -ENST00000269571 NM_004448.2 2064 ERBB2 True 1 False -ENST00000267101 NM_001982.3 2065 ERBB3 True False -ENST00000342788 NM_005235.2 2066 ERBB4 True False -ENST00000391945 NM_000400.3 2068 ERCC2 False 3A True -ENST00000285398 NM_000122.1 2071 ERCC3 False True -ENST00000311895 NM_005236.2 2072 ERCC4 False True -ENST00000355739 NM_000123.3 2073 ERCC5 False True -ENST00000222329 NM_006494.2 2077 ERF False True -ENST00000288319 NM_182918.3 2078 ERG True False -ENST00000377482 NM_018948.3 54206 ERRFI1 False True -ENST00000305188 NM_001017420.2 157570 ESCO2 False True -ENST00000206249 NM_001122740.1 2099 ESR1 True 1 False -ENST00000272342 NM_019002.3 54465 ETAA1 False True -ENST00000266517 NM_018638.4 55500 ETNK1 False False -ENST00000405192 NM_001163147.1 2115 ETV1 True False -ENST00000319349 NM_001079675.2 2118 ETV4 True False -ENST00000306376 NM_004454.2 2119 ETV5 True False -ENST00000396373 NM_001987.4 2120 ETV6 False True -ENST00000397938 NM_005243.3 2130 EWSR1 True False -ENST00000378204 NM_000127 2131 EXT1 False True -ENST00000428826 NM_001991.3 2145 EZH1 True False -ENST00000320356 NM_004456.4 2146 EZH2 True 1 True -ENST00000342995 NM_203407.2 340602 EZHIP True False -ENST00000389301 NM_000135.2 2175 FANCA False True -ENST00000289081 NM_000136.2 2176 FANCC False True -ENST00000383807 NM_001018115.1 2177 FANCD2 False True -ENST00000233741 NM_018062.3 55120 FANCL False 1 True -ENST00000355740 NM_000043.4 355 FAS False True -ENST00000441802 NM_005245.3 2195 FAT1 False True -ENST00000403359 NM_001190274.1 80204 FBXO11 False True -ENST00000608872 NM_012164 26190 FBXW2 False False -ENST00000281708 NM_033632.3 55294 FBXW7 False True -ENST00000295727 NM_017521.2 54738 FEV False False -ENST00000294312 NM_005117.2 9965 FGF19 True False -ENST00000334134 NM_005247.2 2248 FGF3 True False -ENST00000168712 NM_002007.2 2249 FGF4 True False -ENST00000425967 NM_001174067.1 2260 FGFR1 True 1 False -ENST00000358487 NM_000141.4 2263 FGFR2 True 1 False -ENST00000260795 NM_000142.4 2261 FGFR3 True 1 False -ENST00000292408 NM_213647.1 2264 FGFR4 True False -ENST00000366560 NM_000143.3 2271 FH False True -ENST00000285071 NM_144997.5 201163 FLCN False True -ENST00000527786 NM_002017.4 2313 FLI1 True 4 False -ENST00000282397 NM_002019.4 2321 FLT1 True False -ENST00000241453 NM_004119.2 2322 FLT3 True 1 False -ENST00000261937 NM_182925.4 2324 FLT4 True False -ENST00000250448 NM_004496.3 3169 FOXA1 True True -ENST00000262426 NM_001451.2 2294 FOXF1 True True -ENST00000330315 NM_023067.3 668 FOXL2 True True -ENST00000379561 NM_002015.3 2308 FOXO1 False True -ENST00000318789 NM_001244814.1 27086 FOXP1 True True -ENST00000370768 NM_003902.3 8880 FUBP1 False True -ENST00000268171 NM_001289823.1 5045 FURIN True False -ENST00000254108 NM_004960 2521 FUS True False -ENST00000368678 NM_153047.3 2534 FYN True False -ENST00000395095 NM_001136198 51343 FZR1 True True -ENST00000262994 NM_002039.3 2549 GAB1 True False -ENST00000361507 NM_080491.2 9846 GAB2 True False -ENST00000376670 NM_002049.3 2623 GATA1 False False -ENST00000341105 NM_032638.4 2624 GATA2 True False -ENST00000346208 NM_002051.2 2625 GATA3 True True -ENST00000228682 NM_005269.2 2735 GLI1 True False -ENST00000078429 NM_002067.2 2767 GNA11 True False -ENST00000275364 NM_007353.2 2768 GNA12 True False -ENST00000439174 NM_006572.5 10672 GNA13 True False -ENST00000286548 NM_002072.3 2776 GNAQ True False -ENST00000371085 NM_000516.4 2778 GNAS True False -ENST00000378609 NM_001282539.1 2782 GNB1 True False -ENST00000380728 NM_004489.4 2874 GPS2 False True -ENST00000300177 NM_013372.6 26585 GREM1 True False -ENST00000330684 NM_001134407.1 2903 GRIN2A False True -ENST00000316626 NM_002093.3 2932 GSK3B True False -ENST00000324896 NM_032999.3 2969 GTF2I True False -ENST00000343677 NM_005319.3 3006 H1-2 False False -ENST00000244534 NM_005320.2 3007 H1-3 False True -ENST00000304218 NM_005321.2 3008 H1-4 True False -ENST00000331442 NM_005322.2 3009 H1-5 False True -ENST00000358739 NM_003509.2 8969 H2AC11 False False -ENST00000357320 NM_003511 8332 H2AC16 False False -ENST00000359611 NM_003514 8336 H2AC17 True False -ENST00000314088 NM_003512.3 8334 H2AC6 False False -ENST00000339812 NM_021058.3 8970 H2BC11 False False -ENST00000356950 NM_080593.2 85236 H2BC12 False False - 8348 H2BC17 False False -ENST00000314332 NM_003518.3 8347 H2BC4 False False -ENST00000289316 NM_021063.3 3017 H2BC5 False False -ENST00000244601 NM_003518 8339 H2BC8 False False -ENST00000366813 NM_002107.4 3020 H3-3A True False -ENST00000254810 NM_005324.3 3021 H3-3B False False -ENST00000366696 NM_003493.2 8290 H3-4 False False -ENST00000340398 NM_001013699.2 440093 H3-5 False False -ENST00000357647 NM_003529.2 8350 H3C1 False False -ENST00000369163 NM_003536.2 8357 H3C10 False False -ENST00000328488 NM_003533.2 8354 H3C11 False False -ENST00000359303 NM_003535.2 8356 H3C12 False False -ENST00000331491 NM_001123375.2 653604 H3C13 False False -ENST00000369158 NM_021059.2 126961 H3C14 False False -ENST00000403683 NM_001005464.2 333932 H3C15 False False -ENST00000244661 NM_003537.3 8358 H3C2 False False -ENST00000540144 NM_003531.2 8352 H3C3 False False -ENST00000356476 NM_003530.4 8351 H3C4 False False -ENST00000360408 NM_003532.2 8353 H3C6 False False -ENST00000446824 NM_021018.2 8968 H3C7 False False -ENST00000305910 NM_003534.2 8355 H3C8 False False -ENST00000316450 440926 H3P6 False False -ENST00000373548 NM_004964.2 3065 HDAC1 True False -ENST00000345617 NM_006037.3 9759 HDAC4 True True -ENST00000427332 XM_011538481.1 51564 HDAC7 True False -ENST00000222390 NM_000601.4 3082 HGF True False -ENST00000337138 NM_001530.3 3091 HIF1A True False -ENST00000376809 NM_001242758.1 3105 HLA-A False True -ENST00000412585 NM_005514.6 3106 HLA-B False True -ENST00000376228 NM_002117.5 3107 HLA-C False True -ENST00000311487 NM_145899 3159 HMGA1 True False -ENST00000403681 NM_003483 8091 HMGA2 True False -ENST00000257555 NM_000545.5 6927 HNF1A False True -ENST00000290295 NM_006361.5 10481 HOXB13 True True 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STK40 False False -ENST00000369902 NM_016169.3 51684 SUFU False True -ENST00000322652 NM_015355.2 23512 SUZ12 False True -ENST00000375746 NM_003177.5 6850 SYK True False -ENST00000294339 NM_001287347.2 6886 TAL1 True False -ENST00000354258 NM_000593.5 6890 TAP1 False False -ENST00000374899 NM_018833.2 6891 TAP2 False False -ENST00000430069 NM_024665.4 79718 TBL1XR1 False True -ENST00000257566 NM_016569.3 6926 TBX3 False True -ENST00000344749 NM_001136139.2 6929 TCF3 False True -ENST00000543371 NM_001146274.1 6934 TCF7L2 False True -ENST00000402399 NM_001098725.1 8115 TCL1A True False -ENST00000340722 NM_004918.3 9623 TCL1B True False -ENST00000380036 NM_000459.3 7010 TEK False False -ENST00000369448 NM_017709.3 54855 TENT5C False True -ENST00000310581 NM_198253.2 7015 TERT True False -ENST00000373644 NM_030625.2 80312 TET1 False True -ENST00000380013 NM_001127208.2 54790 TET2 False True -ENST00000409262 NM_144993 200424 TET3 False True -ENST00000315869 NM_006521.5 7030 TFE3 True False -ENST00000374994 NM_004612.2 7046 TGFBR1 False True -ENST00000295754 NM_003242.5 7048 TGFBR2 False True -ENST00000376499 NM_001303103.1 7088 TLE1 False False -ENST00000262953 NM_003260.4 7089 TLE2 False False -ENST00000558939 NM_005078.3 7090 TLE3 False False -ENST00000376552 NM_007005.4 7091 TLE4 False False -ENST00000370196 NM_005521.3 3195 TLX1 True False -ENST00000296921 NM_021025.2 30012 TLX3 True False -ENST00000258439 NM_001193304.2 55654 TMEM127 False True -ENST00000398585 NM_001135099.1 7113 TMPRSS2 False False -ENST00000237289 NM_006290.3 7128 TNFAIP3 False True -ENST00000355716 NM_003820.2 8764 TNFRSF14 False True -ENST00000361337 NM_003286.2 7150 TOP1 False True -ENST00000269305 NM_000546.5 7157 TP53 False 3A True -ENST00000382044 NM_001141980.1 7158 TP53BP1 False True -ENST00000264731 NM_003722.4 8626 TP63 True True - 6955 TRA True False -ENST00000247668 NM_021138.3 7186 TRAF2 False False -ENST00000392745 NM_003300.3 7187 TRAF3 False True -ENST00000261464 NM_001033910.2 7188 TRAF5 False True -ENST00000326181 NM_032271.2 84231 TRAF7 False False - 6957 TRB True False - 6964 TRD True False - 6965 TRG True False -ENST00000377199 NM_006510 5987 TRIM27 True False -ENST00000166345 NM_004237.3 9319 TRIP13 True True -ENST00000298552 NM_000368.4 7248 TSC1 False 1 True -ENST00000219476 NM_000548.3 7249 TSC2 False 1 True -ENST00000298171 NM_000369.2 7253 TSHR True False -ENST00000264818 NM_003331.4 7297 TYK2 True False -ENST00000291552 NM_006758.2 7307 U2AF1 True 4 False -ENST00000308924 NM_007279.2 11338 U2AF2 False False -ENST00000520539 NM_015902.5 51366 UBR5 True False -ENST00000262803 NM_002911.3 5976 UPF1 False False -ENST00000307179 NM_001128610.2 9101 USP8 True False -ENST00000602142 NM_005428.3 7409 VAV1 True False -ENST00000371850 NM_001134398.1 7410 VAV2 True False -ENST00000523873 NM_001171623.1 7422 VEGFA True False -ENST00000256474 NM_000551.3 7428 VHL False True -ENST00000369458 NM_024626.3 79679 VTCN1 False False -ENST00000286574 NM_007191.4 11197 WIF1 False True -ENST00000332351 NM_024426.4 7490 WT1 True True -ENST00000265428 NM_007013.3 11059 WWP1 True False -ENST00000360632 NM_001168280.1 25937 WWTR1 True False -ENST00000216037 NM_005080.3 7494 XBP1 True False -ENST00000355640 NM_001167.3 331 XIAP True False -ENST00000401558 NM_003400.3 7514 XPO1 True False -ENST00000359321 NM_005431.1 7516 XRCC2 False True -ENST00000282441 NM_001130145.2 10413 YAP1 True False -ENST00000314574 NM_005433.3 7525 YES1 True False -ENST00000262238 NM_003403.4 7528 YY1 True False -ENST00000474710 NM_001164342.2 26137 ZBTB20 True True -ENST00000268489 NM_006885.3 463 ZFHX3 False True -ENST00000336440 NM_001244698.1 677 ZFP36L1 False True -ENST00000282388 NM_006887.4 678 ZFP36L2 False True -ENST00000269394 NM_024702.2 79755 ZNF750 False True -ENST00000544604 NM_001206998.1 84133 ZNRF3 False True -ENST00000307771 NM_005089.3 8233 ZRSR2 False 4 False +enst_id ref_seq entrez_gene_id hugo_symbol oncogene highest_sensitive_level highest_resistance_level summary background highest_resistanc_level tsg +ENST00000265724 NM_000927.4 5243 ABCB1 True ABCB1, an ATP-binding cassette transporter, is altered through amplification in various cancers. ABCB1, a member of the ATP-binding cassette (ABC) transporter family, encodes for a membrane-associated glycoprotein that functions as an efflux pump that transports endogenous molecules and xenobiotics across the blood-brain barrier (PMID: 990323, 2563168, 7910522). ABCB1, also called multi-drug resistance protein 1 (MRD1), has been identified to confer drug resistance when overexpressed in various cancers (PMID: 18056183, 1968964, 7946563, 11294418). As an efflux pump, ABCB1 can reduce the effectiveness of chemotherapies, such as doxorubicin, cisplatin and 5-fluorouracil, by reducing intracellular drug concentration (PMID: 32525624, 34031441, 28340578). ABCB1 overexpression has been identified in various cancers demonstrating chemotherapy resistance, including pancreatic cancer, breast cancer and ovarian cancer (PMID: 38163893, 38020048, 27415012). Preclinical studies demonstrate inhibition of ABCB1 can restore sensitivity to chemotherapeutic drugs in various cancer models (PMID: 36674503, 38367548). False +ENST00000318560 NM_005157.4 25 ABL1 True 1 R1 ABL1, a tyrosine kinase, is frequently altered by chromosomal translocations in leukemia. ABL1 (also ABL) is a non-receptor tyrosine kinase with ubiquitous cellular expression. ABL is located both in the cytoplasm and nucleus and can be activated by growth factor receptors, cellular kinases or DNA damage (PMID: 24421390, 1591775). In response to extrinsic ligand stimulation, ABL signaling regulates cellular proliferation, differentiation, apoptosis, and migration (PMID: 7651539, 7512450). ABL has additional cellular roles including regulation of actin polymerization, vascular development, transcription, and T cell maturation (PMID: 24421390). In chronic myelogenous leukemia (CML) and Philadelphia chromosome-positive acute lymphocytic leukemia (Ph+ ALL), translocations between the ABL and BCR genes result in the driver fusion protein BCR-ABL (PMID: 3460176, 2825022). The BCR-ABL fusion protein is a constitutively activated oncogenic tyrosine kinase that causes ligand-independent activation of signaling pathways in hematopoietic cells (PMID: 3460176, 2825022). The BCR-ABL fusion protein results in loss of auto-inhibition of ABL leading to activation of the kinase (PMID: 8246975). Alternative ABL1 translocations are also observed in myeloid disease (PMID: 9695962). Small molecule inhibitors of BCR-ABL, imatinib and dasatinib, have been developed and are FDA-approved for CML and Ph+ALL (PMID:11870241, 21931113). Mutations in the ABL kinase domain lead to resistance to these treatments and determine sensitivity to other second-generation inhibitors (PMID: 15256671). R1 False +ENST00000502732 NM_007314.3 27 ABL2 True ABL2, a tyrosine kinase, is altered by chromosomal rearrangement in acute lymphoblastic leukemia. ABL2 is a non-receptor tyrosine kinase that is a member of the ABL protein family (PMID: 26645050). ABL2 localizes to actin protrusions and mediates the formation and stabilization of actin filaments in coordination with cortactin (PMID: 30256707). β1 integrins signal via ABL2 pathways to control several cellular processes including neuronal stability, cell adhesion, cell migration, and invasion (PMID: 30256707, 25694433, 23365224). Phosphorylation of ABL2 by receptor tyrosine kinases and SRC family kinases results in ABL2 activation, autophosphorylation and subsequent activation of downstream signaling molecules, such as the transcription factor STAT3 (PMID: 21892207). ABL2 is localized in the cytoplasm and is overexpressed in a variety of solid tumors, resulting in enhanced cellular proliferation, invasion, and metabolic changes (PMID: 26645050). Recurrent ABL2 fusion proteins are found in patients with acute lymphoblastic leukemias and gangliogliomas (PMID: 29507076, 29880043, 25098428, 10706884). ABL2 fusions result in increased ABL2-mediated signaling, suggesting that ABL2 functions as an oncogene (PMID: 25207766). ABL-targeted small molecule kinase inhibitors may be efficacious in cancers with ABL2 positive rearrangements (PMID: 29464092, 19451690, 25207766). False +ENST00000321945 NM_139076.2 84142 ABRAXAS1 False ABRAXAS1, a tumor suppressor and DNA repair protein, is recurrently altered by mutation and deletion in various cancer types. The ABRAXAS1 is a DNA repair protein that mediates recruitment of BRCA1 to DNA double-strand breaks (DSBs) for DNA damage checkpoint regulation and DNA damage repair through direct binding to BRCA1. The ABRAXAS1-BRCA1 complex plays an important role in tumor suppression. ABRAXAS1 copy loss and somatic mutations have been observed in multiple human cancers, including endometrial, colon, lung, liver, kidney cancers, and in leukemia, with the highest mutation rate found in endometrial cancer (2.5%) (PMID: 25066119). A novel germ line mutation in Abraxas which abrogates BRCA1-dependent DNA repair function has been identified and shown to increases familial breast cancer susceptibility (PMID: 22357538). True +ENST00000272928 NM_020311 57007 ACKR3 True ACKR3, a chemokine receptor, is infrequently altered in cancer. ACKR3, also known as CXCR7, encodes for the atypical chemokine scavenger receptor specific for stromal-derived factors CXCL12 and CXCL11 (PMID: 16107333, 16940167). The ACKR3-CXCL12 signaling axis promotes cancer cell survival, migration, adhesion, angiogenesis and metastasis from ERK activation through MAPK signaling (PMID: 16940167, 20018651). As a scavenger receptor, ACKR3 is responsible for creating a CXCL12 gradient and influences cell migration and weakens CXCR4 activity through ACKR-CXCL12 internalization (PMID: 18267076). The oncogenic and tumor suppressive role of ACKR3 is likely tissue-type specific. Overexpression and silencing of ACKR3 in breast cancer and lung cancer cell lines and mouse models demonstrate tumorigenesis and cell survival (PMID: 17898181). In contrast, ACKR3 activation in neuroblastoma and colon cancer cell lines demonstrates suppression of tumor growth, cell growth and migration (PMID: 22916293, 24255072). Amplification of ACKR3 has been identified in various cancers, including breast cancer and hepatocellular carcinoma (PMID: 27572688, 26912435). Downregulation of ACKR3 has been identified in undifferentiated neuroblastoma (PMID: 22916293). Loss of ACKR3 in non-small cell lung cancer cell models has demonstrated attenuation of EGFR tyrosine kinase inhibitor resistance through inhibition of the MAPK-ERK signaling pathway (PMID: 31273063). True +ENST00000331925 NM_001199954.1 71 ACTG1 False ACTG1, a cytoskeletal protein, is infrequently altered across various cancer types. ACTG1 is a cytoskeletal protein that is a member of the actin family (PMID: 24098136, 19497859, 6420066). Actin proteins comprise cellular filaments and can be classified into three groups: alpha, beta and gamma actin, with ACTG1 functioning as cytoplasmic gamma-actin (PMID: 24098136). ACTG1 is highly expressed in the cytoskeleton of diverse cell types, as well as in the Z-discs and costamere structures of adult striated muscles (PMID: 6420066). ACTG1 monomers are important for a variety of cellular functions including cell motility, muscle contraction, cell signaling, cell junction establishment and maintenance of cell shape (PMID: 24098136). ACTG1, along with ACTB, is highly expressed in dividing cells and is critical for adequate muscle function (PMID: 6420066). Germline mutations in ACTG1 have been identified in patients with hearing loss and in Baraiser-Winter Syndrome, a developmental disorder characterized by short stature, ptosis and hearing loss (PMID: 13680526, 14684684, 22366783). Somatic ACTG1 mutations are relatively rare in human cancers; however, a SNP in ACTG1 is associated with extreme toxicity to vincristine, a therapy commonly used to treat childhood acute lymphoblastic leukemia (PMID: 25084203). Overexpression of ACTG1 has also been implicated in hepatocellular carcinoma with mechanisms related to altered glucose metabolism and cellular proliferation (PMID: 30881024, 30675230). True +ENST00000263640 NM_001111067.2 90 ACVR1 True ACVR1, a receptor protein, is mutated in various cancer types including diffuse intrinsic pontine glioma (DIPG). ACVR1 (activin receptor type 1), also known as ALK2, is a transmembrane protein with cytosolic serine/threonine kinase activity that participates in signaling of transforming growth factor β (TGF-B) superfamily members. It signals by binding to bone morphogenetic proteins (BMPs) and activins and forms a heteromeric complex with other receptors. This complex is composed of two type 1 receptors, which are essential for intracellular signaling, and two type 2 receptors, which are essential for ligand binding. Binding of the ligand to the type 2 receptor stabilizes the complex and results in phosphorylation of type 1 receptors, thus resulting in downstream signaling mediated by the SMAD family of proteins (PMID: 15621726). In normal tissues, signaling through ACVR1 regulates cell survival, differentiation and proliferation. Somatic gain-of-function mutations in ACVR1 are the basis of the autosomal dominant condition fibrodysplasia ossificans progressive (FOP), which results in heterotopic ossification in humans (PMID: 25337067), and similar mutations are present in diffuse intrinsic pontine glioma (DIPG) (PMID: 24769718). False +ENST00000257963 NM_004302 91 ACVR1B False ACVR1B, an activin receptor, is infrequently altered in cancer. ACVR1B encodes for a serine/threonine kinase activin A type IB receptor that functions as a transducer for activin-like ligands that are growth and differentiation factors (PMID: 30335480). ACVR1B mediates TGF-β pathway activation through phosphorylation of the SMAD proteins (PMID: 15689496, 30335480). Knockdown of ACVR1B in pancreatic cancer cell lines and models induces cellular growth, tumorigenesis and dysregulated TGF-β signaling, suggesting that ACVR1B functions predominantly as a tumor suppressor gene (PMID: 11248065, 24886203). Inactivating mutations of ACVR1B have been identified in pancreatic cancer and ER-negative breast cancer (PMID: 24886203, 26408346, 8519692). True +ENST00000241416 NM_001278579 92 ACVR2A True ACVR2A, an activin receptor, is infrequently altered in cancer. ACVR2A encodes for a serine/threonine kinase activin A type II receptor that functions as a transducer for activin-like ligands that are growth and differentiation factors (PMID: 35643319). ACVR2A regulates various biological processes through the mediation of TGF-β pathway activation and phosphorylation of SMAD proteins (PMID: 26497569, 32235336, 28569204). Mutations of ACVR2A are associated with an increased risk of the hypertension disorder preeclampsia (PMID: 29506428, 19126782). The oncogenic function of ACVR2A is likely tissue-specific. Knockdown of ACVR2A in colorectal cancer cell lines induces increased cellular migration, suggesting that ACVR2A functions predominantly as a tumor suppressor gene in this context (PMID: 30310521). However, ectopic expression of ACVR2A in gastric cancer cell lines induces increased cellular proliferation, migration and invasion, suggesting that ACVR2A functions predominantly as an oncogene in this context (PMID: 33420656, 32440149). Loss of ACVR2A expression and ACVR2A mutations are frequently identified in microsatellite instability-high cancers, including colorectal cancer and gastric cancer (PMID: 14988818, 32440149). True +ENST00000381312 NM_018702.3 105 ADARB2 True ADARB2, a double-stranded RNA adenosine deaminase, is infrequently altered in cancer. ADARB2, a member of the RNA-editing enzyme family, encodes for a double-stranded RNA adenosine deaminase that lacks RNA-editing activity (PMID: 10836796, 8943218). Despite lacking deaminase activity to initiate adenosine-to-inosine RNA-editing, ADARB2 has been suggested to regulate the activity of other ADAR-family RNA-editing enzymes through binding of double- and single-stranded RNA (PMID: 10836796, 35850307). ADARB2 is predominantly expressed in brain tissue and functions in regulating long-term memory formation and cognitive processes, however, the underlying molecular mechanism of such is unclear (PMID: 29719497). Overexpression of ADARB2 in glioblastoma cell lines and models inhibits RNA-editing of glutamate receptor GRIA2 and subsequently promotes cellular migration and invasion, suggesting that ADARB2 functions predominantly as an oncogene (PMID: 28167531). ADARB2 amplification has been identified in glioblastoma (PMID: 35922651). Preclinical studies suggest that ADARB2 overexpression in glioblastoma confers resistance to temozolomide (PMID: 35922651). False +ENST00000412232 NM_032777 25960 ADGRA2 True ADGRA2, an adhesion G protein-coupled receptor, is infrequently altered in cancer. ADGRA2, an orphan member of the adhesion G protein-coupled receptor family, encodes for an endothelial transmembrane receptor that functions primarily in regulating angiogenesis (PMID: 21071672, 25373781). ADGRA2 is a WNT7-specific coactivator that drives WNT signaling, and thus angiogenesis, through interaction with the GPI-anchored glycoprotein RECK in the central nervous system (PMID: 30026314, 21071672). Interaction between ADGRA2 and RECK is essential for neural crest development and regulation of the blood-brain barrier (PMID: 27979884, 28803732, 28858624). Mutations in ADGRA2 have been associated with hemorrhagic transformation and increased parenchymal hematoma risk (PMID: 32991049). Overexpression of ADGRA2 in various cancer cell lines and models induces cellular adhesion and increased cellular proliferation, suggesting that ADGRA2 functions predominantly as an oncogene (PMID: 28600358, 29402834). ADGRA2 alterations have been identified in colon cancer and leiomyosarcoma (PMID: 29844865, 31300531). False +ENST00000394143 NM_153834.3 139378 ADGRG4 False ADGRG4, a class B adhesion G protein-coupled receptor, is infrequently altered in cancer. ADGRG4, a member of the subfamily G of the class B adhesion G protein-coupled receptors, encodes for an orphaned G protein-coupled receptor (PMID: 37863265). ADGRG4 is theorized to have functional relevance as an in vivo sensor for mechanical forces in enterochromaffin and Paneth cells of the small intestine (PMID: 37863265). Although there is a lack of functional evidence demonstrating the biological and oncogenic function of ADGRG4, it has been identified as frequently mutated and amplified in various cancers, suggesting a possible role as an oncogene. Amplification of ADGRG4 has been identified in patients with uterine corpus endometrial cancer and breast cancer, and is correlated with poor overall survival (PMID: 35413679, 38834774). False +ENST00000396623 NM_144650 137872 ADHFE1 True ADHFE1, a hydroxyacid-oxoacid transhydrogenase, is infrequently altered in cancer. ADHFE1 encodes the hydroxyacid-oxoacid transhydrogenase enzyme which functions in the oxidation of gamma-hydroxybutyrate to succinic semialdehyde in mammalian tissue (PMID: 16616524). This oxidation reaction is coupled to the reduction of 2-ketoglutarate to D-2-hydroxyglutarate (PMID: 30250890). The promotion of reductive carboxylation by ADHFE1 supports increased acetyl-CoA synthesis and lipogenesis (PMID: 22106302). As ADHFE1 regulates multiple cellular functions, such as DNA replication and cell cycle control, depending on the tissue, its role in cancer has varied depending on cancer type (PMID: 34179501). MYC-induced overexpression of ADHFE1 in breast cancer cell lines promotes tumorigenesis through the accumulation of D-2-hydroxyglutarate and mitochondrial ROS, suggesting that ADHFE1 functions primarily as an oncogene in breast cancer (PMID: 29202474, 30250890). However, silencing of ADHFE1 in colorectal cancer patient-derived xenograft mice models and colorectal cancer cell lines increases tumor growth and cell proliferation (PMID: 31632063). Hypermethylation of ADHFE1 has been identified in various different types of cancer, including breast cancer, colon cancer and gastric cancer (PMID: 34179501). False +ENST00000351017 4301 AFDN False AFDN, a scaffold protein, is infrequently altered in cancer. AFDN encodes for a multi-domain scaffold protein that functions primarily in cell-cell adhesion processes through interaction with adhesion molecules at adherens junctions (PMID: 10477764, 30463011). AFDN maintains the structural integrity of epithelial cells through interaction with nectin and the actin cytoskeleton (PMID: 11024295). Knockdown of AFDN in various cancer cell lines and models induces cellular migration, invasion and tumor growth, suggesting that AFDN functions predominantly as a tumor suppressor gene (PMID: 21478912, 25879875, 39047222, 35931706). AFDN loss has been identified in breast cancer and is associated with poor patient outcomes (PMID: 21478912). AFDN has been identified as a recurrent fusion partner with the gene KMT2A in acute myeloid leukemias with the t(6;11)(q27;q23) translocation (PMID: 34894139, 34864370). True +ENST00000265343 NM_014423 27125 AFF4 True AFF4, a scaffolding protein involved in transcriptional regulation, is infrequently altered in cancer. "AFF4 (AF4/FMR2 family member 4 ) is a scaffolding protein that helps assemble and is a core component of the transcription super elongation complex (SEC) (PMID: 31147444, PMID: 22895430). The SEC functions to remove RNA polymerase II from proximal-promoter pausing, thus regulating the rapid induction of gene transcription. AFF4 has also been shown to play a role in the transcriptional activation of HIV-1 viral genes (PMID: 28134250, PMID: 26007649). AFF4 has many direct transcriptional targets such as MYC and JUN, and has been linked to transcriptional upregulation of TMEM100, ZNF711, and FAM13C, among others (PMID: 25730767). Germline gain-of-function mutations in the highly conserved fourteen amino acid ALF (AF4/LAF4/FMR2) homology domain of AFF4 underlie the germline syndrome CHOPS (C-cognitive impairment and coarse facies; H-heart defects; O-obesity; P-pulmonary involvement; S-short stature and skeletal dysplasia)(PMID: 25730767, PMID: 31058441). AF4-domain-mutation of the AFF4 gene specifically in Purkinje cells in the brain was identified as the cause of neurodegeneration in a ""robotic mouse"" model that developed early-onset de novo ataxia and cataracts (PMID: 12629167). In cancer, alterations of the SEC can allow unregulated transcriptional elongation and lead to tumorigenesis. AFF4-KMT2A (MLL) fusions have been identified in pediatric acute leukemia, whereby the AF4 domain of AFF4 interacts with selectivity factor 1 (SL1) on chromatin to load TATA-binding protein (TBP) onto the promoter to initiate RNA polymerase II-dependent and constitutive transcription (PMID: 28701730, PMID: 27865805, PMID: 26593443). Overexpression of AFF4 has been observed in human head and neck squamous cell cancer (HNSCC) (PMID: 29741610) and melanoma (PMID: 33417923). In preclinical models, AFF4 overexpression enhanced proliferation, migration and invasion of HNSCC and melanoma cells through SOX-2 and c-Jun, which could be reversed with AFF4 depletion via siRNA. In bladder cancer cell line models, METTL3, an important RNA N6-adenosine methyltransferase, was found to be overexpressed resulting in m6A modification of AFF4, leading to enhanced promoter binding and transcription of MYC (PMID: 30659266)." False +ENST00000312916 NM_018046.4 55109 AGGF1 True AGGF1, an angiogenic factor, is infrequently altered in cancer. AGGF1 encodes for an angiogenic factor that functions in regulating angiogenesis and vascular development (PMID: 27522498). AGGF1 interacts with the angiogenic factor TNFSF12 and activates the AKT signaling pathway to promote angiogenesis (PMID: 14961121, 27522498). Germline mutations of AGGF1 have been implicated in the congenital condition Klippel-Trenaunay syndrome (PMID: 27522498, 23197652). Overexpression of AGGF1 in various cancer cell lines and models induces increased tumor angiogenesis and vascular invasion, suggesting that AGGF1 functions predominantly as an oncogene (PMID: 25796501, 34354374, 31881864). AGGF1 amplification has been identified in various cancers, including hepatocellular carcinoma and colorectal cancer (PMID: 29340079, 31881864). False +ENST00000373204 NM_012199.2 26523 AGO1 True AGO1, an enzyme involved in RNA-mediated gene silencing, is overexpressed in various cancer types. AGO1 (also Argonaute-1) is an RNA silencing protein that is a member of the Argonaute family (PMID: 15105377, 23746446). AGO1 regulates RNA-mediated gene silencing, or RNA interference (RNAi) (PMID: 15105377, 23746446). Argonaute proteins are an essential component of the RNA-induced silencing complex (RISC), which is guided to mRNA targets by mircoRNAs (miRNAs) and small interfering RNAs (siRNAs) (PMID: 19239886, 23654304, 17928262). Upon single-stranded RNA-mediated complementarity-based recognition of mRNAs, AGO1 inhibits translation of the mRNA target (PMID: 22231398). In addition, AGO1 has diverse roles in the regulation of small RNA processing including translation repression, regulation of miRNA maturation and heterochromatin formation (PMID: 22961379, 22231398). AGO1 is altered by overexpression in various cancers, such as in colorectal and hepatocellular cancer (PMID: 29487329, 20146808). Somatic mutations in AGO1 have been identified, however, have not been functionally characterized. Loss of AGO1 in hepatocellular cancer cell lines resulted in decreased proliferation and invasion, suggesting that AGO1 functions as an oncogene (PMID: 29487329, 24086155). False +ENST00000220592 NM_012154.3 27161 AGO2 False AGO2, an enzyme involved in the RNA-mediated gene silencing, is overexpressed in various cancer types. AGO2 is an essential protein that regulates RNA-mediated gene silencing, or RNA interference (RNAi). AGO2 is the catalytic component of the RNA-induced silencing complex (RISC) and has endonuclease activity (PMID: 15105377, 23746446). Upon single-stranded RNA-mediated, complementarity-based recognition of mRNAs, AGO2 either cleaves or inhibits translation of its targets (PMID: 19239886, 23654304). In addition, AGO2 has diverse roles in the regulation of small RNA processing including translation repression, regulation of miRNA maturation and heterochromatin formation (PMID: 26284139). Oncogenic proteins, such as mutant KRAS, can also complex with AGO2 to mediate gene silencing (PMID: 26854235). AGO2 is altered by amplification and overexpression in various cancers, such as ovarian, breast and prostate (PMID: 20146808, 24427355). In contrast, AGO2 protein levels are depleted in some melanoma tumor samples (PMID: 24169347). Differential AGO2 expression levels have been linked to dysregulated RNA processing (PMID: 23201202). False +ENST00000279146 NM_003977.2 9049 AIP True AIP, an aryl hydrocarbon receptor-interacting protein, is infrequently altered in cancer. AIP, a member of the FKBP family, encodes for an aryl hydrocarbon receptor-interacting protein (PMID: 9111057). AIP interacts with various proteins, such as phosphodiesterases and G-proteins, to regulate the cAMP-dependent protein kinase pathway (PMID: 29726992). The cAMP-dependent protein kinase pathway is involved in the regulation of pituitary cell proliferation and hormone secretion and is frequently dysregulated in pituitary tumors (PMID: 24373949). Germline mutations of AIP have been identified in familial isolated pituitary adenoma and sporadic macroadenomas (PMID: 23371967). The oncogenic function of AIP is likely tissue-specific. Overexpression of AIP in colon epithelial cells and diffuse large B-cell lymphoma samples induces increased cellular migration, invasion and increased cellular survival, suggesting that AIP functions predominantly as an oncogene in these contexts (PMID: 35347323, 31042473). In contrast, loss of AIP function in pituitary tissue induces cellular proliferation and tumor growth, suggesting that AIP functions predominantly as a tumor suppressor gene in this context (PMID: 18381572). AIP has been shown to interact with the RET signaling pathway in somatotropic cells, and AIP mutations have been found to disrupt the RET-mediated apoptotic pathway, thereby promoting tumor growth (PMID: 34588620). True +ENST00000262713 NM_032876.5 84962 AJUBA False AJUBA, a scaffolding protein included in many protein complexes, is altered by mutation in various cancer types including head and neck, orpharyngeal, and esophageal cancer. AJUBA is a scaffolding protein that is a member of the Zynzin/Ajuba LIM-domain containing protein family (PMID: 31740385, 15520811). AJUBA is a promiscuous protein that can shuttle between the nucleus and cytoplasm to mediate protein-protein interactions (PMID: 15520811, 17909014). Binding of AJUBA modulates the activity of many protein complexes involved in regulating diverse cellular processes including cellular adhesion, tension sensing, cellular motility, mitosis and microRNA processing, among others (PMID: 31740385, 12417594, 13678582, 20616046, 17621269). In addition, AJUBA is an important mediator of many signaling pathways including WNT, MAPK and Hippo pathways (PMID: 31740385, 24336325). For example, AJUBA interacts with LATS2, an important kinase in the Hippo pathway, to mediate downstream signaling (PMID: 24336325). In addition, AJUBA functions as a transcriptional co-repressor that interacts with SLUG domain proteins (involved in the epithelial to mesenchymal transition), nuclear hormone receptors and SP1 (PMID: 17909014, 20133701). Reduced activity of AJUBA in cancer-derived cell lines results in enhanced proliferation, anchorage-independent growth and increased growth in murine xenografts (PMID: 30006462, 24336325), suggesting that AJUBA predominantly functions as a tumor suppressor. However, AJUBA expression has also been found to be an indicator of poor prognosis and cancer progression in several tumor types (PMID: 27172796, 29299158, 30597111, 28422308). Somatic mutations in AJUBA are found in various cancer types including head and neck, orpharyngeal, esophageal squamous cancer, among others (PMID: 25631445, 30046007, 29127303, 25839328, 25303977). AJUBA alterations are predicted to be loss-of-function and patients with these alterations may be sensitive to mitotic inhibitors (PMID: 25631445, 28126323). True +ENST00000349310 NM_001014431.1 207 AKT1 True 1 AKT1, an intracellular kinase, is altered predominantly by mutation in various cancer types including breast and endometrial cancers. AKT1 is a serine/threonine protein kinase that is a critical downstream effector in the PI3K (phosphoinositide 3-kinase) signaling pathway. Following activation of PI3K, cytosolic inactive AKT1 is recruited to the membrane and engages PIP3 (PtdIns3,4,5-P3), leading to phosphorylation and activation of AKT1 (PMID: 28431241). AKT1 can activate a number of downstream substrates, including GSK3, FOXO and mTORC1, which are critical for cellular survival, proliferation, and metabolism (PMID: 9843996, 7611497). Negative regulation of AKT1 occurs when PI3K signaling is terminated by PTEN phosphatase activity (PMID: 28431241). AKT1 is frequently activated in cancers, typically through activation of the PI3K pathway or by inactivation of PTEN (PMID: 28431241). Activating mutations in AKT1 (PMID: 17611497, 23134728, 20440266) and infrequent AKT1 gene amplification (PMID: 18767981) have been identified in human cancers, which allow for phosphoinositide-independent AKT1 activation. The ATP-competitive AKT1 inhibitor AZD5363 has demonstrated activity in patients with AKT1-mutant cancers (PMID: 28489509). Negative feedback mechanisms can mediate AKT-inhibitor resistance in human cancers with dysregulated AKT signaling (PMID: 29535262, 29339542). False +ENST00000392038 NM_001626.4 208 AKT2 True AKT2, an intracellular kinase, is altered by mutation or amplification in various cancer types. The AKT2 protein is a serine/threonine protein kinase that is a critical downstream effector in the PI3K signaling pathway. AKT2, along with closely related AKT1 and AKT3, are members of the AGC kinase family. Effects of AKT activation include cell cycle progression and increased migration, differentiation and glucose homeostasis (PMID: 12094235). AKT2 activation occurs when its pleckstrin homology domain (PHD) dislodges from the kinase domain (KD), localizes to the cell membrane, and several of its key residues become phosphorylated (PMID: 9374542). AKT2 is an oncogene that is activated in numerous cancers, mostly through amplification of the 19q13.1-q13.2 chromosomal region (PMID: 1409633, 9496907) or overexpression (PMID: 11756242), which promote invasion and metastasis (PMID: 12517798). Germline autosomal dominant mutations in AKT2 are associated with familial diabetes mellitus in humans (PMID: 15166380). There are numerous drugs that target the PI3K/AKT pathway, including inhibitors of AKT itself, and inhibitors of PI3K and mTOR (PMID: 19629070). False +ENST00000263826 NM_005465.4 10000 AKT3 True AKT3, an intracellular kinase, is altered by mutation or amplification in various cancer types. The AKT3 protein is a serine/threonine protein kinase that is a downstream effector in the PI3K signaling pathway. AKT3, along with closely related AKT1 and AKT2, are members of the AGC kinase family. Effects of AKT activation include cell cycle progression and increased migration, differentiation and glucose homeostasis (PMID: 12094235). AKT3 activation occurs when its pleckstrin homology domain (PHD) dislodges from the kinase domain (KD), localizes to the cell membrane, and several of its key residues become phosphorylated (PMID: 1209423)5). AKT3 is an oncogene and is amplified in many cancers, including glioblastoma (PMID: 19597332, 25737557). There are numerous drugs that target the PI3K/AKT pathway, including inhibitors of AKT itself, as well as inhibitors of PI3K and mTOR (PMID: 19629070). False +ENST00000295897 NM_000477.5 213 ALB False ALB, an abundant protein in blood plasma, is infrequently altered in various cancer types. ALB (also serum albumin) is the most abundant protein in blood plasma and composes half of human serum (PMID: 30097614, 25161624). ALB is produced in the liver as the precursor prealbumin before transport to relevant sites for processing (PMID: 2503514). The main function of ALB is to serve as a carrier for proteins that aren’t soluble, including hormones, fatty acids, metals, toxins and bilirubin, among others (PMID: 26055641). In addition, ALB associates with drugs, which can either positively or negatively impact their activity (PMID: 26055641, 25161624, 31704999). Paciltaxel, a breast cancer therapy, is an example of a drug that can be pre-loaded onto albumin prior to injection in an effort to improve drug efficacy (PMID: 25161624). Receptor-mediated endocytosis of ALB is a mechanism of nutrient scavenging in rapidly proliferating cancer cells (PMID: 30097614, 26055641). ALB is then bound by the internal scavenging receptors gp30 and gp18, which break ALB into amino acids and fatty acids (PMID: 8463286). The Fc receptor is an important regulator of endocytic recycling of ALB; downregulation of this receptor is found in cancer (PMID: 27384673). Patients with various malignancies, including cancer, may experience hypoalbuminemia (low albumin) and hyperalbuminemia (high albumin) (PMID: 27612919). Serum albumin levels can be utilized as prognostic markers in several cancer types, with hypoalbuminemia predominantly a predictor of poor outcome (PMID: 28838406, 29183294,31531785). Variants in albumin have been identified; however, the exact function of these alterations is unclear (PMID: 23558059). False +ENST00000258494 NM_001034173 160428 ALDH1L2 True ALDH1L2, a mitochondrial aldehyde dehydrogenase, is infrequently altered in cancer. ALDH1L2 encodes for a folate-dependent mitochondrial aldehyde dehydrogenase that functions in lipid metabolism and various CoA-dependent pathways, such as B-oxidation and the Krebs cycle (PMID: 21238436, 33168096). ALDH1L2 is the mitochondrial homolog of the cytosolic aldehyde dehydrogenase, ALDH1L1 (PMID: 20498374). ALDH1L2 is a key enzyme in the production of reduced NADPH for the mitochondria, allowing for the reduction of oxidized glutathione, and facilitates the regeneration of tetrahydrofolate (PMID: 27211901, 24805240, 33168096, 30500537). Knockdown of ALDH1L2 in various cancer cells inhibits metastasis and cell growth, suggesting that ALDH1L2 functions predominantly as an oncogene (PMID: 26466563, 35565854). Amplification of ALDH1L2 has been identified in various types of cancer, including glioblastoma and colorectal cancer (PMID: 35565854, 20498374). False +ENST00000261733 NM_000690 217 ALDH2 False ALDH2, an acetaldehyde dehydrogenase, is infrequently altered in cancer. ALDH2, a member of the acetaldehyde dehydrogenase family, functions in the oxidation-reduction reaction of ethanol and aldehydic products (PMID: 22339434). The removal of endogenous aldehydes generated by ROS-mediated peroxidation is a significant function of ALDH2 as high levels of aldehydic products, such as malondialdehyde, have been associated with poor patient prognosis (PMID: 31597313, 31652642, 31168172). ALDH2 deficiency in various tumor cell and mouse models leads to acetaldehyde-induced DNA interstrand crosslinks, DNA double-strand breaks and tandem mutations, suggesting that ALDH2 functions predominantly as a tumor suppressor gene (PMID: 32066963, 21734703, 28114741, 29323295). Loss of ALDH2 function has been identified in various cancers, including lung adenocarcinoma, hepatocellular carcinoma and esophageal cancer (PMID: 31071657, 28027570, 16822169). The ALDH2 variant, ALDH2*2, is one of the most commonly identified polymorphisms associated with ALDH2 deficiency and leads to higher susceptibility to cancer risk with alcohol consumption (PMID: 17431955, 35048370). True +ENST00000389048 NM_004304.4 238 ALK True 1 R2 ALK, a receptor tyrosine kinase, is recurrently altered by chromosomal rearrangements in various cancer types including anaplastic large cell lymphoma, non-small cell lung cancer and inflammatory myofibroblastic tumors. ALK is a receptor tyrosine kinase that is a member of the insulin receptor family (PMID: 24060861). Ligand binding to ALK results in activation of downstream signaling including the JAK-STAT, RAS-MAPK, PI3K-mTOR and JUN pathways (PMID: 24060861, 24715763). ALK signaling plays an important role in nervous system development (PMID: 9053841) as well as regulation of cell growth, differentiation, and transformation (PMID: 19737948). ALK translocations are common in cancer and predominantly result in the constitutive activation of ALK kinase activity. The nucleophosmin (NPM1)-ALK fusion protein is found in 60% of anaplastic large cell lymphomas (ALCLs) (PMID: 9736036) while the EML4-ALK fusion protein is found in 3-5% of non-small cell lung cancer (NSCLC) (PMID: 25079552). Additional ALK translocations have been found in a variety of tumor types including inflammatory myofibroblastic tumor (IMT), neuroblastoma and rhabdomyosarcoma (PMID: 24060861). ALK is found overexpressed or somatically mutated in multiple cancers, and secondary mutations in ALK are common after treatment with tyrosine kinase inhibitor therapy (PMID: 24060861). The ALK kinase inhibitors crizotinib, ceritinib, alectinib, and brigatinib have been FDA-approved for the treatment of ALK-rearranged non-small cell lung cancer (PMID: 27413075, 25754348, 25170012). R2 False +ENST00000319144 NM_001139.2 242 ALOX12B True ALOX12B, an enzyme involved in lipid metabolism, is altered by mutation, deletion and amplification in various cancer types. ALOX12B (also 12R-LOX) is a lipoxygenase that is a member of the LOX protein family (PMID: 24021977). 12R-LOX, the enzyme encoded by the gene ALOX12B, mediates fatty acid metabolism by catalyzing the addition of an oxygen molecule to arachidonic acid, generating the molecule 12R-HPETE (PMID: 24021977). 12R-LOX is active primarily in the skin and other epithelial tissues (PMID: 9618483, 10100631, 10446122) and plays an important role in the establishment of the epidermal barrier function (PMID: 17403930, 21558561). Another LOX family member, eLOX3, is required for the downstream synthesis of hepoxilins after 12R-HPETE generation; these play key roles in epithelial permeability and signaling (PMID: 15629692, 24021977, 19558494). ALOX12B also mediates immunosuppressive activity by decreasing antigen presentation on T cells (PMID: 22503541). Inactivating mutations in ALOX12B have been observed in autosomal recessive congenital ichthyosis, a clinically and genetically heterogeneous disease characterized by dried, scaling skin (PMID: 11773004, 16116617, 15629692, 19131948, 17139268). Somatic missense, nonsense mutations and deletions of ALOX12B are found in a wide range of cancers, including melanoma and other skin cancers; however, these alterations have yet to be functionally validated (cBioPortal, MSKCC, April 2020). Amplification of ALOX12B in breast and ovarian cancer has been associated with reduced cytolytic activity by the immune system (PMID: 25594174). In addition, ALOX12B is activated in cancer cells treated with therapies that induce arachidonic acid via a p53-dependent mechanism (PMID: 30258081). True +ENST00000330258 NM_152424.3 139285 AMER1 False AMER1, a tumor suppressor involved in WNT signaling, is inactivated by mutation or deletion in various cancer types, most frequently in colorectal cancer. AMER1 (APC membrane recruitment 1) is an APC-binding protein that regulates the cellular localization of the APC tumor suppressor, thereby regulating APC-dependent cellular morphogenesis, cell migration and cell-cell adhesion (PMID: 17925383, 20843316, 27462415). AMER1 also functions as a negative regulator of WNT/β-catenin signaling (PMID: 21248786, 17510365, 20843316). In this capacity, AMER1 acts as a scaffold protein by assembling β-catenin and members of the destruction complex at the plasma membrane, which is necessary for β-catenin degradation (PMID: 17510365, 21498506). The AMER1 gene is mutated in approximately 5-10% of Wilms tumors, a pediatric kidney cancer (PMID: 17204608, 21248786, 19137020, 18311776, 26274016). Missense and truncating AMER1 mutations are found in approximately 7-10% of colorectal cancers and correlate with reduced WNT signaling (PMID: 26071483). This data is consistent with AMER1 functioning as a tumor suppressor, as loss of AMER1 results in activation of WNT/ β-catenin signaling (PMID: 17510365, 17510365). True +ENST00000301030 NM_013275.5 29123 ANKRD11 False ANKRD11, a tumor suppressor and chromatin regulator, is inactivated by mutation or deletion in various cancer types. ANKRD11 is an ankyrin repeat domain protein that binds and suppresses the function of the p160 coactivator family (PMID: 15184363), thereby inhibiting ligand-dependent transcriptional activation. ANKRD11 is also a coactivator of the p53 tumor suppressor (PMID: 18840648), thereby influencing many pathways relevant to cancer, including transcriptional initiation, cell cycle regulation, ion transport and Notch signaling. Studies in murine and human neural precursors demonstrate that ANKRD11 can function as a chromatin regulator that binds histone deacetylases and alters gene expression (PMID: 25556659). Heterozygous mutations in ANKRD11 have been reported to cause KBG syndrome, a rare disorder characterized by intellectual disability, behavioral problems, and macrodontia (PMID: 21782149). ANKRD11 is hypermethylated in breast cancer leading to decreased transcriptional activity, suggesting that ANKRD11 functions as a putative tumor suppressor gene (PMID: 22538187). True +ENST00000376087 NM_001256053 22852 ANKRD26 True ANKRD26, an ankyrin repeat protein, is altered by mutation in various cancers. Germline ANKRD26 mutations are implicated in ANKRD26-related thrombocytopenia and predispose to hematological malignancies. ANKRD26 encodes for an ankyrin repeat domain protein that functions primarily in regulation of megakaryopoiesis (PMID: 24430186). ANKRD6 is negatively regulated by RUNX1 and FLI1 through protein-protein interaction with the 5’ untranslated region (UTR) of ANKRD6 (PMID: 24430186). Mutations in the 5’ UTR region are implicated in the genetic non-syndromic autosomal dominant thrombocytopenic disorder ANKRD26-related thrombocytopenia, also known as thrombocytopenia-2, and induces persistent activation of the MAPK/ERK pathway and impairs proplatelet formation (PMID: 26478096, 24430186). ANKRD26-related thrombocytopenia is associated with predisposition to hematological malignancies (PMID: 37065357, 28976612). Overexpression of ANKRD26 in patient-derived megakaryocytes induces increased MAPK/ERK pathway signaling and thrombopoietin/myeloproliferative leukemia virus oncogene (TPO/MPL) signaling, suggesting that ANKRD26 functions predominantly as an oncogene (PMID: 24430186). Germline mutations of ANKRD26 have been identified in hematological malignancies (PMID: 36626254). False +ENST00000257430 NM_000038.5 324 APC False APC, a tumor suppressor involved in WNT signaling, is recurrently altered in colorectal cancer. APC is a negative regulator of the pro-oncogenic WNT/ β-catenin signaling pathway (PMID: 8259518, 8259519). The main tumor suppressive role of APC is to modulate intracellular levels of β-catenin (PMID: 11978510). APC is an essential member of the destruction complex, which targets cytosolic β-catenin for ubiquitination and degradation (PMID: 10984057). When the activity of APC is lost, there is an aberrant increase in WNT-pathway activation, often leading to hyperplasia and eventually tumor progression (PMID: 8259511). A threshold of APC expression is required to suppress tumor formation, and this level is finely balanced (PMID: 11743581). Germline mutations in the APC gene cause familial adenomatous polyposis (FAP) (PMID: 1651174, 1651562), also known as Turcot Syndrome, Gardner Syndrome, or Flat Adenoma Syndrome (FAS) (PMID: 8593545), which is associated with a very high risk of polyposis and colorectal cancer (PMID: 1528264, 31171120). In addition, heritable mutations in APC may be responsible for the development of attenuated FAP (PMID: 34666312) or gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS) (PMID: 21813476). APC mutations have been observed in 50-80% of sporadic colorectal cancers (PMID: 17143297). Somatic mutations in APC function as tumor-initiating events and are also observed in a number of other human cancers including breast, stomach, and prostate (PMID: 27302369, 29316426). The majority of APC mutations are loss-of-function and occur in a region important for β-catenin binding (PMID: 10784639, 1338904). Inhibitors of the WNT pathway are currently in clinical development (PMID: 24981364). True +ENST00000257254 NM_005161.4 187 APLNR True APLNR, a G-protein coupled receptor, is altered by mutation in various cancer types and may promote resistance to immunotherapy. APLNR (also AGTRL1) is a transmembrane receptor that is a member of the G-protein coupled receptor (GPCR) protein family (PMID: 28783722). GPCR proteins can bind ligands, which initiate a conformational change allowing the receptor to function as a guanine nucleotide exchange factor (GEF) and exchange GDP for GTP on an associated G protein (PMID: 28091541). APLNR binds the hormones APELA and APLN to activate downstream signaling pathways, including the MAPK and PI3K signaling cascades (PMID: 17412318). APLNR has diverse cellular functions including the regulation of cardiac function, blood vessel formation, proliferation, hypoxia and apoptosis, among others (PMID: 27083318, 17412318, 15530405, 29807055, 27825851, 30718358). In addition, APLNR interacts with the non-receptor tyrosine kinase JAK1 to initiate IFNγ-mediated downstream signaling and to mediate antigen presentation to the immune system (PMID: 28783722). Loss-of-function mutations in APLNR have been identified in patients with melanoma and lung cancer who exhibit resistance to T-cell based immunotherapies, such as ipilimumab, pembrolizumab and nivolumab (PMID: 28783722). However, APLNR is also found to be overexpressed in some cancer types and ALPNR-mediated signaling promotes angiogenesis, suggesting that APLNR may have context-specific roles in cancer progression (PMID: 27083318, 30783205, 30718358, 31267692). True +ENST00000374690 NM_000044.3 367 AR True AR (androgen receptor), a transcription factor, is most frequently altered in advanced or castration-resistant prostate cancer. AR (androgen receptor) is a nuclear receptor that is activated following binding of androgenic hormones (PMID: 1865110, 8809738). The AR protein acts as a steroid-hormone activated transcription factor that regulates gene transcription. In the absence of androgen, AR is predominantly maintained in an inactive conformation in the cytoplasm (PMID: 9175625, 12269826). Upon androgen binding, AR undergoes an activating conformational change that allows for its translocation into the nucleus, homodimerization and binding to DNA at sites with androgen response elements (ARE) motifs (PMID: 9175625, 12000757, 11376111, 8360187). In concert with accessory coactivators and corepressors, AR serves to activate or repress the transcription of AR-mediated target genes (PMID: 11931767, 17679089). Germline loss-of-function mutations in AR cause genetic XY males and rodents to develop as external phenotypic females, also lacking internal sexual secondary organs (PMID: 4402348, 2341409, 2041777, 3186717, 2594783). AR signaling is important in prostate cancers, particularly in tumors that become resistant to androgen deprivation therapies, termed castration-resistant prostate cancers (CRPC). AR is frequently altered in CRPCs resulting in continued activation despite a castrate level of androgen (PMID: 26566796). Mutations in AR can lead to clinical resistance to antiandrogen therapy in CRPC (PMID: 23580326). False +ENST00000377045 NM_001654.4 369 ARAF True 2 ARAF, an intracellular kinase, is infrequently altered by mutation or amplification in various cancer types. ARAF is a serine/threonine protein kinase and signaling component in the mitogen-activated protein (MAP)-kinase signaling pathway. ARAF is a member of the RAF kinase family, which also includes BRAF and CRAF (PMID: 17555829). ARAF is ubiquitously expressed, with the highest physiological levels found in the urogenital organs (PMID: 10768864). Upon activation by RAS proteins, ARAF forms dimers with BRAF and CRAF, resulting in phosphorylation and activation of the downstream signaling effectors MEK and subsequently ERK. Activation of the RAS signaling cascade ultimately leads to increased cell growth and proliferation (PMID: 21779496). ARAF activating mutations are found at low frequencies in cholangiocarcinomas, lung, uterine and histiocytic carcinomas (PMID: 25608663, 26566875). The most common oncogenic ARAF mutation impairs a phosphorylation site that negatively regulates RAS binding and ARAF activation, leading to hyperactivity of the MAP-kinase signaling pathway (PMID: 24569458). ARAF-mutant cancers may be sensitive to RAF and MAPK family inhibitors, such as sorafenib (PMID: 24569458). False +ENST00000274498 NM_015071 23092 ARHGAP26 True ARHGAP26, a GTPase activating protein that regulates RhoA, is altered by chromosomal rearrangement in gastric cancer. ARHGAP26 encodes for a GTPase activating protein which functions in hydrolysis of GTPases (PMID: 9858476). ARHGAP26 negatively regulates Rho GTPases through conversion to the inactive GDP-bound form (PMID: 9858476, 31004081, 25079317). Rho GTPases modulate actin-mediated cellular functions including cellular adhesion, migration and cell division (PMID: 31013840, 12606561).The oncogenic effect of ARHGAP26 is likely tissue specific. Fusion of ARHGAP26 with CLDN18 has been recurrently identified in gastric cancer and identified to promote tumorigenesis in preclinical studies (PMID: 29961079, 25079317, 32983960). Overexpression of circular RNA ARHGAP26 in gastric cancer cell lines and models induces cellular proliferation, invasion and migration (PMID: 30719998, 28544609). Conversely, downregulation of ARHGAP26 in ovarian and glioblastoma cancer cell lines and models suppresses cellular proliferation, invasion and migration, suggesting that ARHGAP26 functions predominantly as a tumor suppressor gene in this context (PMID: 31004081, 17611651). Inactivation and methylation of ARHGAP26 has been identified in acute myeloid leukemia and promyelocytic leukemia (PMID: 16404424, 10908648, 17611651). True +ENST00000404338 NM_004491.4 2909 ARHGAP35 True ARHGAP35, a GTPase activating protein that regulates RhoA, is altered by mutation and deletion across a variety of solid tumor types. ARHGAP35 (also GRLF1) is a GTPase activating protein (GAP) that negatively regulates the activity of Rho-family small GTPases (guanosine triphosphatases) (PMID: 31013840). Rho GTPases modulate actin-mediated cellular functions including cellular adhesion, migration and cell division (PMID: 31013840, 12606561). ARHGAP35 encodes the protein p190A which, along with the paralog p190B, function as the main GAP proteins that regulate Rho cellular activity (PMID: 8537347). GAP proteins, such as p190A, enhance nucleotide hydrolysis and inhibit GTPase signaling activity (PMID: 27628050). p190A interacts with a variety of effector molecules, including RHOA, RHOC and RAC1, among others, to regulate cell adhesion and migration (PMID: 28287334, 27646271). In addition, p190A associates with TFII-I and eIF3A to mediate gene expression and translation, respectively (PMID: 28007963, 15629714). p190A is also implicated in several other cellular processes including entosis, dendritic spine formation and endothelial permeability (PMID: 18045538, 18267090, 17562701). Somatic mutations in ARHGAP35 have been identified in a variety of tumor types in pan-cancer studies, most predominantly in uterine carcinomas (PMID: 24132290, 24390350). ARHGAP35 mutations have also been associated with Hürthle cell carcinoma, colorectal cancer and renal angiomyolipoma (PMID: 30107175, 28176259, 27494029). These alterations commonly occur as nonsense or frameshift mutations throughout the ARHGAP35 gene (PMID: 31013840, 27646271). However, disruption of p190A in functional assays has both growth inhibitory and proliferative effects, suggesting that p190A may function as a tumor suppressor or oncogene depending on the context (PMID: 31013840, 27646271). True +ENST00000397843 NM_015313 23365 ARHGEF12 True ARHGEF12, a Rho guanine nucleotide exchange factor, is infrequently altered in cancer. ARHGEF12, or leukemia-associated RhoGEF, encodes a protein of the diffuse B-cell lymphoma (Dbl) family of guanine nucleotide exchange factors that activates small GTPase Rho (PMID: 23255595). ARHGEF12 has been implicated in regulating various cellular pathways including cell morphology and polarization, invasion, the final steps of cytokinesis and integrin force regulation (PMID: 23885121, 33419897, 21572419). ARHGEF12 is implicated in an oncogenic positive feedback loop with RhoA-effector DIAPH1 and RhoA in the LPA-stimulated Rho/ROCK signaling pathway, promoting bleb-associated cancer cell invasion and tumor cell morphology (PMID: 17575049). Loss of ARHGEF12 has been identified in breast cancer and colorectal cancer (PMID: 19734946). Rare chromosomal rearrangements of ARHGEF12 have been identified in acute myeloid leukemia and acute lymphoblastic leukemia, and have been suggested to lead to loss of ARHGEF12 function to promote tumorigenesis (PMID: 33419897, 34237703, 19734946). True +ENST00000426542 NM_001177693.1 64283 ARHGEF28 True ARHGEF28, an intracellular kinase that regulates cell growth and metabolism, is infrequently altered in cancer. ARHGEF28 (also Rgnef and p190RhoGEF) is a Rho guanine exchange factor (GEF) that catalyzes the exchange of GDP for GTP (PMID: 24467206, 24006257). ARHGEF28 activates small RhoA GTPases by catalyzing the dissociation of GDP and facilitating a conformational change leading to GTP binding. ARHGEF28 activity is required for focal adhesion establishment, regulation of cell motility, contractility, and initiation of cell signaling (PMID: 24467206). ARHGEF28 binds and functions as either a GEF or a scaffolding protein to initiate FAK activation and cell contractility (PMID: 24467206, 24006257). Functional studies have demonstrated that the RhoA-FAK pathway is important for cancer cell proliferation and migration in breast and lung cancer models (PMID: 19147981, 23358651, 21224360). Both familial and sporadic mutations in ARHGEF28 have been identified in the neurological disease amyotrophic lateral sclerosis (ALS) (PMID: 23286752); however, somatic mutations in ARHGEF28 are infrequent in human cancers. False +ENST00000324856 NM_006015.4 8289 ARID1A False 4 ARID1A, a tumor suppressor involved in transcriptional regulation, is inactivated by mutation in various cancer types including endometrial and bladder cancers. ARID1A, also known as BAF250A, is a member of the SWI/SNF chromatin-remodeling complex, and plays a role in altering chromatin structure for various cellular functions, including transcription, DNA synthesis and DNA repair (PMID: 25387058, 23208470). ARID1A binds to AT-rich regions of DNA and helps recruit other members of the SWI/SWF complex, such as SMARCA and BAF complexes. Together, these complexes are involved in ATP-dependent chromatin remodeling via nucleosome displacement and thus allow for gene expression activation (PMID: 12672490, 10078207, 11073988). In a mouse model of colon cancer, ARID1A loss specifically altered enhancer-mediated gene regulation (PMID: 27941798). Germline mutations in ARID1A result in Coffin-Siris syndrome, which is characterized by developmental delay and coarse facial features (PMID: 11170086). Additionally, ARID1A has been identified as a tumor suppressor in multiple cancer types, including gynecologic cancers, ovarian clear cell carcinomas and endometrial cancers (PMID: 21900401, 21590771, 20826764). True +ENST00000346085 NM_020732.3 57492 ARID1B False ARID1B, a tumor suppressor involved in transcriptional regulation, is inactivated by mutation or deletion in various cancer types. ARID1B (AT-rich interactive domain-containing protein 1B), also known as BAF250B, is a member of the SWI/SNF chromatin-remodeling complex, and plays a role in altering chromatin structure for various cellular functions, including transcription, DNA synthesis and DNA repair (PMID: 15170388, 25387058). ARID1B binds to AT-rich regions of DNA and helps recruit other members of the SWI/SWF complex, such as SMARCA and BAF complexes. Together, these complexes are involved in ATP-dependent chromatin remodeling via nucleosome displacement and thus allow for gene expression activation (PMID: 12672490, 10078207, 11073988). ARID1B can substitute for ARID1A in BAF complexes despite ARID1A being more commonly present (PMID: 15170388). Like ARID1A, germline mutations in ARID1B result in Coffin-Siris syndrome, which is characterized by developmental delay and coarse facial features (PMID: 22426309). Inactivating ARID1B mutations have been identified in breast cancer (PMID: 22722201), gynecologic carcinosarcoma (PMID: 25233892), pancreatic cancer (PMID: 22233809) and neuroblastoma (PMID: 23202128). True +ENST00000334344 NM_152641.2 196528 ARID2 False ARID2, a tumor suppressor involved in transcriptional regulation, is inactivated by mutation or deletion in various cancer types. ARID2, also known as BAF200, is a subunit in the PBAF complex, a subtype of the SWI/SNF complex, which facilitates nuclear receptor-mediated, ligand-dependent transcriptional activation by modulating chromatin structure to make DNA more accessible (PMID: 19234488, 11780067). ARID2 contains a conserved AT-rich DNA interaction domain and is thought to confer specificity to the PBAF complex (PMID:15985610). Most ARID2 mutations found in tumors are inactivating, suggesting ARID2 is a tumor suppressor gene. ARID2 mutations are most commonly found in hepatocellular carcinoma (HCC), where they often lead to an inactive, truncated protein (PMID: 21822264). ARID2 mutations are also found in melanoma and non-small cell lung cancer (NSCLC) (PMID: 23047306, 22817889), and are associated with loss of heterozygosity (LOH). True +ENST00000263620 NM_005224.2 1820 ARID3A False ARID3A, a transcription factor important in B cell differentiation, is infrequently mutated in a diverse range of cancers. ARID3A (also Bright) is a member of the ARID family of DNA binding proteins. ARID3A functions as a transcription factor that regulates the transcription of genes relevant in B-cell biology, including the immunoglobulin heavy chain in lymphocytes (PMID: 24678314). Expression of ARID3A is tightly controlled during B cell differentiation with the highest expression occurring in hematopoietic stem cells, pre-B cells, transitional B cells, activated B cells, memory B cells and plasma cells (PMID: 15203319, 26685208, 21199920). ARID3A associates with BTK (Bruton's tyrosine kinase) and E2F1 to mediate DNA binding and regulation of transcription (PMID: 9780002, 15203319). Overexpression of ARID3A in murine studies results in autoimmunity highlighting the importance of ARID3A in B cell regulation (PMID: 15203319, 21963220). In addition to the role of ARID3A in B cells, ARID3A can also cooperate with TP53 to activate the expression of p21, a protein involved in cell cycle arrest, in a range of cell types (PMID: 22172947). Additional roles for ARID3A gene regulation have been identified, including in colorectal cancer studies (PMID: 26121572, 24366420). However, somatic mutations in ARID3A are relatively rare in human cancers. True +ENST00000346246 NM_001307939.1 10620 ARID3B True ARID3B, a DNA binding protein highly expressed in squamous epithelium, is infrequently mutated in a diverse range of cancers. ARID3B (also BDP) is a member of the ARID family of DNA binding proteins. ARID3B functions as a transcription factor that is most highly expressed in squamous epithelium (PMID: 24704276). ARID3B can homodimerize or heterodimerize with other ARID3 family members and interact with additional transcription factors including the Rb-associated proteins RBP1 and RBP2 to regulate gene expression in a variety of cellular contexts (PMID: 10446990). Expression of ARID3B is required for B cell differentiation (PMID: 27537840) and has been implicated in the regulation of oncogenic genes in the context of ovarian cancer (PMID: 26121572), oral squamous cancer (PMID: 25858147), and neuroblastomas (PMID: 16951138). ARID3B activity is also important in regulating cancer stemness (PMID: 25858157), the maintenance of mesenchymal stem cells (PMID: 16530748) and the organization of the chromatin state (PMID: 26776511). Somatic mutations in ARID3B are relatively rare in human cancers; however, ARID3B is overexpressed in ovarian cancer and neuroblastoma (PMID: 24704276). Consistent with these data overexpression of ARID3B in ovarian cancers has been shown to be transforming in preclinical studies (PMID: 25327563). False +ENST00000378909 NM_001017363.1 138715 ARID3C False ARID3C, a DNA binding protein expressed in lymphocytes, is infrequently mutated in a diverse range of cancers. ARID3C (also Brightlike) is a member of the ARID family of DNA binding proteins (PMID: 24704276). ARID3C functions as a transcription factor and shares substantial sequence homology with homologs ARID3A and ARID3B. The highest expression of ARID3C has been identified in B lineage lymphocytes and activated follicular B cells (PMID: 21955986). While the function of ARID3C has not been extensively characterized, ARID3C can bind ARID3A at known ARID3A chromatin binding sites (PMID: 21955986). Importantly, ARID3A and ARID3C co-regulate immunoglobulin heavy chain transcription in B lymphocytes (PMID: 21955986). Somatic mutations in ARID3C are rare in human cancers and further functional studies are required to delineate the role of ARID3C in cancer (PMID: 24704276). False +ENST00000355431 NM_002892.3 5926 ARID4A False ARID4A, a DNA binding protein involved in E2F transcription, is infrequently mutated in a diverse range of cancers. ARID4A (also RBBP1, RBP1) is a member of the ARID family of DNA binding proteins (PMID: 18728284). ARID4A, and the homologous gene ARID4B, function as transcription factors that regulate gene expression and chromatin state (PMID: 17043311). Both ARID4A and ARID4B bind retinoblastoma protein (Rb) and function as repressors of E2F-mediated transcription by acting as adaptors to recruit the mSin3A histone deacetylase (HDAC) histone-modifying complex to E2F target genes (PMID: 1857421, 11283269). The ARID4A-RB complex is involved in many cellular functions including cellular differentiation, cellular proliferation, apoptosis and DNA damage. ARID4A also interacts with breast cancer metastasis suppressor 1 (BRMS1), a protein that mediates anti-metastasis gene expression programs (PMID: 18211900, 14581478). Deletion of ARID4A in murine models results in a hematopoietic disorder, suggesting that ARID4A functions as a tumor suppressor in some cellular contexts (PMID: 18728284). Somatic ARID4A mutations are relatively rare in human cancers; however, alterations have been identified in several cancer types including colorectal cancer (PMID: 24382590). True +ENST00000264183 NM_001206794.1 51742 ARID4B False ARID4B, a DNA binding protein that mediates E2F binding, is infrequently mutated in a diverse range of cancers. ARID4B (also RBB1L1) is a member of the ARID family of DNA binding proteins (PMID: 18728284). ARID4B, and the homologous gene ARID4A, function as transcription factors that regulate gene expression and chromatin state (PMID: 17043311). Both ARID4A and ARID4B bind retinoblastoma protein (Rb) and function as repressors of E2F-mediated transcription by acting as adaptors to recruit the mSin3A histone deacetylase (HDAC) histone-modifying complex to E2F target genes (PMID: 1857421, 11283269). The ARID4B-RB complex is involved in many cellular functions including cellular differentiation, cellular proliferation, apoptosis and DNA damage. ARID4B also interacts with breast cancer metastasis suppressor 1 (BRMS1), a protein that mediates anti-metastasis gene expression programs (PMID: 22693453). Somatic ARID4B mutations are relatively rare in human cancers; however, mutations have been identified in several cancer types including relapsed childhood acute lymphoblastic leukemia (PMID: 26189108). Decreased expression of ARID4B has been identified in several cancer types including prostate cancer (PMID: 29797600), suggesting that ARID4B functions predominantly as a tumor suppressor. True +ENST00000357485 NM_212481.1 10865 ARID5A False ARID5A, an RNA binding protein, is infrequently mutated in a diverse range of cancers. ARID5A (also MRF1) is an RNA binding protein that is a member of the ARID transcription factor family (PMID: 29787158). ARID5A binds the 3’UTR of IL-6 mRNA (PMID: 23676272) and regulates IL-6 mRNA stability in response to cytokine stimulation (PMID: 23676272). ARID5A expression is increased in macrophages and T-cells in response to LPS, IL-1β, and IL-6 treatment (PMID: 23676272). IL-6 induces the expression of ARID5A in T-cells leading to differentiation into inflammatory T-cells (such as Th17 cells) via a STAT3 dependent mechanism (PMID: 24782182, 27022145). Loss of ARID5A in murine hematopoietic and lung tissues results in a reduction of STAT3 and IL-6 expression and a blunting of the immune response, suggesting that ARID5A plays a critical role in inflammation, T-cell differentiation and autoimmunity (PMID: 27022145, 28379390). IL-6 stability is also important for the regulation of key cell signaling pathways including the NF-κB and MAPK pathways (PMID: 28168301). In addition, ARID5A has been implicated in RNA binding to other T-cell-related mRNAs, including T-bet, and DNA binding in collaboration with Sox9 in chondrocytes (PMID: 21346191). Somatic ARID5A mutations are rare in human cancers; however, several mutations have been identified in a diverse range of cancers. False +ENST00000279873 NM_032199.2 84159 ARID5B False ARID5B, a tumor suppressor involved in transcriptional regulation, is altered at low frequencies in various cancer types. ARID5B (AT-rich interactive domain 5b) is part of the ARID family of transcription factors, which bind to AT-rich DNA and play a role in diverse biological functions including embryonic development, lymphocyte development, cell-type-specific gene expression and cell growth regulation (PMID:15640446). ARID5B is a binding partner of the demethylase PHF2 (PMID: 21532585); the ARID5B-PHF2 complex binds to the promoters of SOX9 target genes to transcriptionally activate chondrogenesis (PMID: 24276541). ARID5B polymorphisms confer increased risk of pediatric acute lymphoblastic leukemia (ALL) as determined by genome-wide association studies (PMID: 19684604, 19684603). It was further determined that these patients show significant association with the clinical phenotype of intracellular accumulation of methotrexate polyglutamates, which is consistent with greater sensitivity to methotrexate-based chemotherapies (PMID: 19710713). However, it is unknown how these alleles confer a greater risk of childhood ALL development. True +ENST00000375687 NM_015338.5 171023 ASXL1 False ASXL1, a tumor suppressor and epigenetic regulator, is inactivated by mutation in various cancer types, most frequently in myeloid malignancies. ASXL1 is a member of the Polycomb group of proteins, and is a chromatin binder that is involved in transcription regulation. ASXL1 is a member of the ASXL gene family that includes ASXL1, ASXL2 and ASXL3, which all have a C-terminal plant homology domain (PHD domain) that is predicted to recognize histone H3 tails via methylated lysines (PMID: 23147254). ASXL1 interacts directly with the Polycomb Repressive Complex 2 (PRC2) and has a role in the recruitment of PRC2 to chromatin and subsequent H3K27me3 histone modifications (PMID: 22897849). Mutations in ASXL1 result in the inability of Polycomb target genes to be effectively repressed leading to dysregulated gene expression, such as at the HOXA gene cluster (PMID: 22897849). ASXL1 also independently interacts with the chromatin protein BAP1 (PMID: 22878500). The BAP1-ASXL1 complex can regulate the H2AK119 ubiquitin mark placed by the Polycomb Repressive Complex 1 (PRC1) (PMID: 20436459). Germline heterozygous mutations in ASXL1 have been found in patients with Bohring-Opitz syndrome, a developmental disorder that results in distinctive craniofacial abnormalities (PMID: 21706002). Recurrent somatic ASXL1 loss-of-function mutations are very common in hematopoietic malignancies including myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CMML), myelofibrosis (MF), and acute myeloid leukemia (AML) (PMID: 23147254, 30651633). Furthermore, ASXL1 mutations frequently co-occur with N/K-Ras mutations in CMML to promote leukemogenesis (PMID: 21455215). True +ENST00000435504 NM_018263.4 55252 ASXL2 False ASXL2, a tumor suppressor and epigenetic regulator, is inactivated by mutation in various cancer types including acute myeloid leukemia. ASXL2, a member of the Polycomb group of proteins, is a chromatin binder that is involved in transcription regulation. ASXL2 belongs to the ASXL gene family that includes ASXL1, ASXL2 and ASXL3, all which have a C-terminal plant homology domain (PHD domain) that is predicted to recognize histone H3 tails via methylated lysines (PMID: 23147254). ASXL2 shares several conserved domains with ASXL1, a protein that regulates gene expression by interaction with the chromatin Polycomb Repressive Complex 2 (PRC2), and mutations in these genes are mutually exclusive in acute myeloid leukemia (AML), suggesting they may have similar functions and may contribute to transformation in the same way (PMID: 23147254, 19270745, 12888926). ASXL2 interacts with the chromatin-modifying enzyme BAP1 (PMID: 22878500), has been found to regulate nuclear receptors such as the retinoic acid receptor, LXRα and PPARγ (PMID: 25065743, 24321552, 21047783) and was identified as a protein that regulates bone density such that deletion of ASXL2 leads to deficient osteoclast formation in mice (PMID: 21490954, 26051940). True +ENST00000262053 NM_005171.4 466 ATF1 True ATF1, a transcription factor, is rarely altered by chromosomal rearrangements in a variety of cancer types. ATF1 is a leucine zipper transcription factor that binds to cAMP-inducible promoters. The protein is activated via phosphorylation by several kinases, such PKA, and dimerizes and binds to cAMP-responsive elements within promoters across the genome (PMID:8663317, 1655749). Direct interaction and activation of ATF1 by BRCA1 suggest involvement in response to cellular DNA damage (PMID: 10945975). Additionally, EGF-induced expression of specific transcription factors requires ERK/MAPK activation of ATF1 (PMID:12414794) in human cells. False +ENST00000236959 NM_004044 471 ATIC True ATIC, a bifunctional enzyme in the de novo purine synthesis pathway, is infrequently altered in cancer. ATIC encodes for a bifunctional enzyme which functions in both 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) formyltransferase and inosine monophosphate (IMP) cyclohydrolase activity for de novo purine biosynthesis (PMID: 36063996, 29063699). ATIC is the rate-limiting enzyme of the de novo purine synthesis pathway and produces the intermediate formyl-AICAR (FAICAR) and IMP in the final two steps of the pathway (PMID: 9598063). Overexpression of ATIC in various cancer cell lines and models induces cellular proliferation, invasion and metastasis, suggesting that ATIC functions predominantly as an oncogene (PMID: 35251351, 34803509, 29246230). ATIC amplification and rearrangements have been identified in various cancers, including multiple myeloma and lung adenocarcinoma (PMID: 33226193, 35251351, 10706082). False +ENST00000278616 NM_000051.3 472 ATM False 1 ATM, a kinase involved in DNA damage response, is inactivated in various solid and hematologic malignancies. Germline ATM mutations are a defining feature of ataxia telangiectasia syndrome, a neurodegenerative, autosomal disorder that predisposes to various cancers. ATM is a member of the protein superfamily of phosphatidylinositol 3-kinase related serine/threonine kinases (PIKKs). ATM functions as a tumor suppressor that initiates DNA damage checkpoint signaling after accumulation of DNA double-strand breaks (DSBs) or after accumulation of other forms of cellular stress (PMID: 23219553). Activated ATM can phosphorylate hundreds of substrates in order to initiate and amplify the DNA damage response (PMID: 17525332) resulting in DNA repair, cell cycle arrest and/or apoptosis. Germline homozygous/compound heterozygous loss-of-function mutations in ATM have been identified in the autosomal recessive disorder ataxia telangiectasia (A-T), a disorder that presents with a variety of neurologic conditions, lung and skin disorders, and immunodeficiency (PMID: 21792198). Patients with A-T are also predisposed to a wide variety of cancers, particularly childhood lymphomas and leukemia as well as breast cancer (PMID: 21792198), whereas heterozygous carriers are at increased risk for adult-onset breast (PMID: 27112364, 31171119, 33471974), pancreatic (PMID: 22585167, 34529012), prostate (PMID: 33436325), gastroesophageal junction (PMID: 35078243), and other cancers. Somatic mutations in ATM have been identified in lymphoid malignancies and a selection of solid tumors (PMID: 12400598, 27413114). ATM-mutant cancers are increasingly sensitive to DNA damaging agents due to deficits in DNA repair pathways, and ATM loss may result in better response to checkpoint inhibition in some cancers (PMID: 27413114, 29489427). True +ENST00000295598 NM_000701 476 ATP1A1 True ATP1A1, the catalytic subunit of the Na+/K+-ATPase complex, is frequently altered in cancer. ATP1A1 encodes the catalytic alpha1 subunit of the Na+/K+-ATPase (NKA) complex, which functions in maintaining the balance of ionic homeostasis and cellular signal transduction (PMID: 34251542). ATP1A1 binds ATP on its ATP-binding sites for the NKA complex's energy conversion to allow the transport of sodium and potassium ions across the cellular membrane (PMID: 34251542). Normal expression of ATP1A1 is dependent on different tissue types as lower and higher expression levels have been identified in various tissues. Selective inhibition of ATP1A1 in non-small cell lung cancer cell lines impairs cell proliferation and migration whereas overexpression of ATP1A1 in renal cancer cell lines impairs cell proliferation and migration, suggesting that ATP1A1 functions as both an oncogene and tumor suppressor depending on the tumor type (​​PMID: 17471453, 28484360). Overexpression of ATP1A1 has been identified in various cancer types, including non-small cell lung cancer, breast cancer and glioma (PMID: 17471453, 28529692, 18300910). In contrast, loss of ATP1A1 has been identified in renal cell carcinoma and aldosterone-producing adenoma (PMID: 28484360, 34681640). True +ENST00000369762 NM_001183.5 537 ATP6AP1 False ATP6AP1, a V-ATPase accessory protein involved in organelle acidification, is recurrently mutated in follicular lymphomas. ATP6AP1 (also VAS1, Ac45) is a vacuolar H-ATPase (V-ATPase) accessory protein (PMID: 27231034). V-ATPase is a multi-protein complex that couples ATP hydrolysis to a proton pump for the luminal acidification of organelles and secretory vesicles across membranes (PMID: 27231034). ATP6AP1, in addition to the second accessory protein ATP6AP2, guide V-ATPase into subcellular compartments such as the secretory vesicles (PMID: 22044156). The highest expression of ATP6AP1 is found in neuronal cells, neuroendocrine cells and osteoclasts (PMID: 18227071, 11983866). In addition, ATP6AP1 has roles in membrane trafficking, membrane fusion, and activation of amino acid-induced mTORC1 activation (PMID: 22736765, 26691987). ATP6AP1 is an X-linked gene and mutations in ATP6AP1 have been identified in males that have defects in glycosylation (PMID: 27231034, 29127204). Somatic ATP6AP1 frameshift and nonsense mutations have been identified in follicular lymphoma (PMID: 26691987, 25713363), suggesting that ATP6AP1 functions as a tumor suppressor. False +ENST00000276390 NM_001693.3 526 ATP6V1B2 False ATP6V1B2, a component of the V-ATPase complex, is recurrently mutated in follicular lymphoma. ATP6V1B2 is a component of the vacuolar H-ATPase (V-ATPase) complex (PMID: 27231034). V-ATPase is a multi-protein complex that couples ATP hydrolysis to a proton pump for the luminal acidification of organelles and secretory vesicles across membranes (PMID: 27231034). ATP6V1B2 encodes the non-catalytic B2 subunit of the V-ATPase complex, which predominantly functions in ATP hydrolysis and is ubiquitously expressed in most tissues (PMID: 18667600). In addition, ATP6V1B2 has roles in vacuolar fusion, T cell motility, amino acid-induced mTORC1 activation, and SIRT1-mediated regulation in adipocytes (PMID: 26177453). ATP6V1B2 mutations have been associated with dominant developmental disorders including deafness-onychodystrophy syndrome and Zimmermann-Laband syndrome (PMID: 25915598, 24913193, 28396750). Recurrent somatic mutations in ATP6V1B2 are found in patients with follicular lymphoma (PMID: 28064239, 26691987, 30720463). Loss-of-function mutations in ATP6V1B2 result in the activation of autophagy, enhanced mTOR signaling, impaired lysosomal acidification and altered amino acid sensing (PMID: 30720463). True +ENST00000350721 NM_001184.3 545 ATR False 1 ATR, a tumor suppressor involved in DNA damage repair, is mutated in various cancer types. ATR (ataxia telangiectasia and Rad3-related protein) is a serine/threonine kinase involved in the DNA damage response. ATR responds to DNA damage and single-strand DNA by activating cell-cycle checkpoint and DNA repair pathways (PMID:12791985, 20818375, 17157788). It is also involved in regulating telomere maintenance, initiation of DNA replication and meiosis (PMID: 17687332,15220931, 23824539). Germline mutations of ATR are associated with cancer predisposition and Seckel syndrome, a condition associated with central nervous system disorders (PMID: 22341969, 12640452). Somatic mutations are associated with microsatellite instability and are found in colon cancer, urothelial cancer, gastric cancer, endometrial cancer and myelomas (PMID: 11691784,16288216,17879369, 26282654,19470935). Preclinical data has shown that kinase inhibitors of ATR may enhance chemotherapy response and treatment of DNA repair-pathway-deficient cancers (PMID: 26517239, 21552262, 26312880). True +ENST00000320211 NM_130384 84126 ATRIP False ATRIP, a DNA damage checkpoint protein, is infrequently altered by deletion in cancer. ATRIP is the regulatory binding protein of the serine/threonine kinase ATR and functions in the DNA damage response (PMID: 22258451). ATRIP responds to DNA damage through interaction with replication protein A (RPA)-coated single-stranded DNA, allowing the ATRIP-ATR complex to localize to sites of DNA damage or to stressed replication forks (PMID: 12791985). The ATRIP-ATR complex is also involved in regulating telomere maintenance, initiation of DNA replication and meiosis (PMID: 17687332,15220931, 23824539). Germline truncating mutations in ATRIP are associated with Seckel syndrome, a condition associated with central nervous system disorders (PMID: 23144622). Loss of ATRIP has been identified in various cancers, including myeloma and ovarian cancer (PMID: 26282654, 19737971). True +ENST00000373344 NM_000489.3 546 ATRX False ATRX, a tumor suppressor involved in transcriptional regulation, is infrequently altered in cancer. ATRX (alpha thalassemia/mental retardation syndrome X-linked) is a chromatin regulator that functions as a member of the SWI/SNF helicase family (PMID: 20110566, 17609377). ATRX is involved in the incorporation of histone H3.3 during telomere replication (PMID: 20110566). Loss of ATRX activity results in aberrant DNA methylation, histone composition and transcription, suggesting that ATRX functions predominantly as an epigenetic regulator (PMID: 29535300). Germline mutations in ATRX result in a severe form of X-linked mental retardation often associated with alpha-thalassemia (ATRX) syndrome (PMID: 8968741). Loss-of-function mutations or reduced ATRX expression is strongly correlated with an alternate lengthening of telomeres (ALT) phenotype in tumors (PMID: 21719641). Somatic mutations have been associated with chromosomal instability and epigenetic remodeling in a variety of human cancers (PMID: 23104868, 24148618, 29535300). Patients with ATRX mutations may be increasingly sensitive to agents that target DNA repair pathways (PMID: 27657132). True +ENST00000377617 NM_002973.3 6311 ATXN2 False ATXN2, an RNA binding protein, is infrequently mutated in a diverse range of human cancers. ATXN2 is an RNA binding protein that regulates protein translation. Through interactions with poly(A) binding protein (PABP), ATXN2 regulates mRNA translation and localizes to stress granules and P-bodies, cellular components important for regulation of mRNA degradation and translation (PMID: 22508507, 15342467). In addition, ATXN2 may function to transport RNA between actively translating polysomes and stress granules (PMID: 22508507). ATXN2 also has roles in actin filament formation, secretion, receptor signaling, RNA metabolism, and cell specification (PMID: 22508507, 15342467). Abnormal expansion of the CAG repeat sequence in ATXN2, resulting in an extended polyglutamine sequence, are found in a range of neurological disorders including Spinocerebellar ataxia, Parkinson’s disease and amyotrophic lateral sclerosis (ALS) (PMID: 21562247, 29756284, 21670397, 27663142, 25098532). Somatic mutations in ATXN2 are rare in human cancers and are found infrequently in a diverse range of tumor types. True +ENST00000295900 NM_000333.3 6314 ATXN7 True ATXN7, a transcriptional regulator that mediates chromatin remodeling and deubiquitination, is recurrently altered by mutation and fusion in thyroid, colorectal and breast cancers. ATXN7 (also SCA7) is a chromatin-modifying protein that functions as a transcriptional co-activator (PMID: 16494529). ATXN7 is a component of the multi-subunit SAGA transcriptional complex that has multiple enzymatic functions including histone acetylation (PMID: 21746879) and deubiquitination (PMID: 21746879). The SAGA complex facilitates transcriptional regulation by remodeling chromatin via GCN5-mediated histone acetylation to promote general transcription factor binding to DNA (PMID: 21746879). In addition, the SAGA complex mediates targeting of the transcriptional pre-initiation complex to promoters and deubiquitination via the cofactors ATXN7L3, USP22, and ENY2 to mediate protein translation (PMID: 18206972). SAGA-dependent histone H2B deubiquitination is also critical for the DNA damage response, an activity that is especially important during class switch recombination (PMID: 21746879, 18206972). Trinucleotide repeat expansions in the coding region of the ATXN7 gene are associated with spinocerebellar ataxia type 7 (SCA7), a neurological disorder that results in macular dystrophy and progressive retinal degeneration (PMID: 9288099, 9781533, 10330346, 10640674, 3062533). In SCA7-mutant murine models and in patients with SCA7, CAG trinucleotide expansions in ATXN7 result in an abnormal polyglutamine tract (polyQ) and in nuclear accumulation of protein (PMID: 14985428). Somatic mutations in ATXN7 are found in patients with thyroid cancer and cluster predominantly in the polyglutamine domain of the protein where the germline expansions occur in SCA7 (PMID: 28584132). ATXN7 mutations are predicted to be gain-of-function and induce proliferation in thyroid cells in collaboration with the RAS oncogene (PMID: 28584132). In addition, ATNX7 fusion proteins have been found in patients with colorectal and breast cancer (PMID: 27296891). False +ENST00000312783 NM_003600.2 6790 AURKA True AURKA, an intracellular kinase, is altered by mutation, amplification or overexpression in various cancer types including breast and colorectal cancers. AURKA (Aurora kinase A) is a cell-cycle regulatory serine/threonine kinase that promotes entry into and proper progression through mitosis. AURKA is expressed in actively proliferating cells, specifically in the G2 and mitotic phases of the cell cycle, and has multiple roles in promoting cell division, including recruitment of microtubule-nucleating proteins to centrosomes to mediate spindle assembly and regulating entry into mitosis (PMID: 12884918, 16186253, 18566290). AURKA amplification has been observed in multiple tumor types, including leukemia, colorectal, and pancreatic cancers (PMID: 18820130, 9606188, 12631597). Overexpression of AURKA can promote cellular transformation and may potentiate the activity of other oncogenes, such as RAS (PMID: 15592510). Small-molecule inhibitors of AURKA (and the related Aurora B and C kinases) are currently being investigated as general inhibitors of cell proliferation and potential anti-mitotic chemotherapeutic drugs (PMID: 24965505). False +ENST00000585124 NM_004217.3 9212 AURKB True AURKB, an intracellular kinase, is infrequently altered in cancer. AURKB (Aurora Kinase B) is a cell-cycle regulatory serine/threonine kinase that promotes entry into and proper progression through mitosis. AURKB protein is expressed in proliferating cells during G2 and mitosis and phosphorylates multiple proteins to maintain genome integrity. AURKB aids in the establishment of proper chromosome-spindle attachments in the spindle assembly checkpoint and is essential for cytokinesis (PMID: 11050385,12707311, 14767480). Increased AURKB expression is seen in certain cancers, such as hepatocellular carcinomas (PMID: 20799978), but the functional implication of dysregulated AURKB expression has not been established. Forced over-expression of AURKB was reported to promote aneuploidy in fibroblast cells, suggesting a potential role in promoting chromosome instability (PMID: 12234980). False +ENST00000262320 NM_003502.3 8312 AXIN1 False AXIN1, a tumor suppressor involved in WNT signaling, is mutated at low frequencies in various cancer types. AXIN1 is a scaffolding protein that is a component of the beta-catenin destruction complex. In this complex, AXIN1 and AXIN2 provide scaffolding for the tumor suppressor APC, the kinase GSK3, and beta-catenin (PMID: 14600025), enabling beta-catenin degradation in the absence of WNT ligand binding at the plasma membrane (PMID: 9734785). AXIN proteins interact with the receptors LRP5 and LRP6 to facilitate GSK3 recruitment to the plasma membrane following WNT extracellular stimulation, leading to activation of WNT signaling and targeting of beta-catenin to the nucleus to regulate transcription (PMID: 20128690, 23169527). The activation of WNT signaling, mediated in part by AXIN proteins, can activate many pathways relevant to cancer including cellular proliferation, cell cycle progression, apoptosis, and stem cell fate decisions (PMID: 15735151, 27617575). Germline mutations in AXIN1 have been associated with gastrointestinal cancers (PMID: 25236910). Truncating somatic mutations in AXIN1 have been associated with hepatocellular carcinoma and hepatoblastomas, suggesting that AXIN1 functions as a putative tumor suppressor gene (PMID: 12101426, 10700176). True +ENST00000307078 NM_004655.3 8313 AXIN2 False AXIN2, a tumor suppressor involved in WNT signaling, is mutated at low frequencies in various cancer types. AXIN2 is a scaffolding protein that is a component of the beta-catenin destruction complex. In this complex, AXIN1 and AXIN2 provide scaffolding for the tumor suppressor APC, the kinase GSK3, and beta-catenin (PMID: 14600025), enabling beta-catenin degradation in the absence of WNT ligand binding at the plasma membrane (PMID: 9734785). AXIN proteins interact with the receptors LRP5 and LRP6 to facilitate GSK3 recruitment to the plasma membrane following WNT extracellular stimulation, leading to activation of WNT signaling and targeting of beta-catenin to the nucleus to regulate transcription (PMID: 20128690, 23169527). The activation of WNT signaling, mediated in part by AXIN proteins, can activate many pathways relevant to cancer including cellular proliferation, cell cycle progression, apoptosis, and stem cell fate decisions (PMID: 15735151, 27617575). Germline mutations in AXIN2 have been associated with gastrointestinal and colorectal cancers (PMID: 25236910, 21541676) as well as familial tooth agenesis and predisposition to colorectal cancer (PMID: 15042511). AXIN2 expression has also been shown to predict prostate cancer recurrence (PMID: 26771938). Truncating mutations in AXIN2 have been associated with colorectal cancer and are predicted to result in gain-of-function activity, however, further studies are required to confirm that these alterations are indeed activating (PMID: 11017067). True +ENST00000301178 NM_021913.4 558 AXL True AXL, a receptor tyrosine kinase, is altered by mutation, amplification or overexpression in various cancer types. AXL is a receptor tyrosine kinase (PMID: 28072762) whose primary ligand is the vitamin K-dependent growth factor GAS6 (growth arrest-specific protein 6). Activation of AXL via GAS6 requires an additional interaction with phosphatidylserine, a phospholipid that is only accessible to apoptotic cells (PMID: 28072762). AXL activates the JAK/STAT, MAPK/ERK, and PI3K/AKT signaling pathways (PMID: 18620092) leading to proliferation, survival, and chemoresistance in AXL-expressing cells (PMID: 23982172). Additionally, AXL has been shown to be essential for the epithelial-to-mesenchymal transition (EMT) and can mediate metastasis in cancer (PMID: 16585512). While somatic mutations in AXL are rare, AXL is overexpressed in many human cancers including lung, breast, pancreatic and hematopoietic cancers (PMID: 1656220). AXL overexpression has been implicated in resistance to chemotherapy and targeted agents and decreased immune response, making AXL a target for drug development (PMID: 28072762). Currently, inhibitors specifically targeting AXL or multi-targeted kinase inhibitors with good potency against AXL are under clinical development (PMID: 25337673). False +ENST00000558401 NM_004048.2 567 B2M False B2M, a tumor suppressor and regulator of the immune system, is inactivated by mutation or deletion in various cancer types including non-Hodgkin's lymphoma. B2M (beta2-microglobulin) is a component of the human leukocyte antigen (HLA) class I molecule that is expressed by all nucleated cells (PMID: 8717519). Specifically, B2M serves as the light chain of the MHC class I molecule, which functions to present peptides derived from cellular proteins to CD8+ T lymphocytes, a process critical to adaptive immune responses (PMID: 8717519). Deletion of B2M in mice results in loss of MHC class I presentation and all CD8+ T cells (PMID: 2112266). Somatic B2M loss-of-function mutations have been identified in colorectal cancer and melanoma and are predicted to result in immune evasion (PMID: 22833104). Additionally, serum levels of free, soluble B2M are increased in many hematological and solid malignancies. Various non-immunologic context-dependent functions have been ascribed to soluble B2M; these include serving as a mitogenic or pro-apoptotic paracrine factor in various tumor types (PMID: 23848204, 19056512). Elevated serum B2M is a strong prognostic indicator of poor outcomes in many hematological malignancies, particularly multiple myeloma and non-Hodgkin lymphomas, although the precise mechanism underlying this correlation is not fully understood (PMID: 8507875, 15809451, 8471438). True +ENST00000297574 79870 BAALC True BAALC, a cytoplasmic protein, is frequently overexpressed in cancer. BAALC is a highly conserved mammalian cytoplasmic protein expressed in the central nervous system and in human hematopoietic cells (PMID: 11707601). BAALC is suggested to play a role in the hematopoietic system due to its expression in early progenitor cells, however, the function of BAALC is still largely unknown (PMID: 11707601, 33968759, 26171200). Overexpression of BAALC promotes tumorigenesis through the downregulation of apoptosis and upregulation of cancer cell proliferation, invasion, migration and anchorage-dependent growth (PMID: 33968759, 22549446). BAALC overexpression has been identified in a variety of tumor types including cytogenetically normal-acute myeloid leukemia (AML) and acute lymphoblastic leukemia (PMID: 11707601, 20535151). BAALC is used as a prognostic marker for survival outcome, as high BAALC expression has been correlated with poor prognosis in patients with AML (PMID: 21869843, 26171200). False +ENST00000359435 NM_001033549.1 29086 BABAM1 False BABAM1, a protein involved in the DNA damage response, is infrequently altered in cancer. BABAM1 (also MERIT40 or NBA1) is a component of both the BRCA1-A (breast cancer type 1 susceptibility protein) and BRISC (BRCC36 isopeptidase) multiprotein complexes (PMID: 22974638, 28009280). The BRCA1-A complex recognizes ubiquitinated histones H2A and H2AX at DNA double-strand break (DSB) sites, facilitating damage-dependent BRCA1 localization and DNA repair (PMID: 19261748). BABAM1 has been implicated in the earliest stages of DNA interstrand cross-links repair (PMID: 26338419). The BRISC complex cleaves lysine 63 ubiquitinated substrates, playing a role in interferon responses and proper mitotic spindle assembly (PMID: 24075985, 26195665). Germline variants of BABAM1 have been reported to confer susceptibility to ovarian cancer (PMID: 20852633); however, somatic BABAM1 mutations appear to be rare in human cancers. False +ENST00000257749 NM_001170794.1 60468 BACH2 False BACH2, a transcription factor important in immune cell differentiation, is infrequently mutated in a diverse range of human cancers. BACH2 is a transcription factor that functions predominantly as a transcriptional repressor and mediates innate and adaptive immunity (PMID: 29625895). BACH2 is an important regulator of terminal differentiation in both B and T cells (PMID: 29669243, 29625895). In B cells, BACH2 activity is required for the formation of germinal centers, somatic hypermutation of immunoglobulin genes, plasma cell lineage commitment, negative selection of pre-B cells and class switch recombination (PMID: 29540581, 29129929, 23852341). In T cells, BACH2 expression is required for memory cell activity and BACH2 downregulation is required for effector cells to appropriately differentiate (PMID: 29669243, 29625895, 28855027). In addition, BACH2 regulates the expression of KLRG1 on the surface of CD8+ T cells in order to initiate their entry into the effector or memory pool (PMID: 29669243, 29625895). Expression of BACH2 is also required to maintain the function of alveolar macrophages in the airway and to regulate the inflammatory response (PMID: 28993481). BACH2 represses the expression of several gene programs associated with immune cell differentiation programs, cell cycle, and cytokine production (PMID: 23728300, 29540581, 29529253). The activity of BACH2 is mediated by several upstream signaling pathways, including the ERK/MAPK and mTOR pathways (PMID: 29529253, 29129929, 28993481). BACH2 also competes with BCL6 DNA binding to activate TP53-mediated checkpoint control and tumor suppression (PMID: 23852341). Germline loss-of-function mutations and polymorphisms in BACH2 are associated with autoimmune and allergic disorders such as Crohn’s disease and asthma (PMID: 28530713, 23728300). Heterozygous loss of BACH2 leads to lymphocytic defects due to transcriptional and epigenetic dysfunction (PMID: 28530713), consistent with BACH2 functioning as a haploinsufficient tumor suppressor. Somatic mutations in BACH2 are rare; however, reduced expression or promoter somatic hypermutation of BACH2 has been identified in mantle cell lymphomas and are implicated in drug resistance (PMID: 28592433). True +ENST00000460680 NM_004656.3 8314 BAP1 False BAP1 is a tumor suppressor and deubiquitinating enzyme. Germline mutations of BAP1 predispose to various cancer types, including malignant mesothelioma, uveal and cutaneous melanoma, and renal cell carcinoma. BAP1 (BRCA-associated Protein-1) is a nuclear ubiquitin hydrolase that has been implicated in several cellular processes including cell proliferation, DNA repair, chromatin regulation of gene expression, and stem cell pluripotency (PMID: 19815555, 20805357, 18757409). By deubiquitinating host cell factor-1 (HCF-1), a chromatin-associated protein that helps regulate transcription, BAP1 regulates cell proliferation (PMID: 19815555). BAP1 has been shown to regulate gene expression by forming a ternary complex with HCF-1 and the YY1 transcription factor (PMID: 20805357) and to enhance cell death by increasing progression through the G1-S checkpoint (PMID: 18757409). BAP1 loss alters class I histone deacetylase (HDAC) expression, which may result in altered therapeutic response to HDAC inhibitors in BAP1-depleted cancer cells (PMID: 25970771). Germline mutations of the BAP1 tumor suppressor gene predispose to several tumors, most commonly including uveal melanoma, mesothelioma, cutaneous melanoma, and renal cell carcinoma (PMID: 21874000, 23277170, 23849051, 32690542). Somatic BAP1 mutations are also common in these tumor types, among others (PMID: 23867514, 21642991, 23277170). True +ENST00000260947 NM_000465.2 580 BARD1 False 1 BARD1, a tumor suppressor involved in the DNA damage response, is altered by mutation in breast and ovarian cancers. BARD1 is an adaptor protein that functions as an E3 ligase when in complex with BRCA1 (PMID: 8944023, 32094664, 11573085). BRCA1 is a well-characterized tumor suppressor that functions to maintain genome integrity by repairing DNA double-stranded breaks through homologous recombination and cell-cycle checkpoint activation (PMID: 20029420, 11278247). The BARD1-BRCA1 complex is involved in diverse cellular processes including various stages of DNA repair, gene expression, replication fork maintenance and chromatin regulation (PMID: 32094664, 28976962, 17873885, 29367421, 27239795). BARD1 interacts with BRCA1, binds DNA lesions on newly replicated DNA, and adds ubiquitin molecules to lysine residues on histone H2A (PMID: 32094664, 30804502). The BARD1-BRCA1 complex then mediates the resection of DNA lesions, evicts the antagonistic repair protein 53BP1, and recruits several DNA response proteins to damaged sites, including RAD51 (PMID: 32094664, 28976962, 12832489, 27239795). Poly ADP-ribose (PAR) mediates early recruitment of the BRCA1-BARD1 complex to damaged DNA sites (PMID: 25634209). Loss of BARD1 expression in murine models of breast cancer results in similar phenotypes as BRCA1 deletion, underscoring the likelihood that they function similarly (PMID: 18443292). Germline mutations in BARD1 predispose to breast and ovarian cancer, among other cancers (PMID: 11807980, 20077502, 23334666, 25058500, 28726808, 31371347). Some BARD1 variants function as dominant-negative mutations, suggesting that BARD1 predominantly functions as a tumor suppressor (PMID: 22350409, 26738429). Somatic mutations in BARD1 are also found in human cancers and emerging data suggest that BARD1 can function as an oncogene or tumor suppressor in different cellular contexts (PMID: 18089818, 29292755, 26738429). True +ENST00000449228 NM_001127240.2 27113 BBC3 False BBC3, a pro-apoptotic protein, is infrequently altered in cancer. BBC3 (BCL2 binding component 3, also known as PUMA) is a pro-apoptotic BCL-2 family protein. BBC3 contains a BH3 (BCL-2 homology 3) domain, which allows for binding to anti-apoptotic BCL2 family members, including BCL-xL and BCL-2 (PMID: 23175245). This binding releases the pro-apoptotic factors BAK and BAX, which in turn initiate apoptosis via permeabilization of the mitochondrial membrane (PMID: 11463392, 17322918). BBC3 is a transcriptional target of TP53, but is also activated independently of TP53 in response to cellular stress; thus, BBC3 is considered both a p53-dependent and -independent pro-apoptotic factor (PMID: 14585359, 19641508). Although methylation-dependent silencing of BBC3 has been described in Burkitt lymphomas, somatic mutation of BBC3 is not commonly found in human cancers (PMID: 17267315, 18573879). However, BBC3 function can be altered as a consequence of perturbations of other factors in the apoptosis pathways, such as mutations in TP53, which abrogate the ability of TP53 to induce BBC3 expression (PMID: 21478674). BBC3 is a highly efficient effector of apoptosis, and BH3 mimetic peptides and small molecule therapeutics targeting anti-apoptotic proteins are being investigated as therapeutic options in cancers with dysregulated BBC3 activity (PMID: 17921043, 11463391, 19641508). True +ENST00000370580 NM_003921.4 8915 BCL10 False BCL10, a tumor suppressor and pro-apoptotic protein, is infrequently altered in cancer. BCL10 (B-cell CLL/lymphoma 10) is an adaptor protein involved in apoptosis and NF-kB signaling. The protein forms part of the CARD11-BCL10-MALT1 (CBM) complex, which is a regulator of NFkB signaling in lymphocytes following antigen stimulation (PMID: 25087226, 15541657). BCL10 was discovered at the breakpoint of a recurrent translocation in mucosa-associated lymphoid tissue (MALT) B-cell lymphoma and subsequent experiments showed its role in apoptosis and NFkB regulation (PMID: 9989495, 10319863). Mutations in BCL10 have been found at low frequency in lymphomas and germ cell tumors (PMID: 10582682, 10408401). True +ENST00000357195 NM_138576.3 64919 BCL11B False BCL11B, a transcription factor expressed in T cells and the central nervous system, is altered by mutation, deletion, or chromosomal rearrangement in hematopoietic malignancies. BCL11B (also RIT1) is a transcription factor that is a member of the BCL family. BCL11B is predominantly expressed in T cells and the nervous system (PMID: 23211040). The activity of BCL11B is required for T cell development including lineage commitment, proliferation, differentiation and survival of T cells (PMID: 23211040) as well as in the development of cells in the central nervous system (PMID: 28424591, 29416501). In murine models, loss of BCL11B results in unsuccessful V(D)J recombination and lack of pre-T cell receptor (TCR) presentation on the cell surface (PMID: 12717433), highlighting the importance of BCL11B in T cell biology. BCL11B functions in a transcriptional complex with GATA3 to regulate gene expression in type 2 T helper cells (Th2 cells) (PMID: 29514917). BCL11B has many additional functions including regulation of chromatin state (PMID: 29466755), binding the nuclear hormone receptor NR2F1 (PMID: 23211040), and regulation of cyclin-dependent kinase during the cell cycle (PMID: 16950772). BCL11B acts as either a transcriptional activator or repressor in a context-specific manner (PMID: 23211040). Germline mutations in BCL11B have been identified in individuals with developmental disorders and immune deficiencies (PMID: 29985992, 27959755). Somatic mutations, fusions, and deletions of BCL11B are found in patients with adult T-ALL (PMID: 26219558, 25023966, 21878675). BCL11B functions as a haploinsufficient tumor suppressor, as most alterations are hemizygous (PMID: 26219558) and reduced expression of BCL11B is associated with poor prognosis in T-ALL (PMID: 25023966). True +ENST00000333681 NM_000633.2 596 BCL2 True BCL2, an anti-apoptotic protein, is frequently altered in non-Hodgkin lymphomas. BCL2 (B-cell lymphoma 2) is a key regulator of cell apoptosis, and is part of the BCL2 family of proteins that orchestrate the intrinsic apoptotic pathway (PMID: 24355989). BCL2 is considered a pro-survival factor that inhibits BAX-mediated mitochondrial permeability, thus preventing cytochrome c release and downstream caspase 9 activation through APAF1 (PMID: 9390557, 9219694, 9390557). BCL2 is commonly linked to the immunoglobulin (Ig) heavy chain locus in follicular B-cell lymphomas via the t(14;18) chromosomal translocation (PMID:2875799). This results in robust expression of BCL2 and downstream pro-survival signals, a key step in lymphomagenesis (PMID:7632929). Progression of follicular lymphoma to a more aggressive disease state is often associated with MYC translocation, suggesting a synergy between BCL2 and MYC in cancer progression (PMID:1638027, 12015982). BCL2 is found to be translocated and overexpressed particularly in haematological malignancies, but is infrequently mutated (PMID: 3262202, 16193090). Venetoclax is a small molecule inhibitor of BCL2, and has been approved for treatment in patients with relapsed chronic lymphocytic leukemia (CLL) harboring a specific genetic alteration (PMID: 26639348). False +ENST00000307677 NM_138578.1 598 BCL2L1 False BCL2L1, a regulator of apoptosis, is altered by mutation or amplification in various cancer types including colorectal cancer. BCL2L1 (Bcl-2-like protein 1) belongs to the BCL-2 family of proteins and has a dual pro- and anti-apoptotic role ascribed to its different transcript isoforms produced by alternative splicing (PMID: 8358789). The two isoforms, BCL-XL and BCL-XS, inhibit and activate apoptosis, respectively. BCL-XL sequesters activators of apoptosis such as BID, thus blocking downstream activation of the apoptosis effector proteins BAX and BAK, which normally control mitochondrial membrane potential and the release of cytochrome C (PMID: 17115033, 20584903, 9393856). Inhibition of apoptosis by BCL-XL is overcome by caspase-mediated cleavage (PMID: 9771973, 21256112). Although the pro-apoptotic effect of BCL-XS is poorly understood, it has been shown to interact with BCL2 and BCL-XL (PMID: 10777212, 11526448). BCL2L1 is often amplified in colorectal cancers (CRC) and its expression affects anchorage-independent growth and cell proliferation, though it is not considered a driver of tumorigenesis (PMID: 22009326). Nevertheless, preclinical data has shown small molecules targeting BCL-XL may have therapeutic potential in a subset of CRCs and other cancers (PMID: 26134786, 25313317, 23824742). False +ENST00000393256 NM_138621.4 10018 BCL2L11 False BCL2L11, a tumor suppressor and pro-apoptotic protein, is altered by mutation in various cancer types. BCL2L11 (also BIM) is a pro-apoptotic tumor suppressor that is a member of the BCL2 protein family (PMID: 9731710, 9430630). BCL2L11 expression activates apoptosis by triggering the release of cytochrome c from the mitochondria. Cytochrome c release initiates a series of signaling events that result in apoptosome formation and activation of caspase-mediated programmed cell death (PMID: 19934277, 26405162, 16243507). The anti-apoptotic protein BCL2 sequesters BCL2L11; therefore, the relative levels of BCL2L11 and BCL2 regulate many cellular processes including cell survival and tissue homeostasis (PMID: 9430630, 10576740, 25176652). There are several alternatively-spliced BIM isoforms with various levels of pro-apoptotic activity (PMID: 22728771). Expression of BIM is epigenetically downregulated in several cancer types, including chronic myeloid leukemia and acute lymphoblastic leukemia (PMID: 19403302, 20647567). Furthermore, BCL2L11 activity, in addition to a BCL2L11 single nucleotide polymorphism (SNP), has been shown to be a predictor of response to tyrosine kinase inhibitors (TKIs) in several contexts (PMID: 22145099, 24223824). Thus, Bcl-2 homology 3 (BH3) mimetics may have utility in cancers that are resistant to TKIs through a BIM-dependent mechanism (PMID: 18949058). Chemoresistance mechanisms may also arise due to downregulation of BCL2L11 expression (PMID: 18174237). True +ENST00000250405 NM_004050 599 BCL2L2 True BCL2L2, a regulator of apoptosis, is infrequently altered in cancer. BCL2L2, a member of the BCL-2 protein family, encodes for a mitochondrial outer membrane protein that primarily functions to promote anti-apoptotic signaling (PMID: 11423909). BCL2L2 expression is upregulated by various signaling factors, such as MYC, CREB or p53, and repressed by microRNA (PMID: 17336089, 24070634, 29117536). In addition to apoptotic regulation, BCL2L2 is essential to spermatogenesis and is largely expressed in Sertoli cells, Leydig cells and spermatocytes (PMID: 11423909, 11420255, 10809232). Overexpression of BCL2L2 in various cancer cell lines and models suppresses cell death and induces cellular proliferation and invasion, suggesting that BCL2L2 functions predominantly as an oncogene (PMID: 12615727, 23740614, 25846734). BCL2L2 upregulation has been identified in various cancers, including non-small cell lung cancer and bladder cancer (PMID: 17459056, 21205209). Upregulation of BCL2L2 has been suggested to confer chemoresistance based on preclinical studies (PMID: 28979809, 28742199, 32005716). False +ENST00000164227 NM_005178 602 BCL3 True BCL3, an NFkB regulatory protein, is altered by translocation or overexpression in various cancer types. BCL3, an atypical IkB family member, finely regulates the classical and non-classical NFkB pro-inflammatory response by both repressing and activating NFkB signaling (PMID: 31930327, 1532257). Phosphorylation of BCL3, regulated by the MAPK and AKT pathways, promotes its nuclear localization, stabilization, and recruitment to DNA (PMID: 28689659). BCL3 promotes proliferation via myc and cyclin D, contributes to invasion and metastasis, and evades apoptosis via HDM2, DNA-dependent protein kinases, caspases, and AKT (PMID: 31930327). In cancer, BCL3 is translocated adjacent to the IGH gene forming the oncogenic t(14;19)(q32.3;q13.1) IGH-BCL3 fusion in chronic lymphocytic leukemia (PMID: 2083219, 2180580, 1532257). BCL3 overexpression is associated with poor prognosis in various cancers, including colorectal cancer, in which it has been shown to promote stemness (PMID: 20414006, 30792270). BCL3 may also play a role in immune evasion of cancer cells through upregulation of PD-L1 (PMID: 30135206). False +ENST00000232014 NM_001706.4 604 BCL6 True BCL6, a transcriptional repressor involved in immune cell development, is frequently altered by chromosomal rearrangement in lymphomas. BCL6 (B-cell CLL/lymphoma 6) is a zinc-finger transcription factor that is considered a transcriptional repressor and helps regulate genes involved in lymphocyte activation, differentiation, cell cycle progression and apoptosis (PMID: 9019154, 10981963). It also suppresses terminal differentiation of germinal center B-cells, and downregulation of BCL6 is necessary for further B-cell differentiation (PMID: 18452090, 11452114). BCL6 is a proto-oncogene that is commonly translocated in diffuse large B-cell lymphoma (DLBCL) and non-Hodgkin's lymphoma (PMID: 15202519, 8167331). This translocation, as well as BCL6 somatic mutations found in DLBCL, glioblastoma multiforme (GBM) and breast cancer, are proposed to deregulate BCL6 expression, resulting in its oncogenic potential (PMID: 25038272, 18452090, 24662818). In vitro studies have shown that inhibition of BCL6 results in reduced cell viability and increased apoptosis (PMID: 24662818). False +ENST00000261822 NM_001024808 605 BCL7A False BCL7A, a subunit component of the SWI/SNF complex, is recurrently downregulated in various types of cancer. BCL7A, a member of the BCL7 family, encodes for a subunit of the ATP-dependent chromatin remodeling switch/sucrose non-fermenting (SWI/SNF) complex (PMID: 29213114, 18809673). BCL7A functions in negatively regulating the Wnt signaling pathway and positively regulating the apoptotic pathway (PMID: 25569233). Ectopic expression of BCL7A in acute myeloid leukemia cell and xenograft models represses tumor growth and cellular proliferation, suggesting that BCL7A functions predominantly as a tumor suppressor gene (PMID: 36941700). Downregulated BCL7A has been identified as a risk factor and prognostic biomarker for various types of cancer, including glioma, non-Hodgkin lymphoma, cutaneous T-cell lymphoma and ovarian cancer (PMID: 34362400, 19336552, 15897551, 31077237). True +ENST00000234739 NM_004326.3 607 BCL9 True BCL9, a transcriptional adaptor protein, is recurrently altered by chromosomal translocations in hematologic malignancies. BCL9 is a transcriptional adaptor protein that is a regulator of WNT signaling (PMID: 11955446, 16377174). BCL9 is a nuclear protein that binds the β-catenin-TCF complex, the transcriptional coactivator complex that is downstream of the WNT signaling pathway (PMID: 11955446). BCL9 is also a member of the WNT enhanceosome, a multiprotein complex that regulates the activity of TCF/LEF-responsive enhancer genes (PMID: 28296634). As a component of the WNT enhanceosome, BCL9 recruits additional co-regulators that activate the transcriptional activity of β-catenin depending on the cellular context (PMID: 11955446, 28103279). Namely, BCL9 interacts with Pygo, a protein that binds H3K4 methylation sites on chromatin, implicating BCL9 in epigenetic regulation (PMID: 19305417, 18498752). In addition, BCL9 is a critical mediator of cell-type specific WNT-dependent transcriptional activity (PMID: 18347063, 19699733. 28174279, 30366904). BCL9-mediated WNT signaling regulates several cellular functions including migration, gene expression, mesoderm patterning, proliferation, and adhesion, among others (PMID: 15371335, 19305417, 19738061). Downregulation of BCL9 in biochemical experiments results in translocation of β-catenin from the nucleus to the cytoplasm, leading to altered gene expression (PMID: 15371335). Overexpression of BCL9 and recurrent BCL9 fusions have been identified in patients with B-cell malignancies and acute myeloid leukemia (PMID: 9490669, 10602418), suggesting that BCL9 functions as an oncogene. Inhibitors that target the β-catenin-BCL9 interaction may be efficacious in patients with increased BCL9 activity (PMID: 22914623). False +ENST00000378444 NM_001123385.1 54880 BCOR False BCOR, a transcriptional repressor, is altered in various solid and hematologic malignancies including acute myeloid leukemia. BCOR (BCL6 co-repressor) is a transcriptional repressor that is required for normal germinal center formation in B cells (PMID: 27505670). BCOR is a chromatin regulatory protein that functions in a variety of non-canonical epigenetic repressive complexes and binds the transcriptional repressor BCL6 (PMID: 27505670, 29337181). Depletion of BCOR results in loss of Polycomb protein binding at target genes, which is critical for maintaining repressed chromatin (PMID: 9337181). Additionally, the presence of RING1 and RNF2 in the BCOR complex suggests BCOR involvement in the ubiquitination of histones (PMID: 19738629). BCOR functions as a tumor suppressor that is a key regulator of early embryonic development, mesenchymal stem cell function, hematopoiesis and vertebrate laterality (PMID: 17517692, 18795143, 19578371, 10898795). Germline mutations in BCOR are responsible for the inherited oculofaciocardiodental and Lenz microphthalmia syndromes (PMID: 15004558). BCOR fusions are recurrent in soft tissue and endometrial stromal sarcomas (PMIDs: 22387997, 25176412, 24805859, 25360585), as well as in acute promyelocytic leukemia (APL) (PMID: 20807888). These fusions lead to oncogenesis by activating various anti-apoptotic pathways. BCOR has been identified as both the N-terminal and the C-terminal fusion partner depending on the type of cancer in which it is expressed, suggesting differing mechanisms for oncogenesis in these tumors (PMID: 25360585). Somatic BCOR truncating mutations have also been identified in retinoblastoma and hematologic malignancies, including acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) (PMID: 22237022, 22012066, 24047651, 25550361). True +ENST00000218147 63035 BCORL1 False BCORL1, a transcriptional repressor, is recurrently mutated in hematopoietic malignancies, astrocytomas, and intracranial germ cell tumors. BCORL1 is a transcription factor that functions to repress gene expression (PMID: 17379597). BCORL1, a homolog of the BCOR repressor, interacts with histone deacetylases to mediate transcriptional repression (PMID: 17379597). In addition, BCORL1 interacts with the CtBP corepressor and plays a role in repression of E-Cadherin, an important gene in the epithelial to mesenchymal transformation. Loss of BCORL1 results in promotion of migration and invasion in hepatocellular cancer cell lines (PMID: 26879601). BCORL1 also binds proteins in the epigenetic Polycomb Repressive 1 (PRC1) complex and mediates chromatin state changes (PMID: 27568929). Somatic mutations in BCORL1 are found in patients with adult and pediatric acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), astrocytomas and intracranial germ cell tumors (PMID: 21989985, 24047651, 24896186, 27470916, 27425854) and are predicted to be loss-of-function mutations resulting in truncation of the C-terminus of the protein. Mutations in BCORL1 are associated with age-related clonal disorders of hematopoiesis, which are hematopoietic defects that can transform to MDS or AML (PMID: 25326804, 26132940, 27084249). Overexpression of BCORL1 is also found in a subset of tumors, including in hepatocellular cancer (PMID: 26879601). BCORL1 mutations have also been shown to be relevant to vemurafenib resistance in melanoma (PMID: 29605720). True +ENST00000305877 NM_004327.3 613 BCR True BCR, a signaling molecule, is recurrently altered by chromosomal rearrangement in chronic myeloid leukemia and other hematopoietic malignancies. BCR is a signaling molecule with serine/threonine kinase activity (PMID: 23940119). BCR has been reported to function as both a guanine nucleotide exchange factor (GEF), which promotes the activation of RhoA family GTPases (PMID: 23940119), and a GTPase activating protein (GAP), which inactivates GTPase activity by stimulating the activity of the small GTP binding proteins Rac1, Rac2, and Cdc42 (PMID: 7889565). In keratinocytes, BCR promotes the formation of stress fibers and focal adhesions, an important function for cellular migration (PMID: 23940119). Loss of BCR in mice results in normal development, however; mice develop a neutrophil expansion due to an increase in reactive oxygen metabolite production (PMID: 7889565). BCR also functions as a mediator of signaling and has modular domains that serve as binding sites for GRB2, GRB10, 14-3-3 and the ABL proteins (PMID: 15719031). BCR is most commonly studied as a translocation partner in the BCR-ABL1 fusion protein (or Philadelphia chromosome), which leads to a constitutively active kinase. The BCR-ABL1 fusion protein is found in essentially all cases of chronic myeloid leukemia (CML) and a small proportion of patients with acute lymphocytic leukemia (ALL) and acute myeloid leukemia (AML). BCR-ABL1 binds signaling molecules, including SOS and GRB2, and initiates downstream signaling pathways including the PI3K/AKT and RAS/MAPK pathways (PMID: 15719031). BCR-ABL1-translocated cancers are sensitive to the kinase inhibitor imatinib, and second-generation kinase inhibitors have been identified that target drug resistance mechanisms that arise in response to imatinib (PMID: 17457302). False +ENST00000263464 NM_182962.2 330 BIRC3 True BIRC3, an anti-apoptotic protein, is altered in various cancer types. BIRC3 (baculoviral IAP repeat containing 3, or cIAP2) is a member of the inhibitor of apoptosis (IAP) family of proteins and contains catalytic ubiquitinase activity (PMID: 8548810, 20651737). BIRC3 activates the canonical NFκB signaling pathway following tumor necrosis factor (TNF) α binding to TNFR1 (TNF receptor 1). TNFR1 activation triggers assembly of a complex wherein BIRC3 mediates ubiquitination of several factors, resulting in derepression of NFκB (PMID: 20651737, 11907583). BIRC3 also activates non-canonical NFκB signaling by mediating ubiquitination of NIK (NFκB-inducing kinase) (PMID: 20651737, 11907583). In addition, BIRC3 functions as an inhibitor of apoptosis by directly ubiquitinating caspases 3 and 7 (PMID: 20651737), targeting them for degradation. BIRC3 and its homolog, BIRC2 (cIAP1), are functionally redundant in preclinical model systems, but also have non-overlapping expression patterns suggesting distinct biological functions (PMID: 20651737, 21430708). Overexpression of BIRC3 has been associated with cancer evasion from apoptosis with amplification identified in lung and breast cancer and gliomas (PMID: 12651874, 27074575, 31713298). Somatic BIRC3 truncating mutations and deletions have been identified in patients with chronic lymphocytic leukemia and associated with poor prognosis (PMID: 26837699, 22308293). The efficacy of SMAC (second mitochondria-derived activator of caspases) mimetics as single agents and in combination with proteasome inhibitors are being investigated as a therapeutic for hematological and solid cancers (PMID: 30766663, 32170726). True +ENST00000355112 NM_000057.2 641 BLM False BLM is a tumor suppressor involved in DNA repair. Germline mutations of BLM are associated with Bloom syndrome and predispose to certain cancers. BLM (also Bloom syndrome protein) is a DNA helicase that functions by unwinding double-stranded DNA intermediates during multiple cellular functions, including double-strand break repair by homologous recombination, telomere maintenance and replication (PMID: 21047263, 24606147). BLM gene expression is cell cycle regulated and BLM has been shown to interact with the E3 ubiquitin-protein ligase Mindbomb 1 (MIB1) and a highly conserved DNA topoisomerase 2β-binding protein 1 (TopBP1) (PMID: 24239288). The helicase activity of BLM is critical for preserving the fidelity of the genome, and deleterious mutations result in a strong predisposition for a broad spectrum of cancers across multiple tissue types, generally characterized as highly aggressive and occurring early in life. Germline mutations in BLM lead to the rare genetic disorder Bloom syndrome (BS), an autosomal recessive disorder characterized by severe chromosomal instability and increased cancer risk (PMID: 17407155). Heterozygous inherited deleterious mutations in BLM have been associated with an increased risk for breast cancer (PMID: 23028338) and colorectal cancers (PMID: 26358404), albeit with a moderate penetrance for the latter. Somatic mutations in BLM are rare in human cancers, however, truncating mutations in BLM have been identified in colorectal cancers with a microsatellite instability (PMID: 11532193). True +ENST00000372037 NM_004329.2 657 BMPR1A False BMPR1A is a transmembrane receptor kinase. Germline mutations of BMPR1A are associated with juvenile intestinal polyposis and Cowden syndrome. BMPR1A is a transmembrane serine/threonine kinase receptor that belongs to the transforming growth factor β (TGF β) family (PMID: 22992590). TGFß signaling controls multiple biological processes including cellular proliferation, differentiation and tissue homeostasis (PMID: 22992590, 11057902). BMPR1A functions as a type I receptor and therefore must associate with the type II receptor BMPR2 to initiate ligand binding (PMID: 22992590). BMP receptors receive signals from growth factor and cytokine BMP ligands and transduce these signals through SMAD and non-SMAD pathways to regulate cell growth, differentiation and apoptosis (PMID: 10712517, 9738456, 19762341). BMPR1A signaling also plays a role in apoptosis, osteoblast function and adipocyte differentiation (PMID: 15090551). Germline mutations of BMPR1A are found in individuals with juvenile polyposis syndrome, juvenile intestinal polyposis and Cowden syndrome (PMID: 15235019, 11536076). BMPR1A mutations are associated with increased risk of gastrointestinal polyps and colon cancer (PMID: 25389115, 21203531). True +ENST00000288602 NM_004333.4 673 BRAF True 1 BRAF, an intracellular kinase, is frequently mutated in melanoma, thyroid and lung cancers among others. BRAF is a serine/threonine kinase that plays a key role in the regulation of the mitogen-activated protein kinase (MAPK) cascade (PMID: 15520807), which under physiologic conditions regulates the expression of genes involved in cellular functions, including proliferation (PMID: 24202393). Genetic alterations in BRAF are found in a large percentage of melanomas, thyroid cancers and histiocytic neoplasms as well as a small fraction of lung and colorectal cancers. The most common BRAF point mutation is V600E, which deregulates the protein's kinase activity leading to constitutive BRAF activation, as BRAF V600E can signal as a monomer independently of RAS or upstream activation (PMID: 20179705). Other BRAF mutations have been found that affect the protein's propensity to dimerize (PMID: 16858395, 26343582, 12068308). The product of these alterations is a BRAF kinase that can activate MAPK signaling in an unregulated manner and, in some instances, is directly responsible for cancer growth (PMID: 15520807). Inhibitors of mutant BRAF, including vemurafenib and dabrafenib, are FDA-approved for the treatment of late-stage or unresectable melanoma. False +ENST00000357654 NM_007294.3 672 BRCA1 False 1 BRCA1, a tumor suppressor involved in the DNA damage response, is mutated in various cancer types. BRCA1 (breast cancer susceptibility gene 1) is a tumor suppressor gene that functions as a multifunctional ubiquitin E3 ligase. BRCA1 has been implicated in regulating diverse cellular processes including transcription, protein ubiquitination, cell cycle regulation and DNA damage response, with a particularly important role in DNA repair during homologous recombination (PMID: 22193408). BRCA1 forms protein complexes with known tumor suppressors including RAD51, BRCA2, BARD1 and PALB2; specifically, BRCA1 and BARD1 facilitate resection of DNA ends and enhance the activity of the recombinase RAD51 (PMID: 14636569, 20729832, 20930833, 20871615, 20729858, 28976962). BRCA1 was the first breast and ovarian cancer susceptibility gene identified and cloned. Germline heterozygous loss-of-function mutations result in autosomal dominant hereditary breast and ovarian cancer (HBOC) syndrome, which is associated with an increased lifetime risk of breast, ovarian, prostate, pancreatic, and other cancers (PMID: 22193408, 31171119). BRCA1 was also more recently implicated in Fanconi anemia complementation group S, a rare Fanconi anemia subtype that results from biallelic mutations in the gene (PMID: 25472942, 29133208, 29712865, 32843487). BRCA1 mutations are predicted to disrupt protein-protein interactions, which facilitate DNA repair (PMID: 1157308, 10918303). Somatic mutations in TP53 in breast tumors are seen almost exclusively with BRCA1 and BRCA2 mutations, suggesting that TP53 loss of function may be a necessary step in the tumorigenesis of BRCA-associated carcinomas (PMID: 14672397). PARP inhibitors are FDA-approved for patients with germline BRCA1-mutant ovarian and breast cancers (PMID: 25366685). True +ENST00000380152 NM_000059.3 675 BRCA2 False 1 BRCA2, a tumor suppressor involved in the DNA damage response, is mutated in various cancer types. BRCA2 (breast cancer susceptibility gene 2) is a tumor suppressor gene that functions as a DNA repair protein. BRCA2 has been implicated in regulating diverse cellular processes including transcription, cell cycle regulation, and DNA damage response, with a particularly important role in DNA repair during homologous recombination (PMID: 22193408). BRCA2 forms protein complexes with known tumor suppressors including RAD51, BRCA1, and PALB2; specifically, BRCA2 binds single-stranded DNA and loads RAD51 monomers at sites of DNA double-strand breaks (PMID: 14636569, 20729832, 20930833, 20871615, 20729858, 28976962). RAD51 requires the BRCA1-BRCA2-PALB2 complex to initiate homologous recombination (PMID: 11239455). Germline, heterozygous loss-of-function mutations result in autosomal dominant hereditary breast and ovarian cancer (HBOC) syndrome, which is associated with an increased lifetime risk of developing breast, ovarian, prostate, pancreatic, and other cancers (PMID: 15800615, 22193408, 31171119, 31343663). Biallelic BRCA2 mutations were also more recently implicated in Fanconi anemia complementation group D1 (PMID: 12065746, 34680915). Somatic mutations in TP53 in breast tumors are seen almost exclusively with BRCA1 and BRCA2 mutations, suggesting that TP53 loss of function may be a necessary step in the tumorigenesis of BRCA-associated carcinomas (PMID: 14672397). PARP inhibitors are FDA-approved for patients with germline BRCA2-mutant ovarian and breast cancers (PMID: 25366685). True +ENST00000303407 NM_007371 8019 BRD3 True BRD3, a transcriptional activator, is altered by translocation in NUT midline carcinoma. BRD3 (bromodomain containing 3) is a member of the bromodomain and extraterminal (BET) subfamily of bromodomain-containing proteins that regulate transcription through the recognition and binding of acetylated lysine residues on histones and transcription factors (PMID: 25849938, 31780938). BRD3 is an epigenetic reader (PMID: 31780938) and acts as a transcription regulator via association with the transcription factor GATA1 (PMID: 21536911). BRD3 has been shown to regulate processes such as skeletal myogenesis and erythroid maturation, among others (PMID: 28733670, 21536911). Translocations of BRD3 that fuse the gene to the 5' end of NUTM1 result in the oncogenic BRD3-NUTM1 fusion, which has been identified as a driver of NUT midline carcinoma (PMID: 25688404, 32328562). Inhibition of the BET protein family has been proposed as a therapeutic strategy across several cancer types (PMID: 25849938). False +ENST00000263377 NM_058243.2 23476 BRD4 True BRD4, a transcriptional coactivator, is altered by amplification or chromosomal rearrangement in various cancer types. BRD4 is a member of the bromodomain and extraterminal (BET) family of proteins, and is important in transcriptional activation and elongation at specific gene enhancer elements (PMID: 20871596). BRD4 binds to acetylated histone lysine motifs and helps recruit members of the transcriptional regulator complex, including P-TEFb and Mediator, which are necessary for PolII-dependent transcriptional elongation (PMID: 24751816). BRD4 has been shown to have a role in inflammation (PMID: 21068722, 25263595), viral gene expression (PMID: 16109376) and heart failure (PMID: 23911322). A subset of regulatory elements termed 'super-enhancers' are bound by high levels of BRD4 and are particularly prone to transcriptional perturbations of BRD4 inhibition (BETi) via small molecules (PMID: 24905006, 23582323). For example, BETi results in significant reduction of MYC downstream activity via its super-enhancer. As such, experimental data has shown that MYC-driven cancers are particularly sensitive to BETi, including multiple myeloma (PMID: 21889194) and medulloblastoma (PMID: 24297863). A chromosomal BRD4-NUT fusion product is a driver of disease in most cases of NUT midline carcinoma and is sensitive to BETi (PMID: 20871596). Resistance to BETi can arise due to BRD4 hyperphosphorylation in breast cancer (PMID: 26735014), and SPOP mutations, which can lead to BRD4 stabilization in prostate cancer (PMID: 28805820). False +ENST00000259008 NM_032043.2 83990 BRIP1 False 1 BRIP1 is a tumor suppressor involved in DNA repair. Germline mutations of BRIP1 are associated with Fanconi anemia and predispose to certain cancers. BRIP1 (BACH1 and FANCJ) is a member of the RecQ DEAH helicase family. DEAH helicases participate in pre-messenger RNA splicing and ribosome biogenesis (PMID: 20168331). This family of genes includes those that have been implicated in heritable human diseases, including BLM, WRN and RECQL4 (PMID: 24606147). Specifically, BRIP1 interacts with the BRCT motif-containing domain of BRCA1 (PMID: 17033622). In the HCC1937 cell line that produces BRCA1 with a truncated C-terminal, BRIP1 failed to co-immunoprecipitate with BRCA1, suggesting this domain is important for interaction with BRIP1 (PMID: 11301010). In the same study, two intact BRCT repeat units on BRCA1 were shown to be necessary for the BRCA1 and BRIP1 interaction; a mutation at K52R on BRIP1 may control the interaction of the two proteins. Germline heterozygous mutations in BRIP1 primarily predispose individuals to ovarian cancer (PMID: 21964575, 26315354, 29368626, 32359370) with controversial or inconclusive evidence for other cancer types (PMID: 11301010, 17033622, 19127258, 30099541, 33471974, 33471991). Biallelic mutations in BRIP1 are implicated in Fanconi anemia complementation group J (PMID: 16116423, 16116424, 27107905). Cell lines that are deficient in BRIP1 are sensitive to mitomycin C, a crosslinking agent (PMID: 16153896). True +ENST00000309383 NM_032430 84446 BRSK1 False BRSK1, a serine/threonine kinase, is infrequently altered in cancer. BRSK1 (Brain Specific Kinase 1, aka SAD-B) and its related isoform BRSK2 are AMP-activated protein kinase (AMPK) subfamily serine/threonine kinases that are phosphorylated by LKB1 and carry out tumor suppresive functions (PMID: 14976552). Activated BRSK1 regulates cell cycle progression by phosphorylating tubulin, which is critical for centrosome duplication (PMID: 19648910). Activated BRSK1 also phosphorylates and downregulates Wee1A and Cdc25-B/C, which regulates neuronal polarity and leads to G2/M arrest in response to UV- or MMS-induced DNA damage (PMID: 15705853, 20026642, 15150265). Truncating mutations of BRSK1 are found in MSI-high gastric and colorectal cancers (PMID: 27677186). Additionally, loss of BRSK1 expression in breast cancer has been associated with higher-grade disease (PMID: 25036402). True +ENST00000256015 NM_001731.2 694 BTG1 False BTG1, an adaptor molecule that regulates transcription factor binding, is recurrently altered by deletions and mutations in hematopoietic malignancies. BTG1 is a member of a family of proteins that regulate cell proliferation. BTG1 acts as an adaptor molecule that stimulates the activity of transcription factors including HOXB9 and RARα (PMID: 19746446). In addition, BTG1 regulates the activity of an epigenetic complex containing PRMT1, an arginine methyltransferase (PMID: 26657730). Expression of BTG1 is important for regulation of cell cycle arrest, apoptosis, and cell proliferation in a variety of cellular contexts (PMID: 26622543). Deadenylation of poyl(A) tails on mRNA is also mediated by BTG1 binding to CNOT7, allowing for regulation of mRNA turnover and decay (PMID: 19746446). BTG1 transcriptional control is important for cerebellum and pre-B cell development as demonstrated in murine models (PMID: 27036158, 26524254). Loss of BTG1 enhances the stem cell renewal capacity of hematopoietic progenitor cells and mediates the upregulation of BCL6, leading to suppression of the tumor suppressor genes TP53 and p19ARF (PMID: 29408281). Somatic BTG1 loss-of-function mutations occur in diffuse large B cell lymphomas (DLBCL) and deletions occur in B-cell precursor acute lymphoblastic leukemia (BCP-ALL) and acute lymphoblastic leukemia (ALL) (PMID: 22343534, 29407587, 27151989), suggesting that BTG1 functions as a tumor suppressor. Secondary mutations in BTG1 have also been identified in patients with chronic lymphocytic leukemia (CLL) treated with the BCL-2 inhibitor venetoclax (PMID: 29463802). True +ENST00000290551 NM_006763 7832 BTG2 False BTG2, a cell cycle transcription coregulator, is infrequently altered in cancer. BTG2, a member of the BTG/TOB gene family, is a transcription coregulator that controls cell cycle progression through either enhancing or inhibiting transcription factor activity (PMID: 9712883, 8944033). BTG2 has two highly conserved domains in the N-terminal portion of the protein, box A and box B, that allow for interaction with target molecules to regulate cell proliferation (PMID: 9712883, 8944033). BTG2 has been identified to regulate pathways that control cell growth, cell differentiation, cell death, cell migration and senescence (PMID: 23876794, 22562501, 24981574, 20020054, 15302583). Silencing miR-27a, an inhibitor of BTG2, in pancreatic cancer cell lines increases BTG2 levels and results in the inhibition of cellular proliferation, suggesting that BTG2 functions predominantly as a tumor suppressor gene (PMID: 31724333). Loss of BTG2 expression has been identified in various cancers, including breast cancer, ovarian cancer and non-small cell lung cancer (PMID: 35401805, 34485119, 35388633). True +ENST00000308731 NM_000061.2 695 BTK True R2 BTK, an intracellular kinase, is overexpressed in B-cell malignancies. BTK (Bruton’s agammaglobulinemia tyrosine kinase) is a cytoplasmic tyrosine kinase that plays an important role in B-cell activation. The B-cell receptor (BCR) activates BTK when BCR-associated tyrosine kinases (such as SYK and LYN) phosphorylate BTK at the plasma membrane (PMID: 8629002, 29861875). The main target of BTK phosphorylation is phospholipase C-γ2 (PLCγ2) which leads to the activation of downstream signaling pathways including NFAT, NFkB and MAPK pathways (PMID: 8691147, 10811867). BTK signaling is also implicated in chemokine receptor signaling in lymphocyte trafficking and in Toll-like receptor signaling in the immune response (PMID: 17239630, 23967355). Loss-of-function mutations in BTK result in X-linked agammaglobulinemia (XLA), a disorder that results in the failure of pre-B cells in the bone marrow to differentiate into mature circulating B cells (PMID: 8380905). While somatic mutations in BTK are not common, BTK signaling is critical for growth of B-cell derived malignancies such as chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), multiple myeloma (MM) and Waldenstrom's Macroglobulinemia (WM) (PMID: 24658273). BTK is also overexpressed in B-cell malignancies (PMID: 21422473, 23962569). BTK inhibition has been a successful means of therapy in hematologic malignancies. The tyrosine kinase ibrutinib targets BTK and is FDA approved for the treatment of patients with MCL, CLL, and WM (PMID: 25361916). However, acquired resistance to ibrutinib has been observed through mutations in BTK itself and in downstream effectors such as PLCγ2 (PMID: 24869598). R2 False +ENST00000287598 NM_001211.5 701 BUB1B True BUB1B, a spindle assembly checkpoint kinase, is altered in various cancers. BUB1B encodes for the BUBR1 protein, a serine/threonine kinase involved in mitosis where it is a core component of the spindle assembly checkpoint (PMID: 33207204). By inhibiting the anaphase-promoting complex/cyclosome, BUBR1 delays the onset of anaphase and mediates proper chromosome segregation (PMID: 23079597, 33207204). While the full spectrum of BUBR1 interacting partners remains to be elucidated, HDAC2 has been identified as a potential upstream regulator (PMID: 36577966). Functional studies indicate that BUBR1 interacts with multiple signaling pathways implicated in cancer progression. In hepatocellular carcinoma (HCC) cell lines, downregulating BUBR1 decreases protein expression levels of mTOR and in vitro evidence suggests that BUBR1 may activate the MTORC1 signaling pathway (PMID: 32977361). In cholangiocarcinoma cell lines, knockdown of BUBR1 decreases phosphorylated c-Jun and inhibits translocation of JNK, suggesting a potential role in the JNK-c-Jun signaling pathway (PMID: 33431813). Additionally, BUBR1 knockdown promotes apoptosis in HCC, lung adenocarcinoma and thyroid cancer cell lines, supporting its role as an oncogene (PMID: 32977361, 26000094, 35517426). BUBR1 is overexpressed in various cancers including prostate cancer, gastric adenocarcinoma, multiple myeloma, lung adenocarcinoma, thyroid cancer, HCC and sarcoma, and is often associated with less favorable prognosis (PMID: 27143916, 34620840, 26000094, 35517426, 32977361, 33872216). Overexpression of BUBR1 is also correlated with resistance to chemotherapy in vitro and in vivo (PMID: 34620840, 39043653). Biallelic pathogenic germline mutations in the BUB1B gene are associated with the cancer predisposition syndrome premature chromatid separation (mosaic variegated aneuploidy) syndrome (PMID: 15475955). False +ENST00000350061 NM_001128840 776 CACNA1D True CACNA1D, a subunit of the Cav1.3 voltage-gated calcium channel, is infrequently altered in cancer. CACNA1D encodes for the pore-forming α1-subunit of Cav1.3, an L-type voltage-gated Ca2+-channel (PMID: 21406960). Voltage-sensitive calcium channels, such as Cav1.3, function in mediating calcium ion entry into excitable cells to regulate calcium-dependent physiological processes (PMID: 29038230, 26842699, 23913004). CACNA1D directly interacts with the GABA(B) receptor to upregulate MAPK signaling pathways and regulate cellular proliferation (PMID: 22366257). The oncogenic function of CACNA1D may be tissue specific. CACNA1D overexpression and expression of CACNA1D gain-of-function alterations in prostate cancer and aldosterone-producing adenoma cell models induces increased cellular proliferation, suggesting that CACNA1D functions predominantly as an oncogene in these contexts (PMID: 36949059, 23913001, 28781648, 28584016). Amplification and activating mutations of CACNA1D have been identified in gastric cancer, prostate cancer and aldosterone-producing adenoma (PMID: 35590368, 36949059, 24054868, 23913004). Conversely, downregulation of CACNA1D has also been identified in various cancer types, including myeloma, sarcoma and renal tumors (PMID: 28781648). False +ENST00000264705 NM_001306079 790 CAD True CAD, a phosphate synthetase involved in pyrimidine synthesis, is infrequently altered in cancer. CAD encodes for a trifunctional multi-domain protein that functions primarily in pyrimidine biosynthesis through carbamoyl phosphate synthetase activity (PMID: 1967494). De novo synthesis of pyrimidine is required for cellular proliferation (PMID: 12438317). MAPK and mTORC1 phosphorylation causes CAD to become more sensitive to activation and upregulates biosynthesis of pyrimidines for increased cellular proliferation (PMID: 10659854, 23429704). Overexpression of CAD in various cancer cell lines and models induces increased cellular proliferation, suggesting that CAD functions predominantly as an oncogene (PMID: 33670206, 16155188, 32325032). Amplification of CAD has been identified in various types of cancer, including breast cancer, glioblastoma and prostate adenocarcinoma (PMID: 33186350, 31391321, 21982950). False +ENST00000316448 NM_004343.3 811 CALR True CALR, a calcium-binding protein, is altered in various solid and hematologic malignancies including myeloproliferative neoplasms. CALR, also known as calreticulin, is a calcium-binding protein located in the lumen of the endoplasmic reticulum (ER). In the ER, the CALR protein has two primary functions: molecular chaperone in the protein-folding pathway and regulator of calcium homeostasis (PMID: 25918716). As a molecular chaperone, CALR acts to prevent the aggregation and export of partially or incorrectly folded proteins from the ER to the Golgi (PMID: 16467570). The activity of CALR and its paralog CNX (calnexin) is important to ensure the quality of glycoproteins, including membrane-bound proteins, transporters and certain secreted factors (PMID: 10567207). Additionally, CALR is localized to the nucleus and inhibits the function of nuclear hormone receptors, such as the androgen and glucocorticoid receptors, suggesting a role in transcriptional regulation (PMID: 8107808, 8107809, 7556879, 9013706, 7667104). CALR also has important roles in immune regulation including folding of MHC Class I molecules and serving as an “eat me” signal on cancer cells (PMID: 25918716). Recurrent somatic mutations in CALR have been identified in patients with myeloproliferative neoplasms that lack alterations in JAK2 or MPL, suggesting a role in activation of the JAK-STAT signaling pathway (PMID: 24325356, 24325359, 25873496). Alterations in CALR commonly occur as frameshift mutations in the C-terminal region of CALR, truncating the ER-targeting domain of the protein (PMID: 26951227). CALR mutations disrupt the interaction between CALR and membrane receptors (such as MPL) and activate downstream signaling pathways (PMID: 26951227). Somatic CALR mutations are also found in familial cases of thrombocythemia or primary myelofibrosis (PMID: 24553179). False +ENST00000302345 NM_001159772 124583 CANT1 True CANT1, a UDP-preferential nucleotidase, is infrequently altered in cancer. CANT1, a member of the apyrase family, encodes for a calcium-dependent nucleotidase which hydrolyzes the UDP, GDP, UTP and GTP nucleotides with a preference for UDP (PMID: 12600208, 12234496). Alterations of CANT1 have been identified to impair endoplasmic reticulum function and proteoglycan synthesis (PMID: 19853239, 22539336). Germline mutations of CANT1 have been identified to cause dysfunction in cartilage proteoglycan synthesis and are associated with the autosomal recessive condition Desbuquois dysplasia (PMID: 21412251, 25486376,19853239, 30439444). Silencing and knockdown of CANT1 in various cancer cell lines suppresses cell proliferation, migration and invasion, suggesting that CANT1 functions predominantly as an oncogene (PMID: 31102300, 35090419, 35068336, 21435463). Amplification of CANT1 has been identified in various cancer types, including clear cell renal carcinoma and prostate cancer (PMID: 31102300, 21435463). False +ENST00000396946 NM_032415.4 84433 CARD11 True CARD11, a scaffolding protein, is altered in various cancer types including skin cancer and diffuse large B-cell lymphoma. CARD11 (caspase recruitment domain 11) is a cytoplasmic scaffold protein that functions in mediating apoptosis and NF-ĸB signaling via the CARD11/BCL10/MALT1 (CBM) complex (PMID:11278692). Upregulation of CARD11 by protein kinase C (PKC) leads to a conformational change of the protein and formation of the CBM complex, resulting in activation of NF-ĸB through the IĸB kinase (PMID: 26260210, 26212909). In mouse B-cells, CARD11 is a molecular switch defining either the occurrence of activation-induced cell death or proliferation and plasmablast differentiation (PMID: 23027925). CARD11 is an oncogene, and constitutive activation of the CBM complex is a common feature of B- and T-cell malignancies, particularly diffuse large B-cell lymphoma where gain-of-function mutations in CARD11 have been identified (PMID: 18323416). False +ENST00000327064 NM_199141.1 10498 CARM1 False CARM1, a methyltransferase, is overexpressed in various cancer types. CARM1 is a methyltransferase that modifies arginines seventeen and twenty-six of histones and other proteins. CARM1 is recruited, along with EP300 and the NCOA-family of histone acetyltransferases, to active gene promoters, playing a role in transcriptional activation via chromatin remodeling (PMID: 16497732, 19405910). CARM1 is a positive regulator of WNT/β-catenin expression, induces growth and proliferation in colon cancer cells (PMID: 21478268), and synergistically co-activates NF-kB pathway with EP300 in fibroblasts (PMID: 15616592). CARM1 is amplified in a small subset of cancers, such as neuroendocrine, prostate and ovarian tumors (cBioPortal, MSKCC, Nov 2016). False +ENST00000358485 NM_001080125.1 841 CASP8 False CASP8, a tumor suppressor and pro-apoptotic protein, is inactivated by mutation or deletion in various cancer types. CASP8 is a cysteine protease that is a member of the cysteine-aspartic acid protease (caspase) family. CASP8 functions as the main initiator caspase that mediates death receptor-induced apoptosis (PMID: 9729047). Proteolytic activation of CASP8 is induced by the formation of the death-inducing signaling complex (DISC) involving CD95 (Fas/Apo1), tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) receptors and TNF receptors (PMID: 25617598, 18073771). Upon activation, CASP8 can directly cleave other caspases, such as CASP3, or engage the mitochondrial pathway by cleavage of BID (BH3-interacting domain death agonist) (PMID: 9727492, 9501089, 10428830). Conversely, CASP8 has pro-survival activity roles in the anti-apoptotic NF-κB pathway (PMID: 11002417, 10753878, 15746428) and by inhibiting receptor-interacting protein kinase-3 (RIPK3)-dependent necroptosis (PMID: 21368763, 24476434). Other non-proteolytic functions of CASP8 have been identified in neuroblastoma and lung cancer cell lines including the promotion of cell adhesion, (PMID: 18089800, 18089778), motility (PMID: 18216014, 16618751, 18089778), metastasis (PMID: 16397500) and pyroptosis (PMID: 31723262, 31748744). Caspase-8 deficiency state (CEDS) is a rare genetic disorder that is caused by CASP8 mutations and resembles autoimmune lymphoproliferative syndrome (ALPS) (PMID: 12353035). Inactivating somatic mutations, as well as gene silencing by promoter hypermethylation of CASP8, have been observed in different cancers including hepatocellular, gastric, colorectal, central nervous system malignancies and head and neck cancers (PMID: 25631445, 28112728, 15705878, 12949717). True +ENST00000490131 NM_000388.3 846 CASR True CASR, a calcium-sensing G-protein coupled receptor, is rarely altered in cancer. CASR is a calcium-sensing dimeric G-protein coupled receptor with multifaceted signaling roles related to extracellular calcium-sensing, regulation and homeostasis (PMID: 8255296, 32117726). CASR expression is greatest in the kidneys and parathyroid glands; in the kidneys, CASR modulates calcium excretion by inhibiting its reabsorption in the distal tube, while in the parathyroid gland, CASR regulates parathyroid hormone synthesis and secretion, thereby increasing calcium reabsorption (PMID: 22192592, 23565380). These responses to changes in extracellular calcium levels are accomplished by intracellular signaling via G-proteins and beta-arrestin (PMID: 31399503, 22192592). CASR is expressed in many other tissues and has a broad range of cellular interactions and functions in addition to calcium homeostasis, including implications in cellular proliferation, differentiation, inflammation, wound healing, bone metabolism, gastrointestinal nutrient sensing and ion transport (PMID: 34663830, 23228129, 34774235, 37802982). The oncogenic function of CASR is likely tissue-specific. In cancer cells, CASR is associated with suppression of the epithelial-to-mesenchymal transition (EMT) pathway, as demonstrated in renal cell carcinoma and colon cancer cells (PMID: 37804688, 25879211). Knockdown of CASR in renal cell carcinoma in vitro and in vivo results in tumor cell migration, invasion, and increased tumor size and volume, suggesting that CASR functions predominantly as a tumor suppressor gene in this context (PMID: 37804688). However, knockdown of CASR in breast cancer cell lines inhibits proliferation and sensitizes cells to calcium-induced apoptosis, indicating that CASR may function as an oncogene in this context (PMID: 27450451, 37511437). CASR mutations are associated with various disorders, including familial hypocalciuric hypercalcemia and primary hyperparathyroidism (PHPT) (PMID: 35356007, 38021951). True +ENST00000268679 NM_005187 863 CBFA2T3 False CBFA2T3, a transcriptional corepressor, is infrequently altered in various solid tumors and is altered by chromosomal rearrangement in myeloid malignancies. CBFA2T3, a member of the myeloid translocation gene family, encodes for a transcriptional corepressor that interacts with DNA-bound transcription factors to facilitate transcriptional repression (PMID: 12559562, 15203199). CBFA2T3 contributes to the inhibition of the glycolysis pathway through transcriptional repression of glycolytic genes in the HIF-1a pathway (PMID: 23840896, 25974097). The oncogenic function of CBFA2T3 may be likely tissue specific. Ectopic expression of CBFA2T3 in breast cancer cell lines reduced colony growth, suggesting that CBFA2T3 functions predominantly as a tumor suppressor gene in that context (PMID: 12183414). Loss of CBFA2T3 has been identified in various types of cancer, including breast cancer and lung cancer (PMID: 12183414, 13680524, 34164477). CBFA2T3 has been recurrently identified in the t(16;21) (q24;q22) chromosomal translocation in the context of therapy-related myeloid malignancies and is associated with poor patient prognosis (PMID: 31040112, 32434928, 22420028, 23407549, 9596646, 23153540). CBFA2T3 fusions are suggested to promote oncogenesis of therapy-related myeloid malignancies through inhibition of all-trans-retinoic acid (ATRA)-mediated myeloid gene expression and retinoic acid receptor (RAR) target gene transcription (PMID: 32434928). True +ENST00000412916 NM_022845.2 865 CBFB False CBFB, a protein involved in transcriptional activation, is altered by chromosomal rearrangement in a subset of acute myeloid leukemia. The CBFB (core-binding factor, beta subunit) gene encodes a heterodimeric transcription factor component, that together with a core-binding factor alpha component, RUNX1/2/3 (Runt related transcription factor) proteins, forms a transcription factor complex (PMID: 8929538). CBFB is a non-DNA binding subunit that functions to enhance the DNA binding of the CBF alpha component. The CBF complex targets specific genes for activation or repression and also recruits activating or repressive cofactors such as p300 and HDACs (Histone deacetylases) (PMID: 23148227, 21059642). CBFB complexed with RUNX1 regulates important steps in hematopoiesis through processes such as cell cycle progression, differentiation and development (PMID: 11561154). With RUNX2, CBFB regulates skeletal development (PMID: 12434152, 24798493). Inversion of chromosome 16 can result in a CBFB-MYH11 (Myosin heavy chain 11) fusion gene and is associated with the M4 type of acute myeloid leukemia, and often with associated eosinophilia (PMID: 23160462). This fusion protein disrupts the CBF complex and results in a block in hematopoiesis (PMID: 20007544). CBFB may also influence solid tumor development, as mutations have been identified in breast and cervical cancer samples (PMID: 22722202, 24390348). True +ENST00000264033 NM_005188.3 867 CBL False CBL, a tumor suppressor and ubiquitin ligase, is inactivated by mutation or deletion in various cancer types including myeloid malignancies. CBL is an E3 ubiquitin-ligase and proto-oncogene that mediates degradation of receptor tyrosine kinases (PMID: 11283727, 23085373). CBL family E3 ligases selectively and negatively regulate activated receptor tyrosine kinases, including EGFR (PMID: 23085373), PDGFR (PMID: 11283727), CSF-1R (PMID: 11283727), MET (PMID: 24384534), and FLT3 (PMID: 17446348), through ubiquitylation that targets these proteins for degradation by the proteasome (PMID: 11283727). The activity of CBL is required to negatively regulate various signaling pathways, most commonly in hematopoietic and immune cells (PMID: 11857085). In addition to receptor tyrosine kinase regulation, CBL-b is also involved in T cell activation and peripheral T cell tolerance (PMID: 24875217, 17704644, 11283727). Germline mutations in CBL result in developmental delays and a predisposition for juvenile myelomonocytic leukemia (PMID: 20694012). Somatic alterations in CBL have been identified in several human cancers including myelodysplastic syndromes, lung adenocarcinoma and cutaneous melanoma (PMID: 26343386, 11857085). In BCR-ABL rearranged mutant chronic myeloid leukemia (CML), CBL expression is downregulated by the BCR-ABL fusion leading to aberrant activation of downstream signaling pathways (PMID: 11857085). True +ENST00000368666 NM_198239.1 8838 CCN6 True CCN6, a matricellular protein, is altered by deletion in breast cancer. CCN6, a member of the WNT1 inducible signaling pathway (WISP) protein subfamily and connective tissue growth factor (CTGF) family, encodes for an extracellular matrix-associated signaling matricellular protein that regulates various cellular functions including cellular adhesion, migration, proliferation, survival and differentiation (PMID: 27252383, 18775791, 18789696). CCN6 primarily functions in the musculoskeletal system and promotes bone growth and cartilage maintenance through the regulation of mitochondrial function in chondrocytes (PMID: 33644064, 27252383). Mutations of CCN6 have been associated with the musculoskeletal disorder progressive pseudorheumatoid dysplasia (PMID: 10471507, 37417608). The oncogenic role of CCN6 may be tissue-type specific. CCN6 knockdown in inflammatory breast cancer cell lines and models induces epithelial-to-mesenchymal transition and anchorage-independent growth, suggesting that CCN6 functions predominantly as a tumor suppressor gene in the context of breast cancer (PMID: 18321996, 20395207, 12082632, 39024552, 29071006). Loss of CCN6 has been identified in various cancers, including breast cancer and hepatocellular carcinoma (PMID: 30793395, 10499627). Conversely, overexpression of CCN6 in pancreatic cancer and chondrosarcoma cell lines and models induces increased cellular migration, invasion and motility, suggesting that CCN6 functions predominantly as an oncogene in these contexts (PMID: 37105075, 30237403). Amplification of CCN6 has been identified in chondrosarcoma (PMID: 30237403). True +ENST00000276014 NM_033031.2 85417 CCNB3 True CCNB3, a protein involved in cell cycle control, is recurrently altered by mutation, amplification or deletion in various cancer types. CCNB3 (Cyclin B3) is a cyclin protein involved in the positive regulation of cell cycle control. In normal cells, cyclin B3 is exclusively expressed in the testis and is only active during spermatogenesis as a meiotic cyclin thought to be linked to the transition from pre-meiotic to meiotic prophase (PMID: 12185076). In vitro studies have demonstrated that cyclin B3 is able to bind to CDK2; however, it is unable to activate the associated histone H1 kinase activity (PMID: 12185076). CCNB3 is most commonly altered by missense mutations or gene amplifications/deletions in multiple cancer types. Gene fusions with CCNB3 occur most frequently in undifferentiated sarcomas, which lead to aberrant expression of CCNB3 in the mutated cells (PMID: 22387997, 25360585). False +ENST00000227507 NM_053056.2 595 CCND1 True CCND1, a regulator of the cell cycle, is amplified in various cancer types including breast, head and neck, and bladder cancers. CCND1 (cyclin D1) is a protein that couples extracellular growth signaling to cell cycle entry through the activation of cyclin-dependent kinase 4 (CDK4) and CDK6 (PMID: 8114739). Upon forming a complex with cyclin D1, CDK4 and CDK6 phosphorylate and inactivate retinoblastoma (RB), thus leading to the induction of a gene expression program regulated by the E2F family of transcription factors that is important in the transition from G1 to S phase in the cell cycle (PMID: 12432268, 8114703). Functions of cyclin D1 include control of cell growth, proliferation, transcription, DNA repair, and migration (PMID: 21734724). Cyclin D1 is an oncogene, and is often overexpressed or amplified in numerous cancers, including breast, lung, melanoma, and oral squamous cell carcinomas (PMID: 20164920, 20029424). Cyclin D1 is not essential for entry into cell cycle progression (PMID: 15315760), however, its amplification/overexpression in human tumors is oncogenic as it allows cancer cells to proliferate independently of extracellular growth signaling cues (PMID: 23644662, 20029424). False +ENST00000261254 NM_001759.3 894 CCND2 True CCND2, a regulator of the cell cycle, is amplified in various cancer types. CCND2 (cyclin D2) is a protein that couples extracellular growth signaling to cell cycle entry through the activation of cyclin-dependent kinase 4 (CDK4) and CDK6 (PMID: 8114739). Upon forming a complex with cyclin D2, CDK4 and CDK6 phosphorylate and inactivate retinoblastoma (RB), thus leading to the induction of a gene expression program regulated by the E2F family of transcription factors that is important in the transition from G1 to S phase in the cell cycle (PMID: 12432268). Cyclin D2 is not essential for entry into the cell cycle (PMID: 15315760) and is rarely amplified or overexpressed in human cancers. However, the cyclin D2 promoter is frequently methylated with loss of protein expression observed in pancreatic, breast, and prostate cancer, suggesting that it may play a role as a tumor suppressor in certain contexts (PMID: 21734724). De novo cyclin D2 mutations can cause stabilization of the protein and may result in megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome, which is characterized by abnormalities in brain development (PMID: 24705253). False +ENST00000372991 NM_001760.3 896 CCND3 True CCND3, a regulator of the cell cycle, is amplified in various cancer types. CCND3 (cyclin D3) is a protein that couples extracellular growth signaling to cell cycle entry through the activation of cyclin-dependent kinase 4 (CDK4) and CDK6 (PMID: 8114739). Upon forming a complex with cyclin D3, CDK4 and CDK6 phosphorylate and inactivate retinoblastoma (RB), thus leading to the induction of a gene expression program regulated by the E2F family of transcription factors that is important in the transition from G1 to S phase in the cell cycle (PMID: 12432268). Cyclin D3 is not essential for entry into the cell cycle (PMID: 15315760) and is rarely amplified in human cancers (PMID: 21734724). However, the cyclin D3-CDK6 complex may play a metabolic, pro-survival role in cancer cells by inhibiting key enzymes in the glycolytic pathway (PMID: 28607489). False +ENST00000262643 NM_001238.2 898 CCNE1 True 3A CCNE1, a regulator of the cell cycle, is amplified in various cancer types. CCNE1 (cyclin E1) is a protein that regulates the activation of cyclin-dependent kinase 2 (CDK2) during the G1/S transition of the cell cycle (PMID: 1833068). The cyclin E1-CDK2 complex phosphorylates p27(Kip1) and p21, which signals for the degradation of cyclin D and promotes the expression of cyclin A, leading to progression through S phase of the cell cycle (PMID:9192873). Cyclin E1-CDK2 phosphorylates and inactivates retinoblastoma protein (RB), thus leading to the induction of a gene expression program regulated by the E2F family of transcription factors that is important in the transition from G1 to S phase in the cell cycle (PMID: 1388095). Cyclin E1-CDK2 is degraded by SCF-Fbw7, an E3 ubiquitin ligase that is commonly mutated in cancer (PMID: 11533444 ). Increased cyclin E expression in cell lines leads to quicker passage through the G1/S phase, but deletion of cyclin E or CDK2 in mice does not result in a G1/S defect (PMID: 12941272). Amplification and overexpression of cyclin E1 has been implicated in many cancers, including breast cancer, and can be indicative of poor prognosis (PMID: 12432043). False +ENST00000576892 NM_152274.4 92002 CCNQ False CCNQ, a cyclin-related gene, is altered by mutation and deletion in the germline of patients with STAR syndrome. CCNQ (also Cyclin M and CCNQ) is a cyclin-dependent kinase binding partner that is a member of the FAM58 cyclin-like family (PMID: 24218572, 28178678). CCNQ forms a heterodimeric complex with cyclin-dependent kinase 10 (CDK10), which phosphorylates the transcription factor ETS2 (PMID: 24218572). Phosphorylation targets ETS2 for degradation via the 26S proteasome leading to altered cell cycle progression and proliferation (PMID: 24218572). In addition, CCNQ activity has been associated with actin organization and ciliogenesis (PMID: 27104747). Germline loss-of-function mutations and deletions in CCNQ have been identified in patients with STAR syndrome, an X-linked hereditary condition characterized by toe syndactyly, telecanthus and anogenital and renal malformations (PMID: 18297069, 29088509). Alterations in CCNQ/cyclin M stabilize ETS2 protein levels, increase c-RAF signaling, and confer tamoxifen resistance in breast cancer cells (PMID: 24218572). Somatic mutations of CCNQ are rare in human cancer; however, CDK10/Cyclin M activity results have tumor suppressive or oncogenic functions in different cancer types (PMID: 22209942, 18242510, 29435072). True +ENST00000324662 NM_001770 930 CD19 True CD19, a transmembrane glycoprotein, is recurrently amplified in hematologic B-cell malignancies. CD19, a member of the immunoglobulin gene superfamily, encodes for the transmembrane glycoprotein coreceptor of the B-cell antigen receptor complex (BCR) found on the cell surface of B-cells (PMID: 23210908). CD19 functions as an adaptor protein to recruit cytoplasmic signaling proteins to the B-cell membrane and as a member of the CD19/CD21 complex to enhance antigen signaling for the B-cell signaling pathways (PMID: 23210908, 11418645). As a coreceptor of the BCR, CD19 mediates signals to drive B-cell survival, differentiation and proliferation (PMID: 15963789, 12496385, 16116172). Upregulation of CD19 in mouse models induces increased MYC signaling, B-cell transformation and lymphoma progression, suggesting that CD19 functions predominantly as an oncogene (PMID: 22826319, 23210908). CD19 amplification has been identified in various types of hematologic B-cell malignancies, including B-cell lymphoma, acute lymphoblastic leukemia and chronic lymphocytic leukemia (PMID: 23210908, 3257143). Individuals with B-cell malignancies expressing CD19 should be considered for immunotherapies targeting CD19. Loncastuximab tesirine, a monoclonal antibody conjugate targeting CD19, is FDA-approved for the treatment of pretreated patients with relapsed or refractory large B-cell lymphoma (PMID: 33989558). Axicabtagene ciloleucel and tisagenlecleucel, CD19-directed CAR-T cell immunotherapies, are FDA-approved for the treatment of patients with certain types of large B-cell lymphoma and relapsed or refractory follicular lymphoma, respectively (PMID: 29226797, 34921238). False +ENST00000085219 NM_001771 933 CD22 False CD22, an endocytic B-cell receptor, is infrequently altered in cancer. CD22, a member of the sialic acid-binding immunoglobulin-like lectin (Siglec) family, encodes for an endocytic receptor expressed primarily on mature B-cells (PMID: 11967115). CD22 functions as an inhibitory receptor that can physically associate with the B-cell receptor (BCR) to inhibit signaling (PMID: 22566885). CD22 contains an immunoreceptor tyrosine-based inhibitory motif (ITIM) at the cytoplasmic tail to recruit tyrosine phosphatase SHP-1 and inositol phosphatase SHIP to negatively regulate BCR signaling (PMID: 23836650, 10748054). Inhibition of BCR signaling prevents internalization and processing of antigens to present to T cells (PMID: 3157869). CD22 has been identified in blasts from patients with B-cell acute lymphoblastic leukemia; however, its oncogenic function has not yet been well characterized in biochemical studies (PMID: 20841423, 21348573). The efficacy of CD22-targeting treatments, such as monoclonal antibodies, antibody-drug conjugates, radioimmunoconjugates and CAR-T therapies, have been investigated in clinical trials in the context of B-cell lymphoid malignancies (PMID: 29296758, 21673350, 32286905). False +ENST00000381577 NM_014143.3 29126 CD274 True CD274 (also known as PD-L1) is an immune receptor ligand. Expression of PD-L1 may help predict response to immunotherapies targeted against PD-L1 and its receptor, PD-1. The CD274 gene encodes programmed death ligand 1 (PD-L1), a member of a family of co-stimulatory immune receptor ligands. PD-L1 acts to inhibit an immune response by binding to the PD-1 cell surface receptor, which is expressed by T cells, B cells and natural killer cells (PMID: 17629517). PD-L1 allows tumor cells to evade the host immune system by suppressing the T cell response. Amplification or overexpression of PD-L1 has been identified in some tumor types and can be predictive of responses to immunotherapy (PMID: 22437870, 26918453, 28652380, 27620277), suggesting that PD-L1 functions as an oncogene. Individuals with tumors expressing PD-L1 should be considered for immune checkpoint therapy. Atezolizumab, a monoclonal antibody targeting PD-L1, is FDA approved for the treatment of patients with locally advanced or metastatic urothelial carcinoma (PMID: 28424325) and metastatic non-small cell lung cancer (NSCLC) whose disease progressed during or following platinum-containing chemotherapy (PMID: 28611199). Pembrolizumab, an anti-PD-1 antibody, is considered first-line therapy for patients with non-small cell lung cancer and metastatic melanomas that express PD-L1, and may be efficacious in other tumors that express PD-L1 (PMID: 28806116). Nivolumab, an FDA-approved monoclonal antibody that targets PD-1, is also effective in tumors with high PD-L1 expression due to the blockade of the PD-1/PD-L1 interaction and activation of a robust immune response (PMID: 28806116). False +ENST00000318443 NM_001024736.1 80381 CD276 True CD276, a cell surface protein involved in the immune response, is overexpressed in various cancer types. CD276 (also B7-H3 and B7RP-2) is an immune checkpoint molecule and member of the B7 immunoglobulin superfamily of proteins (PMID: 27208063). CD276 is a transmembrane protein found in various cell types, including fibroblasts, endothelial cells and osteoclasts; however, post-transcriptional mechanisms reduce the steady-state levels of CD276 protein (PMID: 27208063). Expression of CD276 is also found on antigen-presenting cells in response to inflammation, including on dendritic and natural killer cells, which likely play important roles in T-cell mediated immune response (PMID: 27208063, 22437870, 11224528, 12925852). Loss of CD276 in murine models results in overactivation of the immune system, demonstrating that CD276 negatively regulates T-cell proliferation (PMID: 12925852). CD276 is overexpressed in a variety of human cancers and has been associated with cancer progression and immune evasion (PMID: 24892449, 22473715, 16489649, 18042703, 23940627, 21671471, 31075138). In addition, CD276 is overexpressed on the cell surface of cancer cells and dampens T-cell inhibitory responses, including in pediatric brain tumors (PMID: 32341579, 29860983). Immunotherapies targeting CD276, such as monoclonal antibodies and engineered CAR T-cell therapy, are currently under clinical investigation (PMID: 30753824, 30655315, 22615450, 29914796, 32398947). False +ENST00000324106 NM_006139.3 940 CD28 True CD28, a costimulatory receptor expressed by T cells, is infrequently altered in a diverse range of human cancers. CD28 is a costimulatory receptor required for T cell activation and survival (PMID: 27192564). CD28 is expressed predominantly on T cells and mediates various T cell processes including differentiation, survival, cytokine production, and immune homeostasis (PMID: 27192564, 29163534). The pairing of CD28 with a B7 protein presented on an antigen presenting cell enhances the activity of MHC (major histocompatibility complex)-TCR (T cell receptor signal) complexes and CD28-B7 coupling is required to initiate a T cell response (PMID: 8642283). The ligands that bind CD28 are CD86, which is constitutively expressed on antigen presenting cells, and CD80, which is upregulated after CD28-CD80 binding (PMID: 27192564, 14978077). CTLA4 and CD28 compete for the same ligands, and subsequent CD80 upregulation following CD28 stimulation may promote immune suppression (PMID: 7682233, 27192564). CD28 is expressed on other immune cells, including plasma cells and T regulatory cells, and plays a role in antibody production and the inflammatory response (PMID: 7534672, 12616483). CD28 engagement initiates several signal transduction pathways due to the association of signaling molecules with the cytoplasmic tail of CD28 (PMID: 8067997, 8025954). CD28 function is dysregulated in autoimmune disorders and cancers (PMID: 28711152, 27460989). CD28 agonists and antagonists are FDA-approved for a variety of immune-related disorders to modulate the function of T effector and T regulatory cells (PMID: 27192564). False +ENST00000369489 NM_001779.2 965 CD58 False CD58, a cell surface adhesion molecule expressed in immune cells, is recurrently altered by mutation and deletion in hematopoietic malignancies. CD58 (also LFA-3) is a cell surface ligand that functions as an immune cell adhesion molecule. CD58 binds CD2, a receptor expressed on T lymphocytes, B cells, and natural killer (NK) cells, to promote cell adhesion to target cells and to provide a stimulatory signal for T cells (PMID: 2951597, 29564225). Co-stimulation resulting from CD2-CD58 engagement results in proliferation, cytokine production and effector function in immune cells (PMID: 26041540). Antibodies targeting CD58 result in blunted immune recognition and reduced cytolysis of target cells by cytotoxic T lymphocytes and NK cells in preclinical studies (PMID: 3084649). CD58 expression is reduced in some acute lymphoblastic leukemia (ALL) and lymphomas, resulting in tumor cells lacking the necessary cell surface molecules for immune recognition (PMID: 22137796, 24413734). Somatic mutations and deletions in CD58 have been identified in diffuse large B cell lymphomas (DLBCL) and other lymphomas, contributing to immune evasion (PMID: 26194173, 22137796, 24413734, 27825110). In DLBCL, concurrent downregulation of both CD58 and HLA-1 molecules results in immune escape from T and NK cells (PMID: 22137796). True +ENST00000245903 NM_001252 970 CD70 True CD70, a transmembrane glycoprotein, is altered by amplification in various cancers. CD70, a member of the TNF ligand family, encodes for a surface antigen found on T and B lymphocytes and functions primarily as a regulator for immune responses, inflammation and cell survival through interaction with receptor CD27 (PMID: 21182090, 29046346, 32665635, 8977292). CD70 interaction with CD27 triggers signaling cascades that lead to the activation of T lymphocytes and enhance the adaptive immune system's ability to mount a response (PMID: 19556308). Dysregulation of the CD70/CD27 signaling axis has been implicated in autoimmune disorders due to aberrant T lymphocyte activation contributing to chronic inflammation and tissue damage (PMID: 16175931, 24817699). Overexpression of CD70 in leukemic cell lines and models induces tumor growth and cancer cell survival, suggesting that CD70 functions predominantly as an oncogene (PMID: 16338493, 7540066). CD70 amplification has been identified in various types of cancer, including renal cell carcinoma, glioblastoma and hematological malignancies (PMID: 16489038, 11980654, 17615291, 28031480). Clinical studies are currently investigating the efficacy of anti-CD70 immunotherapies in patients with hematological malignancies (PMID: 36779592, 36845088). False +ENST00000009530 NM_001025159 972 CD74 True CD74, an MHC class II invariant chain, is infrequently altered in cancer. CD74, a member of the major histocompatibility complex (MHC) class II family, encodes for an invariant chain that functions primarily in antigen presentation for the generation of CD4+ T-cell immune responses (PMID: 30723591). CD74 also functions as a cell surface receptor for the cytokine macrophage migration inhibitory factor, which induces a pro-inflammatory cytokine response (PMID: 32004754, 12782713). Overexpression of CD74 in various cancer cell lines and models induces xenograft tumor growth and increases actin polymerization, suggesting that CD74 functions predominantly as an oncogene (PMID: 27626171). Amplification of CD74 has been identified in various types of cancer, including gastrointestinal cancer, glioma and thyroid carcinoma (PMID: 21228923, 34540893, 25600560). CD74 expression is a potential therapeutic target with preclinical studies and clinical trials investigating the efficacy of anti-CD74 inhibitors and antibody-drug conjugates in various types of cancer (PMID: 25600560, 23427296, 22611320, 28466956, 36634212). False +ENST00000221972 NM_001783.3 973 CD79A True CD79A, a component of the B-cell receptor, is altered at low frequencies across various solid and hematologic malignancies. CD79A is a surface immunoglobulin protein that forms a complex with CD79B and composes part of the B-cell receptor (BCR) (PMID: 1439759). CD79A is expressed from an early stage of B-cell development until the final stage of maturation prior to differentiation into plasma cells (PMID: 21841126, 24146823). The CD79A/CD79B complex is important for transmitting signals generated by antigen binding to the BCR into the cell to support B-cell maturation and survival (PMID: 15186779). Following BCR-ligand interaction, CD79A and CD79B are phosphorylated and activated by SRC family kinases leading to activation of downstream oncogenic signaling cascades that affect B-cell maturation (PMID: 17114463, 15699130, 20940318, 22078222,11514602). Activating mutations in CD79A have been identified in diffuse large B-cell lymphoma, particularly the activated B-cell-like subtype (PMID: 20054396), suggesting that CD79A acts as an oncogene. Such aberrations result in increased BCR signaling and ligand-independent clustering of BCRs, resulting in enhanced B-cell survival and differentiation. Antibody-drug conjugates targeting CD79A/B and inhibitors targeting SRC activity, such as dasatinib, can reduce BCR signaling (PMID: 17374736, 20054396). False +ENST00000392795 NM_001039933.1 974 CD79B True CD79B, a component of the B-cell antigen receptor, is recurrently altered in diffuse large B-cell lymphoma. CD79B is a surface immunoglobulin that forms a complex with CD79A to form a component of the B-cell receptor (BCR) (PMID:1439759). The CD79 (Iga/Igb) complex is important for signaling from the BCR to support maturation and survival of B-cells throughout development (PMID:15186779, 8602530). The cytoplasmic portion of CD79B contains immunoreceptor tyrosine-based activation motif (ITAM) domains that become phosphorylated by SRC proto-oncogene family protein kinases. These regions serve as docking sites for signaling complex formation with kinases such as SYK (spleen tyrosine kinase) and for signal regulation (PMID: 17114463, 20940318, 22078222). Activating mutations of CD79B have been identified in diffuse large B-cell lymphoma, particularly the activated B-cell-like subtype (PMID: 20054396) suggesting that CD79B acts as an oncogene. CD79B mutations result in increased surface BCR expression, reduced BCR internalization and dampening of LYN (Lyn proto-oncogene) kinase feedback inhibition, thus resulting in increased BCR signaling. Somatic mutation in the protein's ITAM domain have also been identified and shown to affect signaling (PMID: 20054396). Germline CD79B mutation leads to agammaglobulinemia, a severe immunodeficiency syndrome with B-cell dysfunction (PMID: 17709424). Antibody-drug conjugates targeting CD79B and inhibitors targeting SRC activity, such as dasatinib, can reduce BCR signaling (PMID: 17374736, 20054396, 25925619, 28009435). False +ENST00000344548 NM_001791.3 998 CDC42 True CDC42, a small GTPase, is infrequently altered in cancer. CDC42 is a small GTPase that localizes to the plasma membrane of the cell. CDC42 can switch between active GTP-bound and inactive GDP-bound states, transducing signals to a variety of downstream effectors (PMID: 21115489). CDC42 plays a role in cell polarization, chemotaxis, migration and mitosis (PMID: 14978216, 15642749, 17038317, 26689677). In cancer, CDC42 overexpression has been associated with enhanced proliferation and invasion, suggesting an oncogenic role; however, a tumor suppressor function related to cell polarity maintenance has also been observed (PMID: 21515363). Mutations and copy number alterations of CDC42 are rare events in cancer. CDC42, as well as other Rho GTPases (e.g., Ras oncoproteins), are difficult targets for pharmacological intervention, although some CDC42-specific drugs exist (PMID: 21433396). False +ENST00000367435 NM_024529.4 79577 CDC73 False CDC73, a tumor suppressor involved in transcriptional regulation, is altered at low frequencies in various cancer types. CDC73 (also known as HRPT2) is the nuclear parafibromin protein, a component of the RNA Polymerase-associated factor (PAF1) complex which regulates transcriptional elongation, histone methylation and histone ubiquitination to modulate gene expression (PMID: 20178742, 19522828, 12667454). The PAF1 complex, composed of CDC73, CTR9, LEO1, RTF1, SKI8, and PAF1, associates with the RNA polymerase II subunit POLR2A (PMID: 19522828). CDC73 is a tumor suppressor, and germline mutations are associated with familial hyperparathyroidism-jaw tumor (HPT-JT) syndrome (PMID:12434154, 15531515), while somatic mutations are found in parathyroid carcinomas (PMID: 14585940, 12960210). The CDC73/PAF complex is also important in leukemogenesis by interacting with the MLL oncogene and controlling epigenetic regulation of proleukemogenic target genes, such as MEIS1 and BCL2 (PMID: 23900238). True +ENST00000261769 NM_004360.3 999 CDH1 False CDH1 (E-cadherin), a tumor suppressor involved in cell adhesion, is altered by mutation or deletion in various cancer typess, most frequently in breast and esophagogastric cancers. CDH1, also known as E-cadherin, is a calcium-dependent transmembrane glycoprotein that is mainly expressed in epithelial cells and functions in cell-cell adhesion, signaling cascades and epithelial-to-mesenchymal transition (EMT) (PMID: 18726070). The extracellular portion of E-cadherin facilitates homophilic cell-to-cell adhesion by binding to cadherins on adjacent cells, while the intracellular domain is tethered to the actin cytoskeleton through interactions with catenins and functions to activate signaling cascades that play a role in the EMT (PMID:7885471, 2788574). The transcription factor SNAIL, a key regulator of the EMT during embryonic development, represses expression of the E-cadherin gene in tumor cell lines (PMID: 10655586, 10655587). Lack of E-cadherin function/expression enables cancer progression by altering cellular morphology, decreasing cellular adhesion, and increasing cellular motility (PMID: 10439038, 2070412, 9515965). Along with point mutations and loss of heterozygosity (LOH), epigenetic silencing by hypermethylation of the CDH1 promoter has been associated with the loss of E-cadherin gene expression during cancer progression (PMID: 7543680). Individuals with a germline CDH1 mutation have an increased risk of developing diffuse gastric cancer and lobular breast cancer (PMID: 11729114, 31171119, 32758476). Loss of E-cadherin has also been demonstrated in a variety of sporadic cancer types including gastric cancer, colorectal cancer, and esophageal cancer (PMID: 11313896, 22716209, 21373750). True +ENST00000268603 NM_001797 1009 CDH11 True CDH11, a cadherin protein, is infrequently altered in cancer. CDH11, a member of the cadherin superfamily, encodes for a type II classical cadherin that functions in calcium-dependent cell-cell adhesion (PMID: 7583005). CDH11 activates the WNT signaling pathway to promote cellular proliferation through the upregulation and anchoring of β-catenin (PMID: 30691241, 25787991). Overexpression of CDH11 in breast cancer cell lines induces cellular proliferation, migration and invasion, suggesting that CDH11 functions predominantly as an oncogene (PMID: 29296180, 24681547, 30691241). CDH11 amplification has been identified in various types of cancer, including breast cancer and distant bone metastases (PMID: 28101202, 18708358, 24587095). False +ENST00000269141 NM_001792 1000 CDH2 True CDH2, a cadherin protein, is infrequently altered in cancer. CDH2, a member of the cadherin superfamily, encodes for a classical cadherin that functions in calcium-dependent cell-cell adhesion (PMID: 2831236). CDH2 upregulates the β-catenin and NOTCH signaling pathways to regulate neurogenesis and maintain stemness of radial glia progenitor cells (PMID: 20230753, 24715457). Overexpression of CDH2 in various cancer cell lines and models induces cellular proliferation, migration, invasion, tumor growth and epithelial mesenchymal transition, suggesting that CDH2 functions predominantly as an oncogene (PMID: 10684258, 8978829, 35574323). CDH2 amplification has been identified in various types of cancer, including breast cancer, thyroid cancer, colorectal cancer and ovarian cancer (PMID: 10684258, 8978829, 35756646, 35574323). False +ENST00000360469 NM_001794 1002 CDH4 True CDH4, a cadherin protein, is infrequently altered in cancer. CDH4, a member of the cadherin superfamily, encodes for a classical cadherin that functions in calcium-dependent cell-cell adhesion (PMID: 1712604). CDH4 is primarily expressed in the brain and functions in neurogenesis and segmentation of the central nervous system through its adhesive properties (PMID: 33833667). Overexpression of CDH4 in various cancer cell lines induces cellular proliferation, migration, self-renewal and invasion, suggesting that CDH4 functions predominantly as an oncogene (PMID: 37237299, 29610525). CDH4 amplification has been identified in various types of cancer, including breast cancer, osteosarcoma and glioblastoma (PMID: 22820501, 29610525, 31426573). False +ENST00000447079 NM_016507.2 51755 CDK12 False 1 CDK12, a cyclin dependent kinase, is recurrently mutated in metastatic prostate and serous ovarian cancers. CDK12 (Cyclin-dependent kinase 12) is a kinase involved in the regulation of the cell cycle and the regulation of transcriptional elongation of many DNA-damage-response genes (PMID: 11683387, 22012619). Recurrent inactivating CDK12 mutations in metastatic prostate and serous ovarian cancers have been observed (PMID: 28843286, PMID: 26787835). CDK12 interacts with and phosphorylates the C-terminal domain (CTD) of RNA polymerase II (RNAP) in vitro (PMID: 11683387) and complexes with Cyclin K to maintain genomic stability via regulation of the expression of DNA damage response genes, such as BRCA1, ATR, FANCI and FANCD2. Loss of the CDK12/cyclin K complex renders HEK293 cells sensitive to various DNA damaging agents, including camptothecin, etoposide and mitomycin C (PMID: 22012619, 24662513). CDK12 is one of the most frequently somatically mutated genes in ovarian cancer (PMID: 21720365), which is consistent with its role in the maintenance of genomic stability. The genomic location of CDK12, is adjacent to that of ERBB2, and while there is some laboratory data that associates an amplification of CDK12 to a tumorigenic phenotype (PMID: 28187285, 27880910, 28334900), it is likely that CDK12 amplification is a passenger event in this context, co-occurring with ERBB2 amplification in breast and gastric cancers (PMID: 20932292, 21097718, 26658019). True +ENST00000257904 NM_000075.3 1019 CDK4 True 4 CDK4, an intracellular kinase, is altered by amplification or mutation in various cancer types including soft tissue sarcomas and gliomas. CDK4 (cyclin-dependent kinase 4) is a serine/threonine kinase that regulates the cell cycle G1 to S phase transition. Upon mitogen stimulation, CDK4 forms a complex with cyclin D and cyclin-dependent kinase 6 (CDK6), which leads to activation of the kinases (PMID: 12432268). The active CDK4/CDK6 complex then phosphorylates and inactivates retinoblastoma (RB), thereby inducing the gene expression program regulated by the E2F family of transcription factors, which is important in cell cycle progression. CDK4/6 are in turn negatively regulated by p16INK4a (CDKN2A), which binds to the catalytic domains of the kinases and interferes with cyclin D and ATP binding (PMID: 9751050, 11124804). Amplification and overexpression of CDK4 occur in sarcomas, glioblastoma and breast cancers (PMID: 8221695, 8044775, 8586464, 9916925). CDK4/6 inhibitors have shown clinical efficacy in certain solid tumors, including breast and non-small cell lung cancer (PMID: 27959613, 27217383). Furthermore, CDK4/6 inhibition can trigger anti-tumor immunity by promoting cytotoxic T-cell-mediated clearance of tumor cells (PMID: 28813415). False +ENST00000265734 NM_001145306.1 1021 CDK6 True CDK6, an intracellular kinase, is amplified in various cancer types. CDK6 (cyclin-dependent kinase 6) is a serine/threonine kinase that regulates the cell cycle G1 to S phase transition. Upon mitogen stimulation, CDK4 forms a complex with Cyclin D and cyclin-dependent kinase 4 (CDK4), which leads to activation of the kinases (PMID: 12432268). The active complex then phosphorylates and inactivates retinoblastoma (RB), thus leading to the induction of a gene expression program regulated by the E2F family of transcription factors, which is important in cell cycle progression (PMID: 12432268). CDK4/6 are in turn negatively regulated by p16INK4a (CDKN2A), which binds to the catalytic domains of the kinases and interferes with cyclin D and ATP binding (PMID: 9751050, 11124804). Amplification and overexpression of CDK6 occur in several cancer types, such as esophageal carcinoma, leukemia and lymphoma (PMID:24423610, 9422538, 16782810). CDK4/6 inhibitors have shown clinical efficacy in certain solid tumors, including breast and non-small cell lung cancer (PMID: 27959613, 27217383). Furthermore, CDK4/6 inhibition can trigger anti-tumor immunity by promoting cytotoxic T-cell-mediated clearance of tumor cells (PMID: 28813415). False +ENST00000381527 NM_001260.1 1024 CDK8 True CDK8, an intracellular kinase, is amplified in various cancer types. CDK8 (cyclin-dependent kinase 8) is a serine/threonine kinase that is an important regulator of DNA transcription and cell cycle progression. CDK8 associates with Cyclin C (CCNC), Med12 and Med13 to form a module that associates with the Mediator complex, which is involved in the regulation of DNA transcription (PMID: 7568034). CDK8 associates and phosphorylates the c-terminal domain of RNA polymerase II, and thus plays an important role in transcriptional elongation (PMID:10023686, 11278802). CDK8 is a positive regulator of oncogene-induced proliferation and enables efficient transcriptional elongation through recruitment of pTEF-B and BRD4 to oncogenic genes (PMID: 20098423). However, CDK8 has been shown to restrain Mediator-dependent super-enhancer driven transcription in acute myeloid leukemia (AML) (PMID: 26416749), and thus may have different roles in certain oncogenic contexts. CDK8 is amplified in a large number of colorectal cancers and was specifically shown to modulate beta-catenin activity in this context (PMID: 18794900). False +ENST00000244741 NM_078467.2 1026 CDKN1A False CDKN1A, a tumor suppressor and cell cycle regulator, is altered in various cancer types and is recurrently mutated in bladder cancer. The CDKN1A gene encodes the p21 (WAF1) protein, which is a member of the Cip/Kip family of cyclin-dependent kinase (CDK) inhibitors. p21 inhibits the cyclin-dependent kinases CDC2 and CDK2, leading to G1 phase cell cycle arrest. p21 expression is upregulated by DNA damage through a p53-dependent mechanism (PMID: 8242752). Moreover, activation of the PI3K/AKT mitogenic signaling pathway results in phosphorylation and localization of p21 to the cytoplasm where it can no longer access its CDK targets, leading to enhanced cell proliferation. p21 may play a role in repair of DNA damage through interactions with DNA polymerase accessory factors. Loss of p21 can lead to chromosomal aneuploidy, implying a role in mitotic regulation. p21 expression is tightly regulated at both the transcriptional and protein levels: tumor suppressors and oncoproteins modulate transcription of CDKN1A while post-translational p21 modification regulates proteasomal degradation and subcellular localization (PMID: 9296497, 10319992). The majority of p21 alterations in cancer are truncating, concurrent with its role as a tumor suppressor, and p21 knockout mouse models display an increased incidence of a variety of cancers as compared to mice with intact p21 expression (PMID: 7664346, 12810620). p21 also exhibits anti-apoptotic activity in certain contexts, suggesting that it also possesses an oncogenic role. Inhibitors targeting the checkpoint kinase Chk1 in combination with chemotherapy have been found to have anti-tumor activity in bladder cancer (PMID: 25349305). True +ENST00000228872 NM_004064.3 1027 CDKN1B False CDKN1B, a tumor suppressor and cell cycle regulator, is altered in various cancer types. CDKN1B (cyclin-dependent kinase (CDK) inhibitor 1B), also called p27 or KIP1, is a member of the Cip/Kip protein family and helps control cell cycle progression, proliferation, motility, and apoptosis (PMID: 18354415). The p27 protein is ubiquitously expressed and located both in the nucleus and in the cytoplasm (PMID: 8033212). Nuclear p27 functions as a tumor suppressor by controlling cell cycle progression from G1 to S phase, specifically by inhibiting the binding of cyclins A and E to CDK2 (PMID: 18354415). Conversely, cytoplasmic p27 may have a pro-oncogenic role by stimulating cell migration through mechanisms largely independent of its CDK-inhibiting function (PMID: 15573116, 17909030). The activity of p27 is largely regulated by protein degradation, and proteolysis is triggered by its CDK-dependent phosphorylation and subsequent ubiquitination by SCF complexes (PMID: 16633365). Germline mutations in p27 can cause a multiple endocrine neoplasia (MEN) syndrome (PMID: 17030811). Low p27 levels due to increased protein degradation are prevalent in several different types of epithelial tumors, such as cancers of the upper gastrointestinal tract, skin, hematopoietic malignancies, gliomas, and sarcomas, and are commonly correlated with aggressive tumor growth and poor clinical outcome (PMID: 15573116, 10699961). True +ENST00000440480 NM_001122630.2 1028 CDKN1C False CDKN1C, a cyclin-dependent kinase inhibitor, is infrequently altered in cancer. CDKN1C encodes for a cyclin-dependent kinase inhibitor that primarily functions in the negative regulation of cellular proliferation (PMID: 7729684). CDKN1C inhibits G1-phase cell cycle progression through tight-binding inhibition of cyclin complexes cyclin E-CDK2, cyclin D2-CDK4 and cyclin A-CDK2 (PMID: 7729684). CDKN1C undergoes gene imprinting to silence the paternally-inherited allele through methylation, allowing the maternally-inherited allele to be the active copy (PMID: 16575194). Germline mutations and disruptions in the genomic imprinting of CDKN1C have been associated with the growth disorders Beckwith-Wiedemann syndrome and intrauterine growth restriction, metaphyseal dysplasia, adrenal hypoplasia congenita and genital anomalies (IMAGe) syndrome (PMID: 26077438, 22634751). CDKN1C knockdown in various cancer cell lines and models induces cellular proliferation, migration and invasion, suggesting that CDKN1C functions predominantly as a tumor suppressor gene (PMID: 18483241, 26271467, 29428729). CDKN1C downregulation has been identified in various types of cancer, including breast cancer and esophageal cancer (PMID: 29428729, 15007390, 38822599, 34464504). True +ENST00000304494 NM_000077.4 1029 CDKN2A False 4 The CDKN2A gene encodes two proteins, p16INK4A and p14ARF, that regulate the cell growth and survival. CDKN2A is altered by mutation and/or deletion in a broad range of solid and hematologic cancers. The CDKN2A gene encodes two unique proteins, p16(Ink4a) and p14(ARF), which are important in regulating cell cycle progression (PMID: 8521522). p16(Ink4a) is a cyclin-dependent kinase (CDK) inhibitor, which inhibits CDK4 and CDK6 by preventing their binding to cyclins. This activates the retinoblastoma (Rb) family of proteins, which blocks the G1 to S-phase transition and can result in cell cycle arrest or quiescence (PMID: 15878778, 22025288). p14(ARF) is an inhibitor of MDM2-mediated degradation of the tumor suppressor p53, thus enhancing p53-dependent transactivation and apoptosis (PMID: 9529249). Deletion of CDKN2A in murine models results in the generation of spontaneous tumors, consistent with its role as a tumor suppressor (PMID: 8620534). The CDKN2A locus is also frequently mutated or epigenetically silenced in numerous cancer types, including lymphoma, melanoma, pancreatic cancer, and lung cancer (PMID: 27428416). Furthermore, germline mutations in CDKN2A can lead to familial pancreatic cancers (PMID: 12454511). True +ENST00000276925 NM_004936.3 1030 CDKN2B False CDKN2B, a tumor suppressor and cell cycle regulator, is inactivated by mutation or deletion in various cancer types. CDKN2B (cyclin-dependent kinase (CDK) inhibitor 2B), also known as p15 or INK4B, is a cyclin-dependent kinase (CDK) inhibitor that helps regulate cell cycle progression. p15 inhibits CDK4 and CDK6 by preventing their binding to cyclins. This activates the retinoblastoma (Rb) family of proteins, which blocks the G1 to S-phase transition and can result in cell cycle arrest or quiescence (PMID: 9031081). CDKN2B expression has also been shown to regulate TGFβ-mediated cell cycle arrest (PMID: 8078588). Germline mutations in CDKN2B can result in a predisposition to renal cell carcinoma (PMID: 25873077). Deletion of CDKN2B in murine models can result in tumor progression, consistent with its role as a tumor suppressor (PMID: 14681685) and it is frequently deleted, hypermethylated, or mutated in a variety of tumors (PMID: 9479825). True +ENST00000262662 NM_078626.2 1031 CDKN2C False CDKN2C, a tumor suppressor and cell cycle regulator, is infrequently altered in cancer. CDKN2C (cyclin-dependent kinase inhibitor 2C), also known as p18 or INK4C, is a cyclin-dependent kinase (CDK) inhibitor that helps regulate cell cycle progression. p18 inhibits CDK4 and CDK6 by preventing their binding to cyclins. This activates the retinoblastoma (Rb) family of proteins, which blocks the G1 to S-phase transition and can result in cell cycle arrest or quiescence (PMID: 9031081). Regulation of cell division by p18 is important for B-cell, muscle and cerebellar development (PMID: 21163929, 9528803, 16864777). Consistent with its role as a tumor suppressor, deletions and mutations of p18 are found in multiple cancer types including multiple myeloma, lymphoma, glioblastoma, meningiomas and pituitary cancer (PMID:16960149, 18829482, 18381405, 11485924, 18973139). True +ENST00000498907 NM_004364.3 1050 CEBPA False CEBPA, a tumor suppressor and transcription factor, is recurrently altered by mutation in acute myeloid leukemia. CEBPA is a transcription factor that is a member of the basic region leucine zipper (bZIP) protein family (PMID: 25753223). CEBPA exists as two isoforms (p42 and p30) and binds DNA as a homodimer or heterodimer (as a p42/p30 heterodimer or in complex with other transcription factors, such as AP-1) to activate transcription (PMID: 25753223, 18026136). Through interactions via the transactivation domain, CEBPA can help recruit RNA polymerase II, coactivators such as CBP (Creb binding protein)/p300, and chromatin-modifying complexes such as SWI/SNF (switch/sucrose nonfermentable) (PMID: 12857754, 14660596). CEBPA functions as a regulator of cellular identity and coordinates the differentiation of diverse cell types including hematopoietic, adipose, and epithelial cells (PMID: 7652557, 23160954, 12757710). In hematopoiesis, CEBPA is important for the development of the myeloid lineage and granulocytic differentiation by regulating specific growth factor receptors and cell cycle arrest (PMID: 25753223). Loss of CEBPA in several cell types results in aberrant gene expression changes and cancer progression (PMID: 17638888). CEBPA mutations are found in acute myeloid leukemia (AML) and in inherited AML predisposition syndromes (PMID: 11242107, 12351377, 25311743, 23560626). N-terminal alterations result in the exclusive expression of the CEBPA p30 isoform and commonly co-occur with biallelic C-terminal mutations that disrupt CEBPA homodimerization (PMID: 31309149). The presence of a mutation in the bZIP region, regardless of monoallelic or biallelic status, is predictive of a favorable outcome in patients with AML (PMID: 33951732, 34320176, 34448807, 19171880). True +ENST00000335756 NM_001809.3 1058 CENPA False CENPA, a histone variant in centromere-associated chromatin, is altered by amplification and overexpression in various cancer types. CENPA is a histone variant that replaces the canonical histone H3 protein in nucleosomes at centromeres (PMID: 3558482, 20739937, 21478274, 16622419). Centromeric chromatin has distinct properties including flexible histone tails, which preclude the binding of histone H1, a histone molecule important in heterochromatin formation (PMID: 27499292, 32516549). CENPA is only present at centromeres and is essential for the correct assembly of proteins at the kinetochore, for centromere activity, and for chromosome segregation (PMID: 12906131, 10655499, 15870271, 27499292). Impaired kinetochore assembly and centromere activity can lead to aneuploidy and the development of cancer (PMID: 15380953). In addition, CENPA controls epigenetic mechanisms important for centromere organization, DNA replication, and cell division (PMID: 17339380, 9024683). Overexpression of CENPA is found in many cancer types including hepatocellular carcinoma, prostate cancer, colorectal cancer, and glioblastoma, among others (PMID: 17535684, 12839935, 26295306, 32371391). Amplification and overexpression of CENPA is a marker of poor prognosis, including in patients with breast cancer and osteosarcoma (PMID: 17970049, 24213134, 24440098, 24676531, 22369099). Somatic mutations in CENPA have been identified; however, these alterations have not been functionally validated (PMID: 31337617). Downregulation of CENPA contributes to methotrexate resistance and doxorubicin-induced senescence induced by low doses of doxorubicin in cancer cell lines (PMID: 26337976, 15870702). False +ENST00000394196 NM_001271 1106 CHD2 False CHD2, a chromodomain helicase, is frequently altered in chronic lymphocytic leukemia. CHD2, a member of the chromodomain helicase DNA-binding (CHD) family, encodes for a chromodomain helicase that functions in chromatin remodeling (PMID: 9326634, 25384982). CHD2 is composed of two chromodomains at the N-terminus that serve an autoinhibitory role for DNA-binding and ATPase activities (PMID: 25384982). CHD2 modifies chromatin through remodeling to regulate gene expression related to cellular development and differentiation (PMID: 25621013, 28549158). Expression of inactivating CHD2 mutations in cancer cell lines induces increased activation of signaling pathways associated with DNA modification processes, suggesting that CHD2 functions predominantly as a tumor suppressor gene (PMID: 26031915). Loss of CHD2 function has been identified in chronic lymphocytic leukemia, breast implant-associated anaplastic large-cell lymphoma and B-cell prolymphocytic leukemia (PMID: 26031915, 31774495, 31527074). True +ENST00000357008 NM_001273 1108 CHD4 True CHD4, a helicase, is infrequently altered in cancer. CHD4, a member of the SNF2/RAD54 helicase family, encodes for a helicase that functions in remodeling nucleosome structure through the ATPase/helicase domain of the protein (PMID: 8843877). CHD4 is a core component of the nucleosome remodeling and deacetylase (NuRD) complex, which regulates chromatin structure, gene expression and cell cycle progression (PMID: 11410659, 20693977). CHD4 has also been identified to regulate cellular processes independent of the NuRD complex, which include DNA-damage response, cell cycle progression and signal transduction, through binding to histone H3 with the PHD finger motifs of CHD4 (PMID: 15189737, 20805324, 22749909). Knockdown of CHD4 in various cancer cell lines and models inhibits cellular proliferation and invasion and decreases tumor metastasis, suggesting that CHD4 functions predominantly as an oncogene (PMID: 32070428, 32228507, 36681835). Amplification of CHD4 has been identified in various cancers, including colorectal cancer, uterine serous carcinoma and oral cancer (PMID: 33994851, 23359684, 28683324). CHD4 has been identified to modulate sensitivity to platinum treatment, and suppression of CHD4 is suggested to confer sensitivity (PMID: 34161330, 36603431). False +ENST00000428830 NM_001274.5 1111 CHEK1 False 1 CHEK1, an intracellular kinase, is overexpressed in various solid and hematologic malignancies. CHEK1 (Checkpoint Kinase 1) is a serine/threonine kinase that plays an integral role in the DNA damage checkpoint pathway and prevents damaged cells from continuing through the cell cycle. In response to DNA damage, CHEK1 is activated by the kinases ATR and ATM via phosphorylation (PMID: 12781359). Once activated, CHEK1 acts as an effector kinase, mediating downstream signaling that leads to a diverse range of cellular responses, including cell cycle checkpoint activation, cell cycle arrest, DNA repair and/or apoptosis and replication fork stability (PMID: 23508805). In particular, activated CHEK1 maintains the cyclin B1-CDK1 complex in an inactive cytoplasmic state, which prevents the G2/M transition and prevents mitotic segregation of damaged chromatids (PMID: 21532626). Though CHEK1 mutations are extremely rare (PMID: 12781359) CHEK1 is frequently over-expressed in a variety of tumors, including breast (PMID: 17638866), non-small cell lung cancer (PMID: 24418519 ), and nasopharyngeal cancers (PMID: 15297395). True +ENST00000328354 NM_007194.3 11200 CHEK2 False 1 CHEK2, a tumor suppressor and intracellular kinase, is altered in various cancer types. Germline mutations of CHEK2 are associated with an increased risk of certain cancers including breast, prostate and colorectal cancers. CHEK2 (Checkpoint Kinase 2) is a serine/threonine kinase that plays an integral role in the DNA damage checkpoint pathway and prevents damaged cells from continuing through the cell cycle. In response to DNA damage, CHEK2 is activated by the kinases ATR and ATM via phosphorylation (PMID: 12781359). Once activated, CHEK2 acts as an effector kinase, mediating downstream signaling that leads to a diverse range of cellular responses, including cell cycle checkpoint activation, cell cycle arrest and DNA repair and/or apoptosis (PMID: 25404613). CHEK2 also plays an important role during mitosis by maintaining chromosomal stability (PMID: 24798733, 20364141). Given its role in maintaining genomic stability, CHEK2 alterations are found in a range of cancers including glioblastoma, breast, ovarian, prostate, colorectal, gastric, thyroid, and lung cancer (PMID: 23296741, 24713400, 25583358, 12052256, 15125777). Germline mutations in CHEK2 have been associated with an increased risk of breast, colorectal, and prostate cancers (PMID: 21701879, 12533788, 17106448). True +ENST00000398235 NM_001039690 54921 CHTF8 False CHFT8, a component of the CTF18 replication factor C complex involved in DNA synthesis and repair, is altered by deletion in cancer. The CHTF8 gene, also known as DERPC, encodes the CTF8 subunit of the CTF18 replication factor C (RFC) complex, a proliferating cell nuclear antigen loader that functions in sister chromatid cohesion (PMID: 20826785). CTF8, along with the subunits CTF18 and DCC1, form a trimeric complex to mediate binding to DNA polymerase ε to promote polymorphic modulation of DNA synthesis (PMID: 20826785). Deletion of CHTF8 by itself and in combination with the other subunits of the RFC complex in yeast demonstrate severe defects in sister chromatid cohesion and G2/M cell cycle accumulation (PMID: 11389843). In vitro studies with prostate tumor cell lines and kidney embryonic cell lines demonstrate that CHTF8 expression is significantly reduced in prostate and renal cancer, respectively (PMID: 12477976). Similarly, overexpression of CHTF8 in prostate tumor cell lines demonstrates prostate cancer growth suppression as measured by inhibition of colony growth (PMID: 12477976). True +ENST00000575354 NM_015125.3 23152 CIC False CIC, a tumor suppressor and transcriptional repressor, is recurrently altered by mutation, deletion, and translocation, most frequently in oligodendrogliomas. CIC (also Capicua) is a transcriptional repressor that is a member of the high mobility (HMG)-box protein family (PMID: 32073140). CIC is expressed in a variety of tissues and is a critical regulator of patterning, differentiation, and signaling (PMID: 10652276, 32073140). Chromatin modifiers, such as the Sin/HDAC3 histone deacetylase complex, are recruited to sites bound by CIC to inhibit gene expression of target genes (PMID: 29844126). CIC exists in diverse protein complexes including with ATXN1, which directly binds CIC and modulates its transcriptional repressor activity (PMID: 17190598). The CIC-ATXN1 complex regulates the expression of several transcription factors, including members of the ETS protein family (PMID: 27869830). Loss of CIC expression results in the derepression of ETS transcriptional regulators, such as ETV4, which can activate extracellular remodeling programs and metastasis (PMID: 27869830, 22014525). In addition, CIC is a negative regulator of receptor tyrosine kinase (RTK) and MAPK signaling pathways and acts as a transcriptional repressor in the absence of RTK signaling (PMID: 11714680, 11861482, 29844126, 28178529). CIC is recurrently mutated in oligodendrogliomas, including in 1p/19q-deleted cancers (PMID: 21817013, 22869205, 22588899). Somatic mutations and deletions have also been found in various other cancer types, including in lung and gastric cancers (PMID: 25079317, 27869830). Chromosomal translocations that produce chimeric CIC proteins fused to several partner proteins, including DUX4 or FOXO4, occur in aggressive round cell sarcomas and result in aberrant CIC-mediated transcriptional activation (PMID: 19837261, 25007147, 21813156). True +ENST00000324288 NM_001286402 4261 CIITA False CIITA, a transcriptional coactivator in immune cells, is recurrently altered by deletion, mutation and chromosomal rearrangement in lymphomas. CIITA is a transcriptional coactivator that functions as a master regulator of the genes that encode the major histocompatibility complex class II (MHC class II) proteins (PMID: 24391648). MHC class II proteins present extracellular peptides on the surface of antigen presenting cells to display these peptides to the immune system. CIITA is constitutively expressed in cell types that express MHC class II molecules, including dendritic cells, macrophages and B cells (PMID: 25324123). CIITA and MHC class II expression can be induced in other immune cell types by IFNγ and stimulation with other cytokines (PMID: 25324123). CIITA has multifaceted roles in transcriptional regulation including replacement of the TFIID component in the general transcriptional complex as well as acetyltransferase and kinase activity, which are necessary for the transcription of MHC class I and class II genes (PMID: 24391648). CIITA requires the DNA binding proteins CREB, RFX, and NF-Y to serve as a binding scaffold (PMID: 16730065). Germline mutations in CIITA have been identified in patients with bare lymphocyte syndrome type II, an immune deficiency that leads to a loss of MHC class II protein surface expression (PMID: 7749985). Rearrangements involving CIITA are found in patients with B cell and Hodgkin lymphoma (PMID: 21368758). CIITA fusion proteins cause downregulation of MHC class II expression and overexpression of ligands for PD-1, a receptor that mediates immune suppression (PMID: 21368758). Somatic CIITA loss-of-function mutations and deletions have been associated with some lymphomas, suggesting that CIITA functions as a tumor suppressor (PMID: 28479318, 26599546, 26549456). True +ENST00000427926 NM_007098 8218 CLTCL1 False CLTCL1, a clathrin heavy chain, is infrequently altered in cancer. CLTCL1, a member of the clathrin heavy chain family, encodes for the CHC22 clathrin heavy chain and functions in intracellular trafficking of the GLUT4 glucose transporter (PMID: 26068709). Intracellular trafficking of GLUT4 is triggered in response to insulin, and CLTCL1-dependent GLUT4 trafficking has been identified to occur in compartments within muscles and adipocytes (PMID: 19478182). CLTCL1 downregulation and fusions have been identified in breast cancer and ALK-positive lymphoma; however, the oncogenic function of the protein has not yet been well characterized in biochemical studies (PMID: 22496928, 10807789). False +ENST00000338099 NM_001099642.1 55783 CMTR2 False CMTR2, an RNA cap methyltransferase, is recurrently altered by mutation in non-small cell lung cancer. CMTR2 (also FTSJD1 and HMTR2) is an RNA methyltransferase that modifies the 5’ cap structures of messenger RNA (mRNA). CMTR2 catalyzes the transfer of a methyl group to the 2'-O-ribose on the second nucleotide in the mRNA (cap2) (PMID: 24402442, 21310715). The 5’ cap of mRNA is modified by methylation on both the first and second nucleotide, which is important for effective processing, translation initiation, gene expression, splicing, and stability of mRNA (PMID: 24402442, 15525712). In addition, 2'-O-ribose methylation is important for immune recognition of mRNA transcripts in the host cell (PMID: 21217758). Cap2 methylation occurs on fifty percent of mRNA transcripts, while methylation of the first nucleotide is ubiquitous of all mRNA (PMID: 1057180, 21310715). Somatic loss-of-function mutations in CMTR2 are found in patients with lung squamous cell carcinoma (PMID: 24402442). CMTR2 variants are predominantly truncating mutations, suggesting that CMTR2 may function as a tumor suppressor (PMID: 24402442). True +ENST00000238341 NM_007018 11064 CNTRL False CNTRL, a centrosomal protein, is infrequently altered in cancer. CNTRL encodes for a centrosomal protein that functions in the maturation of the centrosome and a subunit that allows the centrosome to function as a microtubule organizing center (PMID: 11956314). CNTRL regulates cell cycle progression into S-phase and cytokinesis within the mother centriole (PMID: 12732615). CNTRL fusions and upregulated expression have been identified in stem cell myeloproliferative disorders, acute myeloid leukemia and esophageal squamous cell carcinoma; however, the oncogenic function of the gene has not yet been well characterized in biochemical studies (PMID: 10688839, 21403647, 33491601, 32227267). False +ENST00000225964 NM_000088 1277 COL1A1 True COL1A1, a collagen type I alpha 1 chain, is infrequently altered in cancer. COL1A1 encodes for the type I collagen pro-alpha1(I) chain which functions in crosslinking with pro-alpha2(I) chains (COL1A2) and other pro-alpha1(I) chains to create collagen type I within connective tissues (PMID: 3468512, 27894325). Collagen type I interacts with various signaling pathways, including integrins and DDR1, to regulate extracellular matrix production, cellular proliferation and survival (PMID: 32500940, 20093046). Overexpression of COL1A1 in various cancer cell lines and models induces cellular proliferation, migration and invasion, suggesting that COL1A1 functions predominantly as an oncogene (PMID: 29393423, 28482162, 29906404). COL1A1 amplification has been identified in various types of cancer, including breast cancer, gastric cancer and colorectal cancer (PMID: 29906404, 27894325, 29393423). Upregulated expression of COL1A1 has been associated with increased chemoresistance in pancreatic, lung and ovarian cancers (PMID: 27390605, 33680916, 29414301, 34475986). False +ENST00000380518 NM_001844 1280 COL2A1 False COL2A1, a collagen type II alpha 1 chain, is frequently altered in chondrosarcoma. COL2A1 encodes for the type II collagen pro-alpha1(I) chain that functions in crosslinking with two other pro-alpha1(II) chains to create collagen type II within connective tissues (PMID: 7806485). Collagen type II interacts with various signaling pathways such as integrins and RhoA to regulate chondrogenesis and synthesis of the extracellular matrix (PMID: 19624244, 15895462, 26879681). COL2A1 loss-of-function mutations in chondrosarcoma models induce hypertrophic differentiation of chondrocytes, suggesting that COL2A1 functions predominantly as a tumor suppressor gene (PMID: 30854241, 12917109). Inactivating mutations of COL2A1 have been frequently identified in chondrosarcoma (PMID: 23770606, 33147331, 31604924). True +ENST00000367669 NM_022457.5 64326 COP1 True COP1, an E3 ubiquitin-protein ligase, is frequently altered in various cancers. COP1 encodes an E3 ubiquitin-protein ligase that targets both oncogenic and tumor suppressive substrates for ubiquitination and degradation, including c-Jun, p53, ETS factors, β-catenin, CEBPA and p27 (PMID: 27534417, 22673153, 21572435, 34582788, 28611108). The role of COP1 in cancer is context-dependent, and can involve apoptosis, the cell cycle, DNA repair, cell proliferation, transformation and tumor progression (PMID: 21135113). The oncogenic and tumor-suppressive role of COP1 expression has been demonstrated experimentally in vitro and in vivo (PMID: 20959491, 21572435, 21403399, 21403396). Loss of COP1 in wild-type mice suppresses tumor growth and prolongs survival through tumor microenvironment reprogramming and immune response (PMID: 34582788). COP1 is commonly overexpressed in several tumor types, including gastric cancer, hepatocellular carcinoma, breast cancer and ovarian adenocarcinoma, and is associated with poor overall survival (PMID: 23091414, 15492238). Conversely, low COP1 mRNA and protein levels are associated with a less favorable prognosis in renal cell carcinoma, gastric cancer and triple-negative breast cancer (PMID: 27278120, 23933908, 25884720). True +ENST00000231948 NM_016302.3 51185 CRBN False CRBN, a ubiquitin ligase, is recurrently altered by mutation or downregulation in multiple myelomas. CRBN (also cereblon) is a ubiquitin ligase that targets various protein substrates for degradation. CRBN forms a complex with DDB1, CUL4A and ROC1 to coordinate the ubiquitination and degradation of protein substrates via the proteasome (PMID: 16964240). IKZF1 and IKZF3, two lymphoid transcription factors, are key CRBN degradation targets in multiple myeloma cells (PMID: 24292625). Other CRBN degradation targets have been identified including GPST1, a translation termination factor (PMID: 27338790). CRBN has been shown to activate protein synthesis through inhibition of AMPK via the mTOR pathway (PMID: 24993823) and regulate potassium channels in neuronal cells (PMID: 15194823). Germline mutations in CRBN have been identified in individuals with intellectual disorders (PMID: 15557513). Expression of CRBN is required for the sensitivity of multiple myeloma cells to immunomodulatory drugs including thalidomide, lenalidomide, and pomalidomide (PMID: 21860026, 22552008). Somatic CRBN loss-of-function mutations or reduced expression of CRBN are found in patients with multiple myeloma that are refractory to immunomodulatory drugs (PMID: 23480694, 27458004). Specific protein degraders have been developed leveraging the ability of CRBN to bind thalidomide derivatives and target a variety of substrates for degradation (PMID: 25999370). True +ENST00000432329 NM_134442.3 1385 CREB1 True CREB1, a transcription factor, is rarely altered by chromosomal rearrangements in soft tissue sarcomas. CREB1 is a leucine zipper transcription factor that is induced and binds to cAMP-inducible promoters. The protein is activated via phosphorylation by several kinases, such PKA, and dimerizes and binds to cAMP-responsive elements within promoters across the genome (PMID: 15982754). CREB1 has been shown to be required for neuronal development, specifically within sensory and sympathetic neurons, as well as axon extension (PMID: 11988169, 11967539). CREB-dependent signaling pathways are also required for peripheral neuron development and survival. Additionally, signaling pathways activated by CREB1 have been shown to be involved in learning, memory, mood, and addiction (PMID: 19286560, 11889468, 15999345, 9856954). Recently, CREB1 has been shown to be important in late-stage lung development (PMID: 27150575) and survival and development of immune cell function (PMID: 21084670). False +ENST00000262367 NM_004380.2 1387 CREBBP False CREBBP, a tumor suppressor and transcriptional co-activator, is frequently inactivated in hematologic malignancies. CREBBP (CREB binding protein) is a transcriptional co-activator with intrinsic histone acetyltransferase (HAT) activity; it is closely homologous to the co-activator EP300 (PMID: 8004670, 18273021). As a co-factor, CREBBP binds to DNA binding proteins where it functions as a scaffold to recruit a range of transcription complex components (PMID: 9215639, 9445474). CREBBP itself can recruit the basal transcriptional machinery, and through its HAT activity acetylate lysine tails to modify chromatin into a more open conformation for active transcription (PMID: 8576192,8967953). The HAT activity of CREBBP is also active on non-histone proteins, including tumor suppressors such as p53 and tissue-specific transcription factors such as GATA1 (PMID: 9830059, 9859997). In leukemias, CREBBP can be disrupted by translocations that fuse the HAT domain with the MOZ/KAT6A (lysine acetyltransferase 6a) protein t(8;16) (PMID: 9447825). Somatic mutations of CREBBP have been found in leukemia, lymphoma and solid tumors including small-cell lung cancer, squamous carcinoma and bladder cancer (PMID: 24670651, 21796119, 21390130, 25151357, 21390130). Most CREBBP mutations are truncating and commonly co-occur with loss of the wildtype allele, suggesting that CREBBP is a tumor suppressor. Inherited mutations can result in the Rubinstein-Taybi syndrome with stereotypical facial and digit abnormalities along with neurological deficits (PMID:7630403). CREBBP-mutated tumors are dependent on EP300 activity and inhibitors targeting EP300 are efficacious in CREBBP-mutated cell line and mouse models (PMID: 26603525). True +ENST00000354336 NM_005207.3 1399 CRKL True CRKL, an adapter protein, is overexpressed in various cancer types. CRKL is an adaptor protein that facilitates signal transduction from kinases to downstream targets (PMID:10648385). It is a target of the BCR-ABL translocation kinase and enhances transformation in CML (chronic myelogenous leukemia) (PMID:20807813). CRKL can activate the Ras, Rac, and Jun kinase signaling pathways (PMID:12393632, 11443118, 10514505). Pathway activation mediates diverse cellular processes involved in cancer including cell proliferation, EMT (epithelial to mesenchymal transition), and invasion (PMID:26044596, 25661331,25318601). CRKL amplification has been identified in lung carcinomas and gastric cancer (PMID:22591714, 22586683). Amplification can be a means of acquired resistance to targeted therapy in EGFR lung cancer (PMID:22586683). False +ENST00000381566 NM_022148.2 64109 CRLF2 True CRLF2, a cytokine receptor, is recurrently altered by chromosomal rearrangement in B-cell acute lymphoblastic leukemia. CRLF2 is a type I cytokine receptor that signals through the pro-oncogenic JAK-STAT pathway, which regulates processes such as proliferation and development of the hematopoietic system (PMID: 20807819). In order to signal, CRLF2 heterodimerizes with the IL7RA (interleukin 7 receptor), thus forming the receptor for thymic stromal lymphopoietin (TSLP), a cytokine that mediates B-cell precursor proliferation and survival (PMID: 9916685). CRLF2 is expressed on T cells, dendritic cells, monocytes, and basophils (PMID: 11418668). Its activation is linked to a Th2 response, can lead to eosinophilia, and is implicated in reactivity and airway remodeling for asthma, in atopic dermatitis, and in immunity against helminth infections (PMID: 24167583, 26288354, 21841801, 23024277 ). Rearrangement of the gene is seen in precursor B-cell acute lymphoblastic leukemia (PMID: 25207766, 22897847, 19838194). Rearranged receptor can signal through the JAK-STAT and PI3K-MTOR pathways and lead to transformation (PMID: 22685175, 19838194). False +ENST00000438362 NM_001242891.1 7812 CSDE1 False CSDE1, an RNA-binding protein, is altered by mutation in various cancer types, including neuroendocrine tumors. CSDE1 (also UNR) is an RNA-binding protein that regulates RNA stability and protein homeostasis (PMID: 31987048, 29422612). CSDE1 forms complexes with diverse partner proteins to positively or negatively regulate cap-dependent translation, cap-independent translation, and mRNA transcript stability (PMID: 17086213, 31987048). The binding of CSDE1 regulates numerous mRNA targets, including poly(A) binding protein (PABP), MYC and FOS (PMID: 16356927, 31027221). Because CSDE1 is involved in numerous RNA regulatory protein complexes, CSDE1 modulates a variety of cellular processes including apoptosis, neuronal development, cell cycle progression, invasion and sex chromosome dosage compensation (PMID: 31579823, 24012837, 17159903, 11313462). In addition, CSDE1 regulates processes important in protein translation including deadenylation (PMID: 11051545, 15314026). Loss-of-function mutations in CSDE1 have been implicated in autism spectrum disorder (PMID: 31579823). Deletions and loss-of-function alterations have been identified in patients with rare neuroendocrine tumors, including pheochromocytomas and paragangliomas (PMID: 28162975). In addition, CSDE1 may function as an oncogene or tumor suppressor in several cancer types (PMID: 31027221, 27908735, 28162975, 29422612). False +ENST00000286301 NM_005211.3 1436 CSF1R False CSF1R, a cytokine receptor, is altered in various cancer types. CSF1R is a membrane protein that acts as a receptor for colony-stimulating factor 1 (CSF1), a cytokine that regulates the production, differentiation, and function of macrophages. CSF1R-mediated signaling is an important regulator of innate immunity. Co-expression of CSF1R and the ligand CSF1 can lead to tumorigenic activity in cancer cells independent of CSF1R overexpression or amplification, suggesting that CSF1R acts as an oncogene (PMID: 22096574). However, loss-of-function CSF1R mutations and splice variants have also been associated with a predisposition for myeloid malignancies (PMID: 18971950). Kinase inhibitors and neutralizing antibodies that target CSF1R have been shown to effectively target CSF1/CSF1R signaling, resulting in a reduction in the number of tumor-associated macrophages. Experimental data suggest that CSF1/CSF1R blockade could improve the efficacy of immunotherapies by enhancing activation of T cells in the tumor microenvironment. (PMID: 25082815, 22186992, 27199435, 24056773). False +ENST00000361632 NM_000760.3 1441 CSF3R True CSF3R, a transmembrane receptor, is frequently mutated in chronic neutrophilic leukemia and atypical chronic myeloid leukemia. CSF3R (also G-CSF) is a transmembrane receptor for cytokine colony-stimulating factor 3. Activation of the receptor is associated with the increased production of neutrophilic granulocytes and has been used clinically to shorten recovery time for chemotherapy and to mobilize hematopoietic stem cells into the periphery for stem cell collection (PMID: 7521686, 3311216, 7534140). Signaling from the receptor is mediated by JAK (Janus kinase) and SRC (SRC proto-oncogene) family of kinases with downstream activation of STAT, PI3K, and MAPK signaling cascades (PMID:7579336, 9590246) and inhibition mediated through the SOCS (Suppressor of Cytokine Signaling) proteins and tyrosine phosphatases (PMID:12133942, 9590246). Loss of function mutations can lead to severe congenital neutropenia (PMID:10449521, 24753537). Activating mutations can cause receptor dimerization independent of ligand with mutations near the juxtamembrane region, or truncate the receptor leading to altered signal transduction (PMID:23739288, 8246993). These mutations have been found in myeloid disorders such as chronic neutrophilic leukemia, atypical chronic myeloid leukemia and acute myeloid leukemia (PMID: 7542747, 23656643). Solid tumors have been shown to express CSF3R that may be important for disease phenotype or transformation (PMID:16912178, 25908586). False +ENST00000264010 NM_006565.3 10664 CTCF False CTCF, a tumor suppressor and chromatin binding factor, is mutated in various cancers, most frequently in endometrial cancer. CTCF is a versatile regulator of gene transcription that binds DNA with different combinations of its eleven highly conserved zinc finger (ZF) domains. CTCF can recruit histone acetyltransferases (HATs) or histone deacetylases (HDACs), along with other cofactors, and activate or repress transcription, respectively (PMID: 11525835,10734189). The c-MYC oncogene is a well-known CTCF target, which acts in this context as a transcriptional repressor (PMID: 8649389). CTCF also acts as an insulator, playing a role in high order chromatin structural organization and long-range genomic interactions (PMID: 23498937), typically isolating enhancers from promoters which ultimately results in inhibition of gene transcription (PMID: 19846290, 25002401). Insulation is achieved by CTCF-mediated modification of epigenetic marks, such as H3K27me3 removal (PMID: 25294833). CTCF binding prevents CpG methylation and vice versa (PMID: 20591991, 25703332). While complete loss of CTCF is embryonically lethal, CTCF haploinsufficiency has been demonstrated to alter global methylation patterns, predispose mice to a range of cancers and is associated with shortened overall lifespan (PMID: 24794443). Mutations in the CTCF gene usually result in a truncated protein, and they are mainly found in carcinomas of the endometrium (15%), digestive tract (colon and stomach, around 5%) and breast (cBioPortal, MSKCC, March 2015). In addition, both CTCF loss and overexpression lead to global effects in expression profiles. True +ENST00000318988 NM_015343.4 23399 CTDNEP1 False CTDNEP1, a serine/threonine protein phosphatase, is recurrently altered by mutation or reduced expression in medulloblastoma. CTDNEP1 (C-terminal domain nuclear envelope phosphatase 1), also known as Dullard, is a noncanonical serine/threonine protein phosphatase. CTNEP1 is a member of the C-terminal domain phosphatases (CTDPs), a group of seven phosphatases named for the CTD of RNA polymerase II (RNAPII) which is dephosphorylated by one member of the family, CTD phosphatase 1 (CTDP1) (PMID: 38776370, 37374122, 19215094). CTDNEP1 contributes to the regulation of endoplasmic reticulum (ER) and nuclear envelope (NE) membrane biogenesis through the dephosphorylation of lipin-1, a phosphatidic acid phosphatase that associates with the ER and regulates membrane lipid metabolism (PMID: 17420445, 34852214, 37873275, 37374122, 38776370, 23426360). CTDNEP1 binds and interacts with NEP1R1 (nuclear envelope phosphatase 1 regulatory subunit 1), and together this complex functions in maintaining the morphology and regulating the expansion of the ER membrane as well as regulating nuclear pore complex insertion (PMID: 38776370, 38045299). Through interaction with other proteins, CTDNEP1 plays a role in maintaining proper nuclear architecture, nuclear positioning and centrosome reorientation and in regulating cell migration (PMID: 37374122, 36318477, 33567288). Additionally, CTDNEP1 plays an important role in neural induction during embryogenesis by functioning as a negative regulator of bone morphogenetic protein (BMP) signaling through dephosphorylation and degradation of BMP receptors (PMID: 25155999, 37374122, 17141153). Similarly, CTDNEP1 has been found to negatively regulate TGF-ꞵ signaling. CTENDP1 is recurrently mutated in aggressive MYC-driven medulloblastoma, where reduced levels of CTDNEP1 have been shown to lead to MYC activation and tumor progression, thus supporting CTNEDP1's role as a tumor suppressor gene (PMID: 36765089). True +ENST00000302823 NM_005214.4 1493 CTLA4 True CTLA4, a transmembrane receptor, is infrequently altered in cancer and is a promising target for immune blockade therapies. CTLA4 (cytotoxic T-lymphocyte-associated antigen-4) is a transmembrane immunoglobulin receptor that blocks activation of T-lymphocytes (PMID: 9653097). CTLA4 binds to ligand B7-1 and B7-2, present on antigen presenting cells (PMID: 7543139). Binding of these ligands prevents their binding to CD28, the co-stimulatory molecule on T-cells and transduces an inhibitory signal within the T-cell (PMID: 11244047). Germline mutations in CTLA4 lead to immune dysregulation, hyper-activated T-cells and loss of normal circulating B-cells (PMID: 25213377). Polymorphisms and mutations in CTLA4 are associated with autoimmune diseases, including thyroid disorders and diabetes (PMID: 25695113, 25329329). Inhibition of CTLA4 has been employed in immune therapy of cancer by allowing activation of tumor-specific T-cells (PMID: 20525992). Ipilimumab, a monoclonal antibody that targets CTLA4, is FDA approved for the treatment of metastatic melanoma and functions by inhibiting immune system tolerance. Combination treatments with other immunotherapy treatments, including nivolumab, are currently under investigation (PMID: 28087644). False +ENST00000302763 NM_001903 1495 CTNNA1 False CTNNA1, a cytoplasmic adhesion protein, is infrequently altered in cancer. CTNNA1 encodes for a catenin which functions in association with a variety of cadherins to promote cell-adhesion (PMID: 11997091). The intracellular adhesion function of CTNNA1 is regulated through a dual-kinase mechanism located on the carboxy-terminal region and phospho-linker region of the protein (PMID: 25653389). CTNNA1 forms part of the E-cadherin/catenin multiprotein complex and promotes adhesion junction through interaction between other catenins and the actin cytoskeleton (PMID: 34425242, 9819562). Inactivation of CTNNA1 in various types of cancer cell lines and models induces cellular invasiveness and tumor metastasis, suggesting that CTNNA1 functions predominantly as a tumor suppressor gene (PMID: 33057364, 17223851, 29484367, 33364826). Downregulation of CTNNA1 has been identified in various types of cancer, including bladder cancer, acute myeloid leukemia and breast cancer (PMID: 18190825, 25177364, 22080244). True +ENST00000349496 NM_001904.3 1499 CTNNB1 True CTNNB1 (β-catenin), a transcriptional activator, is recurrently mutated in various cancers including endometrial and hepatocellular cancers. CTNNB1 (also β-catenin) is a transcriptional activator involved in the WNT signaling pathway (PMID: 22682243, 22617422). In the absence of WNT ligands, β-catenin is sequestered in the cytosol by its interaction with the APC/AXIN destruction complex. This destruction complex includes GSK3β, a kinase responsible for phosphorylating key β-catenin residues and targeting β-catenin for degradation. Engagement of WNT receptors by WNT ligands results in disruption of the APC/AXIN destruction complex, freeing β-catenin to transit into the nucleus and mediate target gene activation by interaction with transcription factors of the TCF/LEF family. Important transcriptional targets of β-catenin/TCF include Cyclin D1 and MYC (PMID: 10201372, 9727977). β-catenin also influences cell-cell adhesion and cell migration (PMID: 15001769). Somatic gain-of-function mutations in CTNNB1 result in aberrant accumulation of the β-catenin protein and are prevalent in a wide range of solid tumors, including uterine/endometrial carcinoma (PMID: 9721853, 23636398), ovarian (PMID: 19349352, 20942669), hepatocellular carcinoma (PMID: 22634756, 23788652), and colorectal carcinoma (PMID: 22810696), among others. Cancers with CTNNB1 mutations are presumed to be resistant to pharmacologic inhibition of upstream components of the WNT pathway, instead requiring direct inhibition of β-catenin function (PMID: 19351922, 22682243). False +ENST00000361367 NM_014633.4 9646 CTR9 False CTR9, a component of the PAF1 complex involved in RNA polymerase II regulation, is recurrently altered by mutation in Wilms tumor. CTR9 is an adaptor protein that is a component of the transcriptional regulatory PAF1 complex (PAF1c) (PMID: 20060942). CTR9 binds the multimeric PAF1c, which is also composed of the proteins PAF1, LEO1, CDC73, RTF1, and WDR61 (PMID: 25099282, 11884586, 30228257). PAF1c binds RNA polymerase II (Pol II) via the C-terminal domain (CTD) in the unphosphorylated state and dynamically regulates transcription at various stages including initiation, termination, elongation, and polyadenylation (PMID: 25099282, 11884586). In addition to regulating the activity of Pol II, PAF1c and CTR9 function to recruit transcription factors, histone remodelers, and processing factors to chromatin, thereby regulating gene expression via various layers of regulation (PMID: 20060942). The activity of CTR9 and PAF1c coordinate the appropriate placement of histone marks, allowing for regulation of chromatin remodeling (PMID: 22982193). The PAF1c complex also mediates the eviction of Pol II from chromatin in response to DNA damage, implicating the transcriptional complex in mediating genome instability (PMID: 26798134). PAF1c function is ubiquitously expressed to coordinate gene expression; however, PAF1c activity is particularly important during development (PMID: 17721442) and for the maintenance of embryonic stem cell identity (PMID: 19345177). Germline mutations in CTR9 are found in patients with Wilms’ tumor, a childhood renal cancer (PMID: 25099282). CTR9 alterations are predominantly heterozygous and alter CTR9 splicing, likely leading to protein truncation and loss of activity, suggesting that CTR9 acts predominantly as a tumor suppressor (PMID: 25099282, 29292210). However, in breast cancer, CTR9 expression is associated with increased transcription of oncogenic genes and proliferation, demonstrating a context-specific growth-promoting role of CTR9 (PMID: 26494790, 27829357). True +ENST00000264414 NM_003590.4 8452 CUL3 False CUL3, an E3 ubiquitin ligase component, is altered by mutation in non-small cell lung cancer. CUL3 is an E3 ubiquitin ligase that is a member of the cullin protein family (PMID: 27200299). Cullins, such as CUL3, associate with RING domain proteins to form E3 ligase complexes, which covalently attach ubiquitin to target proteins for subsequent degradation by the 26S proteasome (PMID: 15071497). CUL3 functions as a scaffolding protein with BTB-domain adaptor proteins to bring target substrates in proximity to the catalytic RING domain (PMID: 17120193). CUL3 is also involved in many cellular processes including the maturation of endosomes associated with lysosomal degradation, inflammation, proliferation, and cell cycle progression (PMID: 22219362, 30872636, 27200299). In addition, CUL3 interacts with several substrate adaptors that are altered in cancer including KEAP1, KLHL20, and SPOP (PMID: 27200299). A prominent example is KEAP1, which recruits the oxidative stress signaling factor NRF2 to the CUL3-containing E3-ubiquitin ligase complex for degradation (PMID: 19321346, 19638449, 23365135). Germline mutations in CUL3 are found in patients with Gordon’s syndrome, which is characterized by hypertension (PMID: 23689903). Somatic loss-of-function mutations in CUL3 have been identified in patients with non-small cell lung cancer (PMID: 31548347). These alterations disrupt the degradation of NRF2 and subsequently upregulate the oxidative stress response via KEAP1 and NRF2, leading to cancer progression (PMID: 19321346, 19638449, 23365135). True +ENST00000375440 NM_001008895 8451 CUL4A True CUL4, a ubiquitin ligase component of an E3 ubiquitin-protein ligase complex, is infrequently altered in cancer. CUL4 encodes for the ubiquitin ligase component of the cullin-RING-based E3 ubiquitin-protein ligase complex (PMID: 15811626, 16678110). The cullin-RING-based E3 ubiquitin-protein ligase complex mediates ubiquitination of target proteins in response to DNA damage and regulates histone methylation (PMID: 15448697, 16678110, 17041588). Overexpression of CUL4 in various cancer cell lines and models induces metastasis, tumor growth and cellular proliferation, suggesting that CUL4 functions predominantly as an oncogene (PMID: 28576144, 25413624, 28223829). CUL4 amplification has been identified in various types of cancer, including lung cancer, prostate cancer, breast cancer and ovarian cancer (PMID: 34119472, 22422151, 24305877). CUL4 expression is a potential therapeutic target with preclinical studies investigating the efficacy of anti-CUL4 inhibitors in various types of cancer (PMID: 28677427, 33602808). CUL4 is suggested to confer chemoresistance in ovarian cancer by inhibiting BIRC3 expression (PMID: 30718461). False +ENST00000292535 NM_181552.3 1523 CUX1 False CUX1, a transcription factor, is frequently altered in several cancers types by deletion, mutation or translocation. CUX1 (also CUTL1) is a transcription factor that regulates gene expression in a variety of cellular contexts (PMID: 18313863). The CUX1 protein has several alternative spliced protein isoforms which exhibit distinct DNA binding and transcriptional properties (PMID: 12429822). One isoform of CUX1 can function as either a transcriptional repressor or activator, while another is critical in base excision repair (PMID: 25190083). CUX1 also binds at enhancer sites with cohesin and regulates higher-order chromatin structure (PMID: 28369554). In addition, CUX1 regulates key cellular functions including cell cycle, proliferation, migration, neutrophil maturation, DNA damage and TGF-β-mediated signaling (PMID: 11438745, 22319212, 28147323, 18313863). Loss of CUX1 in preclinical models results in various gene expression changes, including de-repression of the PI3K pathway inhibitor PIK3IP1, leading to hematopoietic abnormalities (PMID: 29592892). CUX1 is recurrently deleted in uterine leiomyomas, acute myeloid leukemia and myelodysplastic syndromes (PMID: 9178912, 23212519, 25645650). Deletion of CUX1 occurs in the commonly deleted 7q region and is typically heterozygous, suggesting that CUX1 functions as a haploinsufficient tumor suppressor (PMID: 23212519, 25645650). Somatic loss-of-function mutations and fusion proteins involving CUX1 are also found in a range of human cancers, namely hematopoietic malignancies (PMID: 21674579). While CUX1 can function as a tumor suppressor in some cancer types, increased expression of CUX1 is also transforming in preclinical models and overexpression of CUX1 has been linked to poor prognosis in several human cancers (PMID: 25190083). True +ENST00000241393 NM_003467.2 7852 CXCR4 True CXCR4, a chemokine receptor, is altered in various solid and hematologic malignancies including lymphoplasmacytic lymphoma. CXCR4 is a chemokine receptor specific to the stromal-derived factor CXCL12, a molecule with potent chemotactic activity for lymphocytes (PMID: 20484021). Through autocrine and paracrine interactions, the CXCR4-CXCL12 signaling axis promotes cancer cell proliferation, survival, motility and drug resistance (PMID: 20484021). Expression of CXCR4 in cancer cells has been linked to metastasis to tissues containing high levels of CXCL12, like the bone, lungs, liver and lymph nodes (PMID: 21866172, 20484021, 17891505, 11242036). The CXCR4-CXCL12 axis also induces angiogenesis in several malignancies through hypoxia-induced CXCR4 expression and recruitment of endothelial progenitor cells to tumors (PMID: 15180966, 15882617, 21618540). Germline mutations in CXCR4, including activating C-terminal truncating mutations, cause WHIM syndrome, an immunodeficiency disorder characterized by neutropenia (Abstract: Cao et al. Abstract# 2715, ASH 2012. http://www.bloodjournal.org/content/120/21/2715)(PMID: 24553177, 24711662). Somatic alterations in CXCR4 are found in Waldenström macroglobulinemia (PMID: 24553177), but are rare in other cancers; elevated expression of CXCR4 is a poor prognostic marker in many cancers, including breast, ovarian, melanoma and prostate cancers (PMID: 25669980). Inhibitors of the CXCL4-CXCL12 axis are in several Phase I/II clinical trials for stem cell mobilization and HIV research; these inhibitors have not yet been evaluated in the context of cancer (PMID: 24141062). False +ENST00000398568 NM_001042355.1 1540 CYLD False CYLD is a tumor suppressor and deubiquitination enzyme that negatively regulates the NF-κB pathway. Germline mutations of CYLD are associated with Brooke-Spiegler syndrome, familial cylindromas, multiple familial tricoepithelioma, and spiradenomas. CYLD is a deubiquitinating enzyme that removes lysine-63-linked ubiquitin marks. It negatively regulates NF-κB signaling by deubiquitinating upstream regulators such as TRAF2 and TRAF6 (PMID: 12917689, 12917691). CYLD has a tumor suppressor role, principally via NF-κB pathway inhibition and enhancement of apoptosis (PMID: 12917690). Despite its recognized tumor suppressor role, CYLD also modulates microtubule dynamics and plays roles in cell migration and angiogenesis (PMID: 18222923, 20194890). CYLD is involved in other physiological processes, such as immune response, inflammation, cell cycle progression, spermatogenesis and osteoclastogenesis (PMID: 19373246). CYLD is mutated at low frequencies in various tumors. Around 25% of CYLD alterations are truncating mutations (cBioPortal, MSKCC, Jan. 2017). Germline mutations in CYLD gene have been associated with cylindromatosis, multiple familial trichoepithelioma, and Brooke-Spiegler syndrome (PMID: 26370355, 20502185, 16307661, 26329847). True +ENST00000260433 NM_000103.3 1588 CYP19A1 True CYP19A1, an enzyme that controls estrogen biosynthesis, is altered by mutation and amplification in aromatase inhibitor-resistant ER+ breast cancers. Germline mutations in CYP19A1 are found in aromatase excess and deficiency syndromes. CYP19A1 (also aromatase) is an enzyme that is a member of the cytochrome P450 superfamily (PMID: 11826265). CYP19A1 mediates the conversion of androgen precursors into estrogens, a hormone that functions in reproductive processes as well as in lipid and carbohydrate metabolism (PMID: 11826265). Estrogens bind to estrogen receptors (ER), which dimerize in the nucleus to regulate ER-responsive transcription and chromatin states (PMID: 29259445, 29775582, 22049316). The expression of CYP19A1 is highly context-dependent and is controlled by ten distinct tissue-specific promoters (PMID: 23340254). CYP19A1 is predominantly produced in the ovary in premenopausal, non-pregnant women; however, CYP19A1 production shifts to peripheral tissues, such as adipose, bone and skin tissues, following menopause (PMID: 11826265). Germline mutations in CYP19A1 result in aromatase excess and deficiency syndromes, which can result in early puberty, breast hypertrophy, and abnormal virilization (PMID: 12736278, 8530621). Patients with ER+ (estrogen receptor-positive) breast cancers may receive adjuvant endocrine therapy which may include aromatase inhibitors such as letrozole, exemestane, and anastrozole (PMID: 14668813). Several mechanisms of aromatase-based resistance have been identified, including amplification and mutation of CYP19A1 in patients with ER+ breast cancers (PMID: 14668813, 28112739, 24242068). CYP19A1 activity has also been implicated in several other hormone-positive cancers including endometrial cancers and cholangiocarcinomas (PMID: 27067638, 30284180). False +ENST00000282018 NM_020377.2 57105 CYSLTR2 True CYSLTR2, a G-protein-coupled receptor, is recurrently altered in uveal melanoma. CYSLTR2 is a G-protein coupled receptor (GPCR) that is a member of the rhodopsin-like GPCR family (PMID: 16776669, 13679572). CYSTLTR2 is activated by cysteinyl leukotrienes (CysLTs), which are inflammatory lipid mediators that are involved in allergic processes (PMID: 16776669, 13679572). Activation of Gαq proteins (such as GNAQ and GNA11) by CYSLTR2 promotes Gαq-mediated GDP/GTP exchange and binding to phospholipase C β (PLCB4), resulting in PIP2 cleavage (PMID: 27089179). Following PIP2 cleavage, the second messenger proteins diacylglycerol (DAG) and inositol triphosphate (IP3) activate calcium release (PMID: 27089179). CYSLTR2-mediated signaling promotes the activation of a variety of downstream pathways, including PKC, MAPK, and PI3K signaling, which promote several cellular processes such as endothelial permeability (PMID: 15545522, 25839425, 30559191). Overexpression of CYSLTR2 has been reported in several cancer types including colon cancer (PMID: 28402256, 21203429, 23829413). Recurrent somatic mutations in CYSLTR2 are found in patients with uveal melanoma and other related tumor types (PMID: 27089179, 31671564, 29476293, 27934878). These alterations promote ligand-independent activation of CYSLTR2, resulting in pigmentation defects and melanocytic phenotypes (PMID: 27089179). False +ENST00000374542 NM_001141970.1 1616 DAXX False DAXX, a transcriptional co-repressor, is inactivated in various cancers including pancreatic neuroendocrine tumors. DAXX (death domain-associated protein) is a protein involved in transcriptional regulation and apoptosis (PMID: 16406523, 9215629). DAXX accumulates in both the nucleus and the cytoplasm; in the nucleus, DAXX associates with the promyelocytic leukemia (PML) nuclear body and with ATRX-positive heterochromatic regions. In the cytoplasm, DAXX has been reported to interact with various proteins involved in cell death regulation. The proteins encoded by ATRX and DAXX interact with one another and play multiple cellular roles, including chromatin remodeling at telomeres, where they are required for the incorporation of the histone variant H3.3 (PMID:12953102, 21047901, 20651253, 21029860). DAXX is frequently altered in pancreatic neuroendocrine tumors (PanNETs) (PMID: 21252315). True +ENST00000233078 NM_018959.3 26528 DAZAP1 False DAZAP1, an RNA binding protein, is recurrently altered by rearrangement in acute lymphoblastic leukemias. DAZAP1 is an RNA binding protein that is a member of the Musashi protein family (PMID: 19285026, 21576381). DAZAP1 is highly expressed in the testes and functions as an important regulator of spermatogenesis and development (PMID: 15700540, 18669443, 16772659, 28575377). Several cellular processes related to mRNA stability and protein translation are regulated by DAZAP1 (PMID: 19285026, 21576381). Localization of DAZAP1 is controlled by active transcription and MAPK-directed phosphorylation, and DAZAP1 has been shown to have nuclear shuttling and mRNA transport activities (PMID: 16772659, 15700540, 16848763). DAZAP1 interacts with the mRNA processing enzymes hnRNPA1 and hnRNPA2 to control splicing (PMID: 29505834, 18391021, 18391021, 21858080, 24452013). In addition, the association of DAZAP1 with DAZ, a gene on the Y chromosome and expressed in germ cells, has been implicated in the regulation of translation (PMID: 16848763). Recurrent translocations with DAZAP1 and the partner protein MEF2D are found in B-cell precursor acute lymphoblastic leukemia (B-ALL) (PMID: 28778863, 30630978) and are associated with poor patient outcome (PMID: 27507882, 27824051). MEF2D-DAZAP1 fusion proteins demonstrate oncogenic activity by increasing MEF2D transcriptional activity, HDAC9 expression, and cellular transformation (PMID: 15182431, 27507882, 27824051). HDAC inhibition may be efficacious in patients with MEF2D translocations (PMID: 27507882). False +ENST00000292782 NM_020640.2 54165 DCUN1D1 True DCUN1D1, a component of an E3 ligases complex, is amplified in squamous cell carcinomas. DCUN1D1 (also SCCRO and DCN1) is a component of E3 ligase complexes that mediate neddylation (PMID: 18826954, 31898237). Neddylation is a cellular process that places a ubiquitin-like modification (NEDD8) on E3 ligase-associated substrate proteins via cullin protein scaffolding (PMID: 18826954). DCUN1D1 binds to cullin-RING E3 ligase complexes in the cytoplasm and coordinates nuclear translocation, promoting the optimal transfer of NEDD8 from the E2 complex to cullin-associated substrates (PMID: 28581483, 31898237). DCUN1D1 activity is implicated in the regulation of a variety of proteins, including the activation of the VHL E3 ligase and other cullin ubiquitin ligases (PMID: 26743088, 23201271, 23401859). In addition, DCUN1D1 can relieve the negative inhibition of CAND1, a protein that binds unneddylated cullin-RING complexes (PMID: 25349211). Overexpression of DCUN1D1 is found in cancer, including in non-small cell lung cancer, and may be associated with a poorer prognosis (PMID:22500162, 27285984, 25411243). Amplification of DCUN1D1 is observed in squamous cell carcinomas and is associated with cancer progression (PMID:17018598, 23908357). Inhibitors of enzymes in the neddylation pathway are currently in clinical development (PMID: 26675347, 26423795, 28581483). False +ENST00000256996 NM_000107 1643 DDB2 False DDB2, a DNA damage repair factor involved in the nucleotide excision repair (NER) pathway, is altered by mutation or deletion in squamous cell carcinoma. DDB2 encodes for a DNA binding protein which primarily functions as a subunit of the UV-DDB complex and DCX (DDB1-CUL4-X-box) complexes for DNA repair and protein ubiquitination (PMID: 16223728, 11564859, 10585395, 32789493). DDB2 is essential for the recognition and repair of UV-induced DNA damage as the protein initiates the nucleotide excision repair (NER) pathway on sites of UV damage (PMID: 14751237, 32789493, 11278856). DDB2 has been identified to function in the ubiquitination of histones H2A, H3 and H4 at sites of UV-induced DNA damage to promote subsequent DNA repair (PMID: 16473935). The DCX complex functions in promoting reversible ubiquitination of DNA damage repair factor XPC to promote NER (PMID: 15882621). Germline mutations of DDB2 are associated with the autosomal recessive disease xeroderma pigmentosum, resulting in a decreased ability to repair DNA damage caused by UV rays (PMID: 37142601). Knockdown of DDB2 in various cancer cell lines and models induces epithelial-to-mesenchymal transition, tumorigenesis and cellular proliferation, suggesting that DDB2 functions predominantly as a tumor suppressor gene (PMID: 36568213, 26205499, 15558025). Downregulation of DDB2 has been identified in various types of cancers, including squamous cell carcinoma (PMID: 33276309, 27499003, 32722430). Loss of DDB2 has been suggested to be associated with increased chemoresistance (PMID: 36568213, 35707599). True +ENST00000346473 NM_001195057.1 1649 DDIT3 False DDIT3, a transcription factor, is infrequently mutated by chromosomal rearrangements in various types of sarcomas. DDIT3 (CHOP) is a member of the CCAAT/enhancer-binding protein (C/EBP) family of transcription factors and is involved in negative regulation of adipocyte differentiation (PMID: 7805034). In normal cells, DDIT3 expression and activity is induced by cellular ER stress, specifically DNA damage and irradiation exposure. Overexpression of DDIT3 from ER stress can ultimately lead to activation of apoptotic pathways (PMID: 11121490, 1617653, 8754828, 14685163) due to a decrease in Bcl-2 expression and subsequent translocation of Bax from the cytosol to the mitochondria (PMID: 14685163). Translocations of DDIT3 such as the EWSR1-DDIT3 fusion and the FUS-DDIT3 fusion are found in liposarcomas, which abolish the ability of DDIT3 to arrest cell growth leading to aberrant cellular proliferation (PMID:24790523, 24320889). False +ENST00000367921 NM_006182.2 4921 DDR2 True DDR2, a receptor tyrosine kinase, is mutated at low frequencies in various cancers. DDR2 (Discoidin Domain Receptor 2) is a receptor tyrosine kinase that mediates several downstream signaling pathways. When the extracellular discoidin domain of the receptor is bound by its cognate ligand, collagen, autophosphorylation of the DDR2 intracellular kinase domain is initiated, which results in activation of several downstream signaling pathways, such as the MAPK and PI3K pathways. Activation of these pathways promotes cellular migration, differentiation, proliferation and survival (PMID: 16186108, 17703188, 16626936). DDR2 activation or expression has been implicated in metastasis of various cancer types, such as colorectal cancer, melanoma and breast cancer (PMID: 22071959, 21735168, 21701781, 23644467, 25130389) through mechanisms that are not yet fully understood. Somatic gain-of-function mutations in DDR2 have been identified in squamous cell lung cancers (PMID: 22768234, 22328973) and at lower frequencies in other cancers. Clinical responses to targeted therapy with dasatinib have been reported in patients with squamous cell lung cancer with DDR2 mutations (PMID: 22328973). False +ENST00000399959 NM_001356.4 1654 DDX3X False DDX3X, an RNA helicase, is recurrently altered by mutations in several cancer types, including medulloblastoma and chronic lymphocytic leukemia. DDX3X (also DDX) is an RNA helicase that is a member of the DEAD box protein family. DDX3X is implicated in a variety of cellular functions that regulate RNA structure including RNA transport, translation initiation, splicing, ribosome, and spliceosome assembly (PMID: 17667941, 27180681). In addition, DDX3X mediates cell cycle control by regulating translational initiation of key cell cycle proteins, including Cyclin E1 (PMID: 20837705) and hypoxia-inducible genes, including HIF-1α (PMID: 21448281). Germline mutations in DDX3X are found in patients with intellectual disabilities (PMID: 28135719, 26235985). Somatic loss-of-function mutations in DDX3X are found in patients with medulloblastoma, chronic lymphocytic leukemia, mesothelioma and head and neck cancers (PMID: 22150006, 22722829, 22820256, 21798893, 26928227, 26192917), suggesting that DDX3X predominantly functions as a tumor suppressor. DDX3X is commonly mutated in tumor types with altered WNT signaling and has been implicated as a transcriptional regulator of WNT responsive genes (PMID: 22820256). Expression of DDX3X has been linked to a cancer stem cell population and may mediate resistance to EGFR tyrosine kinase inhibitors (PMID: 25343452). Small molecule inhibitors targeting DDX3X are under preclinical investigation (PMID: 25820276). True +ENST00000505374 NM_024415.2 54514 DDX4 True DDX4, an RNA helicase, is altered by overexpression in ovarian cancers. DDX4 (also VASA) is an RNA helicase that is a member of the DEAD box protein family (PMID: 28612512). Expression of DDX4 is localized predominantly in migratory primordial germ cells, and DDX4 is important for embryonic patterning and germline specification (PMID: 10920202, 11178242, 11178242). More specifically, DDX4 may be a marker of oocyte precursor cells (PMID: 26444630, 22366948, 29725036); however, this result is controversial (PMID: 32123174). DDX4 interacts with the general translation factor eIF5B and mediates translation of many mRNAs involved in germline specification and maintenance (PMID: 10920202, 16630817, 28612512). The eIF5B-DDX4 interaction facilitates ATP hydrolysis and specific RNA unwinding functions, which may be suitable for RNAs with specific structures (PMID: 16630817). Transient DDX4 expression has also been found in the context of regeneration in somatic cells or during wound healing (PMID: 27179696). The activity of DDX4 is also implicated in the transport of PIWI RNAs to the cytoplasm in germ cells, which is important for the suppression of transposable elements (PMID: 28612512, 23587717). DDX4 expression has been found in ovarian cancer cell lines and tissues (PMID: 27179696, 29963162, 29078734, 28245464). Overexpression of DDX4 in cell lines results in aberrant cell cycle progression, resulting in increased cellular proliferation (PMID: 28612512, 29963162). These abnormal proliferative cellular functions have been associated with dysregulation of PIWI, CCNB1 and E2F1 during cell cycle progression in loss-of-function studies (PMID: 28612512). In addition, DDX4 has been found to bind mitotic spindles in cancer cells and has a role in mediating cellular migration (PMID: 28612512). False +ENST00000507955 NM_016222.2 51428 DDX41 False DDX41, an RNA helicase involved in innate immunity, is recurrently altered by mutation in hematopoietic malignancies. Germline mutations of DDX41 predispose to myelodysplastic syndromes and acute myeloid leukemia. DDX41 is an RNA helicase that is a member of the DEAD-box protein family (PMID: 27502187). RNA helicases have diverse cellular functions including roles in RNA metabolism, immune response and viral infection (PMID: 27502187). In dendritic cells, DDX41 functions as a DNA sensor that recognizes double-stranded DNA or cyclic diguanylate monophosphate (c-di-GMP), which are byproducts released during viral or bacterial infection (PMID: 27502187, 21892174). DDX41 activity regulates the STING pathway, which is important in innate immunity (PMID: 27502187, 28602976, 27721487, 25704810, 23142775). The STING pathway activates type I interferon responses mediated by TBK, IRF1, and NFKB, which are critical for mounting an appropriate response to DNA viruses (PMID: 27502187, 27721487, 25609843). In addition to the role of DDX41 in innate immunity, DDX41 associates with spliceosome proteins and has been implicated in mRNA processing and splicing (PMID: 25920683). Germline, hypomorphic mutations in DDX41 are found in families with a predisposition for hematopoietic malignancies such as myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) (PMID: 26712909, 25920683, 31713024, 31484648). DDX41 mutations found in familial carriers predispose individuals to acquire a secondary somatic mutation on the other DDX41 allele, suggesting that DDX41 likely functions as a tumor suppressor (PMID: 26712909). In addition, individuals with a 5q deletion, a recurrent genetic event in myeloid malignancies, exhibit haploinsufficient expression of DDX41 (PMID: 25920683). DDX41 alterations commonly occur in the ATP binding domain, consistent with the importance of ATP binding in DNA sensing (PMID: 27721487). Lenalidomide sensitivity has been reported in patients with DDX41-mutant myeloid malignancies (PMID: 31400013, 25920683). True +ENST00000225792 NM_004396 1655 DDX5 True DDX5, a DEAD-box RNA helicase, is infrequently altered in cancer. DDX5, a member of the DEAD-box family, encodes for an RNA helicase that functions in the regulation of cellular processes through remodeling RNA secondary structures during transcription and pre-mRNA maturation (PMID: 32376686). DDX5 interacts with various different genes, including TP53 and CTCF, to mediate transcriptional regulation in response to DNA damage (PMID: 22986526, 20966046). DDX5 activates signaling pathways, including the WNT, AKT and mTOR pathways, to regulate cell proliferation, cell cycle control and glucose metabolism (PMID: 28411202). Overexpression of DDX5 in various cancer cell lines and models induces cellular proliferation and tumorigenesis, suggesting that DDX5 functions predominantly as an oncogene (PMID: 28216662, 26212035, 22750847). DDX5 amplification has been identified in various types of cancer, including breast cancer and non-small cell lung cancer (PMID: 22750847, 26212035). DDX5 expression is a potential therapeutic target with preclinical studies investigating the efficacy of anti-DDX5 inhibitors in various types of cancer (PMID: 27148684, 28244855). False +ENST00000397239 NM_003472.3 7913 DEK True DEK, a DNA binding and chromatin regulatory protein, is recurrently altered by chromosomal rearrangement in acute myeloid leukemia. DEK is a nuclear protein with roles in DNA binding and chromatin regulation (PMID: 25524609). DEK is ubiquitously expressed and modifies chromatin by altering the superhelical density of DNA, introducing positive supercoils to alter DNA structure (PMID: 11997399, 10837023). DEK also interacts with the chromatin-modifying enzyme p300 and PCAF in order to maintain heterochromatin state and influence gene expression (PMID: 16696975, 21460035). In addition to regulating epigenetic state, DEK facilitates cellular proliferation by resolving conditions of DNA replication stress at the replication fork (PMID: 25347734). DEK forms a complex with the DNA repair protein RAD51 and is a critical mediator of non-homologous end joining (NHEJ) (PMID: 28317934). Loss of DEK expression results in genome instability and sensitivity to DNA damaging agents (PMID: 28317934). DEK is also required for other cellular functions including mRNA splicing, apoptosis, and chemoresistance, among others (PMID: 19679545, 28317934). DEK is overexpressed in several tumor types including breast cancer, colorectal cancer, small cell lung cancer, among others, and increased DEK expression is linked to poor patient prognosis (PMID: 25197373, 23902796, 21663673, 25544761, 24608431). Recurrent DEK rearrangements are found in patients with acute myeloid leukemia which result in increased DEK expression, suggesting that DEK functions predominantly as an oncogene (PMID: 25524609). False +ENST00000393063 NM_177438.2 23405 DICER1 False DICER1 is a tumor suppressor and an endoribonuclease. Germline mutations in DICER1 predispose to various cancer types, including pleuropulmonary blastoma, rhabdomyosarcoma, cystic nephroma, ovarian Sertoli-Leydig cell tumor and endocrine tumors. DICER1 is an endoribonuclease that catalyzes the cleavage of large RNA molecules into silencing RNAs or microRNAs. In addition, DICER1 loads siRNA onto the Argonaute protein and mediates the binding of co-factors to initiate RNA-induced silencing (PMID: 25176334). In this way, DICER1 plays a pivotal role in the post-transcriptional regulation of gene expression (PMID: 25176334). Germline mutations in DICER1 are associated with DICER1-related disorders, a familial tumor susceptibility syndrome that confers increased risk most commonly for pleuropulmonary blastoma (PPB), cystic nephroma (CN), rhabdomyosarcoma (RMS), multinodular goiter, ovarian Sertoli-Leydig cell tumor and other neoplastic conditions (PMID: 19556464, 21266384, 21882293, 24761742). The majority of germline mutations in DICER1 are nonsense, frameshift, or splice-site mutations leading to premature protein truncation and loss of protein function (PMID: 21266384, 19556464, 25176334). Somatic DICER1 mutations have also been identified, predominantly affecting the region of the protein that mediates the interaction of DICER1 with miRNAs (PMID: 25176334). DICER1 has been identified as a haploinsufficient tumor suppressor gene (PMID: 19903759, 20019750), as monoallelic but biallelic loss of DICER1 causes tumor formation. Consistent with the role of DICER1 as a tumor suppressor, reduced expression of DICER1 correlates with a poor outcome in lung, breast, skin, endometrial and ovarian cancer (PMID: 15723655, 19092150, 19782670, 20210522, 20832293). True +ENST00000377767 NM_014953.3 22894 DIS3 False DIS3, the catalytic subunit of the RNA exosome complex, is recurrently mutated in several cancer types including multiple myeloma. DIS3 (also Rrp44) is an exoribonuclease that is a member of the RNase II/RNB protein family (PMID: 31342438). DIS3 is the catalytic subunit of the RNA exosome complex, which coordinates 3’ to 5’ degradation of RNA (PMID: 20531389, 21289487). The exosome complex prominently participates in RNA processing and quality control pathways (PMID: 21289487). In addition, DIS3 regulates the maturation of many RNA targets, including the tumor suppressor let-7 miRNAs, which control the translation of oncogenes such as MYC and RAS (PMID: 25925570, 26305418). Recurrent familial and somatic mutations of DIS3 have been found in patients with multiple myeloma (PMID: 21430775, 24434212, 22573403, 25521164, 23396385, 22237025, 30967618). These DIS3 loss-of-function mutations have been shown to interfere with the exonucleolytic activity, causing defects in RNA processing, cellular proliferation, and protein translation (PMID: 24150935). In contrast, DIS3 amplification and overexpression have been detected in several cancer types, including colon cancer and melanoma, suggesting that the consequence of DIS3 alteration may be context-specific (PMID: 23319804, 24478024, 21343389). True +ENST00000373970 NM_012242.2 22943 DKK1 False DKK1, a negative regulator of WNT signaling, is overexpressed or downregulated in various cancer types. DKK1 is an extracellular ligand that is a member of the Dickkopf protein family (PMID: 28979801, 17143291). DKK1 functions as a negative regulator of the WNT signaling pathway by binding to LRP5/6 co-receptors and precluding WNT-mediated activation of downstream signaling (PMID: 28979801, 17143291, 23258168). WNT signaling is a critical developmental pathway with roles in determining cell fate, tissue identity and polarity (PMID: 28218291). DKK1-mediated antagonism of WNT blocks Frizzled receptor binding to LRP5/6 and results in the activation of the β-catenin destruction complex (containing APC, GSK3β and AXIN), which targets β-catenin for degradation (PMID: 23258168). In the absence of WNT signaling, TCF and LEF transcription factors form a repressive complex, leading to inhibition of β-catenin target genes (PMID: 24316024, 23258168). DKK1 also binds to the receptors Kremen1 and Kremen2 to remove the LRP6 co-receptor from the plasma membrane (PMID: 12050670). In addition, DKK1 is involved in the regulation of many cellular functions including developmental patterning, apoptosis, angiogenesis and invasion (PMID: 22807036, 27608843, 28979801, 11702953, 31568519). Somatic mutations in DKK1 in human cancers are relatively uncommon; however, DKK1 is found to be downregulated or overexpressed in distinct cancer subtypes (PMID: 25144498, 18331598, 26101916, 24916146). DKK1 is also an important regulator of bone metastasis (PMID: 28892080). Therefore, DKK1 may have roles as either a tumor suppressor or oncogene depending on the specific cellular context. False +ENST00000285311 NM_014421.2 27123 DKK2 False DKK2, a negative regulator of WNT signaling, is overexpressed or downregulated in various cancer types. DKK2 is an extracellular ligand that is a member of the Dickkopf protein family (PMID: 28979801, 17143291). DKK2 functions as both a positive and negative regulator of the WNT signaling pathway by binding to LRP5/6 co-receptors (PMID: 24316024, 23258168,12527209). WNT signaling is a critical developmental pathway with roles in determining cell fate, tissue identity and polarity (PMID: 28218291). DKK2-mediated antagonism of WNT blocks Frizzled receptor binding to LRP5/6 and results in the activation of the β-catenin destruction complex (containing APC, GSK3β and AXIN), which targets β-catenin for degradation (PMID: 23258168). In the absence of WNT signaling, TCF and LEF transcription factors form a repressive complex, leading to inhibition of β-catenin target genes (PMID: 24316024, 23258168). DKK2 binds the receptor Kremen2 to remove the LRP6 co-receptor from the plasma membrane; however, even in the absence of Kremen2, DKK2 can activate WNT signaling (PMID: 12527209). DKK2 has also been implicated in the regulation of immune evasion via WNT-independent mechanisms (PMID: 29431745). In addition, DKK2 is involved in the regulation of many cellular functions including developmental patterning, apoptosis, angiogenesis and invasion (PMID: 27431620, 19755393, 21540552, 28979801). Somatic mutations in DKK2 in human cancers are relatively uncommon; however, DKK2 is found to be downregulated or overexpressed in distinct cancer subtypes (PMID: 22964660, 19755393, 24809435, 23204234, 19659606, 27431620) suggesting it may have roles as either a tumor suppressor or oncogene depending on the specific cellular context. False +ENST00000326932 NM_001018057.1 27122 DKK3 False DKK3, a negative regulator of WNT signaling, is overexpressed or downregulated in various cancer types. DKK3 is an extracellular ligand that is a member of the Dickkopf protein family (PMID: 28979801, 17143291). Dickkopf proteins predominantly function as negative regulators of the WNT signaling pathway by binding to WNT pathway signaling receptors, such as LRP5/6 (PMID: 24316024, 23258168,12527209). WNT signaling is a critical developmental pathway with roles in determining cell fate, tissue identity, and polarity (PMID: 28218291). Unlike other DKK proteins, the exact role of DKK3 in WNT signaling is not well established. DKK3 interacts with Kremen1 and Kremen2 receptors, which have roles in LRP5/6 internalization, suggesting that DKK3 potentiates WNT activity (PMID: 20370576). DKK3-mediated antagonism of WNT would result in the activation of the β-catenin destruction complex (containing APC, GSK3β and AXIN), which targets β-catenin for degradation (PMID: 23258168). In the absence of WNT signaling, TCF and LEF transcription factors form a repressive complex, leading to inhibition of β-catenin target genes (PMID: 24316024, 23258168). In addition, DKK3 is involved in the regulation of many cellular functions including developmental patterning, apoptosis, immune response, and invasion (PMID: 21268126, 25573172, 28738084, 26278164). Somatic mutations in DKK3 in human cancers are relatively uncommon; however, DKK3 is found to be downregulated or overexpressed in distinct cancer subtypes (PMID: 27801786, 27467270, 27788486, 26093488). False +ENST00000220812 NM_014420.2 27121 DKK4 False DKK4, a negative regulator of WNT signaling, is overexpressed or downregulated in various cancer types. DKK4 is an extracellular ligand that is a member of the Dickkopf protein family (PMID: 28979801, 17143291). DKK4 functions as a negative regulator of the WNT signaling pathway by binding to LRP5/6 co-receptors and precluding WNT-mediated activation of downstream signaling (PMID: 24316024, 23258168). WNT signaling is a critical developmental pathway with roles in determining cell fate, tissue identity and polarity (PMID: 28218291). DKK4-mediated antagonism of WNT blocks Frizzled receptor binding to LRP5/6 and results in the activation of the β-catenin destruction complex (containing APC, GSK3β and AXIN), which targets β-catenin for degradation (PMID: 23258168). In the absence of WNT signaling, TCF and LEF transcription factors form a repressive complex, leading to inhibition of β-catenin target genes (PMID: 24316024, 23258168). DKK4 also binds to the receptors Kremen1 and Kremen2 to remove the LRP6 co-receptor from the plasma membrane (PMID: 12527209). In addition, DKK4 is involved in the regulation of many cellular functions including developmental patterning, apoptosis, angiogenesis and invasion (PMID: 27272409, 23958302). Somatic mutations in DKK4 in human cancers are relatively uncommon; however, DKK4 is found to be downregulated or overexpressed in distinct cancer subtypes (PMID: 22216841, 17675336, 29904276, 21994129, 26880586, 19059704) suggesting it may have roles as either a tumor suppressor or oncogene depending on the specific cellular context. False +ENST00000254322 NM_006145.1 3337 DNAJB1 False DNAJB1, a subunit of the heat shock factor 40 (HSP40) complex, is recurrently altered by chromosomal rearrangement in fibrolamellar hepatocellular carcinoma. DNAJB1 (DNAJ (Hsp40) homolog, subfamily B, member 1) is a member of the HSP40 protein family and has been linked to several cellular processes, such as the proteasome pathway, endoplasmic reticulum (ER) stress and virus infection (PMID:19340594, 22075554, 23400395, 21698289). DNAJB1 interacts with HSP70 and induces its ATPase activity, which stimulates the association between HSP70 and Hsc70-interacting protein (HIP) (PMID: 24309468). A seminal feature of DNAJB1 is the presence of the DNAJB1-PRKACA chimeric transcript in fibrolamellar hepatocellular carcinoma (FLHCC) tumors. Numerous independent studies have confirmed the presence of the fusion gene in 80-100% of FLCs tumor samples (PMID: 25557953, 25698061, 25605237, 25122662, 24578576, 26489647). The fusion encodes a chimeric protein that couples a segment of DNAJB1, with the catalytic domain of protein kinase A (PKA) that confers constitutive kinase activity. Although analyses of a wider array of cancer types are required to more definitively establish the specificity of DNAJB1-PRKACA to FLCs, the current evidence suggests that DNAJB1-PRKACA may be a tissue biomarker for FLCs and if the chimeric protein is secreted into circulation, it may also serve as a plasma biomarker. False +ENST00000355667 NM_001005360 1785 DNM2 True DNM2, a GTPase, is infrequently altered in cancer. DNM2, a member of the dynamin superfamily, encodes for a GTPase that functions in clathrin-independent and -dependent endocytosis and intracellular membrane trafficking (PMID: 20858595). DNM2 regulates the T-cell receptor-mediated signaling pathways and T-cell activation through interaction with VAV1 (PMID: 15696170). Overexpression of DNM2 in various cancer cell lines and models induces cellular proliferation, migration and invasion, suggesting that DNM2 functions predominantly as an oncogene (PMID: 27885263, 21841817). DNM2 amplification has been identified in various types of cancer, including acute lymphoblastic leukemia, prostate cancer and breast cancer (PMID: 27885263, 24402972, 33250680). DNM2 expression is a potential therapeutic target with preclinical studies investigating the efficacy of anti-DNM2 inhibitors in various types of cancer (PMID: 20571068, 21750222). False +ENST00000340748 NM_001379.2 1786 DNMT1 True DNMT1, a DNA methyltransferase, is infrequently altered in various cancer types. DNMT1 is a DNA methyltransferase that mediates the transfer of methyl groups to CpG sites in DNA (PMID: 21163962, 29033456). DNA methylation at gene promoters predominantly results in gene repression by precluding the binding of important transcriptional machinery (PMID: 23400093). DNMT1 preferentially methylates hemimethylated DNA, namely daughter strands that are newly generated during the cell cycle (PMID: 21163962). DNMT1 plays an important role in a number of physiologic processes such as X chromosome inactivation, genomic imprinting, chromosomal stability, and repression of retrotransposon expression. DNMT1 mutations are rarely found in human cancers; however, DNMT1 overexpression has been observed in colon cancer (PMID: 2014266, PMID: 10463569), gastric cancer (PMID: 14742272), breast cancer (PMID: 14555514), bladder cancer (PMID: 14634451), and acute and chronic myelogenous leukemia (PMID: 11222358). Increased activity of DNMT1 can lead to altered DNA methylation and abnormal transcriptional silencing (PMID: 29033456). The DNMT1 inhibitor azacytidine is FDA-approved for the treatment of patients with specific myelodysplastic syndrome (MDS) subtypes and chronic myelomonocytic leukemia (PMID: 15897554) and may have efficacy in patients with mutations in other epigenetic modifiers that impact DNA methylation state (PMID: 28193779). False +ENST00000264709 NM_022552.4 1788 DNMT3A False DNMT3A, a tumor suppressor and DNA methyltransferase, is recurrently mutated in acute myeloid leukemia and other hematologic malignancies. DNMT3A is a DNA methyltransferase that is responsible for establishing de novo genomic DNA methylation at CpG sites. DNA methylation at gene promoters predominantly results in gene repression by precluding the binding of important transcriptional machinery (PMID: 23400093). DNMT3A functions in concert with another de novo methyltransferase, DNMT3B, and a maintenance methyltransferase DNMT1, assisted by non-catalytic subunit DNMT3L (PMID: 21243710). CpG methylation is important for maintaining epigenetic tissue-specific gene expression patterns, genomic imprinting, X-chromosome inactivation, silencing of parasitic DNA sequences and genome integrity (PMID: 12359337, 15215868). Germline mutations in DNMT3A result in Tatton-Brown-Rahman overgrowth syndrome, a disorder associated with intellectual disability (PMID: 24614070), and overexpression has been linked to melanoma and hepatocellular carcinoma (PMID: 24589714). DNMT3A is recurrently mutated in de novo acute myeloid leukemia (AML) (up to 30% of all cases) (PMID: 21067377, 21399634, 22417203, 23634996), and at lower frequencies in secondary acute myeloid leukemia (PMID: 21993668), myeloproliferative neoplasms (PMID: 21537334), myelodysplastic syndromes (PMID: 21415852, 21519343) and in T-cell acute lymphoblastic leukemia (T-ALL) (PMID: 23341344, 23603912, 23687089). Cancers with enhanced activity of DNMT3A may be sensitive to DNA methyltransferase inhibitors (PMID: 29033456). True +ENST00000328111 NM_006892.3 1789 DNMT3B False DNMT3B, a DNA methyltransferase, is altered by mutation or amplification in various cancer types. DNMT3B is a DNA methyltransferase that is responsible for establishing de novo genomic DNA methylation at CpG sites (PMID: 21243710). DNA methylation at gene promoters predominantly results in gene repression by precluding the binding of important transcriptional machinery (PMID: 23400093). DNMT3B functions in concert with another de novo methyltransferase, DNMT3A, and a maintenance methyltransferase DNMT1, assisted by non-catalytic subunit DNMT3L (PMID: 21243710). CpG methylation is important for maintaining epigenetic tissue-specific gene expression patterns, genomic imprinting, X-chromosome inactivation, silencing of parasitic DNA sequences and genome integrity (PMID: 12359337, 15215868). Germline biallelic mutations in DNMT3B are associated with ICF (immunodeficiency, centromeric instability and facial abnormalities) syndrome (PMID: 10647011, 16501171). Rare mutations in the DNMT3B gene have been identified and dysregulated expression of DNMTs and/or aberrant DNA methylation patterns are found in various cancer types (PMID: 21941284, 22037554, 22895193). Cancers with enhanced activity of DNMT3B may be sensitive to DNA methyltransferase inhibitors (PMID: 29033456). True +ENST00000398665 NM_032482.2 84444 DOT1L True DOT1L, a histone methyltransferase, is infrequently mutated in various cancer types. DOT1L is a histone H3K79 methyltransferase, methylating the histone 3 lysine 79 residue (PMID:12123582). H3K79 methylation is associated with DNA damage response to double strand breaks (PMID:15525939). This modification has also been implicated in diverse cellular and developmental processes including cell division, embryonic development, meiosis, and hematopoiesis (PMID:21724828, 24526115). H3K79 methylation modifies chromatin structure and can promote active transcription (PMID:18285465). In leukemias, this modification promotes active transcription by preventing the binding of the inhibitory Sirtuin1 (SIRT1) complex (PMID:25822366). In mixed lineage leukemia (MLL) translocation leukemias, DOT1L was shown to be important for the transformation activity of the MLL fusion protein, and inhibitors of DOT1L have been employed in the treatment of this subset of leukemias (PMID:18977325, 15851025, 21741596). In breast cancer, DOT1L has been shown to cooperate with a c-Myc-p300 complex to promote epithelial to mesechymal transition and clinically is associated with more aggressive disease (PMID:26199140). Mutations in DOT1L have been identified in large-scale sequencing efforts of solid tumors including colon, small cell lung cancer, and squamous head and neck cancer (PMID:22810696, 26168399, 25056374). False +ENST00000370192 NM_000110 1806 DPYD False DPYD, a pyrimidine catabolic enzyme, is infrequently mutated in cancer. DPYD encodes for dihydropyrimidine dehydrogenase, which is the rate-limiting factor in uracil and thymidine catabolism (PMID: 36172669). Deletions in the gene result in loss of the enzyme’s activity, which has been associated with delayed motor skill development, seizures, and intellectual disability linked to congenital thymine-uraciluria (PMID: 36661700, 35607723). Loss of the gene also increases the risk of toxicity in cancer patients receiving 5-fluorouracil chemotherapy (PMID: 35607723, 36172669, 36757428,36661700). 5-fluorouracil and its oral prodrugs capecitabine and tegafur are used in the treatment of several cancers including colon, stomach, and breast (PMID: 36757428, 36661700, 36172669). Decreased dihydropyrimidine dehydrogenase activity increases exposure to both 5-fluorouracil and its cytotoxic metabolites, resulting in adverse events (PMID: 36757428, 35607723). False +ENST00000344624 NM_013235.4 29102 DROSHA False DROSHA, a ribonuclease involved in microRNA biogenesis, is mutated or amplified at low frequencies in various cancers. DROSHA is an RNA-specific endoribonuclease III involved in the initial steps of microRNA (miRNA) biogenesis. DROSHA, forming a complex with DGCR8, cleaves the double-stranded stem-loop structured pri-miRNA into pre-miRNA, which is subsequently exported to the cytosol where it can be further processed, ultimately leading to specific mRNA silencing (PMID: 14508493, 19239886, 23654304). DROSHA has been reported to be both up- and downregulated in several cancers, suggesting tissue-specific mechanisms in tumorigenesis (PMID: 20832293, 21559780, 20210522). Somatic mutations in DROSHA are found in a small proportion of cancers including in pediatric Wilm’s tumors (PMID: 25670083, 25190313) and DROSHA amplifications have been identified in lung adenocarcinoma (PMID: 26156018). DROSHA mutations are predicted to function through a dominant negative mechanism and globally inhibit miRNA biogenesis (PMID: 25670083). False +ENST00000257600 NM_004416.2 1840 DTX1 False DTX1, a ubiquitin E3 ligase and transcriptional regulator, is recurrently altered by mutation in lymphomas. DTX1 (also Deltex-1) is an E3 ubiquitin ligase that also functions as a transcriptional regulator (PMID: 12670957). DTX1 ubiquitinates substrates, including MEKK1 and C-FLIP, and targets them to the proteasome for degradation (PMID: 15684388, 29374180). High expression of DTX1 is found in germinal center B cells, marginal zone B cells, lymphoid cells and the nervous system (PMID: 22891273, 15684394, 26714454). The activity of DTX1 is important for regulation of T cell anergy and FOXP3 activity in regulatory T cells (PMID: 25695215, 19592273). In addition, DTX1 functions as a transcriptional regulator of Notch in association with the coactivator p300 to inhibit neural progenitor (PMID: 11564735, 14567914), B, NK, and T cell differentiation (PMID: 15187027, 27048872). The mechanism by which DTX1 regulates NOTCH signaling is not fully delineated; however, DTX1 may inhibit NOTCH by targeting the receptor for endosomal recycling (PMID: 29440432) and DTX1 itself is a target of NOTCH transcriptional regulation (PMID: 9056690). Somatic DTX1 mutations are found in patients with splenic marginal zone lymphoma (PMID: 22891273) and diffuse large B cell lymphomas (PMID: 25171927). These DTX1 alterations are predicted to disrupt Notch signaling and contribute to abnormal hematopoietic differentiation (PMID: 22891273, 25171927). DTX1 expression is also downregulated in several tumor types, including head and neck cancers (PMID: 28146432). True +ENST00000344450 NM_020185.4 56940 DUSP22 False DUSP22, a protein phosphatase, is recurrently altered by chromosomal rearrangement in anaplastic large cell lymphoma. DUSP22 (also JKAP, JSP-1) is a dual-specificity phosphatase with several roles in the regulation of downstream signaling pathways. Dual-specificity phosphatases can dephosphorylate phosphotyrosine and phosphoserine/threonine residues within the same substrate (PMID: 19228121). DUSP22 inhibits T-cell receptor signaling by dephosphorylating and inactivating MAPK and ERK2 (PMID: 11733513) In addition, DUSP22 is a negative regulator of focal adhesion kinase (FAK) and is an inhibitor of cell migration via reduced FAK activity (PMID: 20018849). DUSP22 can also positively regulate downstream signaling pathways; for example, DUSP22 binds JNK and activates the JNK pathway (PMID: 11717427, 27711255). Because DUSP22 has been implicated in the regulation of several signaling pathways, DUSP22 is thought to be involved in mediating various cellular functions including cell proliferation, cell death, chemotaxis and T-cell receptor signaling (PMID: 24714587, 28725226, 27711255, 28017968). Fusion proteins including DUSP22 are found in anaplastic large cell lymphomas negative for ALK-rearrangements (PMID: 21030553, 24805854, 26104084). These alterations are predicted to disrupt DUSP22 activity, suggesting that DUSP22 functions as a tumor suppressor (PMID: 27626696). True +ENST00000240100 NM_001394.6 1846 DUSP4 False DUSP4, a protein phosphatase, is deleted in a small subset of prostate and lung cancers. DUSP4 is a protein tyrosine/threonine phosphatase that regulates the mitogen-activated protein kinase (MAPK)/ERK pathway. DUSP4 negatively regulates the MAPK/ERK pathway by dephosphorylating ERK1/2 (PMID: 7535768). In addition, DUSP4 dephosphorylates substrates in the JNK pathway and mediates crosstalk between the JNK/JUN and MAPK/ERK pathways (PMID: 29795445). DUSP4 itself is a transcriptional target of MAPK-activated ERK1/2, and in turn inhibits ERK1/2 through a negative feedback mechanism, thus tempering MAPK-induced cell growth and proliferation (PMID: 22430215). DUSP4 expression has been found to be up- or downregulated in several cancer types; however, somatic mutations in DUSP4 are rare and have not yet been functionally characterized (PMID: 22965873, 22430215). DUSP4 loss has been associated with resistance to MEK inhibition, resulting in activation of associated signaling pathways (PMID: 29795445). True +ENST00000346618 NM_001949.4 1871 E2F3 True E2F3, a transcription factor that regulates the cell cycle, is altered by amplification and overexpression in a variety of cancer types. E2F3 (E2F transcription factor 3) is a member of the E2F family of transcription factors. E2F3 is related to E2F1 and E2F2 with which it shares similar DNA-binding, RB protein-binding, dimerization, and transcriptional activation domains (PMID: 8246996). E2F1-3 also bind induce transcription from to the same E2F recognition motifs in vitro and associate with RB. (PMID: 8246996). Additionally, E2F1-3 are considered inducers of gene expression and their transcription and proteasomal degradation are controlled in a cell cycle-dependent manner as opposed to the constitutively expressed transcriptional repressors E2F4-6 (PMID: 12748276). E2F proteins play overlapping roles in various processes, including DNA replication, progression through from G1 to S stages of the cell cycle, and cell-fate determination but they also appear to have certain distinct functions (PMID: 12748276, 9679057). The RB/E2F axis is considered a pivotal in activating DNA replication and G1/S transition in a manner dependent on RB's inhibitory effect on E2F proteins (PMID: 8246996, 11257102, 9365528). E2F3-specific activity includes TFE3 binding and DDX5 induction, mediation of MYC-induced transition to S phase (together with E2F2), and induction of specific target genes (PMID: 12748276, 10733529, 11511364) E2F3-deficient mice exhibit impaired growth and cell proliferation (PMID: 10733529). Amplification and subsequent overexpression of E2F3 has been observed in prostate and bladder cancer as well as lung cancer and metastatic urothelial carcinoma (PMID: 14716298, 15122326, 18037967, 16953223, 16938365, 15184867, 16909110, 24476821, 25886454). Also, E2F3 appears to be a target for the ETS fusions in certain cancers (PMID: 23940108). False +ENST00000313708 NM_024007 1879 EBF1 False EBF1, a transcription factor for B-cell development, is infrequently altered in cancer. EBF1 encodes for a transcription factor that regulates various processes associated with B-cell lymphopoiesis, transcription and activation (PMID: 20451411). EBF1 and PAX5 work synergistically to regulate B-cell expansion and lineage commitment via a MYC-dependent regulatory loop and other feedback loops (PMID: 33619557, 17101802). The oncogenic function of EBF1 may be tissue-specific. Knockdown of EBF1 in various cancer cell lines induces increased TERT promoter activity, cellular viability and cellular proliferation, suggesting that EBF1 functions predominantly as a tumor suppressor gene in these tissue-specific contexts (PMID: 32364535, 28555080). Downregulation of EBF1 has been identified in various cancer types, including acute lymphoblastic leukemia, colorectal cancer, gastric cancer, and cholangiocarcinoma (PMID: 17344859, 32676457, 29169115, 32364535). Conversely, overexpression of EBF1 in acute myeloid leukemia and breast cancer cell lines induces cellular proliferation, cellular migration, the inhibition of apoptosis and cell cycle progression, suggesting that EBF1 functions predominantly as an oncogene in these tissue-specific contexts (PMID: 35867755)(Abstract: Zhou et al. Abstract# 11486, Blood 2022. https://ashpublications.org/blood/article/140/Supplement%201/11486/490703/EBF1-Promotes-Cell-Proliferation-Migration-and). False +ENST00000270517 NM_016581 51295 ECSIT True ECSIT, a cytosolic adaptor protein, is infrequently altered in cancer. ECSIT is an adaptor protein that functions in the assembly of the mitochondrial complex I (PMID: 17344420). Mitochondrial complex I is the largest subunit of the respiratory chain, functioning in the electron transfer from NADH to ubiquinone as a proton pump for ATP synthesis (PMID: 13771349). ECSIT is directed by an N-terminal targeting sequence to localize to the mitochondria, allowing for interaction with chaperone protein NDUFAF1 and subsequent assembly and stabilization of mitochondrial complex I (PMID: 17344420). Other functions for ECSIT include activation of the inflammatory response through the Toll signaling pathway and embryonic development through the BMP signaling pathway (PMID: 10465784, 14633973). Overexpression of ECSIT in breast cancer cell lines and xenograft mouse models increases cell proliferation, migration and invasion, suggesting that ECSIT functions primarily as an oncogene (PMID: 35571656). Amplification of ECSIT has been identified in breast cancer and ovarian cancer (PMID: 35571656, 35131872). False +ENST00000367682 NM_001077706.2 345930 ECT2L False ECT2L, a protein of unknown function, is altered by mutation in T-cell precursor lymphoblastic leukemia. ECT2L is a protein with unknown function that shares sequence homology with RhoGEF proteins (PMID: 28541439). GEF (guanine nucleotide exchange factors) activate GTPases, which are enzymes that cycle between a GTP-bound active conformation and a GDP-bound inactive conformation. GTPases regulate downstream signaling pathways and are involved in a variety of cellular functions including proliferation, cell adhesion, and cell cycle progression, among others (PMID: 27301673). Additional functional work is required to determine the exact cellular function of ECT2L. Somatic mutations in ECT2L are found in patients with T-cell precursor acute lymphoblastic leukemia (PMID: 22237106). ECT2L alterations predominantly occur as missense, nonsense, and splice site mutations (PMID: 22237106), suggesting that ECT2L acts as a tumor suppressor. True +ENST00000263360 NM_003797.3 8726 EED False EED, a transcriptional repressor, is altered in malignant peripheral nerve sheath tumors and hematologic malignancies. EED (Embryonic Ectoderm Development) is a component of the Polycomb Repressive Complex 2 (PRC2) which is responsible for transcriptional repression by catalyzing di- and tri-methylation of Histone H3 lysine 27 (H3K27) (PMID: 16630818). The EED-EZH2 interaction is necessary for the histone methyltransferase activity of PRC2 (PMID: 23974116), which is important in regulating development and expression of cell identity genes, including the HOX cluster of genes (PMID: 16625203). EED interacts with the PRC1 complex to mediate histone H2A ubiquitination (PMID: 24457600), and germline mutations have been identified with an over-growth syndrome (PMID: 25787343). EED is mutated in malignant peripheral nerve sheath tumors, T-cell precursor acute lymphoblastic leukemia, and myeloid neoplasms (PMID: 25240281, 22237106, 23486531). Loss of PRC2 function can cooperate with Ras pathway signaling in cellular transformation and may sensitize tumor cells to bromodomain inhibitors (PMID: 25119042). True +ENST00000308874 NM_201446.2 51162 EGFL7 True EGFL7, a secreted pro-angiogenic factor, is infrequently mutated in various cancer types. EGFL7 (EGF-like-domain, multiple 7) is a signaling protein involved in EGFR signaling (PMID: 22160377). It is a secreted factor expressed in the endothelium during embryonic and neonatal development and has a proposed role in vasculogenesis and neural stem-cell renewal (PMID: 15085134, 19503073, 15085134, 22160377). EGFL7 expression has also been detected in adult human tissues (PMID: 18556249). Its role in cancer is unclear, but its ability to modulate angiogenesis and immune responses has been proposed to influence tumorigenesis (PMID: 22037871). Elevated expression of EGFL7 has been found in human tumors, including glioma, hepatocellular carcinomas, breast cancer and suggesting a potential role as a biomarker (PMID: 19503073, 19824075, 26328008, 23558933, 23404186). False +ENST00000275493 NM_005228.3 1956 EGFR True 1 R2 EGFR, a receptor tyrosine kinase, is altered by amplification and/or mutation in lung and brain cancers among others. EGFR (Epidermal Growth Factor Receptor) is a transmembrane receptor that is activated by EGF family extracellular ligands (PMID: 24691965). EGFR is a member of the ErbB family of receptors, including the receptors ERBB2, ERBB3, and ERBB4. Binding of EGFR by its ligands, including EGF ligands and transforming growth factor alpha (TGFα), activates downstream signaling pathways including the canonical MAPK and PI3K/AKT/mTOR signaling cascades (PMID: 22239438). EGFR can homodimerize or heterodimerize with other ErbB family members to initiate signaling (PMID: 25621509). Activation of EGFR-mediated signaling ultimately results in cellular proliferation, migration, and differentiation (PMID: 18045542). While EGFR usually is expressed at low levels in normal adult tissues, hyperactivation of this receptor by somatic mutations and/or amplification of the EGFR gene is found in many cancer types such as lung, brain, colorectal and head and neck cancer (PMID: 10880430, 17318210). In lung cancer, activating mutations in EGFR result in a constitutively activated form of the receptor that is sensitive to EGFR tyrosine kinase inhibition (PMID: 15329413). Tyrosine kinase inhibitors targeting EGFR, including afatinib, erlotinib, and gefitinib, have been approved for first-line treatment of non-small cell lung cancer patients (PMID: 14977817, 24868098, 26039556, 25963089). Second site resistance mutations in EGFR can occur in cancers previously treated with these inhibitors (PMID: 29068003). Osimertinib is a second-line tyrosine kinase inhibitor that has been FDA approved for relapsed patients with non-small cell lung cancer with the EGFR resistance mutations T790M, L858R, and exon 19 deletions (PMID: 27923840). Additionally, copy number amplification of the EGFR gene result in receptor overexpression in several cancer types, including brain and colorectal cancers, and these cancers may also be sensitive to EGFR inhibition (PMID: 11426640). R2 False +ENST00000239938 NM_001964.2 1958 EGR1 False EGR1, a transcription factor, is recurrently altered by mutation in lymphomas. EGR1 is a transcription factor that belongs to the EGR family of zinc finger proteins (PMID: 16138117). EGR1 stimulates the transcriptional activity of several key tumor suppressor genes including TGFβ1, PTEN, TP53, and fibronectin (PMID: 16138117). The activity of EGR1 is required to mediate several cellular functions induced by these tumor suppressors including growth control, differentiation, cell attachment and apoptosis (PMID: 16138117). EGR1 is also implicated in immune regulation; EGR1 expression is upregulated after T cell stimulation and mediates B cell development (PMID: 19915002, 18802061). In addition, EGR1 regulates the activity of CBP/p300 transcription coactivators in prostate cells (PMID: 15225550). Loss of EGR1 in preclinical models results in transformation, hematopoietic defects and increased tumor formation in murine models (PMID: 17420284). EGR1 expression has been found to be reduced in a variety of tumor types, suggesting that EGR1 functions as a tumor suppressor (PMID: 9212230). Somatic mutations in EGR1 are found in follicular lymphoma, chronic lymphocytic leukemia, B-cell lymphoma, and splenic marginal zone lymphomas (PMID: 24362818, 22158541, 22891273, 24145436). EGR1 alterations typically occur in the N-terminus and are predicted to be loss-of-function (PMID: 24362818). Conversely, EGR1 expression is overexpressed in prostate cancer and may function as an oncogene in that context (PMID: 12833142, 16138117). True +ENST00000242480 NM_001136177.1 1959 EGR2 False EGR2, a zinc-finger transcription factor, is altered in various cancer types. EGR2, a member of the early growth response (EGR) protein family, encodes a zinc-finger transcription factor that plays a crucial role in processing signals that regulate senescence, apoptosis and immune response (PMID: 11494141, 12687019, 28687085, 33547862). EGR2 plays a key role in the PTEN-induced apoptotic pathway, promoting apoptosis in various cancer cell lines by the direct transactivation of the mitochondrial proteins BNIP3L and BAK (PMID: 11494141, 12687019). EGR2 is also essential for anti-tumor immune system response by regulating the proliferation and survival of CD8+ tumor-infiltrating lymphocytes (TILs) (PMID: 36342511). Mutations in EGR2 are associated with demyelinating neuropathies such as Charcot-Marie-Tooth disorder (PMID: 22327514, 33547862, 12687019). In chronic lymphocytic leukemia, patients with EGR2 missense mutations have an unfavorable prognosis, potentially linked to dysregulated B-cell receptor signaling and hypomethylation of transcription factor binding sites (PMID: 27890934). EGR2 expression is negatively regulated by SFRP1 (secreted frizzled related protein 1), as loss of SFRP1 in epithelial cells enhances TGF-β-mediated EGR2 expression (PMID: 28687085). EGR2 expression is downregulated in breast and ovarian cancer and loss of function mutations in various cancer cell lines and models result in increased cellular proliferation and tumor growth (PMID: 34178038, 11494141). True +ENST00000379607 NM_001412.3 1964 EIF1AX False EIF1AX, a translation initiation factor, is most frequently altered by mutation in uveal melanomas and papillary thyroid carcinomas. EIF1AX (eukaryotic translation initiation factor 1A, X-linked) is a eukaryotic translation initiation factor. EIF1AX triggers the transfer of the methionyl initiator tRNA (Met-tRNAi)-eIF2-GTP ternary complex to the 40S ribosomal subunit (PMID: 16193068). This complex creates the 43S pre-initiation complex which binds to the capped 5'-end of mRNA and subsequently reads the mRNA until it finds the first AUG codon (PMID: 23873042). Mutations in EIF1AX have been observed in uveal melanomas with disomy 3 and are associated with an increased risk of metastasis (PMID: 23793026, 24970262). EIF1AX mutations have also been identified in some cases of papillary thyroid carcinoma and leptomeningeal melanocytic neoplasms (PMID: 25417114, 26769193). Alterations of the EIF1AX gene are predominantly missense mutations that alter the protein's highly conserved N-terminus, which is critical for the initiation of protein translation (PMID: 23793026, 16193068, 24970262). False +ENST00000424014 NM_001414 1967 EIF2B1 False EIF2B1, a subunit of the EIF2B guanine nucleotide exchange factor complex, is infrequently mutated in cancer. EIF2B1 is a subunit of EIF2B, a five-subunit guanine nucleotide exchange factor that plays a key role in mRNA translation regulation (PMID: 29425030, 18974117). The EIF2B five subunit complex is composed of EIF2B1, EIF2B2, EIF2B3, EIF2B4 and EIF2B5, which encode for the α, β, γ, δ and ε subunits, respectively (PMID: 29425030). EIF2B functions as the nucleotide exchange factor for the GTPase EIF2, which initiates translation by bringing methionyl-tRNA to the ribosome (PMID: 29425030). EIF2B complex activity is inhibited when EIF2 is phosphorylated by stress-induced kinases (PMID: 29425030). EIF2B1, along with subunits EIF2B2 and EIF2B4, forms the regulatory subcomplex of EIF2B (PMID: 24811713). EIF2B2 and EIF2B4 have been identified as essential to the translation initiation and nucleotide exchange activity with EIF2, whereas EIF2B1 is required for inhibiting translation (PMID: 29036434). EIF2B1 mutations disrupt the ability of EIF2B to sense phosphorylated EIF2, resulting in increased endoplasmic reticulum stress (PMID: 31882561). The stress conditions have been identified as a cause for patient liver dysfunction and leukoencephalopathy due to unregulated unfolded protein response and cell death (PMID: 31882561, 25761052). True +ENST00000220849 NM_001568 3646 EIF3E False EIF3E, a subunit of the EIF3 complex, is infrequently altered in cancer. EIF3E encodes for a subunit of the eukaryotic translation initiation factor 3 (EIF3) complex, which functions in the initiation of protein synthesis (PMID: 17581632). EIF3E regulates various cellular processes including cellular proliferation, DNA damage response repair and protein degradation through the regulation of translation and binding to other multiprotein complexes (PMID: 25849773, 22508697, 17324924). The oncogenic function of EIF3E may be tissue-specific. Overexpression of EIF3E in various cancer cell lines induces cellular proliferation, cellular invasion and tumor growth, suggesting that EIF3E functions predominantly as an oncogene in these tissue-specific contexts (PMID: 20453879, 25400724). EIF3E amplification has been identified in various types of cancer, including breast cancer, glioblastoma, colon cancer and oral cancer (PMID: 20453879, 24481065, 25400724, 25123227). Conversely, loss of EIF3E in other cancer cell line studies has shown induction of cellular senescence, increased mTORC1 signaling and epithelial-to-mesenchymal transition, suggesting that EIF3E also has tumor suppressive functions in these tissue-specific contexts (PMID: 33868586, 22907435). EIF3E downregulation has been identified in breast cancer and non-small cell lung cancer (PMID: 22907435, 15867213). Preclinical studies of breast cancer cells suggest that loss of EIF3E confers resistance to PARP inhibition (PMID: 33868586). False +ENST00000323963 NM_001967.3 1974 EIF4A2 True EIF4A2, a translation initiation factor, is infrequently altered in cancer. EIF4A2 (eukaryotic translation initiation factor 4A2) is a translation initiation factor required for binding of mRNA ribosomal subunits. EIF4A2 is one of three mammalian isoforms of EIF4A (EIF4A1-3) which are mRNA-dependent ATPases and RNA helicases and members of the DEAD-box family of proteins, a group of proteins named after their shared motifs with roles in various cellular processes (PMID: 10872469, 2563148). More specifically, EIF4A2 is an essential factor in the binding of mRNA to the 43S pre-initiation complex, a rate-limiting step and main target of translational control, in which EIF4A2 unwinds mRNA secondary structure to enable the ribosome to bind to a single-stranded molecule (PMID: 10872469). EIF4A2 and EIF4A1 are highly similar in sequence and function but appear to be expressed in spatiotemporally distinct patterns (PMID: 3046931, 8521730). EIF4A2 has also been implicated in micro-RNA-mediated gene regulation (PMID: 23559250). Downregulation of EIF4A2 expression has been observed in non-small cell lung cancer and correlates with poor prognosis, but mutations in EIF4A2 are rare in human tumors (PMID: 23867391). False +ENST00000280892 NM_001130678.1 1977 EIF4E True EIF4E, a translation initiation factor, is overexpressed in various cancer types. EIF4E (eukaryotic translation initiation factor 4E ) is a component of the eukaryotic translation initiation factor 4F (eIF4F) complex. The eIF4F complex additionally consists of an EIF4A isoform and EIF4G and directs the ribosome to the 5' 7-methylguanosine cap of mRNAs in what is considered a rate-limiting step of translation (PMID: 291969, 3469651). As a vital part of translation initiation, EIF4E controls cellular size and is thought to be a direct target of mTOR, which can phosphorylate the translational repressor 4EBP1, allowing for EIF4E to enter the eIF4F complex (PMID: 12080086). Overexpression of EIF4E has been detected in tumors of the breast, bladder, colon, lung, and cervix and can cause malignant transformation in in vitro studies (PMID: 9330633, 9285563, 8244582, 7829225, 25986608, 10638984, 11401917, 12374671, 16260273, 16280668, 20049173). Furthermore, EIF4E exhibits oncogenic traits in a mouse model of lymphoma and is implicated in drug resistance both in contexts of mTOR, BRAF, and MEK targeting (PMID: 15029198, 16103051, 25079330, 25422161, 25615552). Thus, EIF4E is considered a therapeutic target in certain tumor types on the principles that translational control often is deregulated in cancer cells and that PI3K and mTOR signaling and MAPK-interacting kinases (MNKs) are involved in this process (PMID: 22474009, 25743081, 25425688). A variant in the promoter region of EIF4E has been identified in two families with autistic children (PMID: 19556253). False +ENST00000359651 NM_004433.4 1999 ELF3 True ELF3, a transcriptional activator, is altered by mutation or amplification in various cancer types. ELF3 is a member of the ETS-family of transcription factors. ELF3 binds ETS-consensus sequences present in many gene promoters, either activating or repressing their transcription in physiological conditions (PMID: 21548782, 10773884). ELF3 both activates NF-κB-mediated inflammatory pathways and represses androgen receptor signaling in prostate cancers, leading to cancer progression and increased cell migration, respectively (PMID: 23687337, 23435425). ELF3 regulates β-catenin transcription in colorectal cancer (PMID: 24874735). and plays an important role in the mammary gland (PMID: 10959418). Amplification of ELF3 is a frequent events in breast cancer (cBioPortal, MSKCC, Nov 2016), and oncogenic inactivating mutations in ELF3 have also been identified in ampullary cancers (PMID: 26806338). True +ENST00000308167 NM_001127197 2000 ELF4 True ELF4, a transcription factor, is infrequently altered in cancer. ELF4 encodes for a transcription factor that functions in the transcriptional activation of the hematopoietic growth factor genes CSF2, IL-3, IL-8 and PRF1 (PMID: 16530702, 8895518, 10207087, 14625302, 14976184). ELF4 regulates innate immunity by promoting the development of natural killer cells and CD8+ T-cells and suppressing the inflammatory response of macrophages, Th17 cells and various pro-inflammatory cytokines (PMID: 34326534, 35266071). The oncogenic function of ELF4 is likely tissue-specific. Overexpression of ELF4 in various cancer cell lines and models induces cellular proliferation, colony formation and tumor growth, suggesting that ELF4 functions predominantly as an oncogene in these contexts (PMID: 17213815, 36923538). ELF4 amplification has been identified in various types of cancer, including acute myeloid leukemia and esophageal adenocarcinoma (PMID: 33836003). Conversely, overexpression of ELF4 in lung adenocarcinoma, squamous cell carcinoma and endometrial carcinoma cell lines suppressed cellular growth and invasiveness, suggesting that ELF4 may have tumor suppressive function in these tissue-specific contexts (PMID: 12438253, 26921333). False +ENST00000357992 NM_001973 2005 ELK4 True ELK4, a transcription factor, is infrequently altered in cancer. ELK4, a member of the ETS transcription factor family and ternary complex factor subfamily, encodes for a transcription factor that functions in regulating various cellular processes such as proliferation and homeostasis through transcriptional activation and repression (PMID: 20637912, 37529050, 24758171). ELK4 regulates the KDM5A-PJA2-KSR1 axis through transcriptional activation of KDM5A to promote macrophage M2 polarization (PMID: 34372882). Overexpression of ELK4 in gastric cancer and melanoma cell lines and xenograft models induces increased cellular proliferation, migration and invasion through M2 polarization of macrophages, suggesting that ELK4 functions predominantly as an oncogene (PMID: 34372882, 26028036). ELK4 amplification has been identified in various types of cancer, including gastric cancer, glioma and breast cancer (PMID: 34663788, 21846680, 16457699). False +ENST00000262809 NM_006532 8178 ELL True ELL, an elongation factor, is altered by chromosomal translocations in hematological malignancies. ELL encodes for an elongation factor that functions in increasing the catalytic rate of RNA polymerase II through suppression of transient pausing (PMID: 8596958). ELL co-localizes with transcription factor regulators EAF1 and EAF2 within the nucleus to promote elongation activity (PMID: 16006523). Overexpression of ELL in RAT1 fibroblast cells induces anchorage-independent cellular growth and decreased dependence on growth factors, suggesting that ELL functions predominantly as an oncogene (PMID: 9478981). ELL has been identified as a recurrent fusion partner with the gene KMT2A (also known as MLL) in acute myeloid leukemia and other hematological malignancies (PMID: 10995463, 26185637, 26949571, 33608309). False +ENST00000237853 NM_012081.5 22936 ELL2 True ELL2, a transcription elongation factor, is altered in various cancer types. ELL2, an elongation factor for RNA polymerase II (RNA Pol II), is a member of the eleven-nineteen lysine-rich (ELL) family (PMID: 31511829, 28870994, 32606936). The ELL family proteins are part of the transcription super elongation complex (SEC) which enhances the catalytic rate of RNA Pol II transcription by suppressing transient pausing along the DNA strand, thereby facilitating the transcription process (PMID: 31511829, 28870994, 32606936). ELL2 cooperates in the SEC with positive transcription elongation factor b (P-TEFb), ELL-associated factors (EAFs), AFF family members (AFF1-4) and YEATS domain-containing protein family members (AF9 or ENL) (PMID: 28858629, 28870994, 29179998). ELL2 is also a component of the little elongation complex (LEC), which is involved in RNA Pol II transcription of small nuclear RNA genes (PMID: 31511829, 28870994). ELL2 plays a role in the differentiation of plasma cells where it is highly expressed and contributes to plasma cell immunoglobulin secretion by stimulating alternative RNA processing linked to histone methylation (PMID: 28903037, 28858629, 28870994). Likely due to its role in differentiation, reduced ELL2 expression in plasma cells has been documented in patients carrying the multiple myeloma risk allele at 5q15 (PMID: 29695719, 28903037). The consequence of ELL2 expression in other tissues is mixed. Increased ELL2 expression is associated with glioblastoma progression and poor prognosis (PMID: 28531325). ELL2 is highly expressed in the prostate and functions as an androgen response gene (PMID: 28870994). In patients with androgen receptor (AR)-positive prostate adenocarcinoma, ELL2 has been observed to be downregulated, while in patients with AR-negative neuroendocrine prostate cancer ELL2 is upregulated (PMID: 28870994, 29179998, 32606936). True +ENST00000252034 NM_001278915 2006 ELN True ELN, an extracellular matrix protein, is infrequently altered in cancer. ELN encodes for the structural subunit tropoelastin, the soluble precursor of the structural protein elastin that functions as a major component in the elastic fibers that support connective tissues (PMID: 16982180, 21368178). ELN is an extracellular matrix protein and provides dynamic structural support for elasticity in all tissues (PMID: 23273220). Protease-driven elastin degradation can occur during cancer progression at the extracellular matrix and lead to the generation of bioactive fragments and elastin-derived peptides, which further promote tumorigenesis through promoting chemotaxis and cellular proliferation (PMID: 18076073, 20959825, 12244048). Expression of ELN and elastin-derived peptides in various types of cancer cell lines and models induces epithelial-to-mesenchymal transition and increases cellular invasion, migration and proliferation, suggesting that ELN functions predominantly as an oncogene (PMID: 32171282, 30186741, 20959825). ELN amplification has been identified in various types of cancer, including gastric cancer and colorectal cancer (PMID: 36226731, 22606006, 32171282). False +ENST00000284811 NM_005648.3 6921 ELOC False ELOC encodes a protein that is a component of the VHL ubiquitination complex. A hotspot mutation of ELOC is associated with a distinct subtype of renal cell carcinoma. The ELOC (transcription elongation factor B polypeptide 1) gene encodes the elongin C protein, a subunit of the transcription factor B protein complex which activates RNA elongation during transcription (PMID: 7660129). ELOC is also part of the elongin BC complex, which functions as an E3 ubiquitin ligase and includes the Von-Hippel Landau (VHL) tumor suppressor, TCEB2 (elongin B), CUL2 or CUL5 and RBX1 (PMID: 25298778). Under normoxic conditions, this complex targets the hypoxia inducible factor, HIF1A, for ubiquitination and degradation, thus preventing a hypoxic response (PMID: 23797736). However, dysregulation of this complex, including inactivation of VHL or ELOC, can lead to HIF1A accumulation and a pseudohypoxic response, even under normoxic conditions (PMID: 25298778). ELOC-mutated renal carcinomas are molecularly distinct from conventional clear cell renal cell carcinomas, and lack both VHL mutations and chromosome 3p loss (PMID: 25676555, 23797736). False +ENST00000334736 NM_020193 56946 EMSY True EMSY, a BRCA2-associated transcriptional repressor protein, is altered by amplification in breast cancer and ovarian cancer. EMSY encodes for a transcriptional repressor nuclear protein that associates with BRCA2 and functions in DNA damage response and chromatin remodeling (PMID: 16615912, 17940002). EMSY associates to BRCA2 by binding with the ENT domain and suppresses the activation domain of BRCA2 (PMID: 15978617). EMSY represses the transcription of interferon-stimulated genes (PMID: 23117821). Overexpression of EMSY in breast cancer and ovarian cancer models induces chromosomal instability and mimics BRCA2 loss-of-function mutations, suggesting that EMSY functions predominantly as an oncogene (PMID: 14651845, 21409565, 16145051, 21735447). EMSY amplification has been identified in breast and ovarian cancers (PMID: 21735447, 14651845). False +ENST00000263253 NM_001429.3 2033 EP300 False EP300, a tumor suppressor and histone acetyltransferase, is inactivated in various cancer types. EP300 (p300; E1A-binding protein) is a transcriptional co-activator with histone acetyltransferase (HAT) activity that is homologous to the co-activator CREBBP. EP300 activates transcription by opening chromatin at gene promoters, recruiting transcriptional machinery and acting as a co-factor to recruit transcription factors (PMID: 15186775, 24480624, 11050151, 23474763, 15691758). The HAT activity of EP300 can also regulate the expression of other proteins, including the tumor suppressor p53 and tissue-specific transcription factors like GATA1 (PMID: 9830059, 9859997). Fusion proteins that include the EP300 HAT domain have been identified in rare cases of acute lymphoblastic leukemias (PMID: 25943178). Somatic mutations in EP300 are found in leukemia, lymphoma and solid tumors including small-cell lung cancer, cervical cancer and bladder cancer (PMID: 21390126, 22941188, 24390348, 21822268). EP300 mutations are commonly truncating and often co-occur with loss of the wildtype allele, suggesting that EP300 functions as a tumor suppressor. Small molecule inhibitors targeting EP300 have been found to be efficacious in preclinical and mouse studies (PMID: 26731516). True +ENST00000389561 NM_015409.3 57634 EP400 False EP400, a chromatin remodeling protein, is infrequently altered by mutation in bladder cancer and lymphomas. EP400 is a chromatin remodeling ATPase that functions as a subunit in the TIP60 histone acetyltransferase complex (PMID: 18614019). The TIP60-EP400 chromatin remodeling complex binds at gene promoters and facilitates histone acetylation in order to regulate gene expression and epigenetic state (PMID: 18614019). EP400 is bound at promoters and enhancers enriched with H2AZ and H3.3 histone variants (PMID: 26669263). Loss of EP400 expression results in depletion of H2AZ and H3.3 transcription and deposition on chromatin (PMID: 26669263). EP400 also preferentially binds to H4Kme3-modified histones and regulates the transcription of those genes (PMID: 26814966). Due to the global regulation of gene expression and chromatin state, EP400 activity is required for embryonic stem cell maintenance, regulation of cell cycle, and the DNA damage/repair pathways (PMID: 18614019, 15655109, 27814680). In MYC-altered lymphomas, there is evidence that alternative splicing events occur at EP400 (PMID: 25970242). Somatic mutations in EP400 are infrequent in human cancers; however, alterations have been identified in bladder cancer and childhood lymphoblastic leukemia (PMID: 26625313, 23508829). True +ENST00000263734 NM_001430.4 2034 EPAS1 False EPAS1, a hypoxia-related transcription factor, is mutated or amplified in a small subset of human cancers. EPAS1 (also HIF2α) is a transcription factor that regulates gene expression in conditions of oxygen deficiency (PMID: 11301389). HIF2α binds the hypoxia response element (HRE) present in the promoter of genes that are regulated in the context of reduced oxygen (hypoxia), such as the vascular endothelial growth factor (VEGF) gene (PMID: 11301389). Under normal oxygen conditions, HIF2α is hydroxylated and recognized by the tumor suppressor VHL, leading to ubiquitination and degradation via the proteasome (PMID: 18498744). Under hypoxic conditions, HIF2α escapes degradation and activates genes involved in the hypoxia response, including genes involved in angiogenesis, glycolysis, apoptosis, proliferation and growth (PMID: 22089927, 14645546). HIF2α activity has been implicated in angiogenesis and oncogenesis in neuroendocrine tumor models (PMID: 23533246, 26432405). Gain-of-function EPAS1 mutations are found in pheochromocytomas and paragangliomas, which are rare neuroendocrine tumors where conditions of pseudo-hypoxia occur (PMID: 22931260, 24741025, 23418310). Although HIF inhibitors have been proposed for cancer treatment, the complex and often contradictory roles of these factors suggest careful evaluation (PMID: 22169972). False +ENST00000263735 NM_002354.2 4072 EPCAM False EPCAM, a transmembrane glycoprotein, is overexpressed in various cancer types. EPCAM (epithelial cell adhesion molecule) is a type I transmembrane glycoprotein that is expressed on normal epithelial cells and has important roles in cell signaling, migration, proliferation and differentiation. It functions as a transmembrane glycoprotein that specifically mediates epithelial-specific intercellular cell adhesion (PMID: 21576002). Germline deletions in the EPCAM gene cause Lynch syndrome via epigenetic silencing of MSH2 (MutS protein homolog 2), leading to a predisposition to primarily colorectal and endometrial cancers (PMID: 19098912). EpCAM is also overexpressed in certain types of solid tumors, though its role in this setting is not fully understood. The bi-specific antibody catumaxomab targets both EpCAM and the T-cell antigen CD3 in an attempt to recruit and activate immune effector cells at the tumor site (PMID: 11588051) and is approved for malignant ascites in patients with EPCAM-positive cancers (PMID: 20473913). True +ENST00000336596 NM_005233.5 2042 EPHA3 False EPHA3, a receptor tyrosine kinase, is altered in various cancer types including skin and lung cancers. EPHA3 (ephrin receptor A3) is a receptor tyrosine kinase that preferentially binds glycosylphosphatidylinositol (GPI)-anchored ephrins resulting in activation of downstream signaling pathways that control cell adhesion, cell migration, cells spreading and proliferation (PMID: 11870224). EPHA3 is highly expressed during embryonic development (PMID: 10197531, 9883737, 25391995) and is overexpressed in various cancer types, including sarcoma, leukemia, glioblastoma and hepatocellular cancer (PMID: 25391995, 23410976, 28415715, 2792259 ). EPHA3 loss-of-function mutations have been identified in various cancer types including lung cancer, melanoma and non-melanoma skin cancers resulting in decreased EPHA3 signaling and enhanced cellular proliferation (cBioPortal, MSKCC, Sept. 2017) (PMID: 22829656, 22242939). True +ENST00000273854 NM_004439.5 2044 EPHA5 False EPHA5, a receptor tyrosine kinase, is altered in various cancer types including skin and lung cancers. EPHA5 is a member of the Eph receptor tyrosine kinase family. Unique from its family members, EPHA5 is almost exclusively expressed in the nervous system—specifically in cortical neurons, cerebellar Purkinje cells and pyramidal neurons of the cortex and hippocampus (PMID: 10375373, 7898646, 9191074). EPHA5 plays a major role in brain development, from neurogenesis to plasticity (PMID: 19326470, 20824214, 9530499, 9698392, 9321686). In addition to its role in the nervous system, EPHA5 mediates communication between pancreatic islet cells, thereby regulating glucose-stimulated insulin secretion (PMID: 17448994). Downregulation of EPHA5 due to promoter methylation has been observed in both breast and prostate cancer, and it has been suggested that EPHA5 might represent a biomarker for diagnosis and prognosis of these tumor types (PMID: 19733895, 25609195). Aberrant methylation of the EPHA5 promoter was observed in 91% of cases of acute lymphoblastic leukemia, in particular in older patients (PMID: 23757320). Increased expression and somatic mutations of EPHA5 have been observed in ovarian cancer, pancreatic ductal adenocarcinoma and lung cancer, among others (PMID: 25623065, 19949912, 19956396, 25634010). False +ENST00000369303 NM_004440.3 2045 EPHA7 True EPHA7, a receptor tyrosine kinase, is altered by mutation or deletion in various cancer types, most frequently in skin cancers. EPHA7 (ephrin receptor A7) is a part of the subfamily of the protein-tyrosine kinase family and preferentially binds glycosylphosphatidylinositol (GPI)-anchored ligands. EPHA7 is composed of one tyrosine kinase domain and an extracellular domain that contains a ligand-binding domain, a cysteine-rich domain, and two fibronectin type III repeats (PMID 10197531, 9883737). EPHA7 structurally resembles other members of the Eph family and is associated with promoting cellular transformation, invasion, and proliferation through the JAK2 signaling pathway (PMID: 24003208, 20179713, 22862837). Differential expression levels of EPHA7 and diverse roles in carcinogenesis have been shown in various cancer types (PMID: 26160986). Studies have shown overexpression of EPHA7 in glioblastoma, breast, and gallbladder adenocarcinoma, which promotes cell proliferation and migration through the FGFR1 signaling pathway and is correlated with poor prognosis (PMID 18790757, 15147954, 18366728). Other studies have shown downregulation of EPHA7 by hypermethylation in gastric, colorectal, esophageal squamous cell and prostate cancers, as well as in follicular lymphomas; and its association with tumor progression (PMID 17669470, 16007213, 26160986, 18821581, 29022918, 22036564). True +ENST00000398015 NM_004441.4 2047 EPHB1 True EPHB1, a receptor tyrosine kinase, is altered by mutation in various cancer types. EPHB1 is a transmembrane receptor tyrosine kinase that is a member of the ephrin (EPH) protein family (PMID: 31297055). EPH receptors bind to ephrin ligands on adjacent cells, resulting in cell interaction-dependent bidirectional signaling, which activates forward signaling in cells expressing the EPH receptor and reverse signaling in ligand presenting cells (PMID: 31297055). EPHB1 is a marker of venous endothelial cells and has been found to mediate signaling in a variety of contexts including in cell positioning of colorectal cells (PMID: 12408869, 21235905). EPHB signaling has been implicated in a variety of other cellular processes including immune regulation, epithelial integrity, invasion, cell shape, cellular proliferation and axon guidance (PMID: 12408869, 18424888, 31297055, 26790531, 23669443, 21514363). Differential EPHB1 signaling has been associated with inflammatory intestinal disorders, such as Crohn’s disease (PMID: 15996027). The oncogenic function of EPHB1 is likely tissue-specific. Somatic mutations in EPHB1 are found in patients with metastatic colorectal cancer (PMID: 12408869). These mutations are predicted to be loss-of-function and disrupt epithelial cell adhesion and cellular compartmentalization, leading to metastatic progression (PMID: 12408869). Reduced expression of EPHB1 has also been detected in a variety of cancers including colorectal, gastric, and ovarian cancer, among others (PMID: 18931529, 18424888). Knockdown of EPHB1 in various cell models suppresses cellular proliferation and migration, suggesting that EPHB1 functions predominantly as an oncogene in these contexts (PMID: 25879388, 32368295). Amplification of EPHB1 has been identified in various types of cancer, including lung cancer and gastric cancer (PMID: 32368295, 24716914, 32509099). True +ENST00000358173 NM_004444 2050 EPHB4 True EPHB4, a transmembrane receptor kinase, is infrequently altered in cancer. EPHB4, a member of the ephrin family of receptors, encodes for a transmembrane receptor kinase that functions primarily in regulating angiogenesis, erythropoiesis and vasculogenesis (PMID: 10518221, 16424904, 10603345). EFNB2 binds to EPHB4 to activate the bi-directional ephrin signaling pathway and triggers a signaling cascade for cellular motility by either attracting or repelling cells (PMID: 31949258). Overexpression of EPHB4 in various cancer cell lines and models induces increased cellular survival and tumor growth, suggesting that EPHB4 functions predominantly as an oncogene (PMID: 16816380, 29296810, 15153337, 26073592). Amplification of EPHB4 has been identified in various types of cancer, including breast cancer, lung cancer and esophageal squamous cell cancer (PMID: 16816380, 31934189, 31885720). False +ENST00000222139 NM_000121.3 2057 EPOR True EPOR, a cytokine receptor, is recurrently altered by chromosomal rearrangement in familial erythrocytosis and acute lymphoblastic leukemia. EPOR is a type I cytokine receptor that binds erythropoietin (EPO) (PMID: 17721432, 17124066). EPO initiates red blood cell production by binding EPOR, which is expressed predominantly on erythroid progenitors (PMID: 21307776). EPO-engagement of EPOR results in activation of the non-receptor tyrosine kinase JAK2, leading to the recruitment and phosphorylation of downstream effectors, such as STAT3 and STAT5 (PMID: 17721432, 17124066). Subsequent phosphorylation of STAT proteins enables the translocation of these signaling molecules to the nucleus to activate transcription (PMID: 17721432). EPO-mediated activation of JAK-STAT signaling regulates several cellular functions including proliferation, erythroid differentiation, and apoptosis (PMID: 12239135). Mice lacking expression of EPOR have defective primitive and definitive erythropoiesis, resulting in embryonic lethality (PMID: 23894012, 12239135). Germline EPOR gain-of-function mutations have been identified in patients with familial erythrocytosis and congenital polycythemia (PMID: 8506290, 7795221, 24115288, 27982410). Recurrent EPOR fusion proteins are found in patients with acute lymphoblastic leukemia that results in truncated, active EPOR molecules (PMID: 22897847, 28972016, 26859458, 27870571). Expression of truncated EPOR proteins in hematopoietic assays results in EPO hypersensitivity and transformation (PMID: 26859458). EPOR alterations result in hyperactive JAK-STAT signaling and sensitivity to small molecule JAK2 inhibition (PMID: 26859458). False +ENST00000269571 NM_004448.2 2064 ERBB2 True 1 ERBB2, a receptor tyrosine kinase, is altered by mutation, amplification and/or overexpression in various cancer types, most frequently in breast, esophagogastric and endometrial cancers. ERBB2 (also HER2) is a transmembrane receptor that is a member of the ERBB family of receptor tyrosine kinases, including EGFR, ERBB3, and ERBB4. ERBB2 does not directly bind its own ligand; instead, it potentiates the activity of other ligand-bound ERBB receptors by binding to them (PMID: 12620236). ERBB2 can heterodimerize with any of the other EGFR family receptors (PMID: 10220407, 9130710) initiating downstream signaling activation of several pathways including the MAPK and PI3K/AKT/mTOR signaling cascades (PMID: 22239438, 12853564). ERBB2 can also homodimerize and initiate MAPK, SRC, PI3K and STAT signaling (PMID: 22785351). Activation of ERBB2-mediated signaling ultimately results in cellular proliferation, migration, and differentiation (PMID: 18045542). ERBB2 is activated by gene amplification and overexpression in a range of human cancers including breast, gastric, and endometrial tumors, among others (PMID: 19536107, 24656976). ERBB2 gene amplification in human breast cancers is associated with poor overall survival and time to tumor recurrence (PMID: 3798106, 23000897,9552035, 9469329). Amplified ERBB2 heterodimerizes with ERBB3 to activate oncogenic signaling and drives tumorigenesis in breast cancer (PMID:12853564, 23204226, 12124352, 18632642). Somatic mutations in ERBB2 have been identified in a series of tumors including lobular breast, lung adenocarcinoma, and gastric cancers, among others, with recurrent hotspot alterations in both the extracellular and kinase domains (PMID: 23000897, 23220880, 22908275). Preclinical and clinical studies have demonstrated that many of these mutations are transforming and sensitive to FDA-approved ERBB targeted therapies, including trastuzumab, ado-trastuzumab emtansine, lapatinib, and pertuzumab (PMID:24799465). False +ENST00000267101 NM_001982.3 2065 ERBB3 True ERBB3, a receptor tyrosine kinase, is altered by mutation or amplification in various cancer types. ERBB3 (also HER3) is a transmembrane receptor that is a member of the ERBB family of receptor tyrosine kinases, including EGFR, ERBB2, and ERBB4 (PMID: 19536107, 11252954, 19208461). ERBB3 is unique in that it has limited kinase activity, approximately 1000 fold less than its family member, EGFR (PMID: 8389462, 8058764, 20351256). Thereby, ERBB3 cannot form homodimers (PMID: 15225657) and must heterodimerize with other ERBB family members to initiate downstream signaling (PMID: 8632008). Heterodimerization of ERBB3 with its preferred heterodimer partner, ERBB2, results in activation of several signaling pathways, including the MAPK, PI3K/AKT/mTOR, SRC, and STAT pathways (PMID: 7515147, 8026468, 8264617). Preclinical models of ERBB2-amplified cancers demonstrate that ERBB2-amplified cells exquisitely rely on ERBB3 to drive proliferation and survival (PMID: 12853564, 24651011, 19536107). Moreover, ERBB3 feedback upregulation, localization changes, and ligand overexpression contribute to resistance to ERBB or PI3K/AKT/mTOR inhibitors (PMID: 24520092, 24651011, 19536107). Overexpression of ERBB3 has been correlated with tumor progression and poor prognosis in some human cancers (PMID: 20179223, 20816829). Somatic activating mutations in ERBB3 are found in gastric, bladder, uterine and colorectal cancers, among others (PMID: 23680147). While that are no FDA-approved inhibitors for ERBB3-mutated cancers, preclinical and clinical trials are underway to determine if ERBB targeting compounds alone or in combination with other inhibitors targeting the MAPK pathway are efficacious. False +ENST00000342788 NM_005235.2 2066 ERBB4 True ERBB4, a receptor tyrosine kinase, is altered at low to moderate frequencies in various cancer types, most frequently in melanoma and lung cancer. ERBB4 (also HER4) is a transmembrane receptor that is a member of the ERBB family of receptor tyrosine kinases, including EGFR, ERBB2, and ERBB3 (PMID: 14504474, 9208852, 22427524, 25492965). Binding of ERBB4 by its ligands, including neuregulins (NRG1-4), betacellulin (BTC), HB-EGF or epiregulin (EPR), activates the receptor and initiates downstream signaling pathways including the canonical MAPK and PI3K/AKT/mTOR signaling cascades. ERBB4 forms active kinase dimers with other ERBB isoforms, including the preferential binding partner ERRB2 (PMID: 9130710, 10220407,19208461, 11252954). Somatic activating mutations in ERBB4 have been identified in melanoma (PMID: 22817889, 22842228, 24755198), lung adenocarcinoma (PMID: 18948947), gastric (PMID: 25079317, 25583476), and colorectal cancers (PMID: 22895193); however, the role of ERBB4 in cancer is not well established. Evidence in breast cancer cell lines suggests that ERBB4 is not required for mediating tumorigenesis in ERBB2-positive breast cancer but rather for mediating resistance to ERBB2 inhibitors (PMID: 25590338). Conversely, a subset of literature points to a growth-suppressive role for ERBB4 in breast cancer (PMID: 17120616, 24791013, 16832345, 20603612). The prognostic value of ERBB4 expression in cancer is still debatable, as reports have documented both better and worse outcomes in these tumors; however, this may be due to the lack of discrimination between ERBB4 variants (PMID: 25492965, 18454307). False +ENST00000360905 NM_178040 23085 ERC1 True ERC1, a scaffold protein, is altered by chromosomal rearrangement in various cancers. ERC1, a member of the RIM-binding protein family, encodes for a scaffold protein that functions in regulating the motility and migration of cells by promoting focal adhesion turnover (PMID: 24982445, 27659488). ERC1 associates with the scaffold proteins PPFIA1, also known as liprin-alpha-1, and LL5β to form plasma membrane-associated platforms (PMAPs) on the cellular membrane to support protrusion, cellular motility and invasion (PMID: 37437062). ERC1 is a regulatory subunit of the IKK complex and promotes NF-κB expression by recruiting IκBα to the complex (PMID: 15218148). Overexpression of ERC1 in A549 and HEK293T cells activates NF-kB and other proinflammatory genes as well as increases cellular migration, suggesting that ERC1 functions predominantly as an oncogene (PMID: 37252973). Fusions involving ERC1 have been identified in various types of cancer, including pancreatic cancer and lung adenocarcinoma (PMID: 34733735, 35712652). False +ENST00000300853 NM_001983 2067 ERCC1 False ERCC1, an endonuclease involved in DNA repair, is infrequently altered in cancer. Germline mutations of ERCC1 are associated with Fanconi anemia, Cockayne syndrome and xeroderma pigmentosum, and predispose to certain cancers. ERCC1 encodes for a DNA endonuclease protein which functions primarily in nucleotide excision repair and interstrand crosslink repair of DNA (PMID: 8811092). ERCC1 interacts with endonuclease ERCC4 to form the ERCC1-XPF DNA repair complex (PMID: 23623389). The ERCC1-XPF nuclease is essential for the DNA nucleotide excision repair pathway (PMID: 10320375). Hereditary mutations in ERCC1 have been identified in skin-photosensitive and DNA repair deficient disorders including xeroderma pigmentosum, Cocakyane syndrome and Fanconi Anemia (PMID: 23623389). Somatic ERCC1 mutations are rare in cancer, however ERCC1 polymorphisms have been identified to predispose to certain cancers (PMID: 29544698, 26022132, 29752341). ERCC1 polymorphisms are associated with increased chemosensitivity due to deficiencies in DNA repair pathways (PMID: 34148553, 37141338, 28032496). True +ENST00000391945 NM_000400.3 2068 ERCC2 False 3A ERCC2, a DNA helicase involved in the nucleotide excision repair (NER) pathway, is frequently altered in bladder cancer. Germline mutations of ERCC2 are associated with xeroderma pigmentosum, trichothiodystrophy and Cockayne syndrome, and predispose to certain cancers. ERCC2 is a DNA helicase that is a member of the RAD3/XPD family of protein helicases. ERCC2 is a regulator of the nucleotide excision repair (NER) pathway; NER is used by cells to repair bulky DNA lesions that are caused by environmental mutagens, UV irradiation and certain chemotherapeutic agents, such as cisplatin (reviewed in PMID: 24086042). ERCC2 functions as an ATP-dependent 5' to 3' helicase that unwinds damaged DNA, enabling other NER factors to access the DNA for subsequent repair (PMID: 9351836). Germline mutations of ERCC2 lead to trichothiodystrophy, xeroderma pigmentosum and combined xeroderma pigmentosum and Cockayne syndrome (reviewed in PMID: 19809470). Genetic polymorphisms of ERCC2 are associated with an increased risk of certain cancers, including lung (PMID: 20651612), colorectal cancer, esophageal squamous cell carcinoma (PMID: 16707649) and urothelial cell carcinoma (PMID: 24347488). Somatic ERCC2 mutations occur in approximately 12% of muscle-invasive bladder cancer and have been associated with response to cisplatin-based chemotherapy and checkpoint inhibition (PMID: 24476821, 25096233, 29489427). True +ENST00000285398 NM_000122.1 2071 ERCC3 False ERCC3, a tumor suppressor and helicase involved in DNA repair, is infrequently altered in cancer. Germline mutations of ERCC3 are associated with Cockayne's syndrome, xeroderma pigmentosum and trichothiodystrophy, and may predispose to breast cancer. ERCC3 is an ATP-dependent DNA helicase which is an essential component of the transcription factor II H(TFIIH) complex. ERCC3 functions to unwind the DNA double helix which is required as part of the nucleotide-excision repair (NER) pathway (PMID: 21571596, 8465201, 8107888, 21571596). The TFIIH transcriptional complex also requires activity of ERCC3 for initiation of transcription (PMID: 8152490, 7613092, 8166891). Hereditary ERCC3 mutations are found in individuals with Cockayne's syndrome and trichothiodystrophy (PMID: 4811796, 8408834, 8304337,16947863, 9012405, 23562818). Mutations in ERCC3, likely impairing transcriptional function, have been identified in patients with xeroderma pigmentosum B, a condition resulting in sensitivity to sunlight and increased skin-cancer risk (PMID: 10064601). Loss-of-function ERCC3 truncating mutations have been associated with breast cancer risk, likely due to defects in DNA repair pathways (PMID: 24508195, 27655433). True +ENST00000311895 NM_005236.2 2072 ERCC4 False ERCC4, a tumor suppressor and endonuclease involved in DNA repair, is infrequently altered in cancer. Germline mutations of ERCC4 are associated with Fanconi anemia, Cockayne syndrome and xeroderma pigmentosum, and predispose to certain cancers. ERCC4 (also known as XPF) is a DNA endonuclease protein that is active when in a complex in ERCC1 (PMID: 22101340, 9525876). The ERCC4-ERCC1 complex is required to cut at the junction between double stranded and single stranded DNA and has important functions in nucleotide excision repair, DNA double-strand break repair, and DNA interstrand crosslinks repair (PMID: 22101340, 9525876). Hereditary mutations in ERCC4 have been identified in skin-photosensitive and DNA repair deficient disorders including xeroderma pigmentosum, Cocakyane synrome, XFE progeroid syndrome and Fanconi Anemia (PMID: 23623386, 23623389). Somatic ERCC4 mutations are rare in cancer, however, loss-of-function germline ERCC4 mutations can cause a predisposition for cancer (PMID: 22941649, 24465539). ERCC4-mutant cell are sensitive to DNA damaging reagents due to deficiencies in DNA repair pathways (PMID: 26074087). True +ENST00000355739 NM_000123.3 2073 ERCC5 False ERCC5 is a tumor suppressor and an endonuclease involved in DNA repair. Germline mutations of ERCC5 are associated with xeroderma pigmentosum and Cockayne's syndrome, which predispose to certain cancers. ERCC5 (also known as XPG) is a DNA endonuclease that is involved in the nucleotide-excision repair (NER) pathway (PMID: 8652557, 8206890, 8090225, 17466625). Hereditary variants in ERCC5 have been implicated in several disorders with defective DNA repair including xeroderma pigmentosum, Cocayne's syndrome, cerebrooculofacioskeletal syndrome, and arthrogryposis (PMID: 24700531, 8317483, 2478446). Somatic ERCC5 mutations have not yet been determined to be driver mutations in cancer although aberrant expression has been detected in breast and ovarian cancer (PMID: 18565881, 19289372). ERCC5-mutant cells may be increasingly sensitive to DNA damaging agents due to defects in DNA repair pathways (PMID: 7799936). True +ENST00000222329 NM_006494.2 2077 ERF False ERF, a transcriptional repressor, is altered by mutation at low frequencies in various cancers. ERF is a transcriptional repressor that is a member of the ETS-family of transcription factors (PMID: 21548782). ERF acts as a repressor of ETS2, another member of the ETS family, and its repression leads to EGF-induced cell migration (PMID: 22198386). ERF is a target of the MAP-kinase pathway, and it negatively correlates with expression of oncogenic c-MYC (PMID: 17699159, 17525531). ERF is mutated at low frequencies in various cancers (cBioPortal, MSKCC, Nov 2016). True +ENST00000288319 NM_182918.3 2078 ERG True ERG, a transcription factor, is recurrently altered by chromosomal rearrangement in prostate cancer. ERG (ETS-related gene) is an ETS (E26 transformation-specific) family transcription factor that is important in gene regulation. In normal physiology, ERG is primarily expressed in hematopoietic cells where it is required for normal hematopoiesis (PMID: 18500345) and endothelial cells where it regulates angiogenesis and vascular stability (PMID: 25584796). ERG fusions are the most common alterations of the ERG gene and are found in several cancers, including prostate cancer (PMID: 16254181) and Ewing’s sarcoma (PMID: 8162068). In prostate cancer, approximately 50% of all cases harbor a fusion between ERG and a highly expressed gene (e.g., TMPRSS2) that leads to aberrant overexpression of ERG (PMID: 16254181). In these cases, ERG acts to modify the chromatin landscape of prostate cancer cells, allowing for increased androgen receptor (AR) binding and priming prostate cancer initiation in response to PTEN loss (PMID: 23817021, 28783165). False +ENST00000377482 NM_018948.3 54206 ERRFI1 False ERRFI1, a scaffold protein involved in negative regulation of ERBB receptors, is recurrently altered by mutation and deletion in various cancer types. ERRFI1 (also Mig6) is a scaffold protein involved in ERBB-mediated signaling (PMID: 17940511). ERRFI1 negatively regulates the EGF receptor family and HGF/SF-Met signaling (PMID: 11003669, 26280531, 11843178, 18046415, 15556944, 21576352, 12833145, 16247031). CDC42 binding to ERRFI1 mediates the inhibitory activity on EGF receptor family members (PMID: 10749885, 17599051, 12833145). ERRFI1 regulates many cellular processes including cell signaling, development, tissue homeostasis, and stress response (PMID: 16087873, 19683494, 16782890, 22975324, 22912762, 19710174, 12384522). Murine loss-of-function studies have demonstrated that ERRFI1 is a regulator of keratinocyte development and proliferation (PMID: 17987665). In addition, ERRFI1 loss promotes cancer progression in mouse models, suggesting that ERRFI1 functions as a tumor suppressor (PMID: 16648858, 16819504, 25735773, 29191600). Deletion and downregulation of ERRFI1 have been implicated in various cancer types, including hepatocellular carcinoma, non-small cell lung cancer, and glioblastoma, among others, and is an indicator of poor patient outcome (PMID: 20044804, 21113414, 19439667, 20351267, 10862041, 25753424, 10987304, 15900585, 9287966). The reduction of ERRFI1 expression has also been associated with resistance to trastuzumab, an antibody targeting ERBB2 (PMID: 15856022, 14871811, 22255596). Somatic loss-of-function mutations are also found in patients with various cancer types and these alterations are predicted to activate downstream signaling pathways (PMID: 17940511, 16819504). True +ENST00000305188 NM_001017420.2 157570 ESCO2 False ESCO2, an enzyme required for sister chromatid pairing, is infrequently altered in a diverse range of cancers. ESCO2 is an enzyme that establishes sister chromatid cohesion during the cell cycle (PMID: 15958495). Cohesion between sister chromatids is initiated during DNA replication and must be maintained throughout mitosis or meiosis to ensure proper chromosome-spindle attachments (PMID: 26903600). ESCO2 functions as an acetyltransferase during S phase that acetylates the cohesin component SMC3 and allows for appropriate cohesion distribution (PMID: 18501190). The enzymatic activity of ESCO2 is required for accurate pairing of sister chromatids during cell division and DNA repair (PMID: 22614755). Loss of ESCO2 in cell lines results in premature sister chromatid separation and apoptosis (PMID: 22614755). In addition, ESCO2 forms complexes with several chromatin modifying enzymes, functioning as a transcriptional co-repressor and is bound at pericentric heterochromatin (PMID: 22101327,18501190, 26305936). Germline mutations in ESCO2 have been identified in patients with Roberts syndrome, a disorder characterized by limb and facial abnormalities (PMID: 1582173); however, somatic ESCO2 mutations are infrequent in human cancers. True +ENST00000206249 NM_001122740.1 2099 ESR1 True 1 ESR1 (estrogen receptor alpha) is a transcription factor that is frequently mutated in hormone-resistant metastatic breast cancers. ESR1 is a nuclear receptor that encodes the estrogen receptor alpha (ERα) protein. ERα plays a major role in sexual reproductive development and maintenance, specifically in the female reproductive organs (PMID: 10368776). Binding of the hormone estrogen, the ERα ligand, induces conformational changes to ERα, which allows the receptor to dissociate from HSP90 and dimerize with itself or ERβ. The dimer then translocates to the nucleus where it binds to promoters and enhancers of target genes either directly, via Estrogen Responsive Elements (ERE) in the DNA, or via other transcription factor complexes such as FOS/JUN/SP-1 (PMID: 11162939, 10681512). Once bound, the estrogen receptor recruits co-regulators that modulate the transcription of ESR1 target genes, resulting in changes in proliferation, migration and differentiation (PMID: 21779010). Lack of ERα delays the development of WNT1- and ERBB2 mutant-induced mouse mammary tumors (PMID: 10213494, 12019156) and reduces the occurrence of estrogen and carcinogen-induced mouse mammary tumors (PMID: 20181624, 11156389), indicating the involvement of ERα in tumorigenesis. While mutations in ESR1 are generally very rare in primary cancers (<5%), a number of mutations occurring in the ligand-binding domain (LBD) of the receptor were identified in ~12-25% of hormone-resistant metastatic breast cancer patients (PMID: 24398047, 24185512, 24185510, 24217577). The most recurrent mutations, Y537S and D538G, result in a constitutively active receptor, which is shown to confer acquired resistance to estrogen deprivation therapies. False +ENST00000272342 NM_019002.3 54465 ETAA1 False ETAA1, a replication stress response protein, is infrequently mutated in human cancers. ETAA1 (also ETAA16) is a replication stress protein that promotes fork progression (PMID: 27601467, 27723717, 27723720). In response to replication stress, ETAA1 binds RPA (Replication Protein Complex A), a complex that associates with single-stranded DNA at stalled replication forks and recruits repair proteins to resolve the forks (PMID: 27601467, 27723720, 27818175). The activity of ETAA1 stimulates ATR, a protein kinase involved in DNA sensing (PMID: 27601467), via a distinct arm independent from TOPBP1-mediated repair (PMID: 27723717, 30139873). Specifically, ETAA1 associates with two distinct replication complexes including ATR/ATRIP and BLM/TOP3α/RMI1/RMI2 (PMID: 27723720). Loss of ETAA1 results in genome instability, altered DNA replication and sensitivity to replication stress (PMID: 27723717, 27723720). In addition, reduced ETAA1 expression in murine models results in a diminished T-cell response, suggesting that ETAA1 may have a role in immune cell regulation (PMID: 28607084). ETAA1 is also predicted to function as a surface antigen in Ewing sarcoma (PMID: 16003559). Variants associated with ETAA1 are predictive of susceptibility to pancreatic and colon cancer (PMID: 26098869, 29844832). True +ENST00000266517 NM_018638.4 55500 ETNK1 False ETNK1, a kinase involved in phospholipid biosynthesis, is recurrently altered by mutation in BCR-ABL negative CML and CMML. ETNK1 is a kinase that catalyzes the first step in the phosphatidylethanolamine (PE) biosynthesis pathway (PMID: 13366993). ETNK1 phosphorylates ethanolamine to form phosphoethanolamine, an intermediate which is then processed to PE, a membrane phospholipid (PMID: 13366993, 25343957). PE has a variety of cellular roles including maintaining membrane protein topology, defining membrane architecture, anchoring PE-binding proteins to the membrane as well as regulation of cytokinesis and mitochondrial respiration (PMID: 19703652, 11294902). Somatic ETNK1 mutations are found in BCR-ABL negative chronic myeloid leukemia (CML) and chronic myelomonocytic leukemia (CMML) (PMID: 25343957, 25615281). False +ENST00000319397 NM_005238 2113 ETS1 True ETS1, a transcription factor, is infrequently altered in cancer. ETS1, a member of the ETS family of transcription factors, encodes for a transcription factor that functions in the regulation of various lymphoid cell processes, including survival, differentiation and proliferation, through transcriptional regulation of chemokines and cytokines (PMID: 10698492, 11909962, 32350509, 27069114). Alternative spliced transcript variants of ETS1 have been identified and can result in the p42 isoform, a gain-of-function protein that lacks the autoinhibitory sequences, or the p27 isoform, a dominant negative protein that lacks transactivation activity (PMID: 19377509, 8003962). The oncogenic function of ETS1 is likely tissue-specific. Overexpression of ETS1 in breast cancer cell lines and models induces cellular proliferation, invasion and migration, suggesting that ETS1 can function as an oncogene in this context (PMID: 24706481, 21444677, 22971289). ETS1 amplification has been identified in various types of cancer, including ovarian cancer and prostate cancer (PMID: 11297247, 23064684). Conversely, knockout of ETS1 in other breast cancer cell studies induces cellular proliferation and aberrant lymphoid cell development, suggesting that ETS1 can function as a tumor suppressor gene in this context (PMID: 32477936). Ectopic expression of wildtype ETS1 and the p42 isoform in colorectal and epithelial cancer cell lines induces apoptosis and has been suggested as a potential therapeutic treatment (PMID: 9266972, 7753825). Preclinical studies with breast cancer cell lines overexpressing ETS1 have demonstrated conferral of multidrug resistance (PMID: 20392592). True +ENST00000405192 NM_001163147.1 2115 ETV1 True ETV1, a transcription factor, is altered by chromosomal rearrangement or overexpression in various cancer types. The ETV1 (ETS Translocation Variant 1) gene, belongs to the ETS (E26 transformation-specific) family of transcription factors. The downstream transcriptional targets of ETV1 are diverse and tissue specific. ETV1 is a downstream transcriptional mediator of the MAP kinase pathway and it is tightly regulated by the MAP kinase through transcription, protein stability, and phosphorylation (PMID: 12213813, 19251651, 20927104). The endogenous expression of ETV1 is restricted to several tissues, including specific neurons of the central and peripheral nervous systems (PMID: 16289830, 21746923, 10850491) and the interstitial cells of Cajal (“pacemaker” cells of the gastrointestinal tract) (PMID: 20927104). ETV1 is aberrantly activated in several cancers through distinct mechanisms: In Ewing sarcoma, ETV1 is fused with the EWS protein to generate the chimeric EWS-ETV1 protein. In prostate cancer, ETV1 is aberrantly over-expressed through translocation resulting in either fusion transcript or full-length transcript. In melanoma, ETV1 is aberrantly over-expressed through genetic amplification of its chromosomal locus. In gastrointestinal stromal tumors (GISTs), ETV1 is endogenously highly expressed and required to maintain lineage specification and survival (PMID: 7700648, 17671502, 20160028, 20927104). False +ENST00000319349 NM_001079675.2 2118 ETV4 True ETV4, a transcription factor, is frequently altered by chromosomal rearrangement in prostate cancer and Ewing's sarcoma. ETV4 (also PEA3 and E1AF) is a transcription factor that belongs to the ETS family of transcription factors. The family consists of a highly conserved group of genes that play important roles in cellular proliferation, differentiation, migration, invasion and angiogenesis (PMID: 21548782). ETV4 in particular plays an important role in development, such as in organogenesis of the kidney, mammary gland, and limb buds (PMID: 9285689, 12871699, 19386269). ETV4 is overexpressed in various types of solid cancers, including the esophagus (PMID: 21143918), colon (PMID: 15695237), breast (PMID: 21404275,15387369), ovarian (PMID:12684413), non-small lung (PMID: 11519038) and gastric (PMID: 14604892), where it promotes metastatic progression and correlates with reduced survival. In prostate cancers (~1% of the cases) ETV4 overexpression is associated with translocation of ETV4 to the promoter of a gene highly expressed in prostate (TMPRSS2, KLK2, DDX5, and CANT1) (PMID: 18794152, 16585160, 18451133). Finally, fusions of ETV4 with Ewing's sarcoma (EWSR1) gene have been reported in three cases of Ewing sarcoma (ES) (PMID: 8834175, 8605035, 22429598). The defining feature of this tumor type is chromosomal translocation involving the EWSR1 gene and one of five ETS genes. False +ENST00000306376 NM_004454.2 2119 ETV5 True ETV5, a transcription factor, is rarely altered by chromosomal rearrangement in prostate cancer. ETV5 is an ETS family transcription factor belonging to the PEA3 subfamily involved in multiple cellular processes. PEA3 family members are activated by pathways such as the MAPK and PKA pathway to induce the transcription of gene programs through phosphorylation (PMID: 8895521, 8808707). ETV4 and ETV5 are involved in the proliferation of undifferentiated embryonic stem cells and subsequent induction of differentiation cascades, potentially through changes in Oct3/4 expression (PMID: 26224636). Additionally, ETV5 has been shown to be expressed during embryonic development, especially at sites undergoing branching morphogenesis (PMID: 12871699, 19898483, 19386268). In the testis, ETV5 is exclusively expressed in the Sertoli cells and is required for spermatogonial stem cell self-renewal (PMID: 16107850). False +ENST00000396373 NM_001987.4 2120 ETV6 False ETV6, a transcription factor, is frequently altered by chromosomal rearrangement in hematologic malignancies. ETV6 is a transcription factor that is a member of the ETS protein family. The ETS family is one of the largest families of transcription factors. ETS domains typically bind to a GGAA/T DNA sequence, but can also be involved in protein-protein interactions (PMID: 11175367). ETV6 is essential for hematopoietic stem cells (PMID: 17980166) and may initiate the regulatory cascade leading to their production (PMID: 20412772). Translocations involving band 12p13 around ETV6 are one of the most commonly observed alterations in hematological malignancies (PMID: 22578774). ETV6 has a large number of fusion partners and typically contributes to tumorigenesis by modifying the activity or function of the partner gene or a proto-oncogene close to a translocation site (PMID: 22578774). Somatic mutations occur at a relatively low frequency in solid tumors (cBioPortal, MSKCC, Mar. 2016). Germline ETV6 mutations contribute to hematologic malignancies including ALL (PMID: 25581430, 26573422). ETV6-NTRK3 fusion has been shown to be sensitive to crizotinib (PMID: 25207766). True +ENST00000397938 NM_005243.3 2130 EWSR1 True EWSR1, a multi-functional protein that binds DNA and RNA, is altered by chromosomal rearrangement in various cancer types, most frequently in Ewing Sarcoma. EWSR1 is one of three members of the highly conserved heterogeneous nuclear ribonucleoprotein particle (hnRNP) protein family, FET (PMID: 25494299, 22081015). The EWSR1 protein can bind to DNA or RNA and is known to play a role in transcription via binding to RNA Pol II, RNA processing and metabolism, and DNA damage repair (PMID: 24320889, 25494299). The N-terminal domain of EWSR1 can fuse to the C-terminal domain of a number of transcription factors and give rise to several fusion proteins that have been implicated in Ewing Sarcoma, primitive neuroectodermal tumor, desmoplastic small round cell tumor, myxoid liposarcoma, extraskeletal myxoid chondrosarcoma, and clear cell sarcoma (PMID: 16784984, 25364450, 17691072, 17525681, 17227118, 24320889). False +ENST00000378204 NM_000127 2131 EXT1 False EXT1, a transmembrane glycosyltransferase, is infrequently altered in cancers. EXT1 (Exostoses-1) is an endoplasmic reticulum-resident type II transmembrane glycosyltransferase which is required for the polymerization of heparan sulfate (HS)(PMID: 9756849). HS polymerization is necessary for the formation of fibronectin fibrils and the subsequent formation of the insoluble cell-matrix (PMID: 34890641). The reduction of EXT1, therefore, leads to reduced fibril assembly and global changes in cellular homeostasis, including increased cell size, ER structure and changes to membrane glycome and lipid compositions, which impact the metabolism of the cell (PMID: 33962942). Mutations in EXT1 are associated with hereditary multiple exostoses (HME), an autosomal dominant bone disorder characterized by the formation of osteochondromas and an increased risk for chondro- and osteosarcoma (PMID: 7550340). While somatic mutations of EXT1 are rare in sporadic neoplasms, EXT1 expression can be reduced by the hypermethylation of the CpG island promoter, which has been found as a method of EXT1 loss in cell lines from patients with acute promyelocytic leukemia, acute lymphoblastic leukemia, and non-melanoma skin cancer (PMID: 15385438). True +ENST00000428826 NM_001991.3 2145 EZH1 True EZH1, an epigenetic modifier, is altered by mutation or amplification in various tumors. EZH1 is the catalytic component of the Polycomb repressive complex 2 (PRC2) which methylates histone H3 at lysine 27 (H3K27), resulting in chromatin compaction and target gene repression. Compared to its homolog, EZH2, EZH1-containing PRC2 complexes show weaker methylation activity, target fewer genes, and are more abundant in non-proliferative adult organs (PMID: 19026781). EZH1 plays a role in maintaining embryonic stem cell pluripotency (PMID: 19026780). EZH1 is not commonly altered in cancer, but recurrent mutations in EZH1 are often the second hit in autonomous thyroid adenomas (PMID: 27500488). Dual EZH1/2 inhibitors are being tested preclinically in several cancers (PMID: 24183969, 25395428). False +ENST00000320356 NM_004456.4 2146 EZH2 True 1 EZH2, an epigenetic modifier, is altered by mutation and/or overexpression in solid tumors and hematologic malignancies. EZH2 is the catalytic component of the Polycomb repressive complex 2 (PRC2) which is responsible for transcriptional repression by catalyzing di- and tri-methylation of Histone H3 lysine 27 (H3K27). EZH2 requires other members of the PRC2 complex for full methyltransferase activity, including SUZ12 and EED (PMID: 15225548, 15916951), and PRC2 function is important in repression of developmental regulators such as the HOX genes, and X-inactivation (PMID: 16618801, 12649488). Additionally, non-coding RNA's can guide EZH2 to genomic targets for gene repression (PMID: 17604720, 22659877). EZH2 overexpression is found in many malignancies including lymphoma, bladder cancer, melanoma, prostate cancer, lung cancer, and breast cancer, and is associated with advanced stage and poor prognosis (PMID: 11389032, 16361539, 12374981, 14500907, 16330673, 24097870). Furthermore, gain-of-function mutations in EZH2 occur frequently in follicular lymphoma and diffuse large B-cell lymphomas (PMID: 20081860, 21190999). EZH2 can also act as a tumor suppressor in certain cancer types, and recurrent inactivating mutations are observed in myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN) (PMID: 20601953). Given its importance in multiple cancer types, EZH2 inhibition has shown promise in pre-clinical studies and is a current effort in multiple clinical trials, either through direct inhibition of EZH2 enzymatic activity or through disruption in PRC2 stability (PMID: 26845405). True +ENST00000342995 NM_203407.2 340602 EZHIP True EZHIP, a polycomb binding protein, is recurrently altered by rearrangement and mutation in endometrial stromal sarcomas and posterior fossa ependymomas, respectively. EZHIP is a protein encoded from a single exon on the X chromosome (PMID: 23959973, 27699219). The function of EZHIP is not well-established, however, biochemical studies indicate that EZHIP interacts with Polycomb Repressive Complex 2 (PRC2) (PMID: 21248841). The PRC2 complex catalyzes the tri-methylation of histone H3 at lysine 27 (H3K27me3), a mark important for mediating repression of gene expression (PMID: 21248841). Loss of in neuronal cells results in reduced H3K27me3 and decreased cell growth (PMID: 29909548). In addition, EZHIP is most highly expressed in normal oocytes (PMID: 23959973) and may function as a cancer testis antigen (CTA) to mediate immune recognition in lung adenocarcinoma (PMID: 27699219). Recurrent chromosomal rearrangements involving EZHIP and MBTD1, a Polycomb protein with uncharacterized function, are found in patients with low grade endometrial stromal sarcomas (PMID: 23959973). Gain-of-function mutations are also found in posterior fossa ependymoma, resulting in increased H3K27me3 (PMID: 29275929). False +ENST00000389301 NM_000135.2 2175 FANCA False 1 FANCA is a tumor suppressor and DNA repair protein. Germline mutations of FANCA are associated with the cancer predisposition syndrome Fanconi Anemia. While FANCA is subject to wide variety of mutational types, it has been suggested that there is little prognostic value in the different types as evidenced by no clinical differences in the onset of hematologic disease in patients with a lack of FANCA expression and those which a mutated form of the protein (PMID: 21273304). Cells from Fanconi Anemia (FA) patients and the myeloid leukemia cell line (UoC-M1) show hypersensitivity to DNA cross-linking agents such as diepoxybutane (DEB) and mitomycin C (MMC) when grown and treated with these compounds; diagnostic testing using DEB forms the basis of a gold standard test for FA (PMID: 8374893, PMID: 12637330). True +ENST00000289081 NM_000136.2 2176 FANCC False FANCC, a tumor suppressor and DNA repair protein, is infrequently altered in cancer. Germline mutations of FANCC are associated with the cancer predisposition syndrome Fanconi Anemia. FANCC is a DNA repair protein that is a member of the Fanconi anemia (FA) complementation group (PMID: 21605559). The FA core complex, which includes FANCC and 7 other FA proteins, assemble at sites of damaged chromatin and coordinate the DNA repair response (PMID: 27145721). By scaffolding with BRCA1/2 proteins, the FA core complex facilitates homologous combination via repair of interstrand DNA crosslinks (PMID: 21605559, 16687415). The FA pathway is activated in response to cellular stress, which interrupts replication and transcription (PMID: 23114602). Monoubiquitination of FANCD2 by the core FA complex is required to mediate DNA repair (PMID: 17352736). FANCC directly interacts with transcriptional regulators, such as the co-repressor C-terminal binding protein 1 (Ctbp1) and β-catenin, to modulate gene expression and signaling (PMID: 23303816, 24469828). In addition, FANCC activity is important in several cellular functions including redox regulation, proliferation, genomic stability and apoptosis (PMID: 15327776). Germline mutations in FANCC are found in patients with FA, an inherited bone marrow failure syndrome associated with deficiencies in hematopoietic stem cells, developmental defects, and cancer predisposition (PMID: 24469828). Heterozygous loss-of-function mutations have been associated with hereditary breast and ovarian cancers (PMID: 23779253, 31467304). Furthermore, inactivating mutations in FANCC have been observed in leukemia, oral, breast, and pancreatic cancers, among others (PMID: 16998502, 27165003). FANCC loss and the resulting deficiency in HRR may confer sensitivity to DNA interstrand crosslinking agents (PMID: 20509860). True +ENST00000383807 NM_001018115.1 2177 FANCD2 False FANCD2, a tumor suppressor and DNA repair protein, is infrequently altered in cancer. Germline mutations of FANCD2 are associated with the cancer predisposition syndrome Fanconi Anemia. FANCD2 is a DNA repair protein that is a member of the Fanconi anemia complementation group (PMID: 27145721, 29376519). The Fanconi anemia proteins assemble at sites of damaged chromatin and coordinate the DNA repair response (PMID: 27145721). FANCD2 functions predominantly as a heterodimer in collaboration with FANCI; this complex recruits effector molecules to regions of damaged DNA (PMID: 27405460, 17412408). The FANCD2-FANCI heterodimer is activated via ubiquitination and phosphorylation by components of the Fanconi anemia core complex, including the kinases ATR, ATM, and CHK1 and the E3 ligases FANCL and FANCT (PMID: 29376519). Following DNA repair completion, monoubiquitination of FANCD2-FANCI is reversed by a deubiquitinase complex, resulting in the removal of FANCD2-FANCI from chromatin (PMID: 15694335). FANCD2 has been implicated in various cellular functions including maintenance of cell cycle progression, genomic stability, mitotic apparatus assembly and spindle integrity (PMID: 23934222, 29376519). Loss of FANCD2 expression in murine models results in hematopoietic defects and hypersensitivity to radiation (PMID: 20826722, 16135554). Germline FANCD2 mutations are found in individuals with Fanconi anemia, a condition associated with congenital defects, bone marrow failure, and increased risk of cancer (PMID: 23653579). FANCD2 alterations are found in childhood T-ALL and may be predictive of chemotherapy toxicity (PMID: 17096012, 22829014). FANCD2 overexpression is found in BRCA1- and BRCA2-deficient breast tumors, as well as metastatic melanoma, glioblastomas, and colorectal cancer (PMID: 17891185, 20339950, 27264184). True +ENST00000229769 NM_021922 2178 FANCE False FANCE, a DNA repair protein, is infrequently altered in cancer. FANCE, a member of the Fanconi anemia complementation group, encodes for a DNA repair protein that functions in the Fanconi anemia pathway (PMID: 12093742, 12239156). The Fanconi anemia pathway is a network of proteins and subcomplexes that collectively function in DNA repair and safeguard genomic stability through the activation of the Fanconi anemia core complex (PMID: 12515506). The Fanconi anemia core complex initiates DNA repair through monoubiquitination of FANCD2 and FANCI proteins, which results in DNA interstrand crosslink repair (PMID: 31666700, 32167469). The Fanconi anemia proteins assemble at sites of damaged chromatin to form the Fanconi anemia core complex (PMID: 27145721, 31666700, 24910428). FANCE interacts with FANCC to promote FANCD2 monoubiquitination, activating the subsequent downstream events of the Fanconi anemia pathway (PMID: 12239156). FANCE-null cells demonstrate chromosomal breakage and aberrations, suggesting that FANCE functions predominantly as a tumor suppressor gene (PMID: 24451376, 37779877). Inactivating mutations of FANCE have been identified in esophageal cancer and head and neck carcinoma (PMID: 21279724, 28678401). True +ENST00000327470 NM_022725 2188 FANCF False FANCF, a DNA repair protein, is altered by hypermethylation in cancer. FANCF, a member of the Fanconi anemia complementation group, encodes for a DNA repair protein that functions in the Fanconi anemia pathway (PMID: 15262960, 10615118). The Fanconi anemia pathway is a network of proteins and subcomplexes that collectively function in DNA repair and safeguard genomic stability through the activation of the Fanconi anemia core complex (PMID: 12515506). The Fanconi anemia core complex initiates DNA repair through monoubiquitination of FANCD2 and FANCI proteins, which results in DNA interstrand crosslink repair (PMID: 31666700, 32167469). The Fanconi anemia proteins assemble at sites of damaged chromatin to form the Fanconi anemia core complex (PMID: 27145721, 31666700, 24910428). FANCF functions as an adaptor protein in the assembly of the Fanconi anemia core complex and interacts with the FANCC/FANCE and FANCA/FANCG subcomplexes (PMID: 15262960, 36652992). Inactivation of FANCF in ovarian epithelial cancer cell lines and models induces chromosomal instability, suggesting that FANCF functions predominantly as a tumor suppressor gene (PMID: 12692539, 16418574). Hypermethylation of FANCF has been identified in ovarian cancer and breast cancer (PMID: 16418574, 18414472, 17932744, 34289901). True +ENST00000378643 NM_004629 2189 FANCG False FANCG, a DNA repair protein, is infrequently altered in cancer. Germline mutations of FANCG are associated with the cancer predisposition syndrome Fanconi anemia. FANCG, a member of the Fanconi anemia complementation group, encodes for a DNA repair protein that functions in the Fanconi anemia pathway (PMID: 12861027, 11050007). The Fanconi anemia pathway is a network of proteins and subcomplexes that collectively function in DNA repair and safeguard genomic stability through the activation of the Fanconi anemia core complex (PMID: 12515506). The Fanconi anemia core complex initiates DNA repair through monoubiquitination of FANCD2 and FANCI proteins, which results in DNA interstrand crosslink repair (PMID: 31666700, 32167469). The Fanconi anemia proteins assemble at sites of damaged chromatin to form the Fanconi anemia core complex (PMID: 27145721, 31666700, 24910428). FANCG functions as a scaffold to facilitate the formation of the Fanconi anemia core complex and the D1-D2-G-X3 with BRCA2, FANCD2 and XRCC3 (PMID: 18212739). Knockout of FANCG in human adenocarcinoma cell lines impairs DNA repair pathways and results in chromosome breakage, suggesting that FANCG functions predominantly as a tumor suppressor gene (PMID: 16762635). Germline FANCG mutations are found in individuals with Fanconi anemia, a condition associated with congenital defects, bone marrow failure, and increased risk of cancer (PMID: 23653579). True +ENST00000310775 NM_001113378.1 55215 FANCI False FANCI, a DNA repair protein in the Fanconi Anemia complementation group, is infrequently altered in various cancers. FANCI is a DNA repair protein that is a member of the Fanconi anemia complementation group (PMID: 34256011). FANCI forms a heterodimer with FANCD2, which recruits effector molecules to regions of damaged DNA (PMID: 17460694, 27405460, 17412408). The FANCD2-FANCI heterodimer is activated via ubiquitination and phosphorylation by components of the Fanconi anemia core complex, including the kinases ATR, ATM and CHK1, and the E3 ligases FANCL and FANCT (PMID: 29376519). Following DNA repair completion, monoubiquitination of FANCD2-FANCI is reversed by USP1-UAF1, resulting in the removal of FANCD2-FANCI from chromatin (PMID: 15694335). In the event that DNA repair is unsuccessful, FANCI initiates apoptosis via PIDD1, and thus a reduction in FANCI levels correlates with a reduction in apoptosis (PMID: 34256011, 27097374). FANCI also negatively regulates AKT in response to DNA damage (PMID: 27097374). The roles of FANCI in DNA repair and apoptosis suggest it likely functions as a tumor suppressor, however, there is a lack of experimental evidence to support this designation (PMID: 27097374). On the contrary, cancer cells exploit FANCI to survive the DNA damage caused by chemotherapy, which has been demonstrated in prostate and ovarian cancer cells (PMID: 38023254, 35362384). Additionally, FANCI knockout in mouse models results in hypersensitivity to DNA crosslinking agents, and in vitro knockdown experiments have suggested an oncogenic role for FANCI in cutaneous melanoma, non-small cell lung cancer, ovarian cancer and prostate cancer cells (PMID: 31219578, 38077326, 35703356, 35362384, 38023254). False +ENST00000233741 NM_018062.3 55120 FANCL False 1 FANCL, an E3 ubiquitin ligase involved in DNA repair, is infrequently altered in cancer. Germline mutations of FANCL are associated with the cancer predisposition syndrome Fanconi Anemia. FANCL is an E3 ubiquitin ligase belonging to the Fanconi Anemia (FA) group of proteins. These proteins coordinate homologous recombination repair (HRR) of DNA damage, specifically interstrand DNA crosslinks, by localizing to the site of damage using the BRCA1/2 proteins as a scaffold (PMID: 21605559). Essential for this DNA repair is monoubiquitinated, activated FANCD2 (PMID: 17352736). Monoubiquitination of FANCD2 relies on a nuclear complex of several FA proteins, including FANCL, FANCA, FANCB, FANCC, FANCE, FANCF, FANCG and FANCM; FANCL is the ubiquitin ligase required for FANCD2 monoubiquitination and its resulting HRR activity (PMID: 26149689, 31666700, 27986371, 20154706). Loss of FANCL in the germline can result in Fanconi Anemia, a cancer-predisposing syndrome characterized by hematological abnormalities, bone marrow failure, limb deformities, skin hyperpigmentation and susceptibility to hematologic and solid malignancies, such as acute myeloid leukemia (PMID: 24773018, 25754594). Hematological abnormalities in FA patients may be due in part to the role of FANCL in regulating β-catenin (PMID: 22653977). FANCL is mutated somatically in various cancers including head and neck carcinoma, among others (PMID: 28678401). FANCL loss and the resulting deficiency in HRR may confer sensitivity to PARP inhibitors, such as olaparib, which is FDA-approved for patients with HRR-deficient prostate cancer (PMID: 32343890). True +ENST00000267430 NM_020937 57697 FANCM False FANCM, a DNA repair protein, is infrequently altered in cancer. FANCM (FA complementation group M) encodes for a DNA translocase with DNA-dependent ATPase activity (PMID: 30714416, 20117061, 31663812). FANCM is involved in homologous recombination and repair of interstrand DNA cross-links (ICLs) (PMID: 30714416, 20117061). FANCM participates in the proper functioning of the Fanconi anemia pathway, which helps to suppress the formation of tumors (PMID: 31663812). FANCM also regulates the Bloom’s complex, a complex of proteins in which germline mutations can lead to the cancer predisposition disorder Bloom’s Syndrome (PMID: 31663812). Loss of function of the FANCM gene has not been associated with Fanconi anemia, but rather with infertility and cancer predisposition (PMID: 30714416). The gene is also essential for the viability of alternative lengthening of telomeres (ALT) cancers (PMID: 31663812). FANCM mutations have been identified in patients with breast and ovarian cancers (PMID: 30714416, 36707629). True +ENST00000355740 NM_000043.4 355 FAS False FAS, a death receptor that initiates apoptosis, is recurrently altered by mutation or downregulation in a diverse range of human cancers. FAS (also FAS1, CD95, APO-1) is a death receptor that mediates apoptosis (PMID: 20505730). FAS binds the cognate ligand CD95L, a protein predominantly expressed on T and NK cells, resulting in the death of the associated cell expressing the FAS receptor (PMID: 22042271). The FAS-CD95L interaction results in the formation of a death-inducing signaling complex that includes FADD, caspase 8, and caspase 10 (PMID: 12393594). Proteolytic processing of caspases then triggers a cascade that initiates apoptosis (PMID: 28445729, 28445729). FAS can also activate other downstream signaling cascades, including activation of the NF-KB and JNK pathways (PMID: 8647190). Loss of FAS expression in several murine models of cancer, including ovarian and liver, results in reduced apoptosis and enhanced tumor growth (PMID: 20505730). Germline mutations in FAS are associated with an autoimmune lymphoproliferative syndrome, a disorder associated with chronic lymphadenopathy and an increased risk of lymphoma development (PMID: 7540117, 11418480). Cell surface levels of FAS are frequently downregulated in cancer, allowing cells to evade programmed cell death (PMID: 15907590). Somatic FAS mutations are also found in a variety of tumor types including multiple myeloma, lymphomas, T cell leukemias, and several solid tumor types (PMID: 9373236, 9787134, 10190897, 11059754, 22042271). Mutations are frequently heterozygous and are predicted to be loss-of-function, allowing tumors to evade cell death via apoptosis (PMID: 22042271). True +ENST00000441802 NM_005245.3 2195 FAT1 False FAT1, a tumor suppressor and transmembrane protein, is inactivated by mutation or deletion in various cancer types. FAT1 is a transmembrane protein and member of the cadherin superfamily that is involved in planar cell polarity. FAT1 is involved in the promotion of actin-mediated cell migration as well as inhibition of YAP1-mediated cell proliferation. FAT1 is a potent suppressor of cancer cell growth, owing to its ability to bind β-catenin and abrogate its nuclear localization and transcription of its targets. Alterations in FAT1 decrease its interaction with β-catenin, thus promoting WNT signaling and tumorigenesis. Although most FAT1 alterations in cancer are loss-of-function events (cBioPortal, MSKCC, May 2015), studies suggest that it may be both tumor suppressive or oncogenic in a context-dependent manner (PMID: 8586420, 23076869,19439659, 16682528, 23354438). True +ENST00000403359 NM_001190274.1 80204 FBXO11 False FBXO11, a component of the SCF ubiquitin ligase complex, is recurrently altered by mutation in lymphomas. FBXO11 is an F-box protein that is a subunit of the ubiquitin ligase SCF complex (SKP1-cullin-F-box). FBXO11 is an essential component of the SCF complex which ubiquitinates substrate proteins and targets them for degradation via the proteasome (PMID: 22113614). FBXO11 directly binds SKP1 in the SCF complex and mediates substrate specific recognition (PMID: 16633365). BCL6 is a well-characterized target of SCF-mediated degradation and disruption of this complex results in BCL6 protein stabilization and transformation (PMID: 22113614). Loss of FBXO11 expression in murine models results in an expansion of germinal center B cells due to an overexpression of BCL6 (PMID: 27166359). FBXO11 also mediates the stability of other proteins, including SNAIL, a factor involved in the epithelial-to-mesenchymal transition (PMID: 25203322). Alterations in FBXO11 have been identified in patients with neurological disorders (PMID: 29796876, 30057029). Somatic FBXO11 deletions and loss-of-function mutations are found in diffuse large B cell lymphomas (DLBCL), leading to stabilization of the BCL6 oncogene (PMID: 22113614). True +ENST00000608872 NM_012164 26190 FBXW2 False FBXW2, the substrate binding unit of an E3 ubiquitin ligase complex, is infrequently altered in cancer. FBXW2 is the substrate binding unit of the E3 ubiquitin ligase complex known as SCF (Skp1-Cul1-F-box protein) (PMID: 30918250). FBXW2 is an F-box protein containing WD-40 repeats that is responsible for substrate recognition, substrate binding and substrate specificity for the SCF complex (PMID: 30918250). The binding of SCF to its target proteins results in ubiquitination and subsequent degradation of the target protein (PMID: 30918250). Thus, FBXW2 plays a pivotal role in post-translational protein regulation in the cell. FBXW2 is responsible for the ubiquitination and degradation of proto-oncogenic substrates such as CTNNB1 (PMID: 30918250, 31211237), SKP2 (PMID: 31211237, 28090088), NF-κB p65 (PMID: 34465889) and EGFR (PMID: 35499593), which are instrumental in oncogenic processes in cancers such as non-small cell lung cancer, breast cancer and prostate cancer (PMID: 30918250, 31211237, 28090088, 34465889, 35499593). However, FBXW2 also downregulates inhibitory proteins of the SOX2 transcription factor and therefore plays a role in promoting cell stemness (PMID: 31548378), suggesting FBXW2 may have both oncogenic and tumor-suppressive roles. False +ENST00000281708 NM_033632.3 55294 FBXW7 False 3A FBXW7, a tumor suppressor involved in protein degradation, is inactivated by mutation in various cancer types, most frequently in endometrial and colorectal cancers. The FBXW7 gene encodes an F-box protein subunit involved in substrate recognition by an SCF (Skp1-Cul1-F-box protein)-type ubiquitin ligase complex. Upon substrate identification, this complex modifies the substrate such that it is targeted for protein degradation. Substrates of FBXW7 include the proteins c-MYC, mTOR (PMID: 18787170), NOTCH1, cyclin-E, and JUN, which are instrumental in the regulation of cell division, differentiation and growth, and which are often inappropriately activated in cancer. As most FBXW7 substrates are proto-oncogenes that are processed for degradation by the SCF complex, FBXW7 functions as a tumor suppressor. Inactivation of FBXW7 by mutation or copy number loss results in aberrant accumulation of oncoproteins, which subsequently contributes to malignant transformation (PMID: 18094723, 27399335). Alternate splicing of FBXW7 results in three distinct protein isoforms (α, β, γ) each with differential localization (PMID: 22673505). Mutations in FBXW7 can negatively affect isoform-specific functions, dimerization of subunits, protein localization, SCF assembly or substrate recognition. Most mutations in FBXW7 are point mutations that disrupt substrate binding, while <10% are small deletions or insertions (PMID: 24853181, 17909001). True +ENST00000328850 NM_002005 2242 FES True FES, a cytoplasmic tyrosine kinase, is infrequently altered in cancer. FES encodes for a cytoplasmic tyrosine kinase that functions in the maintenance of cellular transformation (PMID: 15003822). FES is located downstream of cell surface receptors FCER1 and KIT, regulating functions such as cellular differentiation, cell attachment and mast cell signaling (PMID: 11509660, 8999909, 22589410). Mast cell development is controlled by FES through regulation of cross-talk between KIT and β1 integrins to promote cytoskeletal reorganization and cell motility (PMID: 19892014). Knockdown of FES in various cancer cell lines inhibits cell proliferation, migration and invasion, suggesting that FES functions primarily as an oncogene (PMID: 19082481, 28952025). FES overexpression has been identified in various cancer types, including acute myeloid leukemia and breast cancer (PMID: 1984516, 1159660). Inhibition of FES is suggested to induce radiosensitization in cancer (PMID: 31573955). False +ENST00000295727 NM_017521.2 54738 FEV False FEV, an ETS family transcription factor, is infrequently mutated by chromosomal rearrangement in Ewing's Sarcoma. FEV is a transcription factor belonging to the ETS protein family. In normal cells, FEV expression is restricted to a small number of tissues and is thought to act as a transcriptional repressor, as it lacks the N-terminal transcription activation domain found in other ETS family members (PMID: 9121764). However, FEV has also been shown to co-localize with serotonin-producing and cholinergic neurons and be involved in the transcriptional activation of genes in that context. Specific genes involved in neurotransmission, differentiation, and maintenance of neuronal cell types, such as the serotonin transporter and nicotinic acetylcholine receptor, among others, are activated through enhancers containing FEV binding motifs (PMID: 9468386, 10575032). Fusions of FEV with EWSR1, another ETS protein family member, are found as rare chromosomal rearrangements in Ewing Sarcoma (PMID:10976720, 23329308, 9121764). False +ENST00000337706 NM_000800 2246 FGF1 True FGF1, a fibroblast growth factor, is infrequently altered in cancer. FGF1, a member of the FGF family, encodes for a fibroblast growth factor which functions in regulating various cellular processes including proliferation and differentiation (PMID: 1697263, 3523756, 9505167). FGF1 activates cell signaling pathways to regulate cellular proliferation, differentiation and survival through interaction with FGFR1 and integrins (PMID: 18441324, 20422052). In the presence of heparin, FGF1 promotes FGFR1 dimerization and activation through autophosphorylation (PMID: 18411303, 19574212). Knockout of FGF1 in various cancer cell lines and models represses cellular proliferation, suggesting that FGF1 functions predominantly as an oncogene (PMID: 34552869, 36952626, 32615540, 22990650). Amplification of FGF1 has been identified in ovarian cancer and colorectal cancer (PMID: 17538174, 34552869). False +ENST00000264664 NM_004465 2255 FGF10 True FGF10, a fibroblast growth factor, is infrequently altered in cancer. FGF10, a member of the FGF family, encodes for a fibroblast growth factor which functions primarily in mesenchymal-epithelial signaling to promote organ development, tissue repair and cellular differentiation (PMID: 12455635, 11748146, 19498056). FGF10 signals in a paracrine manner through activating FGFR2 and FGFR1 (PMID: 24011590, 16597617). FGF10 expression in various cancer cell lines and models induces cellular proliferation, migration and invasion, suggesting that FGF10 functions predominantly as an oncogene (PMID: 18594526, 25057305). Amplification of FGF10 has been identified in various types of cancer, including gastric cancer, small cell lung cancer and pancreatic cancer (PMID: 26268776, 29748005, 26909576). Preclinical studies have demonstrated FGF10 sensitivity to N-myristoyltransferase inhibitors and inactivation of the FGF10-FGFR2 signaling axis in prostate cancer cell lines (PMID: 14724220, 29038344, 29444487). False +ENST00000376143 NM_004115 2259 FGF14 False FGF14, a fibroblast growth factor, is infrequently altered in cancer. FGF14, a member of the FGF family, encodes for a fibroblast growth factor which functions primarily in the central nervous system to regulate cellular processes, such as neurogenesis, synaptic transmission and plasticity (PMID: 12123606). FGF14 mutations and haploinsufficiency have been associated with increased risk of cognitive disorders, like schizophrenia, due to dysregulation of the central nervous system (PMID: 27163207, 36516086, 17236779). Overexpression of FGF14 in various cancer cell lines and models suppresses cellular proliferation and tumor growth, suggesting that FGF14 functions predominantly as a tumor suppressor gene (PMID: 32707902, 31949485). Downregulation of FGF14 has been identified in lung adenocarcinoma and colorectal cancer (PMID: 32707902, 31949485). True +ENST00000294312 NM_005117.2 9965 FGF19 True FGF19, a fibroblast growth factor, is altered by amplification in various cancer types. The human fibroblast growth factor (FGF) family comprises 22 structurally related polypeptides that play crucial roles in neuronal functions, development, and metabolism. FGFs are classified as intracrine, paracrine, and endocrine FGFs based on their action mechanisms (PMID: 25772309). FGF19 is an endocrine FGF which require α-Klotho or β-Klotho as a cofactor for FGFRs. FGF19 activates FGFR4 with β-Klotho and exhibits metabolic and proliferative activities (PMID: 20018895, 26483756). FGF19 acts as a biomarker for Renal failure, coronary artery disease, intestinal failure-associated liver disease, diabetes, Crohn’s disease, and prostate cancer (PMID: 20013647, 24179013, 23940810, 25595885, 25664662, 23981126, 25518063, 25360305, 25854696). False +ENST00000608478 2247 FGF2 True FGF2, a fibroblast growth factor, is infrequently altered in cancer. FGF2, a member of the FGF family, encodes for a fibroblast growth factor which functions in regulating various cellular processes including differentiation, migration and survival (PMID: 28302677). FGF2 is a pleiotropic ligand that can signal through all FGFRs, activating various downstream pathways such as MAPK/ERK and PI3K/AKT signaling (PMID: 18318041). FGF2 additionally functions as an integrin ligand to promote angiogenesis and stem cell proliferation (PMID: 28302677). FGF2 exists as several isoforms that are generated via alternative translational initiation and differ in subcellular localization and signaling activity (PMID: 16615083). Overexpression of FGF2 in various cancer cell lines and models induces cellular proliferation and invasion, suggesting that FGF2 functions predominantly as an oncogene (PMID: 12898525, 10411093, 27473203, 28515962). FGF2 amplification has been identified in various cancers, including colorectal cancer, pancreatic cancer and prostate cancer (PMID: 27007053, 14522896). False +ENST00000237837 NM_020638 8074 FGF23 True FGF23, a fibroblast growth factor, is infrequently altered in cancer. FGF23, a member of the FGF family, encodes for a fibroblast growth factor primarily secreted by osteocytes and osteoblasts which functions in various cellular processes, including regulation of phosphate homeostasis and vitamin D metabolism (PMID: 15040831, 11062477). FGF23 interacts with αKlotho and FGFR1c to form the FGFR-Klotho complex to modulate phosphate transport and has been implicated in the pathophysiology of phosphate concentration disorders, such as chronic kidney disease (PMID: 32124925, 25326585, 19515808). Overexpression and exogenous expression of FGF23 in various cancer cell lines and models induces metastatic lesions and increased cellular proliferation, migration and invasion, suggesting that FGF23 functions predominantly as an oncogene (PMID: 36604721, 26019137, 28968431). Amplification of FGF23 has been identified in various types of cancer, including breast cancer, colorectal cancer and multiple myeloma (PMID: 31275898, 24574808, 25944690). False +ENST00000334134 NM_005247.2 2248 FGF3 True FGF3, a fibroblast growth factor, is altered by amplification in various cancer types. The human fibroblast growth factor (FGF) family comprises 22 structurally related polypeptides that play crucial roles in neuronal functions, development, and metabolism. FGFs are classified as intracrine, paracrine, and endocrine FGFs based on their action mechanisms (PMID: 25772309). FGF3 belongs to the FGF7 subfamily which includes FGF3, FGF7, FGF10 and FGF22 (PMID: 26369258). For inner ear, FGF3 has fallen into and out of favor as a potential ear-specific inducer. Excess FGF3 can induce the formation of extra otic vesicles (ear rings), whereas insufficient FGF3 can block their formation in chick (PMID: 10906788, 10769226). FGF3 has been identified as a main target of mouse mammary tumor virus (MMTV) insertional activation in mouse mammary tumors (PMID: 6327073). FGF3 specifically cooperate with WNT1 to induce the development of mouse mammary tumors (PMID: 9205106). Endogenous expression of FGF3 in MCF7 cells increases the tumorigenic potential (PMID: 10845805). False +ENST00000168712 NM_002007.2 2249 FGF4 True FGF4, an oncogenic growth factor, is amplified in a diverse range of cancers, most frequently in breast and head and neck cancers. FGF4 belongs to the human fibroblast growth factor family which was originally identified in NIH3T3 transfection assays using human stomach cancer or Kaposi sarcoma derived genomic DNA (PMID: 9715278). In adult and malignant tissues, FGF4 expression is tightly regulated. FGF4 expression is restricted to undifferentiated human embryonal carcinomas (ECs). During induced differentiation, FGF4 expression is repressed (PMID: 9715278). FGF4 gene amplification has been observed in numerous human carcinomas such as breast carcinomas, squamous cell carcinomas of the head and neck and the oesophagus, epithelial ovarian tumors and bladder cancers (PMID: 10368635, 9816285, 9380415, 1532244, 1361954). FGF4 plays a key role in the growth or maturation states of germ cell tumors which is supported by the finding FGF4 expression occurs in a subset of clinical germ cell tumors, especially in those presenting with advanced state (PMID: 1706218). False +ENST00000312465 NM_004464 2250 FGF5 True FGF5, a fibroblast growth factor, is infrequently altered in cancer. FGF5, a member of the FGF family, encodes for a fibroblastic growth factor which functions in regulating various cellular processes including proliferation, differentiation, migration and survival (PMID: 32848626, 27224250). FGF5 binds to receptors FGFR1 and FGFR2 to induce autophosphorylation and activate downstream signaling cascades (PMID: 8386828). FGF5 is an essential regulator of hair growth and has been implicated in early- to mid-stage pattern hair loss (PMID: 24989505, 28280377). Overexpression of FGF5 in various cancer cell lines and models induces cellular proliferation, tumor growth, decreased apoptosis and increased angiogenesis, suggesting that FGF5 functions predominantly as an oncogene (PMID: 31372048, 29152117, 29743851, 25998163). FGF5 amplification has been identified in various cancers, including renal cell cancer, prostate cancer and breast cancer (PMID: 11454700). False +ENST00000228837 NM_020996 2251 FGF6 True FGF6, a fibroblast growth factor, is infrequently altered in cancer. FGF6, a member of the FGF family, encodes for a fibroblast growth factor which functions in regulating various cellular processes including proliferation and differentiation (PMID: 15672378, 11991742, 36607240). FGF6 has been identified in skeletal muscle tissue to support tissue regeneration and promote myoblast migration and proliferation through interaction with FGFR4 (PMID: 9186055, 12769260). Exogenous expression of FGF6 in various types of cancer cell lines and models induces cellular proliferation and transformation, suggesting that FGF6 functions predominantly as an oncogene (PMID: 1549352, 10945637). FGF6 amplification has been identified in various types of cancer, including prostate cancer and head and neck squamous cell carcinoma (PMID: 25950492, 31123723). False +ENST00000267843 NM_002009 2252 FGF7 True FGF7, a fibroblast growth factor, is infrequently altered in cancer. FGF7, a member of the FGF family, encodes for a fibroblast growth factor that functions in regulating various cellular processes including embryogenesis, tissue repair and cellular growth (PMID: 15690149, 35806092, 8331296). FGF7 was identified as a keratinocyte growth factor due to prominent mitogenic activity in keratinocytes rather than fibroblasts and endothelial cells (PMID: 2915979). FGF7 functions as a ligand for FGFR2 to promote dimerization and activate various signaling pathways such as MAPK/ERK and PI3K/AKT signaling (PMID: 2475908, 24002438). Exogenous expression of FGF7 in gastric cancer cell lines and models induces cellular invasion and migration, suggesting that FGF7 functions predominantly as an oncogene (PMID: 28339036). FGF7 overexpression has been identified in urothelial carcinoma, ovarian cancer and fusion-positive rhabdomyosarcoma (PMID: 25623741, 38491511, 34850536). False +ENST00000344255 NM_033164 2253 FGF8 True FGF8, a fibroblast growth factor, is infrequently altered in cancer. FGF8, a member of the FGF family, encodes for a fibroblast growth factor that functions in regulating various cellular processes including cell division, growth and maturation (PMID: 16049112, 12574514). FGF8 functions as a ligand for FGFR1 to promote neuron formation, survival and migration during brain development (PMID: 35833364, 26634071). During embryogenesis, FGF8 has been identified as a key regulator for controlling the growth and differentiation of progenitor cells and directing limb outgrowth and patterning (PMID: 36205075, 37922914, 11101845). Overexpression of FGF8 in various cancer cell lines and models induces cell proliferation, invasion and migration, suggesting that FGF8 functions predominantly as an oncogene (PMID: 25473897, 18386787, 33649301). Overexpression of FGF8 has been identified in breast cancer, ovarian cancer and prostate cancer (PMID: 11953856, 37762545, 10348350). False +ENST00000382353 NM_002010 2254 FGF9 True FGF9, a fibroblast growth factor, is altered by amplification in colorectal cancer. FGF9, a member of the FGF family, encodes for a fibroblast growth factor that functions in regulating various cellular processes including cell division, growth and maturation (PMID: 8663044, 33529250, 35753346). FGF9 has been identified as a key regulator during embryogenesis for lung and skeletal development (PMID: 21750028, 12919696). FGF9 forms a positive feedback loop with SOX9 to promote prostate formation and regulate mammalian sex determination (PMID: 16700629). Overexpression of FGF9 in various cancer cell lines and models induces cell proliferation, migration and invasion, suggesting that FGF9 functions predominantly as an oncogene (PMID: 24334956, 34438248, 25925261). Amplification of FGF9 has been identified in colorectal cancer, and is suggested to mediate anti-EGFR therapy resistance (PMID: 26916220, 32104224, 24334956). False +ENST00000425967 NM_001174067.1 2260 FGFR1 True 1 FGFR1, a receptor tyrosine kinase, is altered by mutation, chromosomal rearrangement or amplification in various cancer types including lung and breast cancers. FGFR1 is a receptor tyrosine kinase that is a member of the fibroblast growth factor receptor (FGFR) family. Binding of FGF ligands to FGFR1 results in the rapid dimerization and activation of downstream signaling pathways including the PI3K/AKT and MAPK pathways (PMID: 16597617). FGFR1 is widely expressed and is necessary for a variety of cellular functions such as embryonic development, skeletogenesis, mitogenesis and differentiation. Cell-type specific FGFR1 regulation is dependent on tissue distribution and ligand availability (PMID: 16597617). Germline mutations in FGFR1 are associated with congenic disorders that present with physical malformations, mental retardation and neurologic deficits (PMID: 23812909). Amplifying or activating mutations in FGFR1 occur in varying frequency in multiple cancers including those of the lung, breast, prostate, head and neck and esophagus (PMID: 21160078, 20179196, 14614009, 16807070, 12147242). In metastatic renal cell carcinoma, FGF signaling mediates acquired treatment resistance from VEGF-directed therapies (PMID: 24387233). Currently, a number of small molecule inhibitors of the FGFR proteins are in use, with the major difference among them being their specificity to FGFR versus other receptor tyrosine kinases (RTKs) (PMID: PMID: 23696246, 24265351). False +ENST00000358487 NM_000141.4 2263 FGFR2 True 1 FGFR2, a receptor tyrosine kinase, is altered by mutation, chromosomal rearrangement or amplification in various cancer types. FGFR2 is a receptor tyrosine kinase that is a member of the fibroblast growth factor receptor (FGFR) family. Binding of FGF ligands to FGFR2 results in the rapid dimerization and activation of downstream signaling pathways including the PI3K/AKT and MAPK pathways (PMID: 28030802). FGFR2 is expressed in ectoderm-derived and endothelial tissues and FGFR2 signaling contributes to a variety of cellular functions including homeostasis, mitogenesis, proliferation and differentiation (PMID: 20094046). Germline mutations in FGFR2 have been identified in syndromes of craniosynostosis, which are characterized by abnormal bone development (PMID: 29392564). Single nucleotide polymorphisms in FGFR2 are linked to the development of ER-positive breast cancer, although the etiology remains unclear (PMID: 18437204). Somatic mutations, fusions and amplifications of FGFR2 have been identified in several human tumors including endometrial, gastric, and breast cancer as well as ameloblastomas (PMID: 18552176, 18636142, 28430863). Currently, a number of small molecule inhibitors of the FGFR proteins are in use, with the major difference among them being their specificity to FGFR versus other receptor tyrosine kinases (RTKs) (PMID: 23696246, 24265351). False +ENST00000260795 NM_000142.4 2261 FGFR3 True 1 FGFR3, a receptor tyrosine kinase, is altered by mutation, chromosomal rearrangement or amplification in various cancers, most frequently in bladder cancer. FGFR3 is a receptor tyrosine kinase that is a member of the fibroblast growth factor receptor (FGFR) family. Binding of FGF ligands to FGFR3 results in the rapid dimerization and activation of downstream signaling pathways including the PI3K/AKT and MAPK pathways (PMID: 28030802). FGFR3 is most highly expressed in neuronal and sensory cell types and FGFR3 signaling contributes to a variety of cellular functions including proliferation, differentiation, cell migration and apoptosis (PMID: 7542215, 20094046). Alternative splicing events in the FGFR3 gene generate two isoforms, FGFR3b and FGFR3c, which have unique tissue expression patterns and ligand-binding specificity (PMID: 8663044, 7512569). Germline mutations in FGFR3 have been identified in syndromes of craniosynostosis, which are characterized by abnormal bone development, in addition to skin and hair follicle disorders (PMID: 10541159, 17568799). Somatic activating mutations in FGFR3 have been identified in up to 70% of bladder cancers and in a low percentage of other solid tumor types (PMID: 11395371, 12743143, 16338952). In addition, a specific FGFR3 translocation is observed in approximately 15% of patients with multiple myeloma, resulting in constitutive expression of FGFR3 (PMID: 17107900). Currently, a number of small molecule inhibitors of the FGFR proteins are in use, with the major difference among them being their specificity to FGFR versus other receptor tyrosine kinases (RTKs) (PMID: PMID: 23696246, 24265351). False +ENST00000292408 NM_213647.1 2264 FGFR4 True FGFR4, a receptor tyrosine kinase, is altered by mutation, chromosomal rearrangement or amplification at low frequencies in various cancer types. FGFR4 is a receptor tyrosine kinase that is a member of the fibroblast growth factor receptor (FGFR) family. Binding of FGF ligands to FGFR4 results in the rapid dimerization and activation of downstream signaling pathways including the PI3K/AKT and MAPK pathways (PMID: 28030802, 10918587). FGFR4 is most highly expressed in liver and lung tissues and FGFR4 signaling contributes to a variety of cellular functions including proliferation, differentiation, and migration (PMID: 10918587). Germline mutations in FGFR4 have been identified in syndromes of craniosynostosis, which are characterized by abnormal bone development (PMID: 21395503). Somatic amplifications and activating mutations are found in rhabdomyosarcomas (PMID: 19809159) and rarely in other solid tumor types. In addition, overexpression of FGFR4 is associated with prostate, colon and liver cancer progression (PMID: 15655558, 23696849, 26498355). Currently, a number of small molecule inhibitors of the FGFR proteins are in use, with the major difference among them being their specificity to FGFR versus other receptor tyrosine kinases (RTKs) (PMID: PMID: 23696246, 24265351). False +ENST00000366560 NM_000143.3 2271 FH False FH is a tumor suppressor and an enzyme that converts fumurate to malate. Germline mutations of FH are associated with hereditary leiomyomatosis and renal cell cancer. FH (fumarate hydratase, also known as fumarase) is an enzyme that converts fumarate to malate as part of the tricarboxylic acid (TCA) cycle. FH exists in a mitochondrial and a cytosolic form, the former of which carries out FH's canonical role in the TCA cycle and the latter of which is likely involved in amino acid metabolism (PMID: 23643539, 14708972). The mitochondrial form of FH is determined by a C-terminal signal sequence (PMID: 18577574). Heterozygous germline mutations of FH cause hereditary leiomyomatosis and renal cell cancer (HLRCC), an autosomal dominant syndrome characterized by multiple cutaneous piloleiomyomas, uterine leiomyomas and papillary type 2 renal cancer (PMID: 20618355, 11865300, 15937070, 12772087, 16155190). Individuals with this disease are at risk for developing cutaneous and uterine leiomyomas, a form kidney cancer (PMID: 19470762). In HLRCC, tumor formation occurs following the inactivation of the wildtype allele, and therefore FH is classified as a tumor suppressor (PMID: 16155190, 20618355). Somatic FH mutations are sporadically found in other cancer types. The mechanism underlying FH-deficient disease is attributed to reduced or ablated FH enzymatic activity (PMID: 12761039, 14708972). True +ENST00000468189 NM_001166243 2272 FHIT False FHIT, a nucleoside triphosphatase, is infrequently altered in cancer. FHIT (Fragile Histidine Triad Diadenosine Triphosphatase) is a member of the histidine triad (HIT) nucleotide-binding superfamily and encodes for the protein P1-P3-bis(5'-adenosyl) triphosphate hydrolase involved in purine metabolism (PMID: 11562178, 19086848, 24370550). FHIT may also play a role in regulating the production of reactive oxygen species and genomic damage as it interacts with and stabilizes the mitochondrial flavoprotein ferredoxin reductase (FDXR) (PMID: 19086848). This gene is located on the FRA3B site of chromosome 3, where carcinogen-induced damage can cause gene loss leading to alterations in the DNA damage response and genomic instability (PMID: 11562178, 19086848, 24370550). The most common alterations in FHIT are deletions, DNA hypermethylation, abnormal transcripts, and reduced expression (PMID: 11562178, 24370550), and loss of FHIT has been documented in various cancers including lung, esophageal, cervical, and breast cancers (PMID: 19086848, 11562178, 30941950, 9823304). FHIT plays a role in cell proliferation and apoptosis as overexpression of FHIT in osteosarcoma cells results in inhibition of proliferation and increased apoptosis (PMID: 30655842). True +ENST00000285071 NM_144997.5 201163 FLCN False FLCN is a tumor suppressor and GTPase activating protein. Germline mutations of FLCN are associated with Birt-Hogg-Dubé syndrome and predispose to renal cell carcinomas. FLCN is a GTPase activating protein (GAP) for RagC/D GTPase proteins involved in amino acid sensing and signaling to mTORC1 (PMID:24095279). Varying cellular processes have been implicated with its function including regulation of oxidative metabolism at the mitochondria, mitochondrial biogenesis, and autophagy (PMID:23150719, 24762438, 25126726). Mutations can activate the mTOR pathway and AKT signaling (PMID:19850877, 24908670). FLCN mutations are found in Birt-Hogg-Dubé syndrome which is characterized by fibrofolliculomas, pneumothorax, and renal cell carcinomas (PMID: 22146830,15956655). Mutations have also been identified in gastric cancer (PMID:16870330). True +ENST00000527786 NM_002017.4 2313 FLI1 True 4 FLI1, a transcription factor of the ETS protein family, is frequently altered by chromosomal rearrangement in Ewing's Sarcoma. FLI1, an ETS family transcription factor, is expressed primarily in hematopoietic cells, where it regulates the expression of genes involved in lineage commitment and development (PMID: 11715049, 10891501). Specifically, FLI1 modulates the response of erythroid cells to erythropoietin (Epo), a major cytokine and regulator of erythropoiesis. FLI1 inhibits Epo-induced differentiation of primary erythroblasts by binding and transcriptionally repressing the retinoblastoma gene (Rb), previously shown to be required for the development of mature erythrocytes from progenitor cells, and instead promotes proliferation of these cells (PMID: 10330185, 24320889). FLI1 is most commonly altered in Ewing sarcoma, where the EWSR1-FLI1 gene fusion is the most common chromosomal alteration leading to aberrant FLI1 expression, transcriptional activity and cell transformation in this tumor type (PMID: 8246959, 7517940, 25453903, 10197607). False +ENST00000282397 NM_002019.4 2321 FLT1 True FLT1, a receptor tyrosine kinase involved in cell survival and tumor angiogenesis, is infrequently altered in cancer. FLT1 (also VEGFRA) is a cell surface receptor that is a member of the vascular endothelial growth factor (VEGF) pathway. Binding of the VEGF ligand, VEGFA, to FLT1 activates pathway signaling, which in turn regulates angiogenesis, cell survival, migration and invasion (PMID: 20127948). In addition, the VEGFA-FLT1 complex has been shown to activate mitogen-activated protein kinase (MAPK) and PI3K/AKT signaling, and thus aberrant activation promotes tumor survival (PMID: 16116481, 20127948). FLT1 has also been shown to rescue tumor cells from hypoxia-induced stress (PMID: 16103078) and to regulate inflammatory response genes in macrophages associated with metastases (PMID: 26261265). Somatic mutations in FLT1 have been identified in a variety of tumor types, however, the impact of these alterations are not well-studied (PMID: 19718025, CBioPortal, MSKCC, March 2018). FLT1 overexpression and activation have been associated with increased transformation and invasion in colorectal, pancreatic, and breast cancer models (PMID: 14521839, 16397214, 16671089). A monoclonal antibody targeting FLT1, icrucumab, is currently being tested in clinical trials (PMID: 23903897). False +ENST00000241453 NM_004119.2 2322 FLT3 True 1 FLT3, a receptor tyrosine kinase, is recurrently altered in acute myeloid leukemia and other hematologic malignancies. FLT3 is a transmembrane receptor tyrosine kinase that predominantly functions in the regulation of hematopoiesis (PMID: 12032772). FLT3 is activated following dimerization and autophosphorylation upon binding to its ligand, FLT3L. Activation of FLT3 results in downstream signaling via several pathways including the MAPK, PI3K/AKT and STAT3/5 pathways, which have key roles in hematopoietic proliferation, differentiation and survival (PMID: 23631653, 12951584). Wildtype FLT3 is important for the growth and differentiation of hematopoietic stem cells and is commonly expressed on immature myeloid and lymphoid cells (PMID: 12951584). FLT3 alterations occur in acute myeloid leukemia (AML), most commonly presenting as FLT3 internal tandem duplications (FLT3-ITD) in about 25% of AMLs or point mutations in the tyrosine kinase domain in about 7% of AMLs (PMID: 24319184). FLT3-ITD expression in murine models is not sufficient to cause leukemogenesis, however, additional oncogenic alterations cooperate with overactivation of FLT3 to cause malignancy (PMID: 25873173). FLT3 small molecule kinase inhibitors have been developed and are currently being tested in clinical trials, both alone and in combination with other epigenetic inhibitors (PMID: 24682858, 28193779). False +ENST00000261937 NM_182925.4 2324 FLT4 True FLT4, a receptor tyrosine kinase, is infrequently altered by mutation in a variety of cancer types. FLT4 (also VEGFR3) is a cell surface receptor that is a member of the vascular endothelial growth factor (VEGF) pathway. Binding of the VEGF ligands, VEGF-C or VEGF-D, to FLT4 activates pathway signaling, which in turn mediates cell proliferation, survival, invasion, and resistance to chemotherapy in leukemia (PMID: 11877295, 16530705). In addition, FLT4 is a critical regulator of lymphangiogenesis and is necessary for the maintenance of the lymphatic endothelium (PMID: 10762646). Germline mutations in FLT4 have been identified in hereditary Nonne-Milroy disease, an autosomal dominant form of primary lymphedema type IA (PMID: 11292664). Aberrant FLT4 expression has been observed in several tumor types including lung adenocarcinoma (PMID: 12875690) and colorectal adenocarcinoma (PMID: 12168824), among others, and has been shown to be hypermethylated in clear cell renal cell carcinomas (PMID: 28754676). However, somatic mutations in FLT4 are not common in human cancers. False +ENST00000256999 NM_004476 2346 FOLH1 True FOLH1, a glutamate carboxypeptidase, is infrequently altered in cancer. FOLH1, also known as PSMA, encodes for a type II transmembrane glycoprotein that is part of the M28 peptidase family (PMID: 29025989). FOLH1 functions as a glutamate carboxypeptidase and catalyzes hydrolytic cleavage of glutamates from peptides and small molecules (PMID: 15837926). The enzymatic activity of FOLH1 has been utilized for the design of FOLH1-selective substrate drugs, such as methotrexate, in which the inactive glutamate form of the drug is cleaved and activated only in tissue expressing FOLH1 (PMID: 15837926, 33499427, 33782486). Overexpression of FOLH1 in various cancer cell lines induces cell proliferation and invasion, suggesting that FOLH1 functions predominantly as an oncogene (PMID: 33748101, 24571890). FOLH1 amplification has been identified in various cancers, including prostate cancer, hepatocellular carcinoma and colorectal cancer (PMID: 10397265, 31289613, 19716160). False +ENST00000312293 NM_000802 2348 FOLR1 True FOLR1, a folate transport protein, is altered by amplification in various cancer types. FOLR1, also known as folate receptor α (FRα), is a folate transport protein anchored in the cell membrane that is crucial for one-carbon folate metabolism, a process that provides precursor molecules for nucleic acid synthesis, methylation and DNA repair (PMID: 27641100, 23822983, 27248175). In addition to its role in one-carbon folate metabolism, FOLR1 also interacts with the JAK–STAT3 and ERK1/2 pathways as a signaling molecule (PMID: 35094917). FOLR1 is normally expressed in low levels in select types of epithelial cells (PMID: 25564455). Overexpression of FOLR1 increases folate uptake from the extracellular environment, which in turn provides a growth advantage to cells that facilitates rapid proliferation (PMID: 36426547, 25816016). However, even when FOLR1 is overexpressed, extracellular folate is primarily imported by another type of folate transport system called the reduced folate carrier, indicating that FOLR1 overexpression doesn’t significantly raise intracellular folate levels (PMID: 37711615). Therefore, FOLR1 overexpression may drive tumor growth by other mechanisms, such as activation of the JAK–STAT3 and ERK1/2 pathways (PMID: 35094917, 28782518). FOLR1 overexpression is associated with a less favorable prognosis in patients with rectal cancer and cervical cancer, suggesting it may play a role as an oncogene (PMID: 36426547, 36245230). FOLR1 is overexpressed in various cancers including ovarian, uterine, brain, breast, endometrial, and lung cancers (PMID: 36426547, 36245230, 15745749). Mirvetuximab soravtansine-gynx, an antibody-drug conjugate targeting FOLR1, is FDA-approved for the treatment of FRα-positive, platinum-resistant epithelial ovarian, fallopian tube or primary peritoneal adult cancer patients treated with up to three prior therapies (PMID: 37711615, 38055253). False +ENST00000250448 NM_004496.3 3169 FOXA1 True FOXA1, a transcription factor, is recurrently altered in prostate and breast cancers. FOXA1 is a member of the Forkhead domain containing (FKHD) family of transcription factors (PMID: 19274050). FOXA1 binds to genomic DNA via the N-terminus of the protein and interacts with histone molecules via the C-terminal transactivating domain. Binding of FOXA1 to core histones H3/H4 facilitates the “pioneering activity” of FOXA1 by opening regions of condensed chromatin (PMID: 16909212); this allows for the recruitment of other transcription factors, including the androgen receptor (AR) and estrogen receptor (ER) (PMID: 21934649). FOXA1 is normally expressed in a number of tissue types, including lung, liver, pancreas, colon, bladder, prostate and breast (PMID: 22115363). Expression of FOXA1 is required for normal prostate development and maturation, prostate specific gene expression and cellular differentiation through its direct interaction with AR and modulation of AR signaling (PMID: 15987773, 21934649, 22649425, 18358809). Luminal-specific deletion of FOXA1 in the mouse prostate results in high rates of epithelial cell proliferation and increased expression of basal cell markers (PMID: 24840332), indicating that FOXA1 may play a role in promoting and maintaining epithelial cell differentiation. FOXA1 is also required for normal mammary ductal morphogenesis and expression of ERα (PMID: 20501593). FOXA1 has emerged as one of the most frequent recurrently mutated genes in hormone-dependent cancers including primary and metastatic castration-resistant prostate cancer (CRPC) and breast cancer (PMID: 25470049, 23000897,22495314). FOXA1 is also frequently mutated in urothelial bladder carcinoma and amplified in a number of other tumor types (PMID: 24476821). Somatic FOXA1 mutations predominantly map to the DNA-binding domain, suggesting that they function as loss-of-function alterations (PMID: 25470049, 23000897, 22495314). True +ENST00000262426 NM_001451.2 2294 FOXF1 True FOXF1, a transcription factor, is infrequently altered by mutation in various cancer types. FOXF1 is a transcription factor that is a member of the forkhead protein family (PMID: 29162563). FOXF1 functions as a master regulator of gene expression and cellular identity in several tissues, including in the developing lung (PMID: 28797033, 28878348, 30153454, 26293303). In addition, FOXF1 has been implicated in a variety of cellular activities including ciliogenesis, cellular proliferation, extracellular matrix remodeling, and metastasis (PMID: 30950350, 28623323). Sporadic and familial mutations in FOXF1 have been implicated in alveolar capillary dysplasia with misaligned pulmonary veins (ACDMPV), a congenital disease that results in respiratory failure (PMID: 31199666, 31074124, 30380203,27071622, 23505205). These FOXF1 alterations are loss-of-function and lead to loss of STAT3-FOXF1 protein interactions and reduced chromatin binding (PMID: 31199666). FOXF1 activity has been found to be both increased and decreased in a variety of cancers, suggesting that FOXF1 may function as a tumor suppressor or oncogene depending on the cellular context (PMID: 27165781, 30253191, 30189360, 28623323, 27042124). In Gastrointestinal stromal tumors (GIST), FOXF1 regulates the expression of two genes, KIT and ETV1, by recruiting them to relevant target genes (PMID: 29162563). Loss of FOXF1 results in reduced GIST cellular proliferation and loss of KIT and ETV1 targeting to enhancers in GIST cells (PMID: 29162563). True +ENST00000330315 NM_023067.3 668 FOXL2 True FOXL2, a transcription factor, is recurrently mutated in adult granulosa cell tumors. FOXL2 is a member of the Forkhead domain containing (FKHD) family of transcription factors (PMID: 15492844). FOXL2 contains a DNA binding domain allowing the protein to bind DNA and subsequently regulate gene expression and mediate the recruitment of other transcription factors (PMID: 15492844). Expression of FOXL2 is the highest in ovarian granulosa cells and is essential for granulosa cell differentiation and ovarian development; FOXL2 is also expressed in the pituitary gland and periocular region (PMID: 24817949). Through interaction with other transcription factors and tumor suppressors, FOXL2 regulates several cell processes, including apoptosis, cell cycle progression and cell adhesion (PMID: 19747961). In addition, FOXL2 has a role in the suppression of SOX9 expression during testes formation (PMID: 28193729). As a potential tumor suppressor, FOXL2 has been shown to inhibit cervical squamous cancer cell proliferation and invasion, while promoting apoptosis (PMID: 24817949). Reduced expression of FOXL2 has also been noted in a majority of juvenile ovarian granulosa cell tumors and somatic FOXL2 alterations have been associated with adult granulosa cell tumors. (PMID: 23372819, 23029457, 24342437). True +ENST00000299162 NM_213596 121643 FOXN4 True FOXN4, a transcription factor, is recurrently altered by amplification in lung adenocarcinoma. FOXN4, a member of the forkhead box family of transcription factors, encodes for a transcription factor that functions in regulating neural and non-neural tissue development by upregulating angiogenic growth factor expression (PMID: 15464224, 21438071, 15363391). FOXN4 modulates NOTCH signaling through interaction with transcription factor ASCL1 to mediate BMP/TGFβ signaling (PMID: 24257627). FOXN4 is considered a candidate prognostic biomarker for lung adenocarcinoma (PMID: 33447073). Overexpression of FOXN4 in lung adenocarcinoma cell lines induces downregulation of EGFR expression, a commonly observed phenotype in transformed small-cell lung cancer (PMID: 34155000). FOXN4 upregulation has been observed in lung adenocarcinoma cell lines following treatment with osimertinib (PMID: 34155000). False +ENST00000379561 NM_002015.3 2308 FOXO1 False FOXO1, a transcription factor, is recurrently altered by mutation in hematologic malignancies and by deletion in prostate cancer. FOXO1 is a member of the Forkhead box O (FoxO) transcription factor superfamily. FOXO transcription factors can regulate cell fate by modulating the expression of genes involved in a variety of cellular processes including: apoptosis, cell cycle, DNA repair, oxidative stress and longevity, and control of muscle growth, as well as cell differentiation and glucose metabolism (PMID: 15137936, 15860415, 16288288, 17646672). FOXO1 plays an important role in the regulation of adipogenesis and differentiation of preadipocytes by binding to the promoter of PPARG, a key mediator of adipogenesis initiation (PMID: 12530968). In addition, FOXO1 is critical for regulating gluconeogenesis via insulin signaling (PMID: 10702299) and for maintaining pluripotency in human embryonic stem cells (PMID: 24116102). FOXO1 activity is repressed after phosphorylation by AKT, leading to exclusion of FOXO1 from the nucleus and, in some contexts, apoptosis (PMID: 17646672). CDK2-mediated phosphorylation of FOXO1 is also important for the regulation of cell cycle progression (PMID:17038621). Chromosomal FOXO1 translocations have been identified in alveolar rhabdomyosarcoma, a skeletal-muscle tumor that is prevalent in children (PMID: 17646672, 8275086). Loss-of-function FOXO1 mutations have been identified in diffuse large B cell lymphomas (DLBCLs) and FOXO1 is frequently inactivated in prostate cancers (PMID: 28986382). True +ENST00000343882 NM_001455 2309 FOXO3 False FOXO3, a transcription factor, is infrequently altered in cancer. FOXO3, a member of the class ‘O’ subfamily of the forkhead family of proteins, encodes for a DNA-binding transcriptional activator that functions in regulating cellular processes such as autophagy and apoptosis (PMID: 10102273, 16751106). FOXO transcription factors can regulate cell fate by modulating the expression of genes involved in a variety of cellular processes including apoptosis, cell cycle progression, DNA repair, oxidative stress and longevity, and control of muscle growth, as well as cell differentiation and glucose metabolism (PMID: 15137936, 15860415, 16288288, 17646672). FOXO3 functions at the G2/M-phase in the cell cycle progression as an activator of the DNA-damage repair response through interaction with growth arrest protein GADD45A (PMID: 11964479). The cellular proliferative signaling pathways controlled by FOXO3 are negatively regulated by various signaling pathways, including PI3K and ERK, in response to external stimuli (PMID: 18601916, 18204439). Overexpression of FOXO3 in breast cancer models and endothelial progenitor cells suppresses cellular proliferation, suggesting that FOXO3 functions predominantly as a tumor suppressor (PMID: 18312651, 15084260, 25093499). Downregulation of FOXO3 has been identified in various types of cancer, including glioma and ovarian cancer (PMID: 19911116, 19160093). Preclinical studies of colorectal cancer cell lines suggest that upregulated FOXO3 expression confers resistance to cetuximab (PMID: 27825133, 27685445). False +ENST00000318789 NM_001244814.1 27086 FOXP1 True FOXP1, a transcription factor, is infrequently altered by translocation in lymphomas. FOXP1 is a DNA binding protein that is a member of the P subfamily of forkhead box transcription factors and primarily functions as a transcriptional repressor (PMID: 10702024, 23792361, 23792361). FOXP1 regulates cell-type specific gene expression programs by binding to regulatory units and recruiting histone deacetylases and other cofactors (PMID: 22124370, 20185820). FOXP1 is required for thymocyte development, the generation of naïve T cells, and the development of lung and esophageal tissue (PMID: 19965654, 17428829). FOXP1 loss has been observed in a range of cancer types, including tumors of the kidney, liver, breast, and endometrium (PMID: 23792361, 16258506, 21210727, 15161711, 21901488, 22904134, 11751404). FOXP1 has also been found to be overexpressed in diffuse large B-cell lymphomas and hepatocellular carcinoma, demonstrating that the impact of FOXP1 alterations is context specific (PMID: 19706818, 15709173, 22422806). FOXP1 is part of a translocation observed in the MALT subtype of lymphomas (PMID: 15703784, 20950788, 24214399, 18487996). True +ENST00000397997 NM_001042555 10818 FRS2 True FRS2, an adaptor protein, is altered by amplification in various cancers. FRS2 encodes for a signal transducing adaptor protein, which functions in linking activated receptor tyrosine kinases to downstream signaling pathways (PMID: 10629055). FRS2 has been identified to link FGFR and EGFR signaling with the MAPK signaling cascade (PMID: 12974390, 10629055). Phosphorylation of FRS2 is regulated by receptor tyrosine kinases and allows for activation of various signaling pathways, including ERK, PI3K and protein ubiquitination pathways (PMID: 23782834). Overexpression of FRS2 in various cancer cell lines and models induces anchorage-independent cellular proliferation, tumor growth and angiogenesis, suggesting that FRS2 functions predominantly as an oncogene (PMID: 25368431, 30755618, 26096936, 23393200). Amplification of FRS2 has been identified in various cancers, including ovarian cancer, bladder cancer and osteosarcoma (PMID: 25368431, 30755618, 30001240). False +ENST00000295633 NM_007085 11167 FSTL1 True FSTL1, a secreted glycoprotein, is infrequently altered in cancer. FSTL1, a member of the follistatin protein family, encodes for a secreted glycoprotein that functions in various cellular and physiological processes such as angiogenesis, organogenesis, cellular differentiation and immune cell response (PMID: 22265692, 17129766). FSTL1 binds directly to BMP4 and TLR4 and regulates the TLR4/NFkB/BMP signaling axis to modulate immune response, cellular survival and differentiation (PMID: 26365350, 21482757, 28883005). The oncogenic role of FSTL1 is likely tissue type specific. Overexpression of FSTL1 in glioma and gastric cancer cell lines induces increased cellular proliferation, migration and invasion, suggesting that FSTL1 predominantly functions as an oncogene in these tissues (PMID: 29212066, 33791149). Amplification of FSTL1 has been identified in various different cancer types, including glioblastoma, esophageal squamous cell carcinoma and prostate cancer (PMID: 18483363, 28883005, 27976415). Conversely, ectopic expression of FSTL1 in ovarian cancer and nasopharyngeal carcinoma cell lines suppresses cellular proliferation, migration and invasion (PMID: 18796737, 26918942). Downregulation of FSTL1 has also been identified in various different cancer types including clear cell renal cell carcinoma and lung cancer (PMID: 18546293, 21718795, 31653686). Upregulated FSTL1 expression is suggested to confer enhanced chemoresistance in breast cancer and esophageal squamous cell carcinoma (PMID: 30336071, 28883005). False +ENST00000370768 NM_003902.3 8880 FUBP1 False FUBP1, a tumor suppressor and single-stranded DNA binding protein, is recurrently inactivated by mutation or deletion in glioma. The protein FUBP1, binds single-stranded DNA, including regulatory DNA elements upstream of genes. Among the motifs it binds is the far upstream element (FUSE), which is located upstream of the MYC oncogene (PMID: 22926519). Regulation of MYC by FUBP1 is complex; while overexpression of FUBP1 can activate transcription of the MYC gene, it has also been reported that inactivating mutations of FUBP1 activate MYC expression (PMID: 20420426). FUBP1 is also known to bind RNA (PMID: 23818605), such as in order to regulate the splicing of MDM2, an important negative regulator of the tumor suppressor TP53 (PMID: 24798327). FUBP1 was reported to be mutated at relatively low frequency (<8%) across a variety of cancers (cBioPortal, Nov 3, 2015). It is most frequently mutated in gliomas, which also show frequent deletion of 1p, where the FUBP1 gene is located (PMID: 22869205, 21817013). True +ENST00000268171 NM_001289823.1 5045 FURIN True FURIN, a protease involved in precursor protein cleavage, is infrequently altered in a diverse range of cancers. FURIN is a proprotein convertase that cleaves precursor proteins after translation (PMID: 12360192). FURIN functions as a serine endonuclease that cleaves proteins at basic amino acid sequences in order to convert a preprocessed protein to an activated state (PMID: 12360192). Many FURIN substrates have been identified including precursors for TGF-β, NOTCH1, hormones, metalloproteinases, and cytokines, among others (PMID: 16627761, 12360192, 28821477). In addition, FURIN is required for the proteolytic processing of viral glycoproteins including the proteins that compose the HIV and influenza viral envelopes (PMID: 10707087, 10087614). FURIN is localized to the Golgi and is ubiquitously expressed, but its upregulation during T cell activation plays a key role in STAT transcription factor signaling and peripheral tolerance (PMID: 18701887, 16627761). Because FURIN regulates the processing of a variety of proteins, FURIN is implicated in many cellular functions including signaling, cell proliferation and metastasis (PMID: 18064302). Somatic mutations in FURIN are rare; however, overexpression of FURIN has been identified in several tumor types, including head and neck cancers (PMID: 28369813). Increased expression of FURIN has been associated with metastasis in various tumor types and several FURIN inhibitors are currently in preclinical testing (PMID: 18064302, 28369813). False +ENST00000254108 NM_004960 2521 FUS True FUS, a DNA- and RNA-binding protein, is altered by chromosomal rearrangement in cancer. FUS, also known as TLS, is a DNA- and RNA-binding protein that is a part of the FET/TET heterogeneous nuclear ribonucleoprotein particle protein family (PMID: 22081015). FUS binds to both RNA and DNA through its N-terminus to regulate various cellular processes including cell proliferation, DNA repair, transcription regulation, RNA splicing and RNA transport (PMID: 25494299,19783543, 19674978). Selective knockdown of FUS in cancer cell lines results in impaired cellular proliferation and increased mitotic arrest, suggesting that FUS predominantly functions as an oncogene (PMID: 25501833). Overexpression and chromosomal rearrangements of FUS have been identified in various cancers, including non-small cell lung cancer, Ewing's sarcoma and acute myeloid leukemia (PMID: 30008867, 12907633, 8187069). False +ENST00000368678 NM_153047.3 2534 FYN True FYN, a receptor tyrosine kinase, is altered by mutation in a variety of cancer types including hematologic malignancies and cholangiocarcinomas. FYN is a membrane-associated tyrosine kinase that regulates cellular processes including cytoskeletal remodeling, cell adhesion, integrin signaling, proliferation, immune response and axon guidance (PMID: 10228160, 7617039, 12372285, 20658524, 15781574). FYN-mediated oncogenic signaling has been implicated in tumor progression by mediating cell proliferation, invasion, and metastasis (PMID: 26624980, 21480388). FYN activity is associated with the activation of oncogenic signaling in tumor cells including the EGFR pathway in glioblastomas and the FLT3 pathway in leukemias (PMID:19690143, 26848862, 24882577,19567819). Activating FYN mutations have been identified in peripheral T-cell lymphomas and cholangiocarcinomas, suggesting that FYN acts as an oncogene (PMID: 24413734, 26437031, 25526346). Kinase inhibitors targeting FYN are in development (PMID: 26493492, 24976598, 21813412). False +ENST00000395095 NM_001136198 51343 FZR1 True FZR1, an adaptor protein involved in cell cycle progression, is infrequently altered in cancer. FZR1, also known as CDH1, encodes an adaptor protein for the E3 ubiquitin ligase anaphase promoting complex/cyclosome (APC/C) (PMID: 18598214). The APC/C functions in cell cycle regulation through promoting mitotic exit, maintaining G1 phase and allowing entry into the S phase (PMID: 7787245). FZR1 activates APC/C through recognition of the KEN box consensus motif, allowing binding during the late meiotic phase until G1/S transition (PMID: 25349192). Functional studies using human-derived cell lines demonstrated FZR1 plays a regulatory role in DNA repair through the downregulation of CtIP, a DNA end resection factor protein, in late G2/S phase of the cell cycle (PMID: 25349192). The tumor suppressive role of FZR1 has been demonstrated through in vitro functional assays in human-derived cell lines as measured by FZR1 negatively regulating BRAF oncogenic function through proteolysis and dimerization disruption (PMID: 28174173). Loss of function FZR1 mutations have been identified in colorectal cancer, melanoma and glioma (PMID: 18535175, 28174173, 18662541). Conversely, human-derived xenograft models of colorectal cancer demonstrated an oncogenic role for FZR1 as measured by oncogenic phosphatase PRL-3-mediated aberrant activation of FZR1, promoting tumor growth (PMID: 30498084). In vitro studies with knocked down FZR1 in multiple myeloma cell lines also demonstrated tumor growth arrest (PMID: 27655696). Amplification of FZR1 has been identified in B-cell acute lymphoblastic leukemia and multiple myeloma (PMID: 28143883, 27655696). Rearrangement of FZR1 has been identified in breast cancer and lung adenocarcinoma (PMID: 25500544). True +ENST00000262994 NM_002039.3 2549 GAB1 True GAB1, a signaling adaptor molecule, is altered by mutation in various cancer types including breast cancer. GAB1 is an adaptor protein that is a member of the IRS1-like docking protein family (PMID: 19737390). GAB1 functions as a signaling effector molecule that localizes to the plasma membrane via interactions with the phospholipid PIP3, resulting in phosphorylation-dependent activity in response to growth factor or cytokine stimulation (PMID: 25460044). The association of GAB1 with adaptor molecules (such as GRB2) and with receptor tyrosine kinases (such as MET and EGFR) is required for the activation of downstream signaling cascades (PMID: 9356464, 9444958, 9658397). In addition, GAB1 mediates the activity and recruitment of intracellular kinases such as PI3K and the MAPK pathway (PMID: 9632795). Sophisticated positive and negative feedback mechanisms control the binding of GAB1 to signaling complexes, which can lead to alternate downstream signaling pathway activation (PMID: 18025104). The activity of GAB1 is important for a variety of cellular functions including the regulation of proliferation, migration, and survival (PMID: 19737390). Rare somatic mutations in GAB1 are found in breast cancers, resulting in increased cytokine-independent oncogenic signaling (PMID: 22751113, 16959974). Overexpression of GAB1 has been identified in several cancer types and aberrant GAB1 activity is associated with resistance mechanisms in BRAF-mutant melanomas due to altered feedback regulation of MET signaling (PMID: 28147313, 17463250, 17312329). False +ENST00000361507 NM_080491.2 9846 GAB2 True GAB2, a signaling adaptor molecule, is altered by amplification and overexpression in various cancer types. GAB2 is an adaptor protein that is a member of the IRS1-like docking protein family (PMID: 19737390). GAB2 functions as a signaling effector molecule that localizes to the plasma membrane via interactions with membrane phospholipids and signaling receptor kinases, resulting in phosphorylation-dependent activity in response to growth factor or cytokine stimulation (PMID: 16369543). The association of GAB2 with adaptor molecules (such as GAB1 and GRB2) and with receptor tyrosine kinases (such as ERBB2 and EGFR) is required for the activation of downstream signaling cascades (PMID: 9356464, 9444958, 9658397). In addition, GAB2 mediates the activity and recruitment of intracellular kinases such as PI3K and the MAPK pathway (PMID: 9632795, 23401857). Sophisticated positive and negative feedback mechanisms control the binding of GAB2 to signaling complexes, which can lead to alternate downstream signaling pathway activation (PMID: 28096188). The activity of GAB2 is important for a variety of cellular functions including the regulation of proliferation, apoptosis, migration and survival (PMID: 19737390). Expression of GAB2 in murine models has been associated with the proliferation of breast cancer cells and promotion of metastasis (PMID: 17310989, 16369543). Amplification and overexpression of GAB2 have been identified in several cancer types, including ovarian and breast cancers, among others (PMID: 18314909, 19509136, 19881546, 23362323, 24385586). False +ENST00000274545 NM_000811 2559 GABRA6 True GABRA6, a subunit of the GABA-A receptor, is infrequently altered in cancer. GABRA6 encodes for a subunit of the GABA-A receptors, which function as ligand-gated chloride channels for the inhibitory neurotransmitter GABA (PMID: 8904987, 10195814). The GABA-A receptors are pentamers that are formed through interaction between 19 possible subunits from distinct subunit classes (PMID: 15258161). GABRA6 is selectively expressed in granule neurons and expression is regulated by NFI binding to the GABRA6 promoter (PMID: 2167378, 15466411). GABAergic signaling, the main inhibitory neurotransmitter system signaling in the central nervous system involving the GABA-A receptor, has been identified to regulate tumor immunity and promote tumorigenesis outside of the central nervous system in various cancer models, suggesting that GABRA6 may function predominantly as an oncogene as a subunit of the GABA-A receptor (PMID: 28524180, 24657659, 32964961). False +ENST00000376670 NM_002049.3 2623 GATA1 False GATA1, a transcription factor involved in red blood cell and platelet development, is altered in several hematologic malignancies including transient leukemia and acute megakaryoblastic leukemia. GATA1 is a transcription factor that functions as a master regulator of hematopoietic differentiation (PMID: 1987478). GATA1 activates the expression of many important genes involved in erythroid and megakaryocyte development (PMID:7568185, 7823932), including the beta-globin gene and erythropoietin receptor (PMID:1924329, 1660143). Appropriate expression of GATA1 in hematopoietic progenitor cells is critical for the maturation of red blood cells, megakaryocytes, mast cells and eosinophils (PMID: 15659348). Loss of GATA1 expression in murine models suppresses the production of red blood cells (PMID: 8901585), highlighting the importance of GATA1 expression in erythroid development. Germline mutations in GATA1 are associated with anemia, thrombocytopenia and porphyria (PMID: 10700180, 11675338, 16783379, 17148589). Inherited GATA1 mutations have been implicated in Diamond Blackfan anemia due to the reduced translation of GATA1 protein (PMID: 24952648). GATA1 mutations observed in Down Syndrome patients are associated with acute megakaryocytic leukemia development and transient myeloid disorders (PMID: 12172547, 12747884). Reduced expression of GATA1 corresponds with the development of hematopoietic malignancies due to inadequate production of erythroid cell types (PMID: 12149188). Recurrent GATA1 rearrangements are found in patients with acute basophilic leukemia (PMID: 21474671). False +ENST00000341105 NM_032638.4 2624 GATA2 True GATA2 is a transcription factor involved in red blood cell and platelet development. Germline mutations of GATA2 are associated with Emberger and MonoMAC syndromes and predispose to leukemias. GATA2 encodes for a DNA-binding transcription factor that functions as a master regulator of hematopoiesis through activation of genes involved in hematopoietic differentiation, including those involved in stem cell maintenance and cell specification (PMID:8078582, 12433372, 25578878, 20887958). In addition, GATA2 has been implicated in the regulation of angiogenesis and lymphangiogenesis (PMID:23892628). Appropriate expression of GATA2 is required in hematopoietic stem and progenitor cells to initiate hematopoietic lineage specification (PMID: 28179280). GATA2 regulates the activation of GATA1, a process termed the “GATA switch”, which then ultimately results in the repression of GATA2 (PMID: 12857954). Germline GATA2 mutations are associated with familial myelodysplastic syndrome, acute myeloid leukemia (AML) and Emberger syndrome, a heritable lymphedema disorder associated with a predisposition to AML (PMID: 21892162, 21892158). Inherited GATA2 mutations are also found in patients with MonoMAC syndrome, an immunodeficiency disorder leading to vulnerability to select infectious agents (PMID: 21670465). The oncogenic function of GATA2 may be tissue-specific. Overexpression of GATA2 in prostate cancer cell lines and models induces cellular invasion and metastasis, suggesting that GATA2 functions predominantly as an oncogene in this tissue-specific context (PMID: 37550764, 24448395). Conversely, GATA2 deficiency in murine models induces suppression of definitive hematopoiesis and cellular proliferation, suggesting that GATA2 functions predominantly as a tumor suppressor gene in this tissue-specific context (PMID: 8078582, 34496012). Somatic GATA2 mutations are found in leukemias and myelodysplastic syndromes and often co-occur with CEBPA mutations (PMID: 23634996, 22649106, 23521373,18250304). GATA2-EV1 translocations have been identified in patients with inversion 3 leukemias (PMID:24703711). In solid tumors, GATA2 expression has been linked with regulation of Ras signaling and metastasis (PMID: 22541434, 25670080, 24448395, 25707769). True +ENST00000346208 NM_002051.2 2625 GATA3 True GATA3, a transcription factor, is altered by mutation or amplification in various cancers, most frequently in breast cancer. GATA3 is a DNA binding protein that controls the development of diverse tissues by activating or repressing transcription of genes important in cell proliferation and differentiation (PMID: 21779441, 19798694). GATA3 regulation has cell-type specific effects on gene expression and is expressed in both hematopoietic and non-hematopoietic tissues (PMID: 12923059, 17129787, 19112489). Haploinsufficiency of GATA3 results in the autosomal dominant HDR (hypoparathyroidism, deafness, and renaldysplasia) syndrome, also known as Barakat syndrome (PMID: 10935639). GATA3 expression is essential in the development of normal mammary epithelium in mice and humans and plays a key role in the pathogenesis of luminal breast cancer (reviewed in PMID: 21779441, 19798694). Gain-of-function and loss-of-function GATA3 mutations have been identified in breast cancer, suggesting that in different contexts GATA3 may function as either an oncogene or tumor suppressor (PMID: 27588951). True +ENST00000335135 NM_002052 2626 GATA4 False GATA4, a transcription factor, is altered by silencing in colorectal cancer and lung cancer. GATA4 encodes for a DNA-binding transcription factor which primarily functions in regulation of embryogenesis and cardiogenesis (PMID: 9367431, 30530745, 27984724). GATA4 co-operates with TBX5 to promote cardiomyocyte gene expression and downregulate endothelial gene expression (PMID: 27984724). The expression of GATA4 is suggested to denote that an epithelial cell is fully differentiated (PMID: 21779441). Downregulation of GATA4 in various types of cancer cell lines and models induces tumor growth, colony formation and cellular proliferation, suggesting that GATA4 functions predominantly as a tumor suppressor gene (PMID: 35017504, 30971692, 31903133, 30142155). Hypermethylation of GATA4 has been identified in colorectal cancer and lung cancer (PMID: 19509152, 15585625). True +ENST00000269216 NM_005257 2627 GATA6 True GATA6, a transcription factor, is infrequently altered in cancer. GATA6 encodes for a DNA-binding transcription factor that functions in the development of diverse tissues through transcriptional activation or repression of genes involved in cellular proliferation and differentiation (PMID: 22824924, 22750565, 27756709, 22733991). GATA6 functions in early and later embryogenesis and ​​organogenesis as a regulator for gut, lung and heart development (PMID: 20581743, 18405344, 11959831). Overexpression of GATA6 in various cancer cell lines and models induces epithelial-mesenchymal transition, cellular proliferation and cell cycle progression, suggesting that GATA6 functions predominantly as an oncogene (PMID: 33060563, 26505174, 30194255). GATA6 amplification has been identified in various types of cancer, including esophageal adenocarcinoma, pancreatic cancer and cholangiocarcinoma (PMID: 33300112, 27325420, 33060563). False +ENST00000381254 NM_001130009.1 348654 GEN1 False GEN1, a homologous recombination repair endonuclease, is infrequently altered in cancer. GEN1, an endonuclease of the Rad2/XPG nuclease family, is a homologous recombination (HR) repair protein that helps maintain genomic stability during DNA replication (PMID: 30590761, 20634321, 19020614). During anaphase, GEN1 accesses chromatin and eliminates intermediates that block proper chromatin segregation including monomeric 5’ flaps, replication fork structures and Holliday junctions (PMID: 21962513, 25209024, 20634321, 19020614). GEN1 has functional redundancies with Holliday junction resolution complexes SLX1-SLX4-MUS81-EME1 and the BTR complex, both of which contain a tumor suppressor protein (PMID: 24831703, 21399624). Silencing SLX-4-MUS81 and GEN1 in vitro results in gross chromosomal abnormalities, while single depletions of SLX1, SLX4, MUS81 or GEN1 alone does not result in these chromosomal abnormalities (PMID: 24831703, 24076221). Although there is a lack of functional evidence demonstrating the biological and oncogenic function of GEN1, rare germline GEN1 mutations have been linked to cases of bilateral breast cancer, familial childhood acute lymphoblastic leukemia and multiple primary malignancies involving lung cancer (PMID: 23104382, 26201965, 38349998). False +ENST00000228682 NM_005269.2 2735 GLI1 True GLI1, a transcription factor, is altered by mutation, amplification or overexpression in various cancer types. GLI1 is a zinc-finger transcription factor that plays an important role in normal neural development and function via regulation of the Sonic hedgehog (Shh) signaling pathway (PMID: 9634234,9584120). The GLI1 transcription factor binds DNA directly to activate Shh target genes in response to pathway activation and can function as both a transcription activator and transcription repressor depending on the signaling context (PMID: 10375510). In the absence of Shh ligand, GLI1 is cleaved by proteases to produce a truncated protein lacking C-terminal amino acids necessary for transcription activation (PMID: 9215627). Following Shh ligand exposure, GLI1 is no longer cleaved and can activate transcription of Shh target genes. GLI1 is an oncogene and is typically mutated or overexpressed in glioblastomas, where it can cause aberrant activation of the Shh-Gli signaling pathway (PMID: 12044012). False +ENST00000078429 NM_002067.2 2767 GNA11 True GNA11, a G protein subunit, is recurrently mutated in uveal melanoma. GNA11 is an alpha subunit of heterotrimeric guanine nucleotide-binding proteins (G-proteins) (PMID: 23640210, 28223438). G proteins, composed of α, β, and γ subunits, are intracellular signaling proteins that initiate signaling cascades following activation by membrane-spanning G-protein coupled receptors (GPCRs) (PMID: 23640210). Following activation by a GPCR, GDP-bound GNA11 (a Gαq protein) exchanges GDP for GTP and activates downstream signaling via binding to phospholipase C β (PLCB4), (PMID: 27089179, 28223438). PLCB4 activates PIP2 cleavage, resulting in activation of the second messenger proteins diacylglycerol (DAG) and inositol triphosphate (IP3) to prompt calcium release (PMID: 27089179). GNA11-mediated signaling promotes the activation of a variety of downstream pathways, including PKC, MAPK, and PI3K signaling, which mediate several cellular processes such as proliferation and differentiation (PMID: 27089179, 23177739). GNA11 alterations inhibit the GTPase hydrolysis activity of the protein, thereby causing GNA11 to remain bound to GTP in a constitutively activated state (PMID: 24077403, 21083380). Somatic mutations in GNA11 are found in patients with uveal melanoma, and more rarely, cutaneous melanoma (PMID: 24077403, 21083380). Alterations in GNA11 are mutually exclusive with the G-protein GNAQ in uveal melanoma (PMID: 24713608). Therapeutic strategies targeting the activation of MAPK signaling pathways may be efficacious in patients with GNA11 mutations (PMID: 29206651, 22733540) due to amplification of the GPCR-independent signaling (PMID: 29738114, 28223438). False +ENST00000275364 NM_007353.2 2768 GNA12 True GNA12, a guanine nucleotide exchange protein, is infrequently altered across various cancer types. GNA12 is a guanine nucleotide binding protein that functions as a subunit of heterotrimeric G protein complexes (PMID: 18814923). Heterotrimeric G proteins consist of an alpha subunit, such as GNA12 or GNA13, which bind and hydrolyze GTP to GDP, in concert with beta and gamma subunits (PMID: 18814923). When bound to GDP, the GNA12 alpha subunit, along with the beta and gamma subunits, form an inhibitory complex; subsequently, activated G protein-coupled receptor binding can initiate a conformation change in GNA12, resulting in the exchange of GDP for GTP and release of the beta/gamma subunits (PMID: 19226283). GTP-bound GNA12 now functions as an activated effector molecule mediating downstream signaling (PMID: 18814923, 19226283). GNA12 activates the small GTPase RhoA and RhoGEFs, which in turn mediate multiple signaling pathways that regulate migration, adhesion, apoptosis, and cellular proliferation (PMID: 26989201, 18814923). GNA12 binds several proteins including HSP90 (PMID: 24435554). Somatic GNA12 mutations are rare in human cancers; however, overexpression of activated GNA12 in preclinical models results in cellular transformation (PMID: 16247467). False +ENST00000439174 NM_006572.5 10672 GNA13 True GNA13, a guanine nucleotide exchange protein, is recurrently altered by mutation in lymphomas. GNA13 is a guanine nucleotide binding protein that functions as a subunit of heterotrimeric G protein complexes (PMID: 18814923). Heterotrimeric G proteins consist of an alpha subunit, such as GNA13 or GNA12, which bind and hydrolyze GTP to GDP, in concert with beta and gamma subunits (PMID: 18814923). When bound to GDP, the GNA13 alpha subunit, along with the beta and gamma subunits, form an inhibitory complex; however, activated G protein-coupled receptor binding initiates a conformation change in GNA13, resulting in the exchange of GDP for GTP and release of the beta/gamma subunits (PMID: 19226283). GTP-bound GNA13 now functions as an activated effector molecule mediating downstream signaling (PMID: 18814923, 19226283). GNA13 activates the small GTPase RhoA and RhoGEFs, which in turn mediate multiple signaling pathways that regulate migration, adhesion, apoptosis, and cellular proliferation (PMID: 26989201, 18814923). Loss of GNA13 expression in mice results in germinal center defects and B-cell dissemination in the blood (PMID: 25274307). Somatic GNA13 mutations are found in patients with diffuse large B-cell lymphoma (DLBCL), Burkitt’s and Hodgkin lymphoma (PMID: 22343534, 26616858, 29650799). These alterations generally occur as nonsense or frameshift loss-of-function mutations and suggest that GNA13 functions predominantly as a tumor suppressor gene in this context (PMID: 23143597, 31586074, 33423045). GNA13 overexpression has also been implicated in cell proliferation and transformation in several types of solid tumors, including ovarian cancer (PMID: 26804165, 29255247, 8002992). True +ENST00000286548 NM_002072.3 2776 GNAQ True GNAQ, a G protein subunit, is recurrently mutated in uveal melanoma. GNAQ is an alpha subunit of heterotrimeric guanine nucleotide-binding proteins (G-proteins) (PMID: 23640210, 28223438). G proteins, composed of α, β, and γ subunits, are intracellular signaling proteins that initiate signaling cascades following activation by membrane-spanning G-protein coupled receptors (GPCRs) (PMID: 23640210). Following activation by a GPCR, GDP-bound GNAQ (a Gαq protein) exchanges GDP for GTP and activates downstream signaling via binding to phospholipase C β (PLCB4), (PMID: 27089179, 28223438). PLCB4 activates PIP2 cleavage, resulting in activation of the second messenger proteins diacylglycerol (DAG) and inositol triphosphate (IP3) to prompt calcium release (PMID: 27089179). GNAQ-mediated signaling promotes the activation of a variety of downstream pathways, including PKC, MAPK, and PI3K signaling, which mediate several cellular processes such as proliferation and differentiation (PMID: 27089179, 23177739). GNAQ alterations inhibit the GTPase hydrolysis activity of the protein, thereby causing GNAQ to remain bound to GTP in a constitutively activated state (PMID: 24077403, 21083380). Somatic mutations in GNAQ are found in patients with uveal melanoma, and more rarely, cutaneous melanoma (PMID: 19078957, 18719078, 23640210). Alterations in GNAQ are mutually exclusive with the G-protein GNA11 in uveal melanoma (PMID: 24713608). Therapeutic strategies targeting the activation of MAPK signaling pathways may be efficacious in patients with GNAQ mutations (PMID: 29206651, 22733540) due to the amplification of the GPCR-independent signaling (PMID: 29738114, 28223438). False +ENST00000371085 NM_000516.4 2778 GNAS True GNAS, an intracellular signaling protein, is mutated in various cancers. The GNAS gene encodes the stimulatory G-alpha subunit of the heterotrimeric guanine nucleotide-binding protein (G-protein) membrane complex. Activation of G-protein signaling by an agonist-stimulated G-coupled protein receptor (GPCR) activates signal transduction cascades, which regulate cellular growth and development (PMID: 23640210). Activating mutations in GNAS that have been linked to the endocrine hyperplasia of McCune-Albright syndrome have also been found in growth-hormone-secreting pituitary tumors. Point mutations in the GNAS gene, many of which involve the residues R201 and Q227, can lead to constitutive signaling activity, resulting in cellular proliferation and oncogenesis (PMID: 23640210). Tumor types that have been found to harbor GNAS mutations include colon, parathyroid, and ovarian cancers, hepatocellular carcinoma, and pancreatic intraductal papillary mucinous neoplasms (precursors of pancreatic adenocarcinoma) (PMID: 23640210). False +ENST00000378609 NM_001282539.1 2782 GNB1 True GNB1, a guanine nucleotide binding protein, is recurrently altered by mutation in myelodysplastic syndromes and acute myeloid leukemia. GNB1 (also MRD42) is a guanine nucleotide binding protein that functions as a subunit of heterotrimeric G protein complexes. Heterotrimeric G proteins consist of an alpha subunit, which binds and hydrolyzes GTP to GDP, in concert with the closely bound beta and gamma subunits (PMID: 18814923). When bound to GDP, the alpha and beta-gamma subunits form an inhibitory complex; subsequently, binding by an activated G protein-coupled receptor (GPCR) can initiate dissociation of the alpha subunit from the beta-gamma complex, resulting in the exchange of GDP for GTP (PMID: 19226283). GNB1 remains bound to a gamma subunit and functions as an activated effector molecule mediating downstream signaling, including activation of the PI3K/AKT, MAPK, and PLCβ pathways (PMID: 18814923, 19226283). Germline alterations in GNB1 are associated with a neurological disorder that presents as a developmental delay with seizures (PMID: 27108799). Somatic GNB1 mutations are found in myelodysplastic syndromes and acute myeloid leukemia (PMID: 25485910). GNB1 alterations impact the G protein alpha and beta-gamma binding surface, resulting in activation of signaling downstream of G proteins and resistance to targeted kinase inhibitors (PMID: 25485910). False +ENST00000370818 NM_004484 2719 GPC3 True GPC3, a cell-surface glypican, is frequently overexpressed in hepatocellular carcinoma. GPC3, a member of the glypican-related integral membrane proteoglycan family, encodes for a cell surface proteoglycan that functions primarily in the negative regulation of cell proliferation during development (PMID: 14610063, 18477453). Glypicans play a role in developmental morphogenesis through the regulation of the Wnt and Hedgehog cell signaling pathways (PMID: 30963603, 35142364). GPC3 inhibits Hedgehog cell signaling by competing with PTC1, the Hedgehog cell signaling receptor, and binding with SHH, the Hedgehog cell signaling protein, to trigger internalization and lysosomal degradation of the GPC3-SHH complex (PMID: 23665349, 22467855). Germline mutations of GPC3 are associated with Simpson-Golabi-Behmel syndrome, an X-linked multiple congenital anomalies and overgrowth syndrome, resulting in an increased predisposition to Wilms tumor, hepatoblastoma and neuroblastoma (PMID: 23530909, 29637653). Knockdown of GPC3 in hepatocellular carcinoma cell lines reduces cellular proliferation and downregulates YAP, suggesting that GPC3 functions predominantly as an oncogene (PMID: 23471984, 25758784). Overexpression of GPC3 is frequently identified in hepatocellular carcinoma, and its expression is associated with poor prognosis (PMID: 33384879, 12824919, 36165051). False +ENST00000380728 NM_004489.4 2874 GPS2 False GPS2, a transcriptional cofactor involved in MAPK signaling, is altered by mutation and translocation in a variety of cancer types including medulloblastoma and glioblastoma. GPS2 (also known as AMF1) is a transcriptional cofactor in the G protein-mitogen-activated protein kinase (MAPK) signaling cascade. GPS2 interacts with transcription factors, nuclear receptors and histone acetyltransferases, thereby regulating transcriptional repression and activation (PMID: 11931768, 11486030, 17895379, 19481530, 24953653, 18218630, 10846067). GPS2 is ubiquitously expressed and localizes to both the nucleus, where it acts as a modulator of transcription, and the cytoplasm, where it modulates proinflammatory TNFα signaling and JNK activity (PMID: 22424771, 19858209, 11486030, 16122992, 20159957). Somatic loss-of-function mutations in GPS2 are found in medulloblastoma and are associated with poor prognosis, suggesting that GPS2 functions as a tumor suppressor (PMID: 22820256, 25030029). Translocations have also been observed in glioblastoma multiforme and undifferentiated spindle cell sarcoma (PMID: 23917401, 25139254). True +ENST00000309156 NM_001030002 2886 GRB7 True GRB7, an adaptor protein, is frequently upregulated in various cancer types. GRB7 encodes an adaptor protein that is a member of a SH2 domain-containing adaptor protein family (PMID: 10893408). GRB7 interacts with multiple receptor kinases including EGFR and ephrin receptors, and is involved in multiple cellular processes including kidney development, angiogenic activity, proliferation, anti-apoptosis, gene expression regulation, and T-cell activation (PMID: 33162827, 32737994, 19473962). Through its interaction with focal adhesion kinase (FAK), GRB7 is also involved in the integrin signaling pathway and cell migration (PMID: 19473962). GRB7 function is regulated by the MAPK/ERK pathway, which has been demonstrated in studies of thyroid cancer and ovarian cancer, among others (PMID: 19473962, 32577949, 29290818) GRB7 has been shown to promote cell cycle G1/S transition and AKT activation in bladder cancer (PMID: 33162827). Knockout of GRB7 in various cancer cell lines and models reduces proliferation and migration and promotes apoptosis, suggesting that GRB7 functions predominantly as an oncogene (PMID: 29190909, 29290818, 28275791). High expression of GRB7 has been observed in various cancer types including bladder cancer, colorectal cancer and thyroid cancer (PMID: 33162827, 34718347, 32577949, 29290818). False +ENST00000300177 NM_013372.6 26585 GREM1 True GREM1 includes a BMP antagonist that binds to BMP ligands. It is over-expressed in various tumor types, and a duplication in the upstream region is associated with colon cancer predisposition. GREM1 encodes for gremlin 1, a DAN (differential screening selected gene abberative in neuroblastoma) family bone morphogenic protein (BMP) antagonist (PMID: 24810382). It is a secreted protein that binds to BMP ligands to prevent BMP receptor activation (PMID:25378054). It regulates kidney formation, skeletal development, and the osteochondroreticular stem cell, responsible for making osteoblasts, chondrocytes, and reticular marrow stromal cells (PMID: 17522159, 21303853, 25594183, 15201225). It is expressed in various tumor cells and in glioma cells acts to maintain stem cell potential (PMID: 24788093, 23826422, 17003113). A duplication including the upstream region of the GREM1 gene is associated with hereditary mixed polyposis syndrome and an increased risk of developing colon cancer (PMID: 21128281, 22561515, 26493165, 29804199, 30584801, 30862463). These duplications cause a dramatic increase in GREM1 expression, ectopic expression of GREM1 in the colonic epithelium and acquisition of stem cell capacity in more mature progenitor cells (PMID: 22561515, 25419707, 26493165). False +ENST00000330684 NM_001134407.1 2903 GRIN2A False GRIN2A, a subunit of the NMDA glutamate receptor, is recurrently altered by mutation in various cancer types, most frequently in melanoma. GRIN2A, also known as GluN2A or NR2A, is a regulatory subunit of the glutamate-gated N-methyl-d-aspartate receptor (NMDAR), which plays an important role in cell death, survival, and migration in cancer cells (PMID: 23540692). NMDARs are best known for their roles in the brain, and high expression is found in neurons in the brain and the spinal cord where they play an important role in controlling cation flow through the receptor (PMID: 7512349). Normal NMDAR activity can promote cell survival in neurons through the PI3K and ERK signaling pathways (PMID: 11902114). Studies have shown a high prevalence of somatic mutations in GRIN2A in malignant melanoma (PMID: 21499247, 22197930), although the mechanism or function of these mutations is still unknown. True +ENST00000361669 NM_000840 2913 GRM3 False GRM3, a G-protein coupled receptor, is infrequently altered in cancer. GRM3 encodes for metabotropic glutamate receptor 3, which belongs to group II metabotropic glutamate receptors (PMID: 27130562). Group II receptors are linked to the inhibition of the cyclic AMP cascade ( PMID:27431857). The G-protein coupled receptor modulates synaptic glutamate and is involved in synaptic plasticity and brain function (PMID: 27130562). Mutations in GRM3 have been associated with psychiatric disorders including schizophrenia and bipolar disorder (PMID: 15310849, 27130562, 27431857). Alterations in GRM3 have been associated with neurological conditions rather than cancer. However, increased GRM3 expression has been observed in patients with glioblastoma and activating mutations in GRM3 have been identified in melanoma cells (PMID: 34290229, 21946352). False +ENST00000316626 NM_002093.3 2932 GSK3B True GSK3B, an intracellular kinase, is overexpressed in various cancer types including ovarian, colon and liver cancers. GSK3B is a multifunctional serine /threonine kinase that is a member of the glycogen synthase kinase protein family. The protein kinase functions as an important regulator of cellular signaling pathways involved in metabolism, cell cycle and proliferation (PMID: 24931005). Unlike most protein kinases, GSK3β is constitutively active in resting cells and undergoes a rapid and transient inhibition in response to a number of external signals. GSK3β activity is regulated by site-specific phosphorylation. Several kinases are capable of regulating the protein kinase including p70 S6 kinase, extracellular signal-regulated kinases (ERKs), p90Rsk, protein kinases A, B and C, and MEK1/2 (PMID: 12615961, 11527574, 16935409, 11394906, 15020233). Dysregulated GSK3B has been implicated in the development of a number of human diseases such as diabetes, cardiovascular disease, neurodegenerative diseases and bipolar disorder (PMID: 12615961, 11527574, 16935409). Overexpression of the protein kinase has also been implicated in tumorigenesis and cancer progression including ovarian, colon, liver and pancreatic carcinomas (PMID: 16556076, 17912008, 11883528, 16556076, 16342409, 18606491). Several GSK3β inhibitors have been studied in preclinical trials, for example pharmacological inhibitors suppress proliferation of the ovarian cancer cells in vitro and prevents the formation of tumors in nude mice generated by the inoculation of human ovarian cancer cells (PMID: 16788573). False +ENST00000324896 NM_032999.3 2969 GTF2I True GTF2I, a transcription factor, is recurrently altered by mutation in thymic tumors and lymphomas. GTF2I (also TFII-I) is a general transcription factor that regulates the transcription of several signaling proteins (PMID: 22037610, 22037610). GTF2I mediates the expression of various genes important in cell cycle control, stress response, and genomic stability, including FOS, BRCA, and STAT proteins, among other others, in association with a variety of transcriptional complexes (PMID: 28657656, 24922507, 24231951, 21407215). GTF2I has also been implicated in heavy chain immunoglobulin transcription in immune cells and plays an important role in T-cell receptor signaling (PMID: 21549311, 11313464, 19701889). In addition, GTF2I can directly bind CTCF, a regulator of epigenetic state, to drive transcriptional initiation at target genes (PMID: 25646466). Germline deletions in GTF2I are found in patients with Williams-Beuren syndrome, a multisystem developmental disorder (PMID: 10198167). Somatic GTF2I mutations have been identified in epithelial thymic tumors and follicular T cell-derived lymphomas (PMID: 24974848, 27369867). GTF2I mutations occur predominantly as missense mutations and are predicted to disrupt protein degradation of GTF2I, leading to increased protein expression (PMID: 24974848). These alterations tend to occur in more indolent thymic tumor subtypes and are associated with a better prognosis (PMID: 28676218). False +ENST00000343677 NM_005319.3 3006 H1-2 False H1-2, a histone variant, is infrequently altered by mutation in various cancer types. H1-2 is a histone H1 variant. H1 histone proteins bind to linker DNA between nucleosomes and influences higher order chromatin structure. The histone H1 family comprises eleven members, each one transcribed by its own gene. A number of studies have shown that H1 levels are altered in cancer and variant-specific changes can be observed in different tumor types. Although H1 variants share significant homology in their globular DNA-binding domain, they are more divergent in their C- and N-terminal tails, and evidence suggests that they may have distinct functions in the nucleus. The so-called “main” H1 variants, which include H1-1, H1-2, H1-3, H1-4, H1-5, H1-6, are mainly transcribed in S-phase and therefore expressed at high levels only in dividing cells (PMID: 18208346, 26474902, 26386351). H1-2 mutations have been identified in follicular lymphoma and impair H1-2 binding to DNA, likely impacting chromatin structure and gene expression (PMID: 24362818). False +ENST00000244534 NM_005320.2 3007 H1-3 False H1-3, a histone H1 linker protein, is infrequently altered by mutation in a diverse range of cancers. H1-3 is a histone H1 linker protein that encodes the non-canonical H1.3 histone variant (PMID: 9031620). Histone variants, such as H1.3, have sequences that differ from the canonical histone protein and appear to be interchangeable with the major protein form (PMID: 9031620). Histone proteins are an essential component of the nucleosome which consists of DNA wrapped around eight histone protein molecules (two sets of each H2A, H2B, H3 and H4 histones), and therefore allow for the effective packaging of DNA in the nucleus (PMID: 11498575). In addition to the core histone molecules, H1 linker histones mediate the stabilization of histone molecules and higher order chromatin state (PMID: 9031620). H1-3 expression is replication-dependent and H1-3 is most highly expressed in the thymus, lung, and spleen (PMID: 28794128). H1-3 is detected on chromatin throughout the cell cycle (PMID: 20104577), is depleted at active promoters and regulatory units (PMID: 21852237), suppresses RAD51/RAD54-mediated homologous pairing (PMID: 26757249) and directly mediates chromatin compaction (PMID: 19794910). H1-3 is also a member of an HDAC3 containing complex that mediates the repression of the retinoic acid receptor and the thyroid hormone receptor (PMID: 26663086). Somatic mutations in H1-3 are rare; however, overexpression of H1-3 has been associated with repression of the oncogenic factor H19 in ovarian cancer cells, suggesting it functions as a tumor suppressor (PMID: 28687618, 25205099). True +ENST00000304218 NM_005321.2 3008 H1-4 True H1-4, a histone H1 linker protein, is infrequently altered by mutation in a diverse range of cancers. H1-4 is a histone H1 linker that encodes the non-canonical H1.4 histone variant (PMID: 28794128). Histone variants, such as H1.4, have sequences that differ from the canonical histone protein and appear to be interchangeable with the major protein form (PMID: 9031620). Histone proteins, essential components of the nucleosome, consists of DNA wrapped around eight histone protein molecules (two sets of each H2A, H2B, H3 and H4 histones), and therefore allow for the effective packaging of DNA in the nucleus (PMID: 11498575). In addition to the core histone molecules, H1 linker histones mediate the stabilization of histone molecules and higher order chromatin state (PMID: 9031620). H1-4 expression is replication-dependent and is ubiquitously expressed in a variety of cell types (PMID: 28794128). Expression of H1-4 is gender-specific and is enriched on the paternal inactive chromosome (PMID: 18927631). H1-4 mediates the binding of the repressive protein HP1α and is depleted from active regulatory regions of the chromatin (PMID: 30007360, 23746450). Loss of HISTH1E in breast cancer cells results in growth suppression, suggesting a role in cell survival (PMID: 18927631). Somatic mutations in H1-4 are rare; however, mutations in HISTH1E have been identified in diffuse large B lymphoma (leg type) (PMID: 28479318). False +ENST00000331442 NM_005322.2 3009 H1-5 False H1-5, an H1 histone linker protein, is infrequently altered by mutation in various human cancers. H1-5 is a histone H1 linker protein that encodes the non-canonical H1.5 histone variant (PMID: 9031620). Histone variants, such as H1.5, have sequences that differ from the canonical histone protein and appear to be interchangeable with the major protein form (PMID: 9031620). Histone proteins are an essential component of the nucleosome, which consists of DNA wrapped around eight histone protein molecules (two sets of each H2A, H2B, H3 and H4 histones), and therefore allow for the effective packaging of DNA in the nucleus (PMID:11498575). In addition to the core histone molecules, H1 linker histones mediate the stabilization of histone molecules and higher order chromatin state (PMID: 9031620). H1-5 expression is replication-dependent and H1-5 is most highly expressed in the thymus and spleen (PMID: 28794128). H1-5 binds chromatin in the embryonic germ layers and binding is progressively lost during epigenetic reprogramming (PMID: 28794128, 28794128). In differentiated cells, H1-5 regulates chromatin structure near genes that encode membrane or membrane-associated proteins (PMID: 22956909). H1-5 has been implicated in the repression of gene expression and a regulator of SIRT1 deacetylase activity (PMID: 22956909). Depletion of H1-5 results in loss of SIRT1 binding, loss of H3K9me2, increased chromatin accessibility and decreased cellular growth (PMID: 22956909). H1-5 has also been shown to bind FOXP3 in T regulatory cells at relevant target genes (PMID: 21654845). Rare somatic mutations in H1-5 have been identified in colon cancer and are predicted to maintain a more undifferentiated chromatin state (PMID: 16959974). Downregulation of H1-5 expression has been associated with various tumor types (PMID: 22956909). True +ENST00000359193 NM_021064.4 8969 H2AC11 False H2AC11, a canonical histone H2A protein, is infrequently mutated by amplification and mutation in a diverse range of cancers. H2AC11 is a canonical histone H2A gene that encodes a protein that functions in the core histone complex. H2AC11 is one of five abundantly expressed H2A genes that encode the H2A.1 histone molecule (PMID: 23956221). Histone proteins, essential components of the nucleosome, consist of DNA wrapped around eight histone protein molecules (two sets of each H2A, H2B, H3 and H4 histones), and therefore allow for the effective packaging of DNA in the nucleus (PMID: 11498575). H2AC11 is expressed in a variety of cell types; however, the function has not yet been well characterized in biochemical studies. Somatic mutations in H2AC11 are rare; however, amplifications have been identified in some tumor types (cbioportal, accessed August 2018). False +ENST00000357320 NM_003511 8332 H2AC16 False H2AC16, a canonical histone H2A protein, is infrequently mutated by amplification and mutation in a diverse range of cancers. H2AC16 is a canonical histone H2A gene that encodes a protein that functions in the core histone complex. H2AC16 is one of five abundantly expressed H2A genes that encode the H2A.1 histone molecule (PMID: 23956221). Histone proteins, essential components of the nucleosome, consist of DNA wrapped around eight histone protein molecules (two sets of each H2A, H2B, H3 and H4 histones), and therefore allow for the effective packaging of DNA in the nucleus (PMID: 11498575). H2AC16 is expressed in a variety of cell types; however, the function has not yet been well characterized in biochemical studies. Somatic mutations in H2AC16 in human cancers are rare; however, amplifications have been identified in some tumor types (cbioportal, accessed August 2018). False +ENST00000359611 NM_003514 8336 H2AC17 True H2AC17, a canonical histone H2A protein, is infrequently mutated by amplification and mutation in a diverse range of cancers. H2AC17 is a canonical histone H2A gene that encodes a protein that functions in the core histone complex. H2AC17 is one of five abundantly expressed H2A genes that encode the H2A.1 histone molecule (PMID: 23956221). Histone proteins, essential components of the nucleosome, consist of DNA wrapped around eight histone protein molecules (two sets of each H2A, H2B, H3 and H4 histones), and therefore allow for the effective packaging of DNA in the nucleus (PMID: 11498575). H2AC17 is expressed in a variety of cell types; however, the function has not yet been well characterized in biochemical studies. In addition, H2AC17 was found to be overexpressed in cervical patient samples (PMID: 29184082). Somatic mutations in H2AC17 in human cancers are rare; however, amplifications have been identified in some tumor types (cbioportal, accessed August 2018). False +ENST00000314088 NM_003512.3 8334 H2AC6 False H2AC6, an H2A histone variant, is infrequently altered by mutation in a diverse range of cancers. H2AC6 is an H2A histone variant (H2A 2C) that functions as a protein in the core histone complex. Histone variants, such as H2AC6, have sequences that differ from the canonical histone protein and appear to be interchangeable with the major protein form (PMID: 9031620). Histone proteins, essential components of the nucleosome, consist of DNA wrapped around eight histone protein molecules (two sets of each H2A, H2B, H3 and H4 histones), and therefore allow for the effective packaging of DNA in the nucleus (PMID: 11498575). H2AC6 expression is replication-dependent and is expressed in a variety of cell types, including during mesenchymal stem cell differentiation (PMID: 23956221, 23717473). Loss of H2AC6 in cell lines results in reduced proliferation and transformation (PMID: 23956221), suggesting that H2AC6 functions as an oncogene. Somatic mutations in H2AC6 in human cancers are relatively rare, however, increased expression of H2AC6 has been identified in chronic lymphocytic leukemia samples (PMID: 19253275). Missense mutations have also been identified in follicular lymphoma and uterine and ovarian carcinosarcomas (PMID: 28064239, 27791010). False +ENST00000339812 NM_021058.3 8970 H2BC11 False H2BC11, a canonical histone H2B protein, is infrequently mutated by amplification and mutation in a diverse range of cancers. H2BC11 is a canonical histone H2B gene that encodes a protein that functions in the core histone complex. H2BC11 is one of fifteen abundantly expressed H2B genes that encode the H2B.1 histone molecule (PMID: 16319397). Histone proteins, essential components of the nucleosome, consist of DNA wrapped around eight histone protein molecules (two sets of each H2A, H2B, H3 and H4 histones), and therefore allow for the effective packaging of DNA in the nucleus (PMID: 11498575). H2BC11 is expressed in a variety of cell types and is replication-dependent; however, the function has not yet been well-characterized in biochemical studies. Due to the ubiquitous expression of H2BC11, murine H2BC11 reporter models are utilized in preclinical studies (PMID: 22690876). In addition, H2BC11 was found to be overexpressed in cervical cancer patient samples (PMID: 29184082). Somatic mutations in H2BC11 are rare in human cancers; however, missense mutations have been identified in follicular lymphoma and uterine and ovarian carcinosarcomas (PMID: 28064239, 27791010). False +ENST00000356950 NM_080593.2 85236 H2BC12 False H2BC12, a canonical histone H2B protein, is infrequently mutated by amplification and mutation in a diverse range of cancers. H2BC12 is a canonical histone H2B gene that encodes a protein that functions in the core histone complex. H2BC12 is one of fifteen abundantly expressed H2B genes that encode the H2B.1 histone molecule (PMID: 16319397). Histone proteins, essential components of the nucleosome, consist of DNA wrapped around eight histone protein molecules (two sets of each H2A, H2B, H3 and H4 histones), and therefore allow for the effective packaging of DNA in the nucleus (PMID: 11498575). H2BC12 is expressed in a variety of cell types and is replication-dependent; however, the function has not yet been well characterized in biochemical studies. In addition, H2BC12 was found to be upregulated after BET inhibitor treatment and in invasive ductal carcinomas (PMID: 27388964, 26732727). Somatic mutations in H2BC12 are rare in human cancers; however, H2BC12 was identified as a candidate cancer gene in diffuse large B cell lymphoma (DLBCL) and follicular lymphoma in large-scale sequencing studies (PMID: 29713087, 28064239). False + 8348 H2BC17 False H2BC17, a canonical histone H2B protein, is infrequently mutated by amplification and mutation in a diverse range of cancers. H2BC17 is a canonical histone H2B gene that encodes a protein that functions in the core histone complex. H2BC17 is one of fifteen abundantly expressed H2B genes that encode the H2B.1 histone molecule (PMID: 16319397). Histone proteins, essential components of the nucleosome, consist of DNA wrapped around eight histone protein molecules (two sets of each H2A, H2B, H3 and H4 histones), and therefore allow for the effective packaging of DNA in the nucleus (PMID: 11498575). H2BC17 is expressed in a variety of cell types and replication-dependent; however, the function has not yet been well characterized in biochemical studies. Somatic mutations in H2BC17 are rare in human cancers; however, missense mutations have been identified in follicular lymphoma (PMID: 28064239). False +ENST00000314332 NM_003518.3 8347 H2BC4 False H2BC4, a canonical histone H2B protein, is infrequently mutated by amplification and mutation in a diverse range of cancers. H2BC4 is a canonical histone H2B gene that encodes a protein that functions in the core histone complex. H2BC4 is one of fifteen abundantly expressed H2B genes that encode the H2B.1 histone molecule (PMID: 16319397). Histone proteins, essential components of the nucleosome, consist of DNA wrapped around eight histone protein molecules (two sets of each H2A, H2B, H3 and H4 histones), and therefore allow for the effective packaging of DNA in the nucleus (PMID: 11498575). H2BC4 is expressed in a variety of cell types and is replication-dependent; however, the function has not yet been well characterized in biochemical studies. In addition, H2BC4 is expressed during terminal differentiation as evidenced in liver cells (PMID: 27402160). Somatic mutations in H2BC4 are rare in human cancers; however, amplifications have been identified in some tumor types (cbioportal, accessed August 2018). False +ENST00000289316 NM_021063.3 3017 H2BC5 False The H2BC5 gene encodes a histone H2B variant. The H2BC5 gene encodes histone H2B type 1D. Histone proteins are an essential component of the nucleosome which consists of DNA wrapped around eight histone protein cores (two sets of each H2A, H2B, H3 and H4 histones), and therefore allow for the effective packaging of DNA in the nucleus (PMID:11498575). Ubiquitination of histone H2B at specific lysine residues leads to transcriptional activation and is a prerequisite for the placement of the activating mark H3K4me3 (PMID: 14563679, 12077605). False +ENST00000244601 NM_003518 8339 H2BC8 False H2BC8, a canonical histone H2B protein, is infrequently mutated by amplification and mutation in a diverse range of cancers. H2BC8 is a canonical histone H2B gene that encodes a protein that functions in the core histone complex. H2BC8 is one of fifteen abundantly expressed H2B genes that encode the H2B.1 histone molecule (PMID: 16319397). Histone proteins, essential components of the nucleosome, consist of DNA wrapped around eight histone protein molecules (two sets of each H2A, H2B, H3 and H4 histones), and therefore allow for the effective packaging of DNA in the nucleus (PMID: 11498575). HIST1H2BC is expressed in a variety of cell types and is replication-dependent; however, the function has not yet been well characterized in biochemical studies. In addition, H2BC8 was identified as a significant prostate cancer biomarker in urine analyses (PMID: 26856686). Somatic mutations in H2BC8 are rare in human cancers; however, missense mutations have been identified in follicular lymphoma and uterine and ovarian carcinosarcomas (PMID: 28064239, 27791010). False +ENST00000366813 NM_002107.4 3020 H3-3A True H3-3A, a histone variant, is recurrently altered by mutation in various pediatric cancers including pediatric glioblastoma. H3-3A is a histone variant that encodes histone H3.3 and is found at actively transcribed genes, transcription factor binding sites and telomeres (PMID: 20211137). Chromatin is the physiological template of human genetic information and is built out of nucleosomes, which are octamers assembled from histones proteins H2A, H2B, H3 and H4 (PMID: 11498575). The exact functions of histone 3.3 are not yet fully understood. Mutations of H3-3A leading to amino acid substitutions at its histone tail are common in pediatric glioblastoma (GBM) and pediatric diffuse pontine glioma and were also reported in chondroblastoma and giant cell tumors (PMID: 22286061, 22286216, 24162739, 24285547, 26399631). Glioblastoma tumors with H3-3A mutations show a different DNA methylation profile when compared to other GBM tumors and H3-3A mutations seem mutually exclusive with IDH1 mutations in GBM (PMID: 23079654). The exact mechanism by which these mutations lead to tumorigenesis are unknown, however, it has been proposed that H3.3 mutations lead to increased expression of oncogenic MYCN (PMID: 23539269). False +ENST00000254810 NM_005324.3 3021 H3-3B False H3-3B, a histone variant, is recurrently altered by mutation in chondroblastomas. H3-3B is one of the “replacement” histone H3.3 variants, which, in contrast to the H3.1 and H3.2 variants, is expressed throughout the cell cycle and is incorporated into chromatin independently of DNA synthesis (PMID: 7199388, 9188772, 14718166,16258499). This feature, which is unique to the H3.3 histone, is attributable to the presence of three unique amino acids, which favor the ability of H3.3 to destabilize nucleosomes in transcriptionally active regions (PMID: 19633671,15776021). Studies in H3-3B knockout mice have shown that H3.3 plays a significant role in the regulation of chromatin, which is important for genome integrity and cell cycle progression (PMID: 23570311). Somatic mutations in H3-3B are seen in approximately 95% of chondroblastomas, with the most common alteration being K36M, which is expected to inhibit methylation at that site (PMID: 26457357, 24162739). In addition, a novel variant in the 3' UTR of the H3-3B gene has been identified in ovarian cancer (PMID:15870878). False +ENST00000366696 NM_003493.2 8290 H3-4 False H3-4, a histone variant, is infrequently altered by mutation in various cancer types. H3-4 is a replication coupled histone variant of unknown physiologic and pathological functions that encodes H3.1t, (PMID: 21481529, 26527279, 25539924). Histone molecules allow for the effective packaging of DNA in the nucleus and are built out of nucleosomes assembled from histone proteins H2A, H2B, H3 and H4(PMID: 11498575). False +ENST00000340398 NM_001013699.2 440093 H3-5 False H3-5, a histone variant, is infrequently altered by mutation in various cancer types. H3-5 is the histone variant H3.5, which is expressed in the human testes (PMID: 21274551). Histone molecules allow for the effective packaging of DNA in the nucleus and are built out of nucleosomes assembled from histone proteins H2A, H2B, H3 and H4 (PMID: 11498575). Histone variants, such as H3.5, are highly conserved compared to the canonical histone protein differing by only a few amino acids. H3-5 is highly expressed in the testes and binds near transcription start sites, implicating H3-5 in transcriptional activation (PMID: 26779285). Somatic H3-5 mutations have not been functionally validated. False +ENST00000357647 NM_003529.2 8350 H3C1 False The H3C1 gene encodes H3.1, an H3 histone variant. The H3C1 gene encodes histone H3.1, a replication dependent histone H3 variant (PMID: 21481529,26527279, 25539924). Histone proteins are an essential component of the nucleosome which consists of DNA wrapped around eight histone protein cores (two sets of each H2A, H2B, H3 and H4 histones), and therefore allow for the effective packaging of DNA in the nucleus (PMID:11498575). Histone variants, such as H3.1 and H3.2 have sequences that differ from the canonical histone protein by only a few amino acids and appear to be interchangeable with the major protein form (PMID: 25561719). False +ENST00000369163 NM_003536.2 8357 H3C10 False H3C10, a histone variant, is infrequently altered by mutation in various cancer types. The H3C10 gene encodes histone H3.1, a replication dependent Histone H3 variant (PMID: 21481529,26527279, 25539924). Histone proteins are an essential component of the nucleosome which consists of DNA wrapped around eight histone protein cores (two sets of each H2A, H2B, H3 and H4 histones), and therefore allow for the effective packaging of DNA in the nucleus (PMID:11498575). Histone variants, such as H3.1 and H3.2 have sequences that differ from the canonical histone protein by only a few amino acids and appear to be interchangeable with the major protein form (PMID: 25561719). False +ENST00000328488 NM_003533.2 8354 H3C11 False H3C11, a histone variant, is infrequently altered by mutation in various cancer types. H3C11 is a replication-dependent histone variant that encodes H3.1 (PMID: 21481529,26527279, 25539924). Histone molecules allow for the effective packaging of DNA in the nucleus and are built out of nucleosomes assembled from histone proteins H2A, H2B, H3 and H4(PMID: 11498575). Histone variants, such as H3.1, have highly conserved sequences compared to the canonical histone protein differing by only a few amino acids. H3C11 K36M mutations have been identified in head and neck cancer; these alterations disrupt methylation/acetylation at that residue with implications for gene expression (PMID: 25484917). False +ENST00000359303 NM_003535.2 8356 H3C12 False H3C12, a histone variant, is infrequently altered by mutation in various cancer types. H3C12 is a replication-dependent histone H3 variant that encodes H3.1 (PMID: 21481529,26527279, 25539924). Histone proteins are an essential component of the nucleosome which consists of DNA wrapped around eight histone protein cores (two sets of each H2A, H2B, H3 and H4 histones), and therefore allow for the effective packaging of DNA in the nucleus (PMID:11498575). Histone variants, such as H3.1 and H3.2 have sequences that differ from the canonical histone protein by only a few amino acids and appear to be interchangeable with the major protein form (PMID: 25561719). False +ENST00000331491 NM_001123375.2 653604 H3C13 False H3C13, a histone variant, is infrequently altered by mutation in various cancer types. H3C13 is a replication-dependent histone H3 variant that encodes H3.2 (PMID: 21481529,26527279, 25539924). Histone proteins are an essential component of the nucleosome which consists of DNA wrapped around eight histone protein cores (two sets of each H2A, H2B, H3 and H4 histones), and therefore allow for the effective packaging of DNA in the nucleus (PMID:11498575). Histone variants, such as H3.1 and H3.2 have sequences that differ from the canonical histone protein by only a few amino acids and appear to be interchangeable with the major protein form (PMID: 25561719). False +ENST00000369158 NM_021059.2 126961 H3C14 False H3C14, a histone variant, is infrequently altered by mutation in various cancer types. H3C14 is a replication-dependent histone H3 variant gene that encodes histone H3.2 (PMID: 21481529,26527279, 25539924). Histone proteins are an essential component of the nucleosome which consists of DNA wrapped around eight histone protein cores (two sets of each H2A, H2B, H3 and H4 histones), and therefore allow for the effective packaging of DNA in the nucleus (PMID:11498575). Histone variants, such as H3.1 and H3.2 have sequences that differ from the canonical histone protein by only a few amino acids and appear to be interchangeable with the major protein form (PMID: 25561719). False +ENST00000403683 NM_001005464.2 333932 H3C15 False H3C15, a histone variant, is infrequently altered by mutation in various cancer types. H3C15 is a replication-dependent histone H3 variant that encodes H3.2 (PMID: 21481529, 26527279, 25539924). Histone proteins are an essential component of the nucleosome which consists of DNA wrapped around eight histone protein cores (two sets of each H2A, H2B, H3 and H4 histones), and therefore allow for the effective packaging of DNA in the nucleus (PMID:11498575). Histone variants, such as H3.1 and H3.2 have sequences that differ from the canonical histone protein by only a few amino acids and appear to be interchangeable with the major protein form (PMID: 25561719). False +ENST00000244661 NM_003537.3 8358 H3C2 False The H3C2 gene encodes H3.1, an H3 histone variant. The H3C2 gene encodes histone H3.1, a replication dependent histone H3 variant (PMID: 21481529,26527279, 25539924). Histone proteins are an essential component of the nucleosome which consists of DNA wrapped around eight histone protein cores (two sets of each H2A, H2B, H3 and H4 histones), and therefore allow for the effective packaging of DNA in the nucleus (PMID:11498575). Histone variants, such as H3.1 and H3.2 have sequences that differ from the canonical histone protein by only a few amino acids and appear to be interchangeable with the major protein form (PMID: 25561719). H3C2 K27M mutations have been found in pediatric diffuse pontine glioma; these alterations disrupt a methylation site that is important for compacting chromatin and transcriptional repression. False +ENST00000540144 NM_003531.2 8352 H3C3 False H3C3, a histone variant, is infrequently altered by mutation in various cancer types. H3C3 is a histone variant gene that encodes the replication-dependent histone H3.1 (PMID: 21481529,26527279, 25539924). Histone proteins are an essential component of the nucleosome which consists of DNA wrapped around eight histone protein cores (two sets of each H2A, H2B, H3 and H4 histones), and therefore allow for the effective packaging of DNA in the nucleus (PMID:11498575). Histone variants, such as H3.1 and H3.2 have sequences that differ from the canonical histone protein by only a few amino acids and appear to be interchangeable with the major protein form (PMID: 25561719). False +ENST00000356476 NM_003530.4 8351 H3C4 False H3C4, a histone variant, is infrequently altered by mutation in various cancer types. H3C4 is a replication-dependent histone H3 variant that encodes histone H3.1 (PMID: 21481529,26527279, 25539924). Histone proteins are an essential component of the nucleosome which consists of DNA wrapped around eight histone protein cores (two sets of each H2A, H2B, H3 and H4 histones), and therefore allow for the effective packaging of DNA in the nucleus (PMID:11498575). Histone variants, such as H3.1 and H3.2 have sequences that differ from the canonical histone protein by only a few amino acids and appear to be interchangeable with the major protein form (PMID: 25561719). False +ENST00000360408 NM_003532.2 8353 H3C6 False H3C6, a histone variant, is infrequently altered by mutation in various cancer types. H3C6 is a replication-dependent histone H3 variant that encodes histone H3.1 (PMID: 21481529,26527279, 25539924). Histone proteins are an essential component of the nucleosome which consists of DNA wrapped around eight histone protein cores (two sets of each H2A, H2B, H3 and H4 histones), and therefore allow for the effective packaging of DNA in the nucleus (PMID:11498575). Histone variants, such as H3.1 and H3.2 have sequences that differ from the canonical histone protein by only a few amino acids and appear to be interchangeable with the major protein form (PMID: 25561719). False +ENST00000446824 NM_021018.2 8968 H3C7 False H3C7, a histone variant, is infrequently altered by mutation in various cancer types. The H3C7 gene encodes histone H3.1, a replication dependent histone H3 variant (PMID: 21481529, 26527279, 25539924). Histone proteins are an essential component of the nucleosome which consists of DNA wrapped around eight histone protein cores (two sets of each H2A, H2B, H3 and H4 histones), and therefore allow for the effective packaging of DNA in the nucleus (PMID:11498575). Histone variants, such as H3.1 and H3.2 have sequences that differ from the canonical histone protein by only a few amino acids and appear to be interchangeable with the major protein form (PMID: 25561719). False +ENST00000305910 NM_003534.2 8355 H3C8 False H3C8, a histone variant, is infrequently altered by mutation in various cancer types. The H3C8 is a replication-dependent histone H3 variant that encodes H3.1 (PMID: 21481529,26527279, 25539924). Histone proteins are an essential component of the nucleosome which consists of DNA wrapped around eight histone protein cores (two sets of each H2A, H2B, H3 and H4 histones), and therefore allow for the effective packaging of DNA in the nucleus (PMID:11498575). Histone variants, such as H3.1 and H3.2 have sequences that differ from the canonical histone protein by only a few amino acids and appear to be interchangeable with the major protein form (PMID: 25561719). False +ENST00000316450 440926 H3P6 False H3P6, a histone variant pseudogene, is infrequently altered by amplification in various cancer types. H3P6 is a pseudogene of H3P6 with unknown function. Chromatin is the physiological template of human genetic information and is built out of nucleosomes, which are octamers assembled from histones proteins H2A, H2B, H3 and H4 (PMID: 11498575). H3P6 is altered by amplification in several cancer types (cBioportal, August 2019). False + 8361 H4C6 False H4C6, a canonical histone H4 protein, is infrequently altered in cancer. H4C6, also known as HIST1H4F, is a canonical histone H4 gene that encodes a protein that functions as a nucleosome subunit of chromatin (PMID: 12408966, 7412879). H4C6 is one of fourteen expressed H4 genes that encode for the histone H4 (PMID: 35202563). Histone proteins, essential components of the nucleosome, consist of DNA wrapped around eight histone protein molecules (two sets of each H2A, H2B, H3 and H4 histones), and therefore allow for the effective packaging of DNA in the nucleus (PMID: 11498575). H4C6 is expressed in a variety of cell types; however, the function has not yet been well characterized in biochemical studies. Hypermethylation of H4C6 has been identified in various different cancer types, including lung cancer, bladder cancer and hepatocellular carcinoma, and has been suggested to be a universal-cancer-only methylation marker (PMID: 31575549, 36898511, 21625442). False +ENST00000373548 NM_004964.2 3065 HDAC1 True HDAC1, a histone deacetylase, is infrequently altered by mutation in liposarcoma. HDAC1 is a histone deacetylase that is termed a Class I HDAC, in a family with HDAC2, HDAC3, and HDAC8 (PMID: 27599530). Histone deacetylases remove the acetyl group from relevant lysine amino acids on either histone or non-histone cellular substrates, altering epigenetic state and gene transcription (PMID: 24691964). HDAC1 activity regulates several key cellular functions including apoptosis, cell cycle, DNA damage response, and metastasis (PMID: 22147512, 27599530). In addition, HDAC1 deacetylates tumor suppressors and oncogenes, including TP53, HIF-1α, MLL and NK-kB (PMID: 11931769, 12829790), impacting their activity. Knockdown of HDAC1 expression in preclinical models results in an anti-proliferative effect, leading to an induction in p21 and p27 and repression of several cyclins and cyclin-dependent kinases (PMID: 22496786). Somatic HDAC1 mutations are found in patients with liposarcoma (PMID: 22328974); however, alterations tend to be rare in human cancers. Increased expression of HDAC1 is associated with poor outcomes in several tumor types including gastric and ovarian cancers, among others (PMID: 25482492). A variety of HDAC inhibitors are FDA-approved for the treatment of several cancers including vorinostat (cutaneous T cell lymphoma), romidepsin (cutaneous T cell lymphoma), panobinostat (multiple myeloma), and belinostat (peripheral T cell lymphoma). These HDAC inhibitors and others are currently in preclinical and clinical testing for efficacy in additional indications (PMID: 27599530). False +ENST00000519065 NM_001527.3 3066 HDAC2 True HDAC2, a histone deacetylase, is infrequently altered in cancer. HDAC2 encodes for a histone deacetylase that functions in the deacetylation of lysine residues on the N-terminal part of core histones H2A, H2B, H3 and H4 (PMID: 28497810). HDAC2 is a component of multiple corepressor complexes and functions in transcriptional repression of various genes involved in physiological cellular processes (PMID: 12724404, 12493763, 10888872). Overexpression of HDAC2 in various cancer cell lines and models induces cellular proliferation, dysregulation of G1/S cell cycle progression and decreased apoptosis, suggesting that HDAC2 functions predominantly as an oncogene (PMID: 34365463, 23175521, 22492270). Amplification of HDAC2 has been identified in various types of cancer, including breast cancer, pancreatic cancer and colon cancer (PMID: 28560068, 34903606, 24948597). A variety of pan-HDAC inhibitors are FDA-approved for the treatment of several cancers including vorinostat (cutaneous T cell lymphoma), panobinostat (multiple myeloma) and belinostat (peripheral T cell lymphoma) (PMID: 27599530). False +ENST00000345617 NM_006037.3 9759 HDAC4 True HDAC4, a histone deacetylase, is infrequently altered by deletion and mutation in a diverse range of cancers. HDAC4 is a histone deacetylase that is termed a Class IIa HDAC, in a family with HDAC5, HDAC7, and HDAC9 (PMID: 27599530). Histone deacetylases remove the acetyl group from relevant lysine amino acids on either histone or non-histone cellular substrates, altering epigenetic state and gene transcription (PMID: 24691964). HDAC4 activity regulates several key cellular functions including cell cycle, DNA damage response and angiogenesis (PMID: 12668657, 19071119). Expression of 53BP1, a DNA damage protein, co-localizes with HDAC4 and regulates the DNA damage-induced G2 checkpoint (PMID: 12668657). Additionally, HDAC4 transcriptionally activates HIF-1α (PMID: 19071119). Somatic HDAC4 mutations are rare in human cancers; however, HDAC4 is predicted to function as an oncogene or tumor suppressor in different cellular contexts. Deletions in HDAC4 are found in patients with melanoma (PMID: 21571862) while overexpression of HDAC4 is associated with gastric and acute lymphocytic leukemia (PMID: 25091122, 23948281). A variety of pan-HDAC inhibitors are FDA-approved for the treatment of several cancers including vorinostat (cutaneous T cell lymphoma), panobinostat (multiple myeloma), and belinostat (peripheral T cell lymphoma). These HDAC inhibitors and others are currently in preclinical and clinical testing for efficacy in additional indications (PMID: 27599530). True +ENST00000427332 XM_011538481.1 51564 HDAC7 True HDAC7, a histone deacetylase, is infrequently altered by mutation in a diverse range of human cancers. HDAC7 is a histone deacetylase that is termed a Class IIa HDAC, in a family with HDAC4, HDAC5, and HDAC9 (PMID: 27599530). Histone deacetylases remove the acetyl group from relevant lysine amino acids either on histone or non-histone cellular substrates, altering epigenetic state and gene transcription (PMID: 24691964). HDAC7 activity regulates several key cellular functions including downstream signaling, B cell lineage commitment, stem cell maintenance and angiogenesis (PMID: 12668657, 19071119, 27810920, 27694895, 26853466). HDAC7 controls thymic effector transcription in natural killer T cells (PMID: 29664401), transcriptionally activates HIF-1α (PMID: 15280364), and acetylates key signaling molecules including STAT3 (PMID: 29126425). Somatic HDAC7 mutations are rare in human cancers; however, overexpression of HDAC7 has been identified in a variety of tumor types including pancreatic, childhood acute lymphocytic leukemia (ALL) and chronic lymphocytic leukemia (PMID: 20636436, 18506539, 23108383). A variety of pan-HDAC inhibitors are FDA-approved for the treatment of several cancers including vorinostat (cutaneous T cell lymphoma), panobinostat (multiple myeloma), and belinostat (peripheral T cell lymphoma). These HDAC inhibitors and others are currently in preclinical and clinical testing for efficacy in additional indications (PMID: 27599530). False +ENST00000357618 NM_000410 3077 HFE True HFE, a transmembrane protein, is altered by mutation in various cancers. Germline HFE mutations are associated with hemochromatosis and predispose to various cancers. HFE encodes a transmembrane protein that functions primarily in regulating iron uptake and competing with transferrin for binding to transferrin receptor 1 (TRF1) (PMID: 18316026, 15056661). HFE regulates iron homeostasis in liver and intestinal cells through binding to TRF1 to modulate production of hepcidin, a peptide hormone which mediates systemic iron changes (PMID: 15467009, 12429850, 12547226, 18316026). HFE mutations have been implicated in dysregulated iron absorption disorders, such as type 1 hemochromatosis and porphyria (PMID: 15280838, 37163822). Knockdown of HFE in head and neck squamous cell carcinoma models repressed cellular proliferation and tumor growth, suggesting that HFE functions predominantly as an oncogene in this context (PMID: 23991213). Germline mutations of HFE have been implicated in increased susceptibility to various cancers, including breast cancer, hepatocellular carcinoma and colorectal cancer (PMID: 26893171, 20099304). False +ENST00000222390 NM_000601.4 3082 HGF True HGF encodes the natural ligand of the tyrosine kinase MET. Aberrant HGF expression with increased MET signaling has been described in various tumor types and results in increased cell survival, motility and metastasis. HGF (hepatocyte growth factor/scatter factor) is a multidomain protein that directly binds to the tyrosine kinase MET, which leads to its dimerization and activation (PMID: 3319692, 2531289). HGF is primarily expressed as pro-HGF and needs proteolytic activation to form HGF (PMID: 22270953, 1826653). MET activation leads to tyrosine phosphorylation and downstream activation of various effector proteins such as PLC, GAB1, GRB2 and SRC. HGF/MET signaling is physiolgically required for liver and skin regeneration as well as Epithelial-to-mesenchymal-transition (EMT) in embryogenesis. In cancer, HGF/MET signaling is involved in stemness, metastasis and angiogenesis (PMID: 22270953). Downstream effectors in the context of cancer involve the WNT-beta-catenin pathway, PI3K-AKT as well as TGFbeta signalling. A number of small molecule and antibody based MET receptor inhibitors have been developed and are tested in clinical trials with variable results. False +ENST00000337138 NM_001530.3 3091 HIF1A True HIF1A, an oxygen-regulated transcription factor, is infrequently mutated in human cancers. HIF1A is a transcription factor subunit that mediates gene expression in hypoxic conditions (PMID: 13130303). HIF-1, a transcriptional activator that is stabilized in the absence of oxygen, is composed of HIF1A, an oxygen-regulated subunit, and HIF1B, a ubiquitously expressed subunit (PMID: 20965423). In normoxic conditions, the E3 ligase VHL ubiquitinates and targets HIF1A to the proteasome for degradation via binding coordinated by hydroxylation (PMID: 13130303). Normal oxygen levels also preclude the binding of the transcriptional activators p300 and CBP to HIF1A, inhibiting HIF1A-dependent transcriptional activation (PMID: 24421387). In hypoxic conditions, VHL can no longer bind HIF1A due to loss of hydroxylation, resulting in protein stabilization of HIF1A (PMID: 13130303). HIF1A regulates an extensive network of transcriptional activity during hypoxia including regulation of genes involved in cell proliferation, cell survival, apoptosis, metabolism, angiogenesis, and cell adhesion, among others (PMID: 13130303, 28741521, 26955619). Vascular endothelial growth factor (VEGF), a gene involved in angiogenesis, is the most well-established HIF1A transcriptional target; most other transcriptional changes are context dependent. Somatic mutations in HIF1A are rare in human cancers; however, overexpression of HIF1A is found in many tumor types. Intratumoral hypoxia is common in malignant tumors, and increased HIF1A expression has been identified in tumors that have mutations in relevant hypoxia-related genes such as VHL (PMID: 26955619, 24446253). False +ENST00000263208 NM_003325 7290 HIRA False HIRA, a histone chaperone protein, is infrequently altered in cancer. HIRA encodes for a histone chaperone that functions in nucleosome assembly with the H3.3 histone variant (PMID: 16251970). HIRA colocalizes with other histone-binding proteins such as UBN1, CABIN1 and ASF1a to form the HIRA chaperone complex and deposit histone H3.3 at its binding sites (PMID: 23602572). HIRA functions in the repression of histone gene transcription during the cell cycle to trigger a block of DNA synthesis (PMID: 12370293). Deficiency in HIRA in various types of cancer cell types and models induces cellular proliferation and invasion, suggesting that HIRA functions predominantly as a tumor suppressor gene (PMID: 36269833, 11238922, 25512559). Downregulation of HIRA has been identified in hereditary leiomyomatosis and renal cell carcinoma (PMID: 36269833). True +ENST00000376809 NM_001242758.1 3105 HLA-A False HLA-A, an MHC class I component involved in the presentation of antigens to the immune system, is infrequently altered in cancer. HLA-A is a heavy chain subunit of the major histocompatibility class I (MHC I) complex. A critical component of the immune system is the presentation of foreign antigens on the cell surface by the MHC molecules (PMID: 10974135). Tumor cells are vulnerable to such an immune response due to the presentation of tumor-specific antigens, such as mutated oncoproteins, on the cell surface (PMID: 24782321, 24244023, 23157435). Several types of tumors are known to evade such an immunological response by crippling the levels of MHC I-presenting antigens on the tumor cell surface (PMID: 24782321, 24244023, 23157435, 11665717). The HLA-A genes encode for the heavy chain subunit of the MHC (PMID: 22434516). A reduction in HLA-A levels is seen in many tumors, which may be due to factors like genomic alteration, transcriptional regulation, protein transportation, and oncogene regulation (PMID: 24244023, 11665717). Genomic alterations are observed only rarely; chromosomal loss resulting in loss of the HLA locus is observed in 13.8% of colon tumors, 17.6% of laryngeal tumors, 15.3% of melanoma tumors and 17.2% of epithelial squamous cell carcinomas (PMID: 9057360). In HCT116 colorectal cancer cells HLA-A1 and HLA-A2 are down regulated by DNA methylation and by the action of the MEK pathway (PMID: 19569244). Similarly, gastric and esophageal cancers also display HLA-A downregulation via action of RAS, MYC and the HER2 oncogene, as well as the MAP kinase signal transduction pathway (PMID: 24244023, 20715101, 20628381). True +ENST00000412585 NM_005514.6 3106 HLA-B False HLA-B, an MHC class I component involved in antigen presentation to the immune system, is infrequently altered in cancer. HLA-B is a heavy chain subunit of the major histocompatibility class I (MHC I) complex. This protein is involved in the presentation of foreign antigens to the immune system. A critical component of the immune system is the presentation of foreign antigens on the cell surface by the MHC molecules (PMID: 10974135, 15719024). Immune recognition leads to the stimulation of a signaling cascade that results in apoptosis of MHC-presenting target cells (PMID: 15719024). Tumor cells are vulnerable to such an immune response due to the presentation of tumor-specific antigens such as mutated oncoproteins on the cell surface (PMID: 24782321, 24244023, 23157435). HLA-B is anchored in the membrane of most cells, and it has a highly polymorphic region that facilitates a wide binding specificity for a variety of antigens that need to be presented to cytotoxic immune T cells (PMID: 25493333). Germline polymorphisms and haplotypes in HLA-B have been linked with various autoimmune syndromes and hypersensitivity to certain medications (PMID: 22188278, 25877443). True +ENST00000376228 NM_002117.5 3107 HLA-C False HLA-C, an MHC class I component involved in antigen presentation to the immune system, is infrequently altered in cancer. HLA-C is a heavy chain subunit of the major histocompatibility class I (MHC I) complex. HLA-C is one of the three MHC I surface receptors that function as a heterodimer in collaboration with β-microglobulin to regulate immune responses (PMID: 15719024). A critical component of the immune system is the presentation of foreign antigens on the cell surface by the MHC molecules (PMID: 10974135, 15719024). Immune recognition leads to the stimulation of a signaling cascade that results in apoptosis of MHC-presenting target cells (PMID: 15719024). Tumor cells are vulnerable to such an immune response due to the presentation of tumor-specific antigens such as mutated oncoproteins on the cell surface (PMID: 24782321, 24244023, 23157435). HLA-C molecules are highly polymorphic and the breadth of these repertoires can predispose to autoimmune diseases such as psoriasis (PMID: 28855257, 16642438). Several types of tumors are known to evade an immunological response by downregulating the levels of MHC I-presenting antigens on the tumor cell surface (PMID: 24782321, 24244023, 23157435, 11665717). A reduction in HLA-C levels in cancer could occur due to many factors including mutation, transcriptional downregulation, epigenetic silencing and protein stability, among others (PMID: 26796069, 26372948, 31564637). HLA-C downregulation may result in reduced efficacy of immunotherapy in patients whose cancers display an evasion of the immune system (PMID: 9057360, 24782321, 23157435, 26796069). True +ENST00000311487 NM_145899 3159 HMGA1 True HMGA1, a chromatin remodeling protein, is altered by amplification in cancer. HMGA1 encodes for the chromatin remodeling protein isoforms HGMA1a and HGMA1b through alternative splicing (PMID: 6297996, 3192537). HMGA1 has three AT-hook DNA binding domains to bind AT-rich regions in the minor groove of the DNA in chromatin, allowing the recruitment of transcription factor and histone modification proteins to remodel chromatin and modulate gene expression (PMID: 8374955). HMGA1 participates in various cellular processes through gene modulation including cell cycle progression, embryologic development, neoplastic transformation, cellular differentiation, apoptosis, cellular metabolism and DNA repair (PMID: 11389094, 8957086, 11134344, 11076660, 12700639, 15924147, 16007157). Overexpression of HMGA1 in cancer cell lines results in increased cell proliferation, tumor growth and metastasis, suggesting that HMGA1 predominantly functions as an oncogene (PMID: 10866296, 22276142). HMGA1 amplification has been identified in various cancer types, including pancreatic cancer, colon cancer, breast cancer and cervical cancer (PMID: 22249617, 34167089, 23545254, 9458084). Chromosomal rearrangements of HMGA1 leading to amplified HMGA1 expression have been identified in various common benign mesenchymal tumors (PMID: 9060829, 9290959, 8946199). False +ENST00000403681 NM_003483 8091 HMGA2 True HMGA2, a chromatin remodeling protein, is altered by amplification in cancer. HMGA2, or HMGI-C, encodes a chromatin remodeling protein that binds to DNA through AT-hook DNA binding domains, allowing recruitment of transcription factor and histone modification proteins to remodel chromatin and modulate gene expression (PMID: 1692833, 3456586). HMGA2 regulates the transcriptional activity of genes, such as cyclin A and ERCC1, through binding to specific AT-rich sites at the gene promoter region (PMID: 14645522, 14627817). HMGA2 expression is upregulated widely in undifferentiated cells during embryogenesis, and eventually expression is downregulated or absent in tissues over the course of fetal development and into adulthood (PMID: 7651535). Overexpression of HMGA2 in cancer cell lines and mice results in tumor growth and metastasis, suggesting that HMGA2 predominantly functions as an oncogene (PMID: 25014774, 10945639). HMGA2 amplification has been identified in various cancer types, including esophageal squamous carcinoma, colorectal cancer and ovarian cancer (PMID: 27027341, 21252160, 17600087). Chromosomal rearrangements of HMGA2 leading to overexpression have been identified in various common benign mesenchymal tumors (PMID: 7670494). False +ENST00000257555 NM_000545.5 6927 HNF1A False HNF1A, a transcription factor, is altered by mutation in various cancer types. Germline mutations of HNF1A are associated with Maturity Onset Diabetes of Young (MODY3) and hepatic adenomas familial (HEPAF), while somatic inactivating mutations are found in a diverse range of cancers. HNF1A is a liver-specific transcription factor that is a member of the hepatocyte nuclear factor protein family. HNF1A, together with other hepatocyte nuclear factors (HNF4A, HNF6) forms tissue-specific regulatory circuits and acts as master regulators of liver and pancreatic islet transcription (PMID:14988562). HNF1A-/- mice showed defects in hepatic function, renal Fanconi syndrome, type II diabetes and hypercholesterolemia (PMID: 11279518). Heterozygous germline mutations in HNF1A cause Maturity Onset Diabetes of Young or MODY3 (PMID: 8945470). Bi-allelic somatic inactivating mutations and deletions in HNF1A are seen in about 40-50% of hepatocellular adenomas (HCAs) (PMID: 12355088). Two HNF1A mutations, W206 (DNA binding domain) and P291 (Trans-activation domain), have been found over represented across different studies (PMID: 16496320, 20393147, 12355088). Among them, W206 is unique to HCA while P291 is common to both HCA and MODY. In rare cases of hepatocellular carcinomas (HCCs), HNF1A mutations were seen in combination with other genetic alterations (PMID: 12355088). True +ENST00000225893 NM_001165923 6928 HNF1B False HNF1B, a transcription factor, is infrequently altered in cancer. HNF1B, a member of the homeobox-containing basic helix-turn-helix family, encodes for a DNA-binding transcription factor that forms a homodimer or heterodimer with HNF1A (PMID: 1763325, 7900999). HNF1B regulates various cellular processes, such as cellular differentiation, apoptosis and autophagy, through the repression and activation of target genes (PMID: 28622294, 25715395). Alterations of HNF1B are found in a large percentage of dominant inherited nephropathy (PMID: 33305128, 21775974). The oncogenic function of HNF1B is likely tissue-specific. Ectopic expression of HNF1B in prostate cancer and serous ovarian carcinoma cell lines suppresses cellular proliferation, migration and invasion, suggesting that HNF1B functions predominantly as a tumor suppressor gene in this tissue context (PMID: 31636385, 33174391, 24105991). Downregulation of HNF1B has been identified in renal cancer, colon adenocarcinoma, glioblastoma, kidney chromophobe and lung squamous cell carcinoma (PMID: 15168014, 28807937, 33173410). Conversely, upregulation of HNF1B has been identified in bladder urothelial carcinoma, cholangiocarcinoma, kidney renal papillary cell carcinoma, liver hepatocellular carcinoma, stomach adenocarcinoma, thyroid carcinoma and uterine corpus endometrial carcinoma (PMID: 33173410). False +ENST00000006015 NM_005523 3207 HOXA11 False HOXA11, a homeobox gene transcription factor, is altered by downregulation and hypermethylation in various cancers. HOXA11, a member of the homeobox gene family, encodes for a transcription factor that primarily functions in embryogenesis and myogenesis (PMID: 36815629, 18942146, 11493536). HOXA11 regulates embryonic development events, such as limb outgrowth and the development of the urogenital tract (PMID: 22190701, 23561734). Germline mutations of HOXA11 have been implicated in the development of radioulnar synostosis with amegakaryocytic thrombocytopenia (PMID: 11101832, 16765069). The oncogenic function of HOXA11 is likely tissue specific. Ectopic expression of HOXA11 in various cancer cell lines and models suppresses cellular proliferation, migration and invasion, suggesting that HOXA11 functions predominantly as a tumor suppressor gene in these contexts (PMID: 28423531, 24259349, 33515421). Downregulation and hypermethylation of HOXA11 has been identified in non-small cell lung cancer, endometrial cancer and glioblastoma (PMID: 24259349, 33515421, 27456940). Conversely, overexpression of HOXA11 in gastric cancer cell lines and models induces cellular proliferation, migration and invasive metastasis, suggesting that HOXA11 may function predominantly as an oncogene in this context (PMID: 37539033). Preclinical studies have suggested downregulation of HOXA11 is associated with poor patient prognosis and confers chemoresistance in the context of glioblastoma (PMID: 27456940). True +ENST00000290295 NM_006361.5 10481 HOXB13 True HOXB13, a transcription factor, is altered by mutation in various cancer types. Germline mutations of HOXB13 predispose to certain cancers, including prostate cancer. HOXB13 is a member of the homeobox (HOX) gene family, which is a group of clustered transcription factors that are evolutionarily conserved and crucial for embryonic development along the anterior-posterior axis (PMID: 1346368). In addition to regulating body axis patterning in embryos, HOXB13 has roles in the regulation of cellular differentiation, proliferation, and cell cycle activity (PMID: 28798948). HOXB13 mediates gene expression in a cell-type specific manner due to variation in interactions with adaptor molecules. HOXB13 has been implicated in prostate cell identity, and mice lacking HOXB13 have prostate defects (PMID: 12668621). HOXB13 functions through the androgen receptor (AR) in both normal adult tissue and prostate cancer by regulating the chromatin state around the AR gene, and can have both growth-enhancing or growth-suppressing effects depending on context (PMID: 15604291, 19917249). Germline HOXB13 mutations have been found in familial prostate cancer and are predictive of prostate cancer risk (PMID: 22236224), while somatic HOXB13 mutations have been identified in several other cancer types (PMID: 28798948). Though HOXB13 is overexpressed during malignant progression of prostate and breast cancer (PMID: 20018680), it is downregulated in colorectal and renal cell cancer models, suggesting that it has context-specific effects in human tumors (PMID: 15928669, 16278676, 15193263, 17453342, 23832664). True +ENST00000451590 NM_005343.2 3265 HRAS True 3A HRAS, a GTPase, is altered in a diverse range of cancers including head and neck squamous cell carcinoma, thyroid, and bladder cancer. HRAS (Harvey Ras) is a membrane-associated GTPase. It plays an important role as an upstream mediator of several pro-proliferative and anti-apoptotic signal transduction pathways, including the mitogen activated protein kinase (MAPK) and PI3 kinase (PI3K) pathways. HRAS, NRAS and KRAS comprise the Ras proto-oncogene family, and all three have a similar structure and function. Transforming, gain-of-function mutations of RAS oncogenes tend to disrupt GTPase activity and promote cell proliferation and angiogenesis (PMID: 12778136). Overexpression of oncogenic HRAS also triggers growth factor-independent cell cycle progression and upregulation of proteins implicated in tumor growth (e.g., matrix metalloproteinases 2 and 9). HRAS mutations are found most commonly in cancers of the thyroid, salivary glands, bladder urinary tract, cervix and prostate (PMID: 21993244, 22589270). Patients with Costello syndrome, a hereditary disorder with germline alterations in HRAS, can develop various malignancies at a young age, including neuroblastoma, rhabdomyosarcoma and transitional cell carcinoma of the bladder (PMID: 22261753, 16170316). RAS mutations (including HRAS) have been found in a significant proportion of RET negative medullary thyroid cancer (PMID: 21325462, 23240926, 22865907, 23264394). And while multikinase inhibitors that include HRAS among its targets are FDA-approved for the treatment of medullary thyroid cancer, the FDA-approval is not based on the HRAS mutant status, therefore not explicitly meeting the OncoKB Level 1 criteria. False +ENST00000199936 NM_002153 3294 HSD17B2 False HSD17B2, a 17β-hydroxysteroid dehydrogenase, is infrequently altered in cancer. HSD17B2 encodes the 17β-hydroxysteroid dehydrogenase enzyme which functions in the catalyzation of estradiol to estrone, testosterone to androstenedione and androstenediol to dehydroepiandrosterone (DHEA) (PMID: 17538076, 19130396). The anti-estrogenic and anti-androgenic function of HSD17B2 maintains cell cycle homeostasis through negative regulation of hormone-induced proliferation and differentiation in endometrial tissue (PMID: 18270252). Overexpression of HSD17B2 in prostate cancer cell lines suppresses cell proliferation and xenograft growth, suggesting that HSD17B2 functions primarily as a tumor suppressor gene (PMID: 30228209). Downregulation of HSD17B2 has been identified in prostate cancer and breast cancer (PMID: 30228209, 18372405). True +ENST00000369413 NM_000862 3283 HSD3B1 True HSD3B1, a 3β-hydroxysteroid dehydrogenase, is altered by mutation and amplification in castration-resistant prostate cancer. HSD3B1 encodes for a 3β-hydroxysteroid dehydrogenase which functions in the formation of steroid hormones through the oxidation and isomerization of hydroxysteroid precursors (PMID: 1944309). HSD3B1 is essential to the androgen biosynthesis pathway to catalyze the rate-limiting step of adrenal precursor steroids (PMID: 20534728). Knockdown of HSD3B1 in breast cancer models suppresses tumor growth and cellular proliferation and migration, suggesting that HSD3B1 functions predominantly as an oncogene (PMID: 28744792). Amplification and mutations of HSD3B1 have been identified in castration-resistant prostate cancer and breast cancer (PMID: 34747051, 28744792). The HSD3B1(1245C) allele upregulates dihydrotestosterone synthesis and is associated with prostate cancer resistance to androgen-deprivation therapy and poor prognosis (PMID: 27575027). False +ENST00000216281 NM_005348 3320 HSP90AA1 True HSP90AA1, a heat shock protein, is infrequently altered in cancer. HSP90AA1, a member of the HSP90 family of heat shock proteins, encodes for a molecular chaperone which functions in maintaining cellular homeostasis and cell cycle control through ATPase activity (PMID: 11812147, 11274138). HSP90AA1 recruits ATP and co-chaperones to substrate proteins, referred to as client proteins, and facilitates assembly, folding and degradation (PMID: 34380015). The numerous client proteins of HSP90AA1 typically include steroid hormone receptors and protein kinases, such as PIM1, AKT and HIF1A (PMID: 10544245, 3900074, 30536958). Knockdown of HSP90AA1 in various cancer cell lines and models suppresses cellular proliferation and induces apoptosis, suggesting that HSP90AA1 functions predominantly as an oncogene (PMID: 35095481, 30153855). Upregulation of HSP90AA1 has been identified in various cancers, including colorectal cancer, breast cancer and hepatocellular carcinoma (PMID: 31687275, 34109171, 30521791). HSP90AA1 has been identified to confer multi-drug resistance in various cancer cell lines through inhibition of apoptosis and promotion of autophagy via the AKT and JNK pathways (PMID: 30153855, 33738259). False +ENST00000421577 NM_001098521 10553 HTATIP2 False HTATIP2, a nuclear transport inhibiting oxidoreductase, is altered by deletion in cancer. HTATIP2, also known as TIP30 or CC3, encodes an oxidoreductase that functions in nuclear transport inhibition through importin binding and transcription regulation (PMID: 15728189). HTATIP2 functions in the stimulation of TAT-mediated transcription, upregulating apoptosis and tumor suppression through transcription promotion of apoptosis-related genes Bad and Siva and tumor suppressor gene NM23-H2 (PMID: 10698937). TAT-mediated transcription enhancement occurs through HTATIP2 phosphorylating the C-terminal domain of the largest RNA polymerase II subunit in a TAT-dependent manner (PMID: 10698937). Overexpression of HTATIP2 in cancer cell lines results in reduced cell proliferation, reduced tumor metastasis and increased apoptosis, suggesting that HTATIP2 predominantly functions as a tumor suppressor (PMID: 30249892, 25617528, 25544767). Loss of HTATIP2 has been identified in various cancer types, including glioma, lung adenocarcinoma and hepatocellular carcinoma (PMID: 25617528, 32545251,19010857). Epigenetic silencing of HTATIP2 through hypermethylation is a mechanism identified in various cancer cells that results in HTATIP2 downregulation and is associated with poor patient prognosis (PMID: 25617528, 19010857). True +ENST00000407780 NM_015259.4 23308 ICOSLG True ICOSLG, an immune costimulatory ligand, is altered by mutation in primary immunodeficiencies. ICOSLG is a T-cell co-stimulator ligand which is constitutively expressed on B-cells and inducible on monocytes and dendritic cells. Co-stimulator ligands like ICOSLG are typically required for activation of T-cells, cytokine production, and antigen recognition by the T-cell receptor. ICOSLG binds to the co-stimulatory receptor, ICOS, which shares similar structural and functional similarities to CD28. ICOSLG expression on plasmacytoid dendritic cells has been associated with disease progression (PMID: 23026134) and may serve as a potential biomarker of trastuzumab resistance in breast cancer (PMID: 25449779). Germline mutations of ICOSLG and its promoter region are associated with common variable immunodeficiency and Alopecia areata (PMID: 23196741, 15963052). False +ENST00000376112 NM_002165 3397 ID1 True ID1, a DNA-binding inhibitor protein, is infrequently altered in cancer. ID1 encodes for a DNA-binding inhibitor protein that interacts with the basic helix-loop-helix family of transcription factors to regulate their activity (PMID: 2156629). As ID1 has no DNA binding activity of its own, interactions with the helix-loop-helix family of transcription factors result in the inhibition of DNA binding and transcriptional activity through the formation of nonfunctional heterodimeric complexes (PMID: 2156629). ID1 has been implicated in the promotion of cell proliferation, cell differentiation and cell cycle proliferation through the inactivation of tumor suppressor genes (PMID: 25924227). Overexpression of ID1 in various cancer cell lines and mouse models has demonstrated increased metastatic ability and cellular proliferation, suggesting that ID1 functions primarily as an oncogene (PMID: 32705157, 24160469, 25938540). ID1 amplification has been identified in various cancers, including pancreatic cancer, gastric cancer and glioblastoma (PMID: 31582374, 22245935, 31292163). False +ENST00000374561 NM_002167.4 3399 ID3 False ID3 encodes a helix-loop-helix protein involved in transcription. Mutations and overexpression of ID3 are found in a variety of cancers. ID3 (Inhibitor for DNA binding 3) is a protein that binds basic helix-loop-helix (HLH) transcription factors and inhibits their activity. ID3 proteins form heterodimers with tissue-specific HLH proteins, such as E proteins, that disrupt their binding to DNA (PMID: 2000388, 2156629, 16034366). ID3 can regulate cell differentiation, cell proliferation, cell invasiveness and angiogenesis (PMID: 8197168, 11840325, 11840326, 10197587, 11058077, 9528806, 16034366). Loss of ID3 expression in mice results in defects in B-cell proliferation and the development of lymphomas (PMID: 10454544). Loss-of-function mutations in ID3 are common in Burkitt's lymphoma and result in disruption of ID3 transcriptional activity (PMID: 23143595). ID3 is also overexpressed in various tumors, with both growth-enhancing and growth-suppressing effects (PMID: 26135667, 26384138, 10537105, 11689883, 11085505) suggesting that ID3 appears to have context-dependent oncogenic and tumor suppressor functions in cancer. True +ENST00000345146 NM_005896.2 3417 IDH1 True 1 IDH1, a cell metabolism enzyme, is recurrently mutated in various cancer types including acute myeloid leukemia and gliomas. The IDH1 (isocitrate dehydrogenase 1) protein is an enzyme that catalyzes the oxidative decarboxylation of isocitrate to α-ketoglutarate (α-KG), a crucial step in the tricarboxylic acid (TCA) cycle. IDH1 utilizes NADP(+) as an electron acceptor and it is predominantly expressed in the cytosol and peroxisomes, playing a role in the cytoplasmic production of NADPH. Cancer-associated mutations in the catalytic site of IDH1 confer a gain-of-function of neomorphic enzymatic activity, allowing the mutant enzyme to convert α-KG to the “oncometabolite” D-2-hydroxyglutarate (2-HG) (PMID: 20171147). 2-HG promotes tumor development by inhibiting a variety of enzymes that require α-KG as a substrate, including enzymes involved in DNA demethylation, histone demethylation, adaptation to hypoxia and collagen maturation. IDH1 mutations have been identified in glioma, cholangiocarcinoma and acute myeloid leukemia (AML) among others (PMID: 19657110, 23630074) and may contribute to the progression of myeloproliferative neoplasms to bone marrow failure or AML (PMID: 29355841). False +ENST00000330062 NM_002168.2 3418 IDH2 True 1 IDH2, a cell metabolism enzyme, is recurrently mutated in various cancer types including acute myeloid leukemia, glioblastoma, and cholangiocarcinoma. The IDH2 (isocitrate dehydrogenase 2) protein is an enzyme that catalyzes the oxidative decarboxylation of isocitrate to α-ketoglutarate (α-KG) in the tricarboxylic acid (TCA) cycle. IDH2 utilizes NADP(+) as an electron acceptor and it is expressed in the mitochondria, where it plays a role in cell metabolism and energy production via TCA cycle. Cancer-associated mutations in the catalytic site of IDH2 confer a gain-of-function of neomorphic enzymatic activity allowing the mutant enzyme to convert α-KG to the “oncometabolite” D-2-hydroxyglutarate (2-HG) (PMID: 20171147). 2-HG promotes tumor development by inhibiting a variety of enzymes that require α-KG as a substrate, including enzymes involved in DNA demethylation, histone demethylation, adaptation to hypoxia and collagen maturation (PMID: 23630074). IDH2 mutations have been identified in hematologic malignancies, particularly in acute myeloid leukemia (AML), as well as in solid tumors such as gliomas and cholangiocarcinomas, and may contribute to the progression of myeloproliferative neoplasms to bone marrow failure or AML (PMID: 29355841).. False +ENST00000270139 NM_000629 3454 IFNAR1 False IFNAR1, a subunit of the interferon receptor, is infrequently altered in cancer. IFNAR1 encodes the protein interferon alpha and beta receptor subunit 1, which, along with the IFNAR2 subunit, composes the type I interferon receptor (IFNAR) (PMID:33552080, 24362405). Binding of type I interferons to the receptor activates the JAK/STAT signaling pathway resulting in transcriptional activation or repression of interferon-regulated genes. IFNAR1 and IFNAR2 form a heterodimer complex and are associated with tyrosine kinase 2 (Tyk2) and JAK1, respectively, which are required for STAT recruitment to the receptor complex. STAT proteins are phosphorylated by the JAKs, which promote their translocation to the nucleus to regulate gene expression (PMID: 24362405, 22410872, 33552080, 32378445, 30555157). IFNAR is widely expressed in lymphocytes, natural killer cells and myeloid-derived suppressor cells (PMID: 36063748). The protein encoded by INFAR1 also functions as an antiviral factor (PMID: 24362405, 30555157). Inhibition of IFNAR1 signaling in natural killer cells has been demonstrated to promote virus clearance (PMID: 33771858). Elevated levels of IFNAR1 have been associated with poor prognosis in breast and head and neck squamous cell carcinoma, while in colorectal cancer elevated levels are positively associated with T-cell infiltration and better response to chemotherapy (PMID: 36063748, 30555157, 32378445). Overexpression of IFNAR1 in mammary adenocarcinoma cells results in elevated PD-L1 expression, suggesting pro-tumorigenic effects in this context (PMID: 32378445). False +ENST00000367739 NM_000416.2 3459 IFNGR1 False IFNGR1, a subunit of the interferon-γ receptor, is altered by deletion in metastatic melanomas that are resistant to immunotherapy. IFNGR1 is a high-affinity subunit of the interferon-γ (IFN-γ) receptor, which is required by macrophages for killing intracellular pathogens such as mycobacteria. After binding to interferon-γ, two IFNGR1 molecules form a heterodimeric complex with two IFNGR2 molecules, which initiates interferon signaling. IFNGR1 binds JAK1, and stimulation of the interferon response results in downstream activation of the JAK-STAT signaling pathway (PMID: 22410872). Three cases of malignancy have been reported in patients with complete IFNGR1 deficiency: human herpesvirus-8 associated Kaposi sarcoma (PMID:15069403), Epstein Barr Virus (EBV) related B-cell lymphoma (PMID: 23800860) and pineal germinoma, an intracranial tumor (PMID: 25216720). Mutations in IFNGR1 can result in enhanced susceptibility to mycobacterial infections, and low expression of IFNGR1 leads to a functional blockade of IFN-γ signaling (PMID:15589309). Somatic mutations in IFNGR1 have not yet been identified in human cancers, however, IFNGR1 expression is reduced in some breast cancers (PMID:22182699) and downregulated in a subset of metastatic prostate cancers (PMID:24953652). In addition, IFNGR1 deletions have been identified in patients with metastatic melanoma that are non-responders to anti-CTLA4 immunotherapies (PMID: 27667683). True +ENST00000307046 NM_001111285.1 3479 IGF1 True IGF1, an insulin growth factor, is infrequently altered by mutation in various cancer types. IGF1 is an insulin-like growth factor that signals through the IGF1 receptor (IGF1R) and the insulin receptor (IR). The main function of IGF1 is to stimulate growth in a wide array of tissues. IGF1 is broadly expressed however the liver produces the majority of circulating IGF1 in response to GH secreted by the pituitary. Circulating IGF1 is bound to IGF-binding proteins (IGFBPs), e.g. IGFBP3, and only the free IGF1 is biologically active. In epidemiologic studies, high circulating levels of IGF1 and low levels of IGFBP3 have been associated with breast, prostate, colon, lung, and genitourinary cancers (PMID: 9593409, 9365156, 9438850, 10203281, 9923856). Genetic variation in the 3-prime region of the IGF1 gene may contribute to increased circulating IGF1 levels (PubMed: 17911177). Tissues can regulate levels of IGF1R and IGFBPs to modify IGF1 signaling and alterations in this local control may result in cancer (PMID: 23569026). False +ENST00000268035 NM_000875.3 3480 IGF1R True IGF1R, an insulin growth factor receptor, is altered by mutation in various cancer types. IGF1R is an insulin-like growth factor receptor (PMID: 19029956), a tyrosine kinase which activates downstream pathways involved in growth and cell survival. IGF1R binds several ligands, including high affinity ligands (insulin-like growth factor I (IGF1)) and low-affinity ligands (insulin, insulin-like growth factor II (IGF2)) (PMID: 12360255, 19029956, 22337149). Binding to ligands activates two oncogenic pathways, the PI3-kinase/AKT pathway and the RAS-MAPK pathway (PMID: 25984556). Missense mutations of IGF1R are observed across the entire gene body, and several of these mutations have been linked to changes in the basal activity of IGF1R (PMID: 22778948). IGF1R is over-expressed in several cancers, and its over-expression in cell lines can induce transformation (PMID: 9196021). IGF1R is frequently mutated/amplified across a variety of cancer types (frequency ~8%) (cBioPortal, Nov 2015, PMID: 25984556). Binding of ligand to IGF1R has been reported to mediate both resistance and sensitivity to both targeted and cytotoxic therapy across a number of cancer types (PMID: 25984556, 22337149). Various therapeutics have been developed to target IGF1R, either as monoclonal antibodies against IGF1R or IGF1R ligands, or as inhibitors of the kinase activity of IGF1R, but these therapeutics have shown limited success in large clinical trials (PMID: 23601239, 24338270 ). False +ENST00000434045 NM_001127598.1 3481 IGF2 True IGF2, an insulin growth factor, is frequently altered by overexpression in various cancer types, including Wilms tumors. Loss of imprinting of IGF2 is associated with Beckwith-Wiedemann syndrome and predisposes to several pediatric cancers. IGF2 is an insulin growth factor which binds to receptor tyrosine kinases to activate downstream mitogenic signaling pathways (PMID: 24080445, 25704323). IGF2 binds to one of several receptor tyrosine kinases, including IGF1R and IR-A, to initiate a cascade that activates mitogenic and metabolic signaling via the PI3K-AKT and MAPK pathways (PMID: 24080445). In most adult tissues IGF2 is imprinted, and thus its expression is restricted to the paternal allele only (PMID: 12637750). Aberrant IGF2 expression, in many cases due to loss of imprinting, is implicated in the development of several tumor types (e.g. breast, ovarian, and Wilms tumors) (PMID: 17686827, 24080445), as well as the progression of tumors to more aggressive disease (e.g. breast cancer, chronic myeloid leukemia) (PMID: 20089431, 9558368, 24080445). Loss-of-imprinting of IGF2 is causative for Beckwith-Wiedemann syndrome, which confers an increased risk of developing childhood tumors such as Wilms’ tumor and hepatoblastoma (PMID: 8968759, 12668598, 23620526). Overexpression of IGF2 is also a critical event in non-islet cell tumor hypoglycemia (PMID: 24616774, 24080445). False +ENST00000367120 NM_014002.3 9641 IKBKE True IKBKE, an intracellular kinase, is altered by mutation and overexpression in various cancer types. Inhibitor of Kappa Light Polypeptide Gene Enhancer in B-Cell, Kinase Epsilon (IKBKE) is a serine/threonine kinase that has important functions in the regulation of inflammatory responses to infection as well as cancer (PMID: 23333767, 19160540). It is activated in cells that are infected with virus and as a result associates with DDX3X and phophorylates its target protein such as interferon regulatory factors (IRF3, IRF7) (PMID: 23333767, 19160540). As a result of their phosphorylation IRFs translocate to the nucleus and activate transcription of pro-inflammatory and anti-viral genes such as IFNB. IKBKE also phosphorylates inhibitors of NF-kappa-B leading to their degredation and further enhancing pro-inflammatory responses (PMID: 23333767, 19160540). It is overexpressed in >30% of primary breast cancer and amplifications affecting IKBKE locus have been observed (PMID: 23333767, 21042276, 17574021). IKBKE has been shown to exhibit oncogenic functions through the phosphorylation of CYLD at serine 418 and TRAF2 at serine 11(PMID: 19481526, 23007157). Additionally IKBKE also phosphorylates NF-kappa-B and AKT1 leading to higher NF-kappa-B activity (PMID: 21908616, 21464307). IKBKE has also been implicated in several other tumor entities (PMID:22942254, 19497997, 20001340, 21271611, 22266464). Recently, IKBKE inhibitors have been developed and are currently tested pre-clinically (PMID: 22305584, 23099093, 19426678). False +ENST00000331340 NM_006060.4 10320 IKZF1 False IKZF1 encodes a transcription factor involved in lymphocyte development. Loss-of-function alterations of IKZF1 are frequently found in B-cell acute lymphocytic leukemia. The IKZF1 gene encodes the Ikaros family zinc finger 1 transcription factor (IKZF1). IKZF1 functions in hematopoietic stem cells to induce lymphoid specification and differentiation (PMID: 19345118, 16518393). As a transcription factor, IKZF1 alters chromatin and regulates gene expression by recruiting histone deacetylases and chromatin remodeling ATPases to target genes (PMID: 10204490). IKZF1 is the target of lenalidomide-induced degradation in multiple myeloma and its degradation is a key component of the drug's activity in myeloma (PMID: 24292625). IKZF1 mutations and deletions are most commonly found in B-cell acute lymphocytic leukemia (B-ALL) and may be a mechanism of leukemic transformation in Philadelphia chromosome-positive (BCR-ABL) B-ALLs (PMID: 17344859, 18408710). Mutation of IKZF1 is associated with poor prognosis in B-ALL (PMID: 19129520). It is also deleted more rarely in other leukemias such as acute myeloid leukemia (PMID: 26069293, 25331116, 24072100). False +ENST00000346872 NM_012481.4 22806 IKZF3 True IKZF3, a hematopoietic-specific transcription factor, is altered by mutation and deletion in hematopoietic malignancies. IKZF3 (also Aiolos) is a transcription factor that functions as a member of the Ikaros protein family (PMID: 9560339). Ikaros family transcription factors are required for normal development of the lymphoid system (PMID: 9560339). IKZF1, IKZF2, and IKZF3 form homo- and heterodimers to increase their affinity to bind DNA and to activate hematopoietic-specific transcription (PMID: 9560339). Specifically, IKZF3 is more highly expressed in committed lymphoid progenitor cells and mediates differentiation into pre-T and pre-B cell precursors and subsequent maturation (PMID: 9155026, 9806640). In addition, IKZF3 interacts with histone modifying complexes, such as the NURD complexes, and mediates their activity during lymphocyte maturation (PMID: 10204490, 10357820). Anti-apoptosis genes, such as BCL-2 and BCL-XL, are regulated by IKZF3, leading to control of lymphocyte survival (PMID: 11714801, 10369681). Expression of IKZF3 is upregulated in chronic lymphocytic leukemias (CLL) (PMID: 19016725, 18184862) and missense hotspot mutations, predicted to stabilize the IKZF3 protein, have been identified in CLL (PMID: 28584254, 23415222). However, deletions in IKZF3 have been identified in acute lymphoblastic leukemia and other hematopoietic malignancies, suggesting IKZF3 may function as both an oncogene and tumor suppressor (PMID: 17344859, 24212482, 24072100). Lenalidomide, a drug with efficacy in multiple myeloma and B cell malignancies, specifically targets IKZF3 and IKZF1 for proteasome-mediated degradation, which contributes to the cytotoxicity of the drug (PMID: 24292625, 24292623). True +ENST00000423557 NM_000572.2 3586 IL10 False IL10, an anti-inflammatory cytokine, is not commonly mutated in cancer. IL-10 is a cytokine that inhibits the secretion of several pro-inflammatory cytokines by regulatory T cells, activated macrophages, and other immune cells (PMID: 11244051). IL-10 expression is tightly regulated by specific transcription factors based on immune cell type, which prevents excessive immune responses and autoimmune disease (PMID: 20154735). In macrophages and dendritic cells, IL-10 is involved in the regulation of the JAK-STAT signaling pathway and can block NF-κB activity (PMID: 14678266). IL-10 deficient mice develop inflammatory diseases with excessive immune responses after pathogen challenge (PMID: 24566625). Conversely, high IL-10 expression in mice has also been shown to promote an anti-tumor immune response (PMID: 18613832). IL-10 mutations have been identified in early-onset immune disorders such as inflammatory bowel disease (PMID: 25373860). Higher IL-10 levels are associated with more aggressive disease and increased macrophage recruitment following chemotherapy in pre-clinical models of breast cancer (PMID: 25559954) and blockade of IL-10 receptors can improve chemotherapy responses in mice (PMID: 25446896). False +ENST00000296870 NM_000588.3 3562 IL3 True IL3, a cytokine involved in immune regulation, is altered by chromosomal rearrangement in acute lymphoblastic leukemia. IL3 is an interleukin that is a member of the beta common (βc) cytokine family, which also includes IL5 and GM-CSF (PMID: 29374162, 23046136, 23535386). IL3 is highly expressed in activated T lymphocytes and is important in mediating the immune responses of mast cells, dendritic cells, and basophils (PMID: 23046136). The main receptor partner of IL3 is IL3R, a heterodimeric cell-surface receptor, which binds IL3 via the cytokine-specific α-subunit to recruit the shared βc subunit (PMID: 29374162). Initiation of IL3-IL3R signaling results in the activation of downstream effector pathways, including the JAK-STAT pathway which mediates STAT-dependent transcription of immune target genes (PMID: 18692472). IL3 signaling regulates various aspects of immune regulation including differentiation, inflammation, proliferation, and survival (PMID: 3087441, 18178860, 23535386). Increased IL3 expression in hematopoietic studies results in leukemic self-renewal and survival, suggesting that IL3 functions predominantly as an oncogene (PMID: 2439154, 10536003). Overexpression of IL3 has also been implicated in autoimmune diseases, resulting in hyper-responsiveness to IL3 stimulation (PMID: 18341658, 6430708, 28031576, 9446636, 26131743). Rearrangements involving IL3 are found in patients with B-precursor acute lymphoblastic leukemias, typically leading to increased IL3 expression and eosinophilic proliferation (PMID: 29424254, 3546615, 30207070). False +ENST00000336909 NM_002184.3 3572 IL6ST True IL6ST, a transmembrane signal transducer, is infrequently altered in cancer. IL6ST encodes gp130, a membrane glycoprotein that serves as the signal transducer for IL-6 family cytokines (PMID: 2261637). IL-6 cytokines bind to IL-6R, which leads to gp130 homodimerization and formation of a hexameric receptor complex with IL-6/IL-6R (PMID: 2261637, 19915009). gp130 then activates the JAK/STAT pathway through the effector STAT3 to regulate diverse cellular processes, including immune responses, development and hematopoiesis (PMID: 10661409, 8632998, 15650055). gp130 also mediates proliferation and cell migration independent of STAT3 by activating YAP, Notch and ERK1/2 signaling pathways (PMID: 25731159, 17256754). The activity of gp130 is negatively regulated by the inhibitor SOCS3 (PMID: 12754506). In-frame deletions in the binding site of gp130 result in the constitutive activation of the signal transducer and subsequent upregulation of its targets, including STAT3, YAP and Notch (PMID: 19020503). Mice engineered to express mutant gp130 exhibit increased STAT3 activation and rapid gastric tumorigenesis compared to wildtype (PMID: 18431520, 14699500). IL6ST is altered, mostly by in-frame deletions and missense mutations in the IL-6/IL-6R binding site, in inflammatory hepatocellular tumors (PMID: 19020503, 24501689). False +ENST00000303115 NM_002185.3 3575 IL7R True IL7R, a subunit of the interleukin 7 receptor, is altered in various hematologic malignancies including pediatric acute lymphoblastic leukemia. IL7R is a component of the interleukin 7 (IL7) receptor that heterodimerizes with the common interleukin 2 receptor gamma chain. IL7R signals through the JAK-STAT pathway (PMID:15067053). IL7 regulates T, B, and NK cell development (PMID:17013389, 25729925, 23242416, 22267219, 21167753). In addition, IL7R signaling regulates VDJ and T-cell receptr (TCR) rearragements (PMID:12594950, 9858510). IL7R mutations leading to loss of function result in severe combined immunodeficiency syndrome (SCID) (PMID:9843216, 24759676). Activating mutations in IL7R result in an oncogene that signals independently of cytokine binding (PMID:21892159). Activating IL7R mutations are most commonly found in pediatric acute lymphoblastic leukemia (PMID: 25207766, 22237106, 21536738). False +ENST00000375774 NM_005537 3621 ING1 False ING1, a nuclear protein, is infrequently altered in cancer. ING1, inhibitor of growth family member 1, is a member of the ING family, which consists of five protein-coding genes (ING1 to ING5) and a pseudogene (INGX) (PMID: 34685579). ING1 encodes a nuclear protein and component of the p53 signaling pathway that interacts with the tumor suppressor protein p53 (PMID: 24008732, 12015309, 11461112, 21286670). ING1 inhibits cellular proliferation via the regulation of pathways involved with apoptosis, cellular senescence, DNA repair, cell migration and invasion (PMID: 34685579, 34493070, 11461112). ING1 modulates transcription through chromatin remodeling via physical association with both histone acetyltransferases (HATs) and histone deacetylases (HDACs); this function is linked to its anti-proliferative and pro-apoptotic effects (PMID: 34493070, 12015309). While mutations in the ING1 gene are rare, reduced levels of ING1 protein have been found in breast and prostate cancers, supporting its role as a tumor suppressor gene (PMID: 24008732, 12015309, 24962136, 34685579). Overexpression of ING1 induces cell cycle arrest and apoptosis in breast and lung cancer cell lines and inhibits tumor metastasis in experimental mouse models (PMID: 24962136, 21286670). True +ENST00000243786 NM_002191.3 3623 INHA False INHA, a regulator of gonadal hormone secretion, is altered by mutation in various cancer types. INHA (Inhibin alpha) is a member of the TGF-beta superfamily of proteins and is the alpha subunit of inhibin A and B protein complexes, which have been implicated in the regulation of cell proliferation, apoptosis, and hormone secretion. In particular, INHA negatively regulates follicle stimulating hormone (FSH) secretion from the pituitary gland (PMID: 3696240, 19602521) and mutations in the gene can lead to male infertility and ovarian failure (PMID: 25617520, 19752047). INHA deletion in mouse models leads to gonadal stromal tumors (PMID: 1448148 ), and polymorphisms in INHA are associated with an increased risk of testicular germ cell tumors (PMID: 18413775), both of which are consistent with its role in the regulation of hormone secretion. True +ENST00000242208 NM_002192.2 3624 INHBA True INHBA, a regulator of gonadal hormone secretion, is altered by mutation in various cancer types. INHBA (inhibin beta A) is a ligand that participates in the formation of activin and inhibin protein complexes that have opposing functions in the gonads and pituitary glands. INHBA can homo- or heterodimerize to regulate follicle stimulating hormone (FSH) synthesis (PMID: 27328872). INHBA interacts with transforming growth factor-β (TGF-β) transmembrane receptors and activates downstream TGF-β signaling (PMID: 25560921). Activin complexes have been associated with regulation of cell differentiation in the ovary, placenta, prostate, and testis (PMID: 9464268, 9207855). Rare somatic mutations in INHBA have been reported (PMID: 18948947) and overexpression of activin has been identified in several cancer types (PMID: 11511564, 9360551, 9714055, 9570994,9543140, 17143484, 9543140, 11994376, 19240652, 19308293). However, there are reports of an anti-tumorigenic effect of the activin signal in many cancers, wherein activin induces growth inhibition and apoptosis mainly through Smad-dependent pathways (PMID: 10869285, 15753386, 16140969, 19493612,22761777), suggesting that INHBA may have context-specific effects on tumor progression. True +ENST00000074304 NM_001134224.1 3631 INPP4A False INPP4A, a lipid phosphatase involved in PI3K signaling, is altered in various cancer types including mesothelioma and asbestos-exposed lung adenocarcinoma. INPP4A is a lipid inositol polyphosphate 4-phosphatase that has a role in negatively regulating the PI3K/AKT signaling pathway. The primary function of INPP4A is to selectively hydrolyze the position 4 phosphate group on the inositol ring, converting PI(3,4)P2 to PI(3)P (PMID: 24069021). INPP4A is predominantly expressed in the brain and maintains the integrity of the brain by regulating excitotoxic neuronal death (PMID 20463662). INPP4A has been implicated in the suppression of cell proliferation and tumor growth in mice via downregulation of the PI3K/AKT pathway (PMID: 21127264, 19325558). Recent studies have shown co-mutations with BAP1 and INPP4A in patients with mesothelioma and asbestos-exposed lung adenocarcinoma (PMID 26463840). False +ENST00000262992 NM_001101669.1 8821 INPP4B False INPP4B, a lipid phosphatase involved in PI3K signaling, is altered by mutation in various cancer types. INPP4B is a lipid inositol polyphosphate 4-phosphatase that has a role in negatively regulating the PI3K/AKT signaling pathway. The primary function of INPP4B is to selectively hydrolyze the position 4 phosphate group on the inositol ring, converting PI(3,4)P2 to PI(3)P (PMID: 24069021). INPP4B has been implicated in the suppression of cell proliferation, cell motility and tumor growth in mice via control of the PI3K/AKT pathway (PMID: 21127264, 19325558, 24069021). INPP4B loss of heterozygosity has been identified in breast and ovarian cancer patients, suggesting that INPP4B functions as a tumor suppressor (PMID: 19647222, 21127264). Loss-of-function studies in breast cancer cell line and murine models demonstrate that reduced expression of INPP4B results in enhanced AKT expression, cell invasiveness, and tumor progression (PMID: 19647222). Loss of INPP4B expression is observed in breast, ovarian, and prostate cancers, and correlates with lower overall survival (PMID 19647222). True +ENST00000298229 NM_001567.3 3636 INPPL1 False INPPL1, a lipid phosphatase involved in PI3K signaling, is altered by amplification in various cancer types including breast cancer. INPPL1 is a phosphatidylinositol phosphatase, an enzyme that catalyzes the conversion of phosphatidylinositol-trisphosphate (PIP3) to its diphosphate counterpart (PIP2), thus negatively regulating PI3K pathway signaling (PMID: 10761925). INPPL1 also plays a role in insulin signaling, EGFR turnover and actin cytoskeleton dynamics (PMID: 9660833, 11349134, 11739414). INPPL1 promotes cell proliferation in vitro, and its overexpression correlates with invasive features in breast cancer (PMID: 19065064, 19082482) and other cancers. INPPL1 is mainly altered by amplification, particularly in breast tumors, but also in esophagus and head and neck cancers (cBioPortal, MSKCC, Nov 2016). True +ENST00000302850 NM_000208.2 3643 INSR True INSR, a receptor tyrosine kinase involved in insulin signaling, is altered by chromosomal rearrangement in colorectal cancers. Germline mutations of INSR are associated with Donohue syndrome. INSR is the insulin receptor, a receptor tyrosine kinase that is a key mediator of insulin in the regulation of glucose metabolism (PMID: 2859121, 22337149). Insulin, IGF-I and IGF-II are the natural ligands of INSR and their binding to INSR leads to receptor auto-phosphorylation as well as phosphorylation of INSR targets (IRS1-4, SHC, GAB1, CBL) (PMID: 19274663). As a result of INSR signaling cells upregulate glucose uptake and proliferation and angiogenesis is increased (PMID: 25864925). High INSR pathway activation has oncogenic functions in several tumor entities (PMID: 25821562, 25694511, 26406954). High INSR activity driven by IGF2 is a mechanism of chemoresistance in GATA2 high prostate cancer (PMID: 25670080). NSR activity seems required for the transformation by ETV6-NTRK3 in secretory breast cancer cells (PMID: 21148487). The INSR pathway seems required for the growth of hormone-dependent breast cancer and targeted inhibition of INSR with small molecules has been shown to synergize with hormonal agents in estrogen-dependent breast cancer (PMID: 22042792, 21908557). False +ENST00000311234 NM_012141 26512 INTS6 False INTS6, a DEAD box subunit of the integrator complex involved in snRNA processing, is infrequently altered by deletion in cancer. INTS6, also known as DICE1 and DDX26, encodes a DEAD box protein subunit of the integrator complex that functions in small nuclear RNA processing (PMID: 19906297). The C-terminus of RNA polymerase II interacts with the integrator complex to mediate the interaction between the complex and promoter of the small nuclear RNA, allowing for transcription and 3′ end processing of the transcripts (PMID: 20457598). INTS6 has been associated with the Wnt signaling pathway, showcasing tumor suppressive activity through the upregulation of Wnt genes in prostate cancer cell lines re-expressing INTS6 (PMID: 19906297). INTS6 is located on the tumor suppressor locus of chromosome 13q14, physically close to both BRCA2 and RB1 (PMID: 10467397). Loss of INTS6 has been identified in various cancer types, including non-small cell lung carcinoma, prostate cancer and esophageal squamous cell carcinoma (PMID: 10467397, 19906297, 12527901). Significant downregulation of INTS6 expression occurs in prostate cancer cell lines due to hypermethylation of the INTS6 promoter region (PMID: 16007164). Ectopic expression of INTS6 in non-small cell lung carcinoma and prostate cancer cell lines suppresses tumor growth and anchorage-independent growth (PMID: 15254679). True +ENST00000268182 NM_003870 8826 IQGAP1 True IQGAP1, a scaffold protein, is infrequently altered in cancer. IQGAP1, a member of the IQGAP family, encodes for a scaffold protein that functions in regulating various cellular processes including actin cytoskeleton organization, cellular adhesion and cell cycle proliferation (PMID: 8670801, 11584017, 19454477). IQGAP1 mediates the EGFR pathway and the Ras-MAPK pathway through direct binding with its multiple protein interaction domains (PMID: 21349850, 23603816). Overexpression of IQGAP1 in various cancer cell lines and models induces increased cellular proliferation, motility and adhesion, suggesting that IQGAP1 functions predominantly as an oncogene (PMID: 15695121, 18281532, 33526450, 31597661). IQGAP1 amplification has been identified in various types of cancer, including head and neck squamous cell carcinoma and hepatocellular carcinoma (PMID: 29846864, 20530982). False +ENST00000245414 NM_002198.2 3659 IRF1 False IRF1, a transcription factor, is infrequently altered by deletion and mutation in hematopoietic malignancies. IRF1 is a transcription factor that is a member of the interferon regulatory protein family (IRF) (PMID: 29599126). IRF1 functions as both a transcriptional activator and repressor of various target genes including the cytokine interferon beta, among others (PMID: 3409321). IRF1 regulates the expression of genes involved in multiple cellular functions including DNA damage, apoptosis, inflammatory response, and adaptive immunity (PMID: 19129219, 15548708, 29599126). IRF1 expression is activated by IFN-γ, resulting in activation of Toll-like receptor signaling via MYD88 (PMID: 24092468, 17457343). In addition, IRF1 activates TP53, a tumor suppressor protein, via the recruitment of p300 and co-regulates the expression of cell cycle genes including p21 and Cyclin D1 (PMID: 8752276, 17409403, 9659924). IRF1 and IRF2 have direct and indirect roles in the repression of each other, with IRF1 predominantly mediating tumor suppression (PMID: 2475256). IRF1 mutations have been identified in clonally expanded CD8+ cells (PMID: 28635960) from patients with rheumatoid arthritis, highlighting the role of IRF1 in inflammation. Somatic mutations in IRF1 are rare; however, deletions of IRF1 have been identified in pediatric B-cell precursor acute lymphoblastic leukemia (PMID: 27090575). The IRF1 gene is also located on a chromosomal region (5q) frequently deleted in leukemias and myelodysplastic syndromes. Exon skipping events leading to loss of IRF1 expression have also been identified in hematopoietic malignancies (PMID: 8438156, 12358902). Reduced expression of IRF1 has been associated with a variety of cancer types including hematopoietic, breast, and melanoma, among others (PMID: 15548708, 10493631), suggesting that IRF1 predominantly functions as a tumor suppressor. True +ENST00000393593 NM_002199 3660 IRF2 False IRF2, a transcription factor, is infrequently altered by deletion in various cancers. IRF2, a member of the interferon regulatory protein family (IRF), encodes for a transcription factor which functions as both a transcriptional activator and repressor of various target genes (PMID: 23243601, 12799427, 7566094). IRF2 regulates the expression of genes involved in immune cell activation, survival, differentiation and signaling (PMID: 36544762, 36370712). IRF2 is constitutively expressed in various immune cells and its expression is upregulated in response to type 1 and type 2 interferons (PMID: 2475256). IRF1 and IRF2 have direct and indirect roles in the repression of each other (PMID: 2475256). Downregulation of IRF2 in various types of cancer cell lines and models induces immune evasion, impaired TP53 function and increased cellular proliferation, suggesting that IRF2 functions predominantly as a tumor suppressor gene (PMID: 31471524, 23264911, 35115027). IRF2 deletion has been identified in various types of cancer, including breast cancer, lung cancer and prostate cancer (PMID: 31471524). True +ENST00000380956 NM_002460.3 3662 IRF4 True IRF4, a transcription factor, is altered by mutation and chromosomal rearrangement in various hematologic malignancies. The IRF4 gene encodes for interferon regulatory factor 4, a transcription factor involved in regulating cytokine responses and lymphocyte development (PMID:18303999, 8999800). It can homo- or heterodimerize with other transcription factors to bind DNA (PMID:12453417). IRF4 is important for immune response and in NFkB signaling as a downstream mediator (PMID: 10601358,17785208). It regulates the development and survival of B- and T-cells (PMID:15249594, 24591370, 24356538). Its activity is also involved in melanocyte pigmentation (PMID:24267888). Expression of IRF4 (also known as MUM1) is used to classify diffuse large B-cell lymphoma subtypes (PMID:12393466). Translocations involving IRF4 and the IgH locus have been identified in multiple myeloma and with additional gene loci in lymphomas (PMID: 9326949, 18987657, 15510210). IRF4 polymorphisms have also been linked to chronic lymphocytic leukemia (CLL) susceptibility and mutations are found in T-cell leukemia and lymphomas (PMID: 18758461, 26437031). False +ENST00000268638 NM_002163.2 3394 IRF8 False IRF8, a transcription factor, is altered by mutation in a variety of hematopoietic malignancies. IRF8 (also ICSBP) is a transcription factor that is a member of the interferon regulatory protein family (IRF) (PMID: 29599126). IRF8 is predominantly expressed in hematopoietic stem, progenitor and terminally differentiated cells including myeloid, NK and dendritic cells (PMID: 28650480). IRF8 functions as a transcriptional activator and repressor that is required to mediate immune cell differentiation and execution of cell-type-specific gene expression programs (PMID: 25024380). IRF8 also regulates the expression of genes involved in several cellular functions including adaptive immunity, cell cycle regulation and apoptosis (PMID: 27338637, 29858012). Loss of IRF8 in murine models results in a hematopoietic malignancy, in part due to STAT5 repression of IRF8 tumor suppressive activity (PMID: 24753251). Homozygous biallelic IRF8 mutations have been identified in NK deficiency syndromes and IRF8 missense mutations have been identified in dendritic cell deficiency syndromes (PMID: 27893462, 21524210), suggesting IRF8 is required for functional NK and dendritic cell development. Somatic hotspot mutations in the IRF8 DNA binding domain have been identified in pediatric-type follicular lymphoma (PMID: 28533310) and in diffuse large B cell lymphoma (PMID: 23292937). In addition, IRF8 downregulation is found in hematopoietic malignancies due to epigenetic and signaling dysregulation (PMID: 21475251, 24753251). True +ENST00000305123 NM_005544.2 3667 IRS1 True IRS1, a signaling molecule involved in insulin signaling, is altered by mutation in various cancer types. Insulin receptor substrate 1 (IRS1) is one of the key mediator of Insulin receptor (INSR) signalling in cells (PMID: 1648180, 19029956). Upon activation of INSR, IRS1 is phosphorylated and activated leading to the activation of the PI3-Kinase and MAPK pathway (PMID: 1648180, 11292874, 21597332). IRS1 has oncogenic functions in multiple tumor entities such as breast cancer and high IRS1 expression is associated with adverse prognosis (PMID: 17030631, 22337149). IRS-1 associates with BCL-2 and increases its anti-apoptotic functions (PMID: 10679027). IRS-1 interacts with GRB2 leading to JAK activation (PMID: 8491186, 8536716, 9492017). ETV6-NTRK3 induced cell transformation requires high levels of IRS-1 phosphorylation (PMID: 12173038). Phosphorylation of IRS1 S307 seems to abrogate its ability to mediate insulin receptor signalling (PMID: 11606564). Drugs that specifically target the insulin receptor pathway and IRS1 activity have been developed and clinically investigated (PMID: 19581933, 20807783). False +ENST00000375856 NM_003749.2 8660 IRS2 True IRS2, a signaling molecule involved in insulin signaling, is altered by amplification and mutation in various cancer types. Insulin receptor substrate 2 (IRS2) is one of the mediators of Insulin receptor (INSR) signalling in cells (PMID: 1648180, 19029956). Upon activation of INSR, IRS2 is phosphorylated and activated leading to the activation of the AKT and MAPK pathway (PMID: 1648180, 11292874, 21597332, 24810113). Dysregulation or IRS2 leads to obesity and diabetes and IRS2 deficiency impairs brain growth (PMID: 15467829, 12904469). IRS1 has oncogenic functions in multiple tumor entities such as squamous cell carcinoma and high IRS1 expression is associated with adverse prognosis (PMID: 24810113, 17030631, 22337149). Nedd4-induced ubiquitination or IRS2 enhances IGF signalling and its mitotic activity (PMID: 25879670). IRS2 amplifications have been observed in colorectal cancer which result in increased susceptibility to anti-EGFR therapy (PMID: 26416732). False +ENST00000272117 NM_002221 3707 ITPKB True ITPKB, an inositol phosphate kinase, is infrequently altered in cancer. ITPKB, a member of the inositol trisphosphate-kinase family encodes for an inositol phosphate kinase that functions in regulating inositol phosphate metabolism in cellular signaling through phosphorylation of inositol polyphosphates (PMID: 24401760, 22981169). ITPKB is one of three isoforms in the inositol triphosphate-kinase family that share the conserved C-terminal catalytic domain but differ in regulation mechanisms (PMID: 24401760). ITPKB regulates calcium homeostasis by inhibiting calcium transport from the endoplasmic reticulum to the mitochondria (PMID: 12747803, 33443159). Knockdown of ITPKB in various patient-derived xenograft models represses cisplatin-resistant tumor growth mediated through NOX4 and sensitizes cancer cells to cisplatin, suggesting that ITPKB functions predominantly as an oncogene (PMID: 31081803). Upregulation of ITPKB has been identified in head and neck squamous cell carcinoma, lung cancer and ovarian cancer (PMID: 31081803). False +ENST00000342505 NM_002227.2 3716 JAK1 True JAK1, an intracellular kinase, is frequently altered in hematologic malignancies and gynecological cancers. The JAK1 gene encodes Janus kinase 1 (JAK1), a ubiquitously expressed member of the JAK family of protein tyrosine kinases (PMID: 25057888, 9096349). JAK1 forms a complex with cytokine receptors to initiate cytokine-mediated signaling. Upon cytokine activation, JAK1 forms oligodimers which phosphorylate tyrosine residues within the cytoplasmic region of the cytokine receptors, leading to recruitment and activation of downstream targets such as STAT1-6 (PMID: 25057888). The STAT proteins then translocate to the nucleus and act as transcription factors, mediating several cellular functions including proliferation, differentiation and antigen presentation (PMID: 23406773). Several activating mutations in JAK1 have been detected in acute lymphoblastic leukemia and other hematological malignancies, and inhibitors of the JAK/STAT pathway have been suggested as a potential therapy in those cases (PMID: 23340138). However, truncating mutations leading to loss-of-function of JAK1 have been frequently reported in gynecologic tumors and other cancers with microsatellite instability (PMID: 24154688, 29121062). Loss of JAK1 function is suggested to mediate immune escape in these tumors through impaired tumor antigen presentation and abolished JAK1-mediated interferon response (PMID: 24154688, 12576323, 29121062). True +ENST00000381652 NM_004972.3 3717 JAK2 True 2 JAK2, an intracellular kinase, is frequently altered by mutation or chromosomal rearrangement in hematologic malignancies. JAK2 is a non-receptor tyrosine kinase that regulates cytokine signaling and requires a cognate receptor to respond to extracellular cytokine signaling (PMID: 25057888, 1848670). Activated JAK2 signaling is necessary for the normal production of blood cells such as erythrocytes and thrombocytes (PMID: 9590173). Activation of JAK2 leads to the recruitment and phosphorylation of downstream effectors, such as STAT3/5 and MAPK, enabling the translocation of these signaling molecules to the nucleus to activate transcription (PMID: 25057888). Gain-of-function mutations in JAK2 have been identified in patients with myeloproliferative disorders, including 95% of polycythemia vera and 50% of essential thrombocytopenia and myelofibrosis malignancies (PMID: 1583762, 23009934, 25629741), suggesting that JAK2 functions predominantly as an oncogene. JAK2 fusions and activating mutations have also been identified in various leukemias and lymphomas (PMID: 9360930, 18270328). The most commonly identified mutation is JAK2 V617F, an alteration that activates kinase activity by impairing the autoinhibitory domain of the kinase, leading to constitutive activation of the JAK/STAT signaling pathway (PMID: 17721432). Murine models engineered to express the JAK2 V617F mutation develop a myeloproliferative disorder (PMID: 28640953). While JAK2 mutations are rare in solid tumors, activation of the JAK2/STAT pathway has been found to be oncogenic in many tumor types (PMID: 26151455). The JAK2 kinase inhibitor ruxolitinib has been FDA-approved for the treatment of patients with high-risk myelofibrosis and polycythemia vera (PMID: 20843246). However, resistance to JAK2 inhibition has been found to occur via the formation of drug-resistant JAK1/JAK2 heterodimers (PMID: 22820254). Additional JAK2 inhibitors are currently being tested in preclinical and clinical trials to improve drug efficacy and reduce off-target effects (PMID: 28673391). False +ENST00000458235 NM_000215.3 3718 JAK3 True JAK3, a non-receptor tyrosine kinase, is recurrently altered by mutation in hematologic malignancies. JAK3 encodes for Janus Kinase 3, a non-receptor tyrosine kinase. JAK3 activation results in activation of the STAT family of proteins (PMID:8986719) and can also signal through the MAPK and AKT pathways (PMID:22120524). JAK3 regulates response to cytokines, chemokines, and metabolism (PMID:8022486, 24498424, 25493954, 26451047). JAK3 signaling plays a crucial role in T-cell development, including regulation of T-cell apoptosis (PMID:11134353). Clinically JAK3 signaling can mediate autoimmune disease and graft rejection (PMID:14593182, 26230873). JAK3 mutations are seen in acute leukemias (PMID:22237106, 16843266), myeloid and lymphoid leukemia subtypes (PMID:23832011, 24446122), and lymphomas (PMID:24837469, 23689514). JAK3 mutations are also found in solid tumors but at lower incidence (PMID:18559588, 26096009, 24821835, 21868263). Loss of function mutations in JAK3 can lead to severe combined immunodeficiency (SCID) (PMID:10075926). False +ENST00000341776 NM_004973.3 3720 JARID2 True JARID2, an epigenetic complex cofactor, is infrequently altered by mutation and deletion in a diverse range of cancers. JARID2 is a transcription factor that mediates the recruitment of epigenetic complexes to chromatin. JARID2 associates with the Polycomb repressive complex 2 (PRC2), which is responsible for transcriptional repression of target genes by catalyzing the placement of the repressive di- and tri-methyl Histone H3 lysine 27 (H3K27) marks on chromatin (PMID: 20123894, 29932905, 29348366, 25620564). In addition, JARID2 binds other histone modifications in order to regulate crosstalk between PRC2 and PRC1 (Polycomb Repressive Complex 1) (PMID: 27892467). PRC2 function is important in the repression of developmental regulators such as the HOX genes and X-inactivation (PMID: 16618801, 12649488). JARID2 activity is also essential in several contexts including skeletal muscle and cardiac tissue development (PMID: 29891551, 30119689). Increased JARID2 expression has been associated with proliferation, migration, and invasion in ovarian, hepatocellular, and bladder cancer cells, among others (PMID: 28765957, 28445934, 27259236, 22431509). Deletions and missense mutations are found in hematopoietic malignancies and non-small cell lung cancer (PMID: 22190018, 23047306, 22053108, 30423295). True +ENST00000371222 NM_002228.3 3725 JUN True JUN, a transcription factor, is altered by amplification and overexpression in various cancer types. JUN (also c-Jun) is a transcription factor that dimerizes with the Activator protein 1 (AP-1) transcription factor complex. The AP-1 complex regulates a plethora of cellular process including differentiation, proliferation, and apoptosis through transcriptional control of several downstream target genes, including p53, cyclin D1 and EGFR (PMID: 12791272, 10072388, 10790372). In its turn, c-Jun is regulated by phosphorylation, mediated in particular by the JNK, p38 and WNT signaling pathways for directing cell proliferation, differentiation, survival and migration processes (PMID: 10080190, 16007074, 20231272). AP-1 is a potent transforming factor in multiple experimental models, although anti-oncogenic effects have also been described in specific contexts (PMID: 11988758, 14668816). Although a direct oncogenic role for AP-1 has not been described in human tumors, mechanisms for a putative role have been explored in for example breast cancer cell lines and models of liposarcoma, a tumor type in which c-Jun amplification has been observed (PMID: 17637753, 17418412). False +ENST00000265713 NM_006766.4 7994 KAT6A False KAT6A, a histone acetyltransferase, is recurrently altered by translocation in acute myeloid leukemia. KAT6A (also MYST3 or MOZ) is a histone acetyltransferase that is a member of MYST family of proteins (PMID: 16626284, 18754862, 17694081). KAT6A functions as a transcriptional coactivator that has intrinsic histone acetyltransferase activity, with the ability to acetylate several histone residues (PMID: 11313971). In addition, KAT6A forms complexes with transcriptional regulators to coordinate gene expression, including the hematopoietic proteins AML1, PU.1, and RUNX, among others (PMID: 11742995, 16702405, 11965546, 12771199). The activity of KAT6A has been implicated in the formation of additional transcriptional complexes with ING proteins that regulate a variety of cellular processes including differentiation, DNA damage, chromatin state and cellular proliferation (PMID: 17694081). Loss of KAT6A expression in murine models results in defects in the hematopoietic stem and progenitor compartments, consistent with a role of KAT6A in hematopoietic gene regulation (PMID: 16651658, 12676584). Dominant germline mutations in KAT6A are found in individuals with intellectual disabilities (PMID: 25728777). Recurrent translocations involving KAT6A are found in patients with acute myeloid leukemia (PMID: 9447825, 8782817, 9558366). KAT6A rearrangements promote leukemic transformation due to aberrant targeting of epigenetic complexes to chromatin, suggesting that KAT6A functions as an oncogene (PMID: 12676584). False +ENST00000259021 NM_007067 11143 KAT7 True KAT7, the catalytic subunit of the HBO1 complex, is infrequently altered in cancer. KAT7 encodes for the catalytic subunit of the histone acetyltransferase HBO1 multimeric complex (PMID: 21753189). The HBO1 complex mediates acetylation of histone H3K14ac, regulating various processes such as transcriptional activation and immune response (PMID: 24065767, 26620551). The multimeric complex also functions in acetylation of other histones, including H4K5ac, H4K8ac and H4K12ac, to regulate DNA replication initiation and inhibit NF-kB signaling (PMID: 16997280, 19187766, 20129055). Overexpression of KAT7 in cancer cell lines induces cell growth, migration and invasion, suggesting that KAT7 functions primarily as an oncogene (PMID: 35868058, 34039960, 19372580). KAT7 amplification and point mutations have been identified in various cancers, including breast cancer and gastric cancer (PMID: 35868058, 36724120). False +ENST00000395288 NM_016506.5 55709 KBTBD4 False KBTBD4, a predicted E3 ligase adaptor protein, is recurrently altered by mutation in medulloblastoma. KBTBD4 is a protein that is a predicted E3 ligase adaptor protein with Kelch-BTB-BACK domains (PMID: 28726821). KBTBD4 has not yet been functionally characterized, however, it is a member of a family of cullin-RING ubiquitin ligase adaptor proteins (PMID: 28726821). Adaptor molecules mediate the specificity of E3 ligase proteins, which ubiquitinate and target proteins for degradation via the proteasome (PMID: 23349464). In-frame insertions in KBTBD4, typically in the Kelch domain, have been found recurrently in patients with Group 3 or Group 4 subtypes of medulloblastoma (PMID: 28726821) and as the sole alteration in several pineal parenchymal tumors of intermediate differentiation (PPTID)(PMID: 30877433). These insertions are predicted by structural studies to occur in the substrate-binding interface of the protein (PMID: 28726821, 23349464). However, this recurrence may be limited to certain populations, as follow-up studies have demonstrated that KBTBD4 insertions were absent in a cohort of medulloblastomas from Brazilian centers (PMID: 31403685). Additional studies are required to determine the role of KBTBD4 mutations in cancer. False +ENST00000399788 NM_001042603.1 5927 KDM5A True KDM5A, a histone methyltransferase, is altered by chromosomal rearrangement and amplification in various cancer types. KDM5A (also known as JARID1A) is a histone demethylase for histone 3 lysine 4 (H3K4) (PMID:17320161). KDM5A's plant homeodomain (PHD) recognizes unmethylated H3K4 to locate the enzyme to specific chromatin regions (PMID: 25686748). Through chromatin modification and transcriptional silencing, KDM5A regulates cellular differentiation and cooperates with the retinoblastoma protein (pRB) in controlling cell cycle progression (PMID:18722178, 15949438, 23093672, 23112189). It also affects cellular metabolism and circadian rhythms (PMID: 26314709, 21960634). In cancer KDM5A promotes tumor progression by targeting cell cycle and angiogenesis genes and enhancing treatment resistance (PMID:23722541, 24716659, 26566863, 20371346). It is amplified in breast and head and neck cancers (PMID:22937203, 24425785). It is translocated in leukemia with the NUP98 gene and alters HOX gene expression (PMID:16419055, 19430464). False +ENST00000375401 NM_004187.3 8242 KDM5C False KDM5C, a tumor suppressor and histone demethylase, is altered in various cancers, most frequently in renal cell carcinoma and endometrial cancer. The KDM5C gene encodes a member of an ARID protein family that acts as an epigenetic regulator by removing di-tri-methyl groups from lysine 4 of histone H3 (H3K4) on transcriptional targets (PMID: 21575681, 24583395, 20054297, 22249190). KDM5C is ubiquitously expressed in almost all human tissues, including white blood cells, with the highest levels of expression found in the brain and skeletal muscle (PMID: 23356856). Loss of KDM5C exerts an essential role in mammalian DNA replication. Moreover, KDM5C silencing induces aberrant H3K4me3 levels at active origins, thus halting DNA replication and ultimately S phase progression (PMID: 25712104). Mutation of the KDM5C gene was first described as causing X-linked intellectual disability (XLID) in 2005 (PMID: 15586325), and has been linked to some forms of cancer (PMID: 21544224, 20181063, 20133580). The prevalence of KDM5C mutations in patients with XLID is estimated to be ~3% (PMID: 23356856), and somatic mutations in this gene have been identified in 4-9% of clear cell renal cell carcinoma (ccRCC) (PMID: 20054297, 24166983, 22138691). Knockdown of KDM5C in von Hippel-Lindau (VHL) -/- ccRCC cells significantly enhanced tumor growth in a xenograft model, suggesting that KDM5C functions as a tumor suppressor in this cancer model (PMID: 21725364, 25111482). Through siRNA screen, KDM5C was identified as a mediator of the human papillomavirus (HPV) E2 tumor suppressor protein in cervical cancer (PMID: 20133580). True +ENST00000317961 NM_004653 8284 KDM5D True KDM5D, a histone lysine demethylase, is altered by reduced expression in various cancers. KDM5D, part of the KDM5 family, is located on the Y chromosome and encodes a male-specific histone demethylase that targets trimethylated H3K4 (PMID: 34127738, 30864186, 35805040, 26747897). KDM5D plays a role in transcriptional regulation, as the demethylation of H3K4 is suggested to repress gene transcription (PMID: 30864186, 26747897). KDM5D is associated with male organ rejection in female recipients due to a short peptide derived from the protein that is a minor histocompatibility antigen (PMID: 35805040). Down-regulation of KDM5D has been observed in various cancer types including lung, prostate, gastric, colorectal and renal cancer, and is in part due to deletions on the Y chromosome; this supports its role as a tumor suppressor (PMID: 34127738, 26747897). In both in vitro and in vivo models of prostate and gastric cancer, knock-down of KDM5D promoted cellular invasion and increased expression of epithelial-mesenchymal transition (EMT) regulators such as N-cadherin, slug and vimentin (PMID: 30864186, 26747897). Overexpression of KDM5D inhibited proliferation and increased apoptosis in colorectal cancer cells and reduced the growth rate of tumors in mice (PMID: 34688635). However, KDM5D was found up-regulated in KRAS-mutant colorectal cancer in male patients and was associated with increased metastases, suggesting KDM5D may function as an oncogene in this tumor-specific context through the repression of genes involved in cell adhesion and immune recognition (PMID:37344599). True +ENST00000377967 NM_021140.2 7403 KDM6A False 4 KDM6A, a histone demethylase, is altered in various cancer types, most frequently in bladder cancer. KDM6A (lysine-specific demethylase 6A) encodes a chromatin-modifying enzyme that mediates transcriptional co-activation by functioning as a di- and tri-methylated histone H3 lysine 27 (H3K27) demethylase. KDM6A is part of the larger ASC-2 complex (ASCOM) that also contains lysine-specific methyltransferase 2D (KMT2D) and lysine-specific methyltransferase 2C (KMT2C). KDM6A is located on Xp11.2, but it escapes X inactivation, resulting in bi-allelic expression in females (PMID: 9499428). Association of KDM6A with KMT2D and KMT2C couples H3K27 demethylation to H3K4 methylation (PMID: 17761849). Germline deletions and point mutations in KDM6A cause Kabuki syndrome, which is characterized by typical facial features, skeletal anomalies, dermatoglyphic abnormalities, mild-to-moderate intellectual disability and postnatal short stature (PMID: 22197486, 22840376, 22901312, 23076834). Early sequencing efforts led to the discovery of inactivating KDM6A mutations in a number of human malignancies including multiple myeloma and esophageal squamous cell carcinoma (PMID: 19330029). Later studies found KDM6A mutations in clear cell renal cell carcinoma (PMID: 21248752), medulloblastoma (PMID: 22722829, 22832583), adenoid cystic carcinoma (PMID: 23685749), urothelial bladder cancer (PMID: 24476821, 21822268, 25092538, 25225064), aristolochic acid-associated upper tract urothelial carcinoma (PMID: 23926199), T-cell acute lymphoblastic leukemia (PMID: 25320243), and pancreatic cancer (PMID: 25719666). In prostate cancer, KDM6A mutations are seen in progression to lethal castration-resistant disease (PMID: 22722839). Loss of KDM6A may confer sensitivity to EZH2 inhibitors (PMID: 28228601). True +ENST00000263923 NM_002253.2 3791 KDR True KDR, a receptor tyrosine kinase, is altered by mutation or amplification in various cancers, most frequently in skin cancers. KDR (kinase domain receptor), also known as VEGFR2 or Flk-1, is a tyrosine kinase receptor for vascular endothelial growth factor (VEGF) and plays a key role in angiogenesis. In hypoxic conditions, hypoxia-inducible factor 1 (HIF1) protein stabilization leads to upregulation of KDR and VEGF (PMID: 23172303). Binding of VEGF to KDR results in stimulation of angiogenesis via receptor dimerization and autophosphorylation, activation of phospholipase C (PLC-gamma) and downstream signaling via protein kinase C (PKC) and RAF/MEK/ERK (PMID: 10327068, 12778165). Mutations of KDR are rare in tumors, and alterations of KDR activity typically occur via KDR amplification and subsequent overexpression. Most therapies blocking KDR signaling target the angiogenesis pathway in general, such as bevacizumab, an antibody that targets VEGF-A (PMID: 15136787). False +ENST00000171111 NM_203500.1 9817 KEAP1 False KEAP1, a tumor suppressor and adaptor protein, is recurrently mutated in lung cancer. KEAP1 encodes a substrate adaptor protein for the E3 ubiquitin ligase complex. This complex is formed by the proteins CUL3 and RBX1 and targets NRF2 for ubiquitination and subsequent proteasomal degradation (PMID:15572695). NRF2 (encoded by the gene NFE2L2) is a master transcriptional regulator of the cellular antioxidant response (PMID: 24142871, 21251164). Activation of NRF2 can provide a fitness advantage for cells by upregulating pathways for handling xenobiotic stress and detoxification (PMID: 21251164). The BTB domain of KEAP1 binds CUL3, and the Kelch-repeat domain binds NRF2 via KEAP1 homodimerization (PMID:21251164). The IVR region contains critical cysteine residues whose thiol side chains are modified in response to oxidative stress. Modification of cysteine residues in the IVR disrupts binding of KEAP1 to NRF2 and CUL3, resulting in the release of NRF2 for transcriptional activation of target genes (PMID:12193649, PMID:14585973). Mutations in KEAP1 tend to occur throughout the body of the gene (cBioPortal, MSKCC, Apr. 2015), and are commonly thought to disrupt KEAP1-dependent regulation of NRF2. This disruption activates NRF2-dependent pathways, including those regulated in the oxidative stress response (PMID: 24142871). True +ENST00000355265 NM_000420 3792 KEL True KEL, a transmembrane glycoprotein, is altered by amplification in various cancers. KEL encodes for a type II transmembrane zinc-dependent endopeptidase glycoprotein expressed solely in erythroid cells and tissues, which functions in the human blood group Kell antigen system (PMID: 7949106, 10438732, 7849312). KEL is highly polymorphic and at least 25 different antigens are encoded, which define the Kel blood group system (PMID: 8542022). KEL functions as a proteolytic enzyme and cleaves large EDN3 to yield bioactive EDN3 to maintain vascular homeostasis (PMID: 10438732, 7849312). Overexpression of KEL in acute erythroleukemia models induces cellular proliferation, migration and invasion, suggesting that KEL functions predominantly as an oncogene (PMID: 35140839). Amplification of KEL has been identified in acute erythroleukemia (PMID: 35140839). False +ENST00000288135 NM_000222.2 3815 KIT True 1 R2 KIT, a receptor tyrosine kinase, is recurrently mutated in gastrointestinal stromal tumors. The proto-oncogene KIT encodes a type 3 transmembrane receptor tyrosine kinase. The receptor is activated through dimerization and autophosphorylation upon binding by its ligand, stem cell factor (SCF) also known as mast cell growth factor (MGF) (PMID: 9438854). KIT activation results in increased intracellular signaling through several pathways including PI3K, MAPK and STAT, ultimately leading to cell proliferation and survival (PMID: 17546049, 11896121, 22089421). For patients with wildtype gastrointestinal stromal tumors (GIST; no KIT or PDGFRA mutations), NCCN recommends testing for germline succinate dehydrogenase (SDH) mutations. About 10-15% of GISTs are wildtype; thus, the absence of a mutation does not exclude the diagnosis of GIST. In patients without KIT mutations, a subset of those with advanced GISTs benefit from imatinib (0-45% of patients) (NCCN Soft Tissue Sarcoma v.2.2017). Activating KIT mutations occur in 80 - 90% of GISTs and are distributed over multiple exons with different frequencies (exons 11 (66.1%), exon 9 (13%), exon 13 (1.2%), and exon 17 (0.6%)) (PMID:15365079, 17268243, 11719439). There are at least eight small molecule tyrosine kinase inhibitors (TKIs) targeting KIT that have been approved by the US Food and Drug Administration with the efficacy of each TKI strongly depending on the location of the activating KIT mutation (PMID: 2427414, 18955458,19164557). R2 False +ENST00000248071 NM_016270.2 10365 KLF2 False KLF2, a transcription factor that regulates the activity of NF-κB, is recurrently altered by mutation in splenic marginal zone lymphoma. KLF2 is a transcription factor that is a member of the Kruppel protein family (PMID: 25428260). KLF2 expression is important for maintenance of quiescence in a variety of cell types, including in non-cycling B-cells and naïve T-cells (PMID: 17681603, 18246069, 16455954, 16455954). Transcriptional activity of KLF2 mediates the suppression of gene expression programs required for B- and T-cell activation (PMID: 17681603, 18246069). In addition, KLF2 represses the transcriptional activity of NF-κB in response to stimulation from a variety of signaling pathway including Toll-like receptor (TLR) and B cell receptor (BCR) signaling, among others (PMID: 25428260). Loss of KLF2 in murine models leads to expanded marginal zone B-cells, likely due to altered differentiation and homing of B cells (PMID: 20691614, 21187409). Somatic inactivating mutations in KLF2 are found in splenic marginal zone lymphoma (PMID: 25428260, 25283840), suggesting that KLF2 functions as a tumor suppressor. Loss-of-function variants in KLF2 result in unrestricted activation of NF-κB, leading to constitutive activation of various B-cell related signaling pathways (PMID: 25428260). True +ENST00000261438 NM_016531.5 51274 KLF3 False KLF3, a transcription factor, is altered by mutation in various cancer types. KLF3 is a transcription factor that is a member of the Kruppel protein family (PMID: 21360637). KLF3 modulates epithelial homeostasis by controlling the activation of epidermal differentiation gene programs (PMID: 32659720). In addition, KLF3 functions as a transcriptional repressor in adipocyte, erythroid and chondrocyte differentiation (PMID: 32385917, 32523103, 30619490, 30324848, 29775748, 23918807). Binding of KLF3 to target genes is important for various cellular activities including differentiation, proliferation, fat accumulation, angiogenesis and inflammation (PMID: 31486564, 32213596, 27226561, 31196982). KLF3 cooperates with other transcriptional and chromatin regulators, such as CBP, CtBP2, and C/EBPα, to activate gene expression (PMID: 32659720, 30619490, 25659434, 10756197). KLF family member-mediated gene regulation is complex due to the competition for binding sites across the genome at enhancers and promoters (PMID: 28541545). In various cell types, altered KLF3 activity mediates gene expression via interactions with long non-coding RNAs and micro RNAs (PMID: 31462890). KLF3 expression is downregulated in several cancer types, including lung and colon cancer, and is indicative of poor patient prognosis (PMID: 32213596, 28423541, 21470678). Somatic mutations are infrequent in human cancers and require functional validation (PMID: 21360637). True +ENST00000374672 NM_004235.4 9314 KLF4 True KLF4, a transcription factor, is altered by mutation in various cancer types including meningiomas. KLF4 is a transcription factor that regulates the development of multiple organs and tissues including the skin, cerebellum, and colon (PMID: 10431239, 12015290, 18604447, 26226504). Overexpression of KLF4 with OCT3/4, SOX2, and c-MYC is able to induce pluripotent stem cells from adult tissues (PMID: 16904174). It is also involved in terminal differentiation of monocytes and the T-cell immune response (PMID: 18390749, 25992862). In certain cancers, KLF4 functions to regulate the differentiation of tumor cells and may have a potential tumor suppressor role (PMID: 25181544, 26113043, 26338995, 26880805, 21224073, 22284679, 26934576). Thus, induction of KLF4 expression is being studied for therapeutic advantage (PMID: 26268924). True +ENST00000377687 NM_001730.4 688 KLF5 True KLF5, a transcription factor, is altered by amplification and mutation in various cancer types. KLF5 (Kruppel-like factor 5) is a zinc-finger-containing transcription factor whose expression is highest in rapidly dividing cells, such as in the crypt epithelium of the intestinal tract or the basal layer of the dermis, and results in the induction of genes regulated by cyclin D1 (PMID: 15077182, 10767086). KLF5 binds to GC-rich regions of DNA and has antagonizing effects on gene expression compared to KLF4, another KLF family member involved in stemness and regulation of cellular differentiation (PMID: 16904174). KLF5 is important in regulating the integrity of intestinal stem cells and has been implicated as a stemness reprogramming factor (PMID: 24626089, 23112162). In tumor models, KLF5 mediates RAS-driven oncogenesis (PMID: 18054006, 15077182) and while amplification of KLF5 is implicated in gastric cancer, it is also thought to regulate breast cancer invasiveness (PMID: 26189798, 26419610). False +ENST00000341319 NM_130446 89857 KLHL6 True KLHL6, an E3 ligase, is infrequently altered in cancer. KLHL6 (kelch like family member 6) encodes a BTB (Broad-Complex, Tramtrack and Bric a brac)-Kelch protein that is selectively expressed in lymphoid tissue and involved in B-cell antigen receptor signaling and germinal center B-cell maturation (PMID: 29695787, 16166635, 30646831). The protein functions as an E3 ligase through assembly with CULLIN3 to form a functional CULLIN-RING ubiquitin ligase (PMID: 29695787, 28807996, 30646831). Mutations in the KLHL6 gene may cause dissociation of CULLIN3 from KLHL6 resulting in loss of E3 ligase catalytic activity (PMID: 30646831, 29695787). KLHL6 gene mutations have been identified in patients with B-cell malignancies including diffuse large B-cell lymphoma (DLBCL), chronic lymphocytic leukemia and multiple myeloma (PMID: 29695787, 29044464, 21642962, 27959900). In vitro and in vivo studies demonstrate that loss of KLHL6 favors DLBCL growth and survival (PMID: 29695787, 30646831). However, KLHL6 has been found to be up-regulated in gastric cancer and is associated with a less favorable prognosis in this tumor type. Consistent with its role as an oncogene in gastric cancer, down-regulation of KLHL6 in human gastric carcinoma cells results in reduced colony formation, proliferation and viability, and suppressed tumor growth in mice (PMID: 29044464). True +ENST00000534358 NM_001197104.1 4297 KMT2A False 1 KMT2A, a histone methyltransferase, is altered by mutation or deletion in various solid tumors, and by chromosomal rearrangement in various hematologic malignancies. KMT2A (also MLL1) is a histone methyltransferase that functions as an epigenetic modulator that methylates lysine residue 4 on the tail of histone H3 (H3K4). Methylation of H3K4 leads to increased genome accessibility, recruitment of transcriptional complexes, and activation of gene expression (PMID: 25998713). KMT2A is crucial for embryogenesis and normal hematopoiesis by stimulating expression of several important developmental genes including the homeobox (Hox) genes (PMID: 24213472). Chromosomal translocations involving KMT2A that result in gain-of-function fusion proteins have been identified in pediatric and adult acute myeloid leukemia (AML) and acute lymphoid leukemia (ALL) and are overrepresented in therapy-related AML. Though KMT2A has a diverse group of fusion partners in leukemia, the most common KMT2A recombination partners include AF4, AF9, and ENL, which are proteins that interact with transcriptional elongation machinery (PMID: 28701730). KMT2A fusion proteins disrupt the normal activity of hematopoietic stem cells and the normal chromatin state, leading to activation of oncogenic signaling pathways (PMID: 16862118). In addition, loss-of-function mutations in KMT2A have been identified in solid tumors including bladder, stomach and endometrial cancers (PMID: 21822268, 23636398). DOT1L inhibitors, which are currently being tested in clinical trials, have been shown to have activity against KMT2A-rearranged leukemias (PMID: 21741597, 21741596). True +ENST00000222270 NM_014727.1 9757 KMT2B False KMT2B, a histone methyltransferase, is mutated at low frequencies in various cancer types. KMT2B (also MLL4) is a histone methyltransferase that functions as an epigenetic modulator that methylates lysine residue 4 on the tail of histone H3 (H3K4). Methylation of H3K4 leads to increased genome accessibility, recruitment of transcriptional complexes, and activation of gene expression (PMID: 25998713). KMT2B methylates H3K4 at enhancer regions, leading to increased expression of target genes and changes in chromatin looping structures (PMID: 25998713, 28759003, 24368734). KMT2B plays a role in regulating cell cycle progression and cell viability and induces transcription of leukemic genes (PMID: 22713656). True +ENST00000262189 NM_170606.2 58508 KMT2C False KMT2C, a tumor suppressor and histone methyltransferase, is altered in various solid and hematologic malignancies. KMT2C (also MLL3) is a histone methyltransferase that functions as an epigenetic modulator that methylates lysine residue 4 on the tail of histone H3 (H3K4). Methylation of H3K4 leads to increased genome accessibility, recruitment of transcriptional complexes, and activation of gene expression (PMID: 25998713). KMT2C specifically binds histones at enhancer regions, leading to increased expression of a wide range of target genes and regulation of enhancer RNA synthesis (PMID: 24081332, 23166019, 28483418, 27926873). KMT2C is ubiquitously expressed and its function is crucial for normal embryonal development and cell proliferation (PMID: 11718452, 17021013). Genetic deletion of the region containing KMT2C is the most common chromosomal abnormality in acute myeloid leukemia (PMID: 25794446, 11891048, 22234698, 25030029), and KMT2C is mutated in various types of cancer (PMID: 25537518, 25303977, 25151357, 28801450). True +ENST00000301067 NM_003482.3 8085 KMT2D False KMT2D, a tumor suppressor and histone methyltransferase, is one of the most frequently mutated genes in cancer. KMT2D (also MLL2) is a histone methyltransferase that functions as an epigenetic modulator that methylates lysine residue 4 on the tail of histone H3 (H3K4). Methylation of H3K4 leads to increased genome accessibility, recruitment of transcriptional complexes, and activation of gene expression (PMID: 25998713). Deletion of KMT2D in human cells leads to genomic instability due to transcriptional stress (PMID: 26883360). In murine models, loss of KMT2D results in accelerated B cell malignancy, impaired B cell differentiation, and defects in class switching (PMID: 26366710). KMT2D activity is critical for the survival and proliferation of KMT2A-rearranged leukemias (PMID: 28609655). Though KMT2D is not as commonly mutated as KMT2A in human cancers, KMT2D is one of the most recurrently mutated genes in follicular and diffuse large B cell lymphoma (PMID: 24476821, 21804550, 21796119, 24476821). True +ENST00000330479 NM_020382.3 387893 KMT5A False KMT5A, a methyltransferase and transcriptional repressor, is mutated or amplified at low frequencies in various cancers. KMT5A encodes the lysine methyltransferase SETD8, which specifically methylates lysine 20 of histone H4 (H4K20me1), a histone mark implicated in DNA replication and DNA repair. KMT5A is typically bound to euchromatin regions and the placement of the H4K20me1 mark is thought to have a role in transcriptional repression (PMID: 12086618, 16517599). KMT5A is also required for proper chromosome segregation during mitosis and subsequent cellular proliferation (PMID: 15200950). Additionally, KMT5A has other methylation targets independent of histones including PCNA, Numb and p53, where methylation has roles in promoting the epithelial-mesenchymal transition, regulating cell proliferation, and suppression of p53-dependent transcriptional programs (PMID: 26717907, 23706821, 22556262, 17707234). KMT5A mutations are rare in human cancers. False +ENST00000249776 NM_033286.3 90417 KNSTRN False KNSTRN, a component of the mitotic spindle, is mutated in cutaneous squamous cell carcinoma. KNSTRN encodes a protein involved in chromosome segregation during mitosis (PMID: 19667759, 22110139). KNSTRN, as part of the SKAP complex, maintains the mitotic spindle architecture and coordinates the dynamics of microtubules during cell division (PMID: 23035123). KNSTRN promotes cell migration in vitro and in vivo by directing the microtubule dynamics in response to signaling by small GTPases (PMID: 26242911). KNSTRN mutations are rare events in cancers, but they are frequent in cutaneous squamous cell carcinoma (cBioPortal, MSKCC, Nov 2016) (PMID: 25194279, 25303977). False +ENST00000311936 NM_004985.3 3845 KRAS True 1 R1 KRAS, a GTPase which functions as an upstream regulator of the MAPK pathway, is frequently mutated in various cancer types including lung, colorectal and pancreatic cancers. KRAS is a member of the RAS family of small GTPases, which catalyze the hydrolysis of GTP to GDP. Under physiologic conditions, these RAS proteins cycle between an active (GTP-bound) and an inactive (GDP-bound) state, to activate the MAPK and PI3K oncogenic pathway signaling downstream of Receptor Tyrosine Kinases (RTKs) (PMID: 22189424). The function of RAS enzymes is regulated by guanine nucleotide exchange factors (GEFs), such as SOS, which enable the exchange of GDP to GTP, as well as by GTPase activating proteins, such as NF1, which increase the ability of RAS to hydrolyze GTP. Once activated, RAS mediates the regulation of cellular proliferation and other cellular functions through the activation of distinct intracellular signaling pathways, including the RAF/MEK/ERK and PI3K/AKT/mTOR pathways. Transforming mutations in KRAS are frequently found in pancreatic, colon, endometrial, ovarian and biliary cancers; almost all of these mutations result in constitutive activation of KRAS, thereby promoting cell proliferation (PMID: 21993244, 24651010). KRAS mutations occur primarily in three major hotspots, G12, G13 and Q61, the first two of which occur in the GTP-ase domain and the latter interferes with the ability of NF1 to bind and regulate KRAS (PMID: 22589270, 21993244, 24651010). Other less well-characterized mutations such as A146T/V/P and L19F have also been characterized and found to be activating albeit at lower frequencies (PMID: 20147967, 20432530, 20570890). Germline KRAS mutations are responsible for both Noonan syndrome (NS) and cardio-facio-cutaneous (CFC) syndrome (PMID: 16474405, 16474404, 19467855, 17056636) that are associated with hyperactivated MAPK pathway, distinctive clinical characteristics and a predisposition to cancer (PMID: 19467855, 17704260). R1 False +ENST00000339824 283455 KSR2 True KSR2, a MAPK scaffolding protein, is infrequently altered in various cancer types. KSR2 is a scaffolding protein that is a member of the kinase suppressor Ras (KSR) family (PMID: 19560418). The KSR protein family has been implicated in the activation of MAPK signaling cascades via direct protein interactions and substrate localization (PMID: 19560418, 26891695). Proteomic analyses show that KSR2 interacts with several components of the MAPK signaling pathway including BRAF, MEK and ERK, as well as other proteins involved in cellular localization, including C-TAK1, 14-3-3 and PP2A1 (PMID: 19560418, 21441910). KSR2 specifically bridges the signaling molecules RAF and MEK to mediate RAF-mediated MEK phosphorylation (PMID: 11850406, 19560418, 29433126). In addition, KSR2 interacts with the phosphatase calcineurin to regulate calcium-mediated MAPK signaling (PMID: 19560418). KSR2 activity is also important for AMPK signaling and for glucose update and fatty acid oxidation (PMID: 19883615). KSR2 plays a role in negative feedback of the MAPK pathway, possibly by allosterically binding RAF (PMID: 19560418, 29433126). KSR2 is an important regulator of body fat as determined in a murine screen (PMID: 18719666). Loss of KSR2 in mice results in increased adiposity, reduced energy expenditure and insulin resistance, a phenotype consistent with human obesity (PMID: 19883615, 21127480). Germline mutations in KSR2 are associated with obesity and linked to hyperphagia, insulin resistance and impaired fatty oxidation in individuals (PMID: 24209692, 29273807). Somatic mutations in KSR2 are rare in human cancers; however, overexpression of KSR2 has been found in several cancer types including breast cancer (PMID: 21403620). Overexpression of KSR2 in preclinical studies is also associated with increased anchorage-independent growth and proliferation (PMID: 22801368). Small molecule inhibitors of KSR have shown preclinical efficacy and synergy with MEK inhibition, likely due to inhibition of negative feedback signaling (PMID: 27556948, 28333549). False +ENST00000316157 NM_015155.2 23185 LARP4B False LARP4B, an RNA binding protein, is altered by deletion and mutation in various cancer types. LARP4B is an RNA binding protein that is a member of the LARP family (PMID: 26501340). LARP4B binds to messenger ribonucleoprotein (mRNP) components, such as RACK1 and poly(A) binding protein (PABP), at 3’ poly(A) regions of mRNA (PMID: 12388589, 32517187, 26644407). These LARP4B-containing mRNP complexes mediate translation by serving as a bridge between protein regulators and ribosomes (PMID: 20573744). Because LARP4B has varied roles in mRNA stability and protein translation, LARP4B is important in many cellular processes including proliferation and growth control (PMID: 26001795, 32517187, 29462618). Somatic mutations in LARP4B are found in hypermutated stomach adenocarcinomas and are predicted to promote nonsense-mediated decay, resulting in loss of protein expression (PMID: 28649990). Additional studies have demonstrated that LARP4B may function as a tumor suppressor in glioma and prostate cancer (PMID: 26933087, 25534202, 31173237). However, LARP4B also has cancer-promoting roles in acute myeloid leukemia and liver cancer, suggesting that LARP4B has context-specific roles in cancer progression (PMID: 31772683, 31173237). False +ENST00000253339 NM_004690.3 9113 LATS1 False LATS1, an intracellular kinase involved in Hippo signaling, is recurrently altered by mutation in various cancer types. LATS1 is a serine/threonine protein kinase that is a regulator of the Hippo signal transduction pathway (PMID: 20935475, 27300434), which is involved in several processes of cancer progression and physiologically has important regulatory functions in organ development and regeneration (PMID: 23467301, 24825474, 24336504). Phosphorylation of LATS1 and co-activator MOB1 by upstream kinases MST1/2 results in LATS1 activation. Under physiologic conditions, activated LATS1 phosphorylates the transcriptional co-activators YAP1 and TAZ (PMID: 19878874). Through such regulation, LATS1 controls the nuclear localization of YAP1/TAZ, thereby regulating expression of genes involved in various cellular functions including proliferation and apoptosis (PMID: 20951342, 18158288). LATS1 is thought to function as a tumor suppressor via the negative regulation of cellular survival pathways mediated by YAP1/TAZ (PMID: 18158288). Somatic loss-of-function alterations in the LATS1 gene are found in several human cancers including malignant mesothelioma (PMID: 25902174, 26928227). In addition, the promoter region of the LATS1 gene is frequently hypermethylated in multiple types of human cancers (PMID: 15746036, 17049657, 23885148). True +ENST00000382592 NM_014572.2 26524 LATS2 False LATS2, an intracellular kinase involved in Hippo signaling, is recurrently altered by mutation in various cancer types. LATS2 is a serine/threonine protein kinase that is a regulator of the Hippo signal transduction pathway (PMID: 20935475, 27300434), which is involved in several processes of cancer progression and physiologically has important regulatory functions in organ development and regeneration (PMID: 23467301, 24825474, 24336504). Phosphorylation of LATS2 and co-activator MOB1 by upstream kinases MST1/2 results in LATS2 activation. Under physiologic conditions, activated LATS2 phosphorylates the transcriptional co-activators YAP1 and TAZ (PMID: 19878874). Through such regulation, LATS2 controls the nuclear localization of YAP1/TAZ, thereby regulating expression of genes involved in various cellular functions, including proliferation and apoptosis (PMID: 20951342, 18158288). LATS2 is thought to function as a tumor suppressor via the negative regulation of cellular survival pathways mediated by YAP1/TAZ (PMID: 18158288). Somatic loss-of-function mutations and deletions in the LATS2 gene are found in several human cancers including malignant mesothelioma (PMID: 26928227, 21245096). LATS2 mutations have been identified to co-occur with NF2 alterations, leading to Hippo pathway dysregulation (PMID: 28003305). True +ENST00000336890 NM_001042771.2 3932 LCK True LCK, a tyrosine kinase that regulates T-cell receptor signaling, is altered by rearrangement in hematologic malignancies. LCK is a tyrosine kinase that is a member of the SRC family of kinases and is important in the regulation of immune signaling pathways (PMID: 20541955). LCK is expressed predominantly on T-cells and mediates pre-T-cell receptor (TCR) and TCR signaling (PMID: 27469439). TCR signaling requires phosphorylation of immunoreceptor tyrosine-based activation motifs (ITAMs) on the TCR after peptide-MHC molecule binding (PMID: 20541955). LCK stably binds the cytoplasmic tails of T-cell co-receptors, such as CD4 and CD8, and is recruited to the ITAMs on the TCR/CD3 co-receptor complex to facilitate ITAM phosphorylation (PMID: 2455897, 2470098). Phosphorylation of the TCR complex results in the recruitment of ZAP70, a protein kinase, which initiates LAT phosphorylation, where LAT serves as a docking site for downstream signaling cascades (PMID: 29915297). LCK can also interact with a variety of signaling molecules to mediate signaling axes including CD55, CD44 and NOTCH1, among others (PMID: 28838952, 9573028, 14583609). Overexpression of LCK in mice results in thymic tumors, suggesting that LCK can function as an oncogene (PMID: 1708890). Aberrant activation of LCK has been identified in several tumor types and rearrangements of LCK are found in lymphoid tumors (PMID: 3463975, 18316591). In addition, LCK activity has been associated with cancer stemness and metastasis in solid tumors (PMID: 30353164). Small molecule kinase inhibitors that target LCK, such as saracatinib, are currently under preclinical investigation (PMID: 28838952). False +ENST00000265165 NM_016269 51176 LEF1 True LEF1, a T-cell and B-cell enhancer transcription factor, is infrequently altered in cancer. LEF1, a member of the T-cell factor/lymphoid enhancer factor family, encodes for a transcription factor expressed in pre-B and T cells (PMID: 10933391). LEF1 binds to the T-cell receptor-alpha enhancer to drive T-cell antigen receptor-alpha chain expression (PMID: 7958926, 2010090). LEF1 functions as a nuclear effector in the Wnt/β-catenin signaling pathway to regulate cellular proliferation and cellular apoptosis (PMID: 8757136, 18316418). Overexpression of LEF1 in various cancer cell lines and models induces tumorigenesis, cellular proliferation, migration and resistance to chemotherapy, suggesting that LEF1 functions predominantly as an oncogene (PMID: 31296250, 18316418, 34639214). Amplification of LEF1 has been identified in acute lymphoblastic leukemia and chronic lymphocytic leukemia (PMID: 25942645, 26950276, 22184516). False +ENST00000266674 NM_003667 8549 LGR5 True LGR5, a G-protein coupled receptor that regulates Wnt/beta-catenin signaling, is infrequently altered by amplification in cancer. LGR5, also known as GPR5, is a G-protein coupled receptor that regulates the Wnt/beta-catenin signaling pathway through binding to R-spondin (PMID: 21693646, 26086949). LGR5 is a marker for adult stem cells in various organs and tissues, stimulating stem cell proliferation and self-renewal through Wnt signaling (PMID: 22969042). Rearrangement of LGR5 has been identified in glioblastoma multiforme (PMID: 25500544). Amplified LGR5 mutations have been identified in various cancer types including basal cell carcinomas, hepatocellular carcinomas, colorectal tumors and ovarian tumors (PMID: 16575208, 18688030). Aberrant expression of LGR5 in breast cancer cells promotes tumorigenesis through long-term potentiation of the Wnt/beta-catenin signal pathway, leading to cancer cell mobility and tumor formation (PMID: 26086949). Conversely, LGR5 has been identified as a negative regulator of Wnt/beta-catenin signaling in the context of B cells, demonstrated by upregulated nuclear beta-catenin and tumor growth suppression following ablation of LGR5 in B-cell lineage acute lymphoblastic leukemia cells (Abstract: Cosgun et al. Abstract# 4515, AACR 2018. https://aacrjournals.org/cancerres/article/78/13_Supplement/4515/628888/). Loss of LGR5 mutations have been identified in colorectal tumors (PMID: 23349017). Methylation of LGR5 promotes tumorigenesis in colorectal cancer cell lines and primary tumors as measured by decreased Wnt signaling, increased risk of metastasis and tumor recurrence (PMID: 22056143). LGR5 promotes tumor suppressive activity through Wnt signaling and loss of this function through alteration promotes tumorigenicity as measured by increased invasion, anchorage-independent growth and enhanced tumorigenicity in xenograft models (PMID: 22056143, 23349017). False +ENST00000368300 NM_170707 4000 LMNA True LMNA, an intermediate filament protein, is infrequently altered in cancer. LMNA encodes for intermediate filament proteins lamin A and C that provide stability and structure of the nuclear lamina through the assembly of a filamentous meshwork (PMID: 8344919, 2188730). LMNA regulates the structural integrity and matrix stiffness of the nuclear envelope, playing an integral role in nuclear assembly and chromatin organization (PMID: 2344612, 23990565, 15317753). LMNA is recruited to DNA double-strand break sites by DNA repair proteins XRCC4 and IFFO1 to immobilize the broken DNA ends and suppress chromosome translocation (PMID: 31548606). Germline mutations of LMNA are associated with laminopathies, such as Emery-Dreifuss muscular dystrophy (PMID: 10080180, 12075506, 12927431). Overexpression of LMNA in various cancer cell lines and models induces tumorigenesis, migration and invasion, suggesting that LMNA functions predominantly as an oncogene (PMID: 22301279, 34680461, 32896989). Amplification of LMNA has been identified in various cancers, including cervical cancer, prostate cancer and hepatocellular carcinoma (PMID: 32896989). False +ENST00000335790 NM_002315.2 4004 LMO1 True LMO1, a transcriptional regulator of the cell cycle and metastasis, is altered in the germline of some patients predisposed to neuroblastoma. LMO1 (Lim-domain-only 1, also known as TTG1 and Rhombotin 1) is a Lim-domain-only protein that functions to regulate the formation of transcriptional complexes (PMID: 23303138). The Lim-domain-only proteins (LMO1-4) are characterized by two tandemly arrayed protein interacting LIM domains. The LIM domain is similar to a zinc finger domain; however, instead of mediating DNA-interactions it mediates protein-protein interactions (PMID: 10704826). LMO1 was first described to have oncogenic functions in T-lymphoblastic leukemia. It is was found to be located near chromosome 11 translocation breakpoints leading to overexpression in these leukemias (PMID: 2034676, 2115645). LMO1 expression can drive leukemogenesis and form protein complexes with TAL1 and other proteins. LMO1 protein complexes regulate transcription of known oncogenes such as MYB, one mechanism through which LMO1 leads to leukemogenesis (PMID: 22897851, 1508213). LMO1 is also described as an oncogene in neuroblastoma. A subset of neuroblastoma is robustly associated with germline sequence variants close to the LMO1 gene (PMID: 21124317). These sequence variants lead to high LMO1 expression through differential GATA transcription factor binding (PMID: 26560027). It is clear that LMO1 is associated with poor survival and a higher risk of metastasis, but the exact mechanisms of action are not well understood (PMID: 23303138). False +ENST00000395833 NM_001142315.1 4005 LMO2 True LMO2, a transcription factor involved in the regulation of hematopoiesis, is recurrently altered by chromosomal rearrangement in T-lymphoblastic leukemia. LMO2 is a transcription factor that is a member of the LIM-domain only protein family (PMID: 26108219, 20861166). LMO2 is expressed in hematopoietic cells and across many tissues during development; however, LMO2 is silenced in mature lymphoid lineages (PMID: 11248806). LMO2 regulates both primitive and definitive hematopoiesis as well as angiogenesis and maintenance of stemness (PMID: 8033210, 21343360). LMO2 functions as a member of a transcriptional complex containing TAL1, GATA1/2, RUNX1, MYB, and E-proteins, but LMO2 itself does not have any intrinsic DNA binding ability, acting predominantly to mediate protein-protein interactions (PMID: 25466247, 9214632). LMO2 is dependent on the binding of other proteins for stability, and these interactions are context-dependent (PMID: 26598604). LMO2 predominantly functions as a bridging protein to coordinate the binding of transcriptional complexes across GATA and E-box motifs and serves as an LDB1 docking site to activate enhancers at erythroid genes (PMID: 28636938). Increased expression of LMO2 in murine models results in a differentiation block, resulting in an accumulation of immature thymocyte progenitors (PMID: 8605871, 7579400). In combination with TAL1 activation or NOTCH1 mutations, LMO2 expression in thymocytes results in enhanced tumor-initiating properties (PMID: 8605871, 21670468). LMO2 also functions as the driver oncogene in X chromosome-linked severe combined immuno-deficiency syndrome therapy associated leukemias (PMID: 14985489). LMO2 overexpression is common in patients with T-acute lymphoblastic leukemia (T-ALL), due to recurrent deletions or translocations that fall upstream of LMO2, resulting in activation (PMID: 20861166, 26998100, 16873670, 25682596), suggesting that LMO2 functions predominantly as an oncogene. False +ENST00000389484 NM_018557 53353 LRP1B False LRP1B, a low-density lipoprotein receptor, is infrequently altered in cancer. LRP1B, a member of the low-density lipoprotein receptor family, functions in various cellular functions such as signal transduction, DNA damage response, synaptic transmission and cell migration (PMID: 19071120, 15082773). LRP1B interacts with cytosolic adapter and scaffold protein binding partners through canonical receptor-mediated endocytosis or its intracellular domain (PMID: 19071120). The LRP1B intracellular domain is soluble and is released from the extracellular domain through regulated intramembrane proteolysis cleavage (PMID: 17227771). The cleaved LRP1B intracellular domain localizes to the nucleus via nuclear localization signaling and mediates transcriptional activity through interactions with various binding partners (PMID: 17227771). LRP1B-deficient cancer cells demonstrate anchorage-independent growth and the inability to suppress colony formation, suggesting that LRP1B functions predominantly as a tumor suppressor gene (PMID: 17227771, 20095042, 27499094). Loss of LRP1B has been identified in various different cancers, including prostate cancer, ovarian cancer and multiple myeloma (PMID: 31270961, 27939411, 30719154). Epigenetic silencing of LRP1B, for example hypermethylation and histone deacetylation, has also been identified in different cancers, which include thyroid cancer and renal cell cancer (PMID: 27499094, 23521319). Loss of LRP1B is suggested to contribute to resistance to liposomal therapies such as pegylated liposomal doxorubicin, due to dysfunction in endocytic activity affecting drug uptake (PMID: 22896685). True +ENST00000294304 NM_001291902.1 4041 LRP5 True LRP5, a receptor involved in WNT signaling, is altered by mutation in various cancer types. Germline mutations in LRP5 are associated with familial exudative vitreoretinopathy and bone loss disorders. LRP5 is a transmembrane receptor that is a member of the LDL-related protein family (PMID: 28979801, 17143291). LRP5 interacts with the co-receptors LRP6 and Frizzled family members at the plasma membrane following WNT ligand binding, leading to initiation of WNT-mediated downstream signaling (PMID: 24316024, 23258168). WNT signaling is a critical developmental pathway with roles in determining cell fate, tissue identity and polarity (PMID: 28218291). LRP5/6 binding by WNT ligands results in phosphorylation of CK1α and GSK3β, which recruit the signaling molecule DVL to the plasma membrane for polymerization and activation (PMID: 23258168, 19619488). DVL inactivates the β-catenin destruction complex (containing APC, GSK3β and AXIN) due to recruitment of AXIN to the co-receptor complex, allowing β-catenin to accumulate and translocate to the nucleus (PMID: 23258168). In the nucleus, β-catenin associates with the transcription factors LEF and TCF, displacing the repressive TLE proteins and forming transcription factor complexes that promote the expression of β-catenin target genes (PMID: 23258168, 19619488). LRP5 can also interact with antagonists of WNT, like the Dickkopf (DKK) proteins or SOST, to inhibit WNT activation (PMID: 17052975). Germline mutations in LRP5 have been identified in several malignancies including familial exudative vitreoretinopathy (FEVR), which causes progressive vision loss, and diseases related to altered bone mass (PMID: 15024691, 20340138, 28341377). LRP5 mutations have been identified in various cancer types, though the functional role of these alterations has not yet been carefully elucidated (PMID: 31575382, 19158955, 18044981, 16266997, 19619488). However, mutations in LRP5 are predicted to result in deregulation of WNT signaling. True +ENST00000261349 NM_002336.2 4040 LRP6 True LRP6, a receptor involved in WNT signaling, is altered by mutation in various cancer types. Germline mutations in LRP6 are associated with early coronary disease, oligodontia, and bone mass disorders. LRP6 is a transmembrane receptor that is a member of the LDL-related protein family (PMID: 27617575, 17143291). LRP6 interacts with the co-receptors LRP5 and Frizzled family members at the plasma membrane following WNT ligand binding, leading to initiation of WNT-mediated downstream signaling (PMID: 24316024, 23258168). WNT signaling is a critical developmental pathway with roles in determining cell fate, tissue identity and polarity (PMID: 28218291). LRP5/6 binding by WNT ligands results in phosphorylation of CK1α and GSK3β, which recruit the signaling molecule DVL to the plasma membrane for polymerization and activation (PMID: 23258168, 19619488). DVL inactivates the β-catenin destruction complex (containing APC, GSK3β and AXIN) due to recruitment of AXIN to the co-receptor complex, allowing β-catenin to accumulate and translocate to the nucleus (PMID: 23258168). In the nucleus, β-catenin associates with the transcription factors LEF and TCF, displacing the repressive TLE proteins and forming transcription factor complexes that promote the expression of β-catenin target genes (PMID: 23258168, 19619488). LRP6 can also interact with antagonists of WNT, like the Dickkopf (DKK) proteins, to inhibit WNT activation (PMID: 21866564, 31412666, 22000856). LRP5/6 also have roles in the regulation of tissue homeostasis and intestinal epithelial development (PMID: 31412666). Germline mutations in LRP6 are associated with several malignancies including tooth agenesis, bone mass disorders, early coronary disease and neural tube defects (PMID: 26387593, 26963285, 31085352, 24203697, 17332414). LRP6 mutations have been identified in various cancer types; however, the functional role of these alterations have not yet been carefully elucidated (PMID: 25500543, 15064719). However, overexpression of LRP6 is found in a variety of cancer types, including liver, breast and colorectal cancer, suggesting that LRP6 predominantly functions as an oncogene (PMID: 31412666, 20194742). False +ENST00000376117 NM_002341.1 4050 LTB True LTB, a tumor suppressor involved in inflammatory signaling, is recurrently mutated in multiple myeloma. LTB (also TNF-C) is a lymphotoxin or cytokine that is a member of the tumor necrosis factor (TNF) superfamily of ligands (PMID: 8621492). LTB forms a heterotrimeric complex with another TNF family member, LTα (one subunit of LTα; two subunits of LTB), which is termed the lymphotoxin protein complex (PMID: 8621492, 27323847). The lymphotoxin protein complex is found on the surface of activated T-, B- and natural killer cells (PMID: 27323847) and serves as the primary ligand for the lymphotoxin beta receptor, which is found on nonlymphoid cells (PMID: 27323847, 8621492). LTB activity is important for follicular dendritic cell development in germinal centers and is an important chemoattractant relevant for B-cell homing to follicles in the lymph node and spleen (PMID: 10917533, 10049949). Lymphotoxin signaling is necessary for normal lymphoid tissue organogenesis and maintenance (PMID: 9256477) and for regulation of stromal cell expression of chemokines in tissues such as the spleen (PMID: 9892622). LTB induces the expression of cytokines and chemokines that promote a positive feedback loop to recruit immune cells (PMID: 10917533, 27323847). Loss of LTB expression in mice results in reduced follicular dendritic cell development, impaired B-cell memory and abnormal lymphoid tissue development (PMID: 9256477). In addition, LTB is a regulator of NF-KB-mediated inflammatory signaling (PMID: 8798772, 28196873). Inflammatory gene expression signatures in autoimmune patients have been linked to lymphotoxin signaling, such as in rheumatoid arthritis (PMID: 25405351). Somatic mutations in LTB are found in patients with multiple myeloma and are predicted to be loss-of-function (PMID: 24429703, 28550183, 26282654). In addition, LTB overexpression has been linked to cancers that are driven by inflammation, such as hepatocellular carcinomas (PMID: 19800575). True +ENST00000263800 NM_002344 4058 LTK True LTK, a receptor tyrosine kinase, is infrequently altered in cancer. LTK (leukocyte tyrosine kinase) is a receptor tyrosine kinase that localizes to the endoplasmic reticulum and is activated by the FAM10A/B proteins (PMID: 31227593, 25331893, 26630010). LTK is a member of the insulin receptor family and is closely related to ALK, with 79% sequence similarity among the tyrosine kinase domains and sensitivity to ALK inhibitors (PMID: 9223670, 31227593, 22347506, 25331893). LTK is normally expressed in pre-B lymphocytes and neuronal tissues (PMID: 9223670, 31227593). When bound to its ligands, LTK phosphorylates Shc and IRS-1 to activate downstream Ras signaling, thus promoting cell growth and inhibiting apoptosis (PMID: 8910363). Activated LTK also transmits anti-apoptotic signals through the PI3-kinase pathway by phosphorylating c-Cbl (PMID: 9223670). Kinase domain mutations in LTK lead to constitutive phosphorylation of the receptor and activation of downstream signaling targets including Shc, ERK, JAK1 and JAK2 (PMID: 22347506). LTK kinase domain mutants also transform epithelial cells and induce neural outgrowth in vitro (PMID: 22347506). LTK is involved in regulating endoplasmic reticulum (ER) protein export, such that knockdown or pharmacological inhibition of LTK leads to significantly fewer ER exit sites compared to wildtype/untreated cells (PMID: 31227593). While LTK is overexpressed among acute myeloid leukemia samples, alteration of LTK in human cancers is not well-characterized (PMID: 14977821). False +ENST00000519728 NM_002350.3 4067 LYN True LYN, a non-receptor tyrosine kinase, is altered by amplification in various cancers. The LYN gene encodes a non-receptor tyrosine kinase of the Src family (PMID: 9202419). LYN is involved in immune responses, B-cell signaling, signal transduction of growth factors and response to DNA damage, among other functions (PMID: 19290919, 10574931, 11825908, 11435302). LYN is a mediator that can positively or negatively regulate different processes depending on the cellular and physiological context (PMID: 15664155). LYN has been described to promote tumor growth, invasion, epithelial to mesenchymal transition (EMT) and ERK signaling in different cancer contexts (PMID: 20215510, 22490227, 22731636). The LYN gene is typically altered by amplification in various tumors, including prostate, breast and ovarian cancers (cBioPortal, MSKCC, Nov 2016). LYN can be pharmacologically targeted with Src-kinase inhibitors, such as dasatinib (PMID: 20215510, 22490227, 18056483). False +ENST00000215739 NM_006767.3 8216 LZTR1 False LZTR1, a ubiquitin ligase adaptor protein, is recurrently altered by mutation in glioblastoma, Noonan syndrome, and schwannomatosis. LZTR1 is a ubiquitin ligase adaptor protein that is a member of the BTB/POZ family (PMID: 30442762). LZTR1 functions as a scaffolding component of the CUL3 E3-ligase complex that targets substrate proteins to the proteasome for ubiquitin-mediated degradation (PMID: 23917401, 30442762). The oncogene RAS is ubiquitinated by the LZTR1-CUL3 complex which is essential for the normal protein turnover of RAS (PMID: 30442762). In addition, LZTR1 also binds RAF1, a signaling molecule in the MAPK pathway (PMID: 30368668). Loss of LZTR1 expression in hematopoietic cell lines results in enhanced MAPK signaling, reduced RAS ubiquitination, and increased association of RAS at the plasma membrane (PMID: 30442762). Germline mutations in LZTR1 have been identified in patients with Noonan syndrome and schwannomatosis (PMID: 24362817, 25335493, 25795793, 30481304). Somatic loss-of-function variants in LZTR1 are also found in patients with glioblastomas and hepatocellular carcinomas (PMID: 28622513), leading to activation of MAPK signaling due to RAS stabilization (PMID: 30442762). Reduced LZTR1 expression in preclinical studies results in resistance to several tyrosine kinase inhibitors, including imatinib, ponatinib, and rebastinib, due to constitutively active RAS signaling (PMID: 30442762). True +ENST00000235310 NM_001127325.1 10459 MAD2L2 True MAD2L2, an adaptor protein involved in DNA repair, is altered by mutation and overexpression in various cancer types. MAD2L2 (also MAD2B and REV7) is a DNA repair protein that functions as an adaptor protein in several DNA repair-associated complexes (PMID: 25896508, 30154076). MAD2L2 is the non-catalytic subunit of polymerase zeta, which functions as an error-prone DNA polymerase that bypasses DNA lesions during replication (PMID: 19258535, 31410467). The H2AX-53BP1 checkpoint complex recruits MAD2L2 to double strand breaks leading to blockage of homologous recombination (HR) (PMID: 25799992). MAD2L2 then promotes non-homologous end-joining (NHEJ), including at unprotected telomeres, by inhibiting 5’ end resection downstream of 53BP1 and RIF1 (PMID: 25799990, 30046110, 30022168). MAD2L2-mediated NHEJ is important for specific cellular functions such as immunoglobulin class switch recombination (PMID: 25799992). MAD2L2 is also a member of the mitotic assembly checkpoint that prevents activation of the anaphase promoting complex/cyclosome (APC/C) during metaphase (PMID: 25896508). Overexpression of MAD2L2 has been found in several cancer types likely contributing to genomic instability (PMID: 17044027). In addition, MAD2L2-dependent translesion synthesis is predicted to contribute to error-prone repair after chemotherapy and, therefore, small molecule inhibitors targeting polymerase zeta are under development (PMID: 31178121). Loss of MAD2L2 activity has been implicated as a mechanism of PARP inhibitor resistance in BRCA1-deficient patients, due to a switch to HR repair; however, HR restoration may render these cancers radiosensitive (PMID: 25799992, 29789392). True +ENST00000393350 NM_001031804.2 4094 MAF False MAF, a transcription factor, is recurrently altered by rearrangement in multiple myeloma. MAF is a transcription factor that is a member of the AP1 protein family (PMID: 19143053). MAF, along with MAFA and MAFB, are categorized as large MAF proteins that regulate gene expression via transactivation domains (PMID: 19143053). MAF coordinates DNA binding as a homodimer, or a heterodimer in complex with other MAF family members (PMID: 19143053), and recruits co-activators (such as EP300, CREBBP, KAT2B, and TBP) to initiate transcription (PMID: 11943779, 18042454, 15328344). MAF activity regulates a variety of cellular processes including migration, cell cycle, proliferation, differentiation, and cell-cell interactions, among others (PMID: 19143053, 16247450, 14998494). In addition, tightly regulated MAF expression is important for context-specific control of transcriptional programs during development and terminal differentiation (PMID: 17569705). The activity of large MAF proteins is also mediated by competition with small MAF proteins for the same binding site (PMID: 8552399). Loss of MAF in murine models results in altered cytokine expression with implications for immune regulation while increased expression of MAF leads to transformation (PMID: 10403649, 16424013, 16247450). Germline mutations in MAF are found in lens development disorders such as pulverulent cataracts (PMID: 12642301). Overexpression of MAF is common in multiple myelomas and T-cell lymphomas, suggesting that MAF predominantly functions as an oncogene (PMID: 19143053). Rearrangements involving MAF and the immunoglobulin gene are recurrent in multiple myelomas and predicted to be a primary initiating event in the disease (PMID: 9616139, 18070707). False +ENST00000373313 NM_005461.4 9935 MAFB True MAFB, a transcription factor, is recurrently altered by chromosomal rearrangement in multiple myeloma. MAFB is a transcription factor that is a member of the AP1 protein family (PMID: 19143053). MAFB, along with MAF and MAFA, are categorized as large MAF proteins that regulate gene expression via transactivation domains (PMID: 19143053). MAFB coordinates DNA binding as a homodimer or a heterodimer in complex with other MAF family members (PMID: 19143053), and recruits co-activators (such as EP300, CREBBP, KAT2B, and TBP) to initiate transcription (PMID: 11943779, 18042454, 15328344). MAFB activity regulates a variety of cellular processes including migration, cell cycle, proliferation, differentiation, and cell-cell interactions, among others (PMID: 19143053, 16247450, 14998494). In addition, tightly regulated MAFB expression is important for context-specific control of transcriptional programs during development and terminal differentiation (PMID: 17569705, 28025141, 8620536). The activity of large MAFB proteins is also mediated by competition with small MAF proteins for the same binding site (PMID: 8552399). Forced expression of MAFB in murine models results in plasma cell neoplasms (PMID: 16424013). Overexpression of MAFB is common in multiple myelomas and T-cell lymphomas, suggesting that MAFB predominantly functions as an oncogene (PMID: 19143053). Rearrangements involving MAFB and the immunoglobulin gene are recurrent in multiple myelomas and predicted to be a primary initiating event in the disease (PMID: 9616139, 18070707, 24638926). False +ENST00000354212 NM_012301.3 9863 MAGI2 False MAGI2, a membrane-associated guanylate kinase, is altered in various cancers. MAGI2 is a membrane-associated guanylate kinase that functions primarily as a scaffold protein at cell junctions (PMID: 10644767, 22361463). With eight protein-binding domains and three isoforms, α, β, and γ, MAGI2 can organize, assemble and anchor many different proteins, particularly cell signaling proteins, at synaptic junctions (PMID: 29542165, 10644767, 22361463). MAGI2 is also known as the synaptic scaffolding molecule (S-SCAM), atrophin-interacting protein-1 (AIP-1) and activin receptor-interacting protein 1 (ARIP1) (PMID: 22593065, 25637633, 17880912). MAGI2 is highly expressed in the brain where it is implicated in AMPA-type glutamate receptor trafficking and is important for overall synapse formation (PMID: 22361463, 22593065, 17644382, 38045729). The scaffolding protein also plays a key role in the glomerulus of the kidney by stabilizing and organizing nephrin as well as regulating the dynamics of the podocyte cytoskeleton and slit diaphragm (PMID: 25271328). MAGI2 enhances the ability of PTEN to suppress the activity of AKT by stabilizing a multiprotein signaling complex with PTEN that localizes to tight junctions and increases signaling efficiency (PMID: 10760291, 17880912). Suppression of MAGI2 in hepatocellular carcinoma cells causes loss of PTEN stability and induces cell migration and proliferation in vitro (PMID: 17880912). MAGI2 promoter methylation occurs in acute lymphoblastic leukemia, gastric cancer, colorectal cancer, lung cancer and breast cancer, among others (PMID: 33530176, 32730644). In addition to the tumor suppressive behavior of the MAGI2 protein, MAGI2-AS3, the long noncoding RNA antisense transcript of MAGI2, has demonstrated tissue-specific oncogenic and tumor suppressive roles (PMID: 35071487, 31837602). True +ENST00000276681 NM_052886.2 114569 MAL2 False MAL2, a transmembrane protein, is infrequently altered in cancer. MAL2, a member of the MAL proteolipid family, is an essential transmembrane protein for the basolateral-to-apical transcytotic pathway (PMID: 11549320, 14576188). MAL2 traffics vesicles from the subapical compartment to fuse with basal cargo-containing endosomes and then subsequently traffics basal cargo vesicles back to the apical surface (PMID: 12370246, 16445687, 20493814). The transcytotic function of MAL2 is regulated by binding partners INF2 and CDC42 (PMID: 20493814). Overexpression of MAL2 in human colorectal cancer cells inhibits cell proliferation and invasion, suggesting that MAL2 functions primarily as a tumor suppressor gene (PMID: 35847380). Despite functioning as a tumor suppressor gene, upregulation of MAL2 has been identified in various epithelial-derived cancers such as breast cancer, renal cell carcinoma and cholangiocarcinoma (PMID: 28562687, 32990678, 19287191). This is suggested to be due to the amplification of chromosomal region 8q24.12 enhancing expression of both MAL2 and known oncogene MYC (PMID: 32059473). The enhanced MAL2 expression is predicted to be associated with earlier stages of cancer progression and eventually, its expression is repressed during metastases as MYC expression increases (PMID: 32059473). True +ENST00000348428 NM_006785.3 10892 MALT1 False MALT1, a paracaspase, is recurrently altered by chromosomal rearrangement in MALT lymphoma. MALT1 is a mucosal-associated lymphoid tissue lymphoma translocation protein 1, a cysteine paracaspase. MALT1 cleaves multiple substrates including BCL10, RELB, and TNFAIP3, and promotes NFkB signaling (PMID: 21873235,18223652,18264101). It associates with CARMA1 and BCL10 to form a complex (CBM) with scaffold function to recruit proteins important for signaling (PMID:24074955,15125833). MALT1 activity is employed in B-cell and T-cell antigen receptor activation and IL2 production (PMID: 23706741, 14614861, 14576442). Germline mutation can lead to immunodeficiency (PMID: 25627829, 23727036). MALT1 is translocated with partner API2 (BIRC3) in Mucosal-associated B-cell lymphomas (PMID: 10339464). The fusion protein causes dimerization and activation of NFkB (PMID: 11262391). MALT1 can also be amplified or overexpressed by translocation with the IgH chain locus in non-Hodgkins lymphomas (PMID: 12560219). MALT1 activity was found to be critical for the growth of activated B-cell type Diffuse Large B-cell Lymphomas (DLBCL) (PMID: 19897720). Inhibitors of MALT1 proteolytic activity are in development for lymphoma therapy (PMID: 23238016). False +ENST00000307102 NM_002755.3 5604 MAP2K1 True 2 MAP2K1, an intracellular kinase, is mutated at low frequencies in various cancer types including melanoma, colorectal and lung cancers. MAP2K1 (also known as MEK1) is a serine/threonine kinase that functions as an effector protein in the mitogen-activated protein kinase (MAPK) signaling cascade (PMID: 25435214, 17496922). The MAPK signaling pathway is involved in the regulation of diverse cellular processes including proliferation, differentiation, cell adhesion and transcription (PMID: 25435214, 17496922). As a component of a three-tiered MAPK cascade, MEK1 activity is dependent on phosphorylation by upstream RAF kinases. Activated MEK1 in turn phosphorylates ERK1/2 (extracellular-signal-regulated kinases1/2) which then serves as a transcriptional regulator (PMID: 22177953). These signaling events are triggered by growth factors, cytokines, and hormones that activate upstream receptor tyrosine kinases, ultimately leading to altered expression of key regulators of cell growth, differentiation, proliferation and survival (PMID: 9069255, 11242034). Dysregulation of MEK1 signaling is commonly associated with genetic alterations in RAS and RAF (PMID: 12068308, 12509763). Hyperactivation of the MAPK pathway is frequently observed in human cancers, such as melanoma, colorectal and lung cancers; however, oncogenic mutations in MEK1 in primary tumors are infrequent (PMID: 22753777, 25351745). The MEK1/2 inhibitors trametinib and cobimetinib are FDA-approved for the treatment of melanoma in combination with RAF inhibition and preclinical and clinical efforts are ongoing to determine the efficacy of MEK1 inhibition for other indications (PMID: 25435214). Some MEK1 mutations may confer resistance to both MEK and RAF inhibitors and can arise as a resistance mechanism to RAF inhibition (PMID: 19915144, 21383288). False +ENST00000262948 NM_030662.3 5605 MAP2K2 True 2 MAP2K2, an intracellular kinase, is altered by mutation in various cancer types. MAP2K2 (also known as MEK2) is a serine/threonine kinase that functions as an effector protein in the mitogen-activated protein kinase (MAPK) signaling cascade (PMID: 25435214, 17496922). The MAPK signaling pathway is involved in the regulation of diverse cellular processes including proliferation, differentiation, cell adhesion and transcription (PMID: 25435214, 17496922). As a component of a three-tiered MAPK cascade, MEK2 activity is dependent on phosphorylation by upstream RAF kinases. Activated MEK2 in turn phosphorylates ERK1/2 (extracellular-signal-regulated kinases1/2) which then serves as a transcriptional regulator (PMID: 22177953). These signaling events are triggered by growth factors, cytokines, and hormones that activate upstream receptor tyrosine kinases, ultimately leading to altered expression of key regulators of cell growth, differentiation, proliferation and survival (PMID: 9069255, 11242034). Germline missense mutations and deletions in MEK2 are found in patients with cardio-facio-cutaneous syndrome (PMID: 20358587, 18456719, 21178588, 24311457, 23379592). Hyperactivation of the MAPK pathway is frequently observed in human cancers; however, oncogenic mutations in MAP2K2 in primary tumors are infrequent (PMID: 24840079). Because of its major role in signaling as a RAF oncogene effector, several inhibitors of wildtype MEK2 and its close structural and functional homolog, MEK1, have been developed (PMID: 20149254, 24840079). The MEK1/2 inhibitors trametinib and cobimetinib are FDA-approved for the treatment of melanoma in combination with RAF inhibition and preclinical and clinical efforts are ongoing to determine the efficacy of MEK1/2 inhibition for other indications (PMID: 25435214). Mutations in MEK2 have been identified in melanomas insensitive to RAF and MEK inhibition and may mediate resistance to MAPK pathway targeted agents (PMID: 24265153, 24055054, 22197931). False +ENST00000353533 NM_003010.3 6416 MAP2K4 False MAP2K4, a tumor suppressor and intracellular kinase, is altered in various cancer types. MAP2K4 is a dual specificity kinase that directly phosphorylates and activates JNK (c-Jun N-terminal kinase) and p38 MAP kinase (PMID: 7716521). MAP2K4 itself is phosphorylated and activated by one of several upstream MAP kinase kinase kinases (MAPKKK). The activation of JNK and p38 MAP kinase pathways occurs in response to a variety of environmental stressors, such as DNA damage, hypoxia, heat shock, ionizing radiation, as well as inflammatory cytokines and growth factors (PMID: 17496914,19629069). Activation of these signaling pathways leads to altered transcriptional activity of downstream effector molecules such as c-Jun, p53, ELK1, ATF2 and several other transcription factors involved in apoptosis, cell survival, growth and differentiation (PMID: 17496914,19629069). Inactivating mutations in MAP2K4 have been identified in a variety of tumor cell lines and human cancers, suggesting that MAP2K4 functions primarily as a tumor suppressor (PMID: 9331070, 9622070, 17496914, 22522925). Loss of heterozygosity of the 17p chromosomal region, where MAP2K4 is located in close proximity to TP53, is observed at a high frequency in many cancers (PMID: 16721048, 16627982, 19603523). In addition, MAP2K4 has been found to act as a suppressor of metastasis in prostate and ovarian cell lines (PMID: 10554023, 12438272). True +ENST00000399503 NM_005921.1 4214 MAP3K1 False MAP3K1, an intracellular kinase, is altered by mutation or deletion in various cancer types, most frequently in breast and endometrial cancer. The MAP3K1 gene encodes MEKK1, a kinase that signals in the pro-oncogenic MAP-kinase and JNK signaling pathways. MAP3K1 is unique among the MAPK signaling molecules in that it also acts as an E3 ubiquitin ligase for ERK1/2, thus allowing for the regulation of pathway output (PMID: 12049732, 25613373). Activation of MAP-kinase and JNK pathways occurs in response to a variety of stimuli such as environmental stress, inflammatory cytokines, pro-apoptotic signals and growth factors (PMID: 10639576, 9528810, 8621725, 11784851, 9078260). Activated MAP3K1 phosphorylates downstream effector molecules such as MAP2K4/7, MAP2K1/2, IKK alpha/beta and other transcription factors involved in apoptosis, cell survival, growth and differentiation (PMID: 7997270, 7624324, 9008162, 12471242) leading to activation of downstream signaling pathways. Germline mutations in MAP3K1 disrupt normal sex development and cause 46,XY sex development disorder (PMID: 21129722, 24135036). Truncating mutations and deletions in MAP3K1 mutations have been identified in breast cancer, predominantly in the luminal A subtype (PMID: 24386504), suggesting that MAP3K1 functions as a putative tumor suppressor. MAP3K1 may also promote oncogenesis and metastasis in some contexts. Elevated MAP3K1 expression has been found in human melanoma samples (PMID: 24003131) and MAP3K1 plays a pro-metastatic role in some cancers, as demonstrated by experimental studies in breast and pancreatic cancer models (PMID: 19513748, 16568086). True +ENST00000265026 NM_004721.4 9175 MAP3K13 True MAP3K13, a serine/threonine kinase, is infrequently altered in cancer. MAP3K13 is a serine/threonine kinase that is a member of the JNK signaling pathway. MAP3K13 phosphorylates MAPK8 (JNK) and MAP2K7, resulting in activation of the JNK pathway (PMID: 11163770, 8637721), which is a mitogen-activated protein kinase (MAPK) pathway activated in response to proinflammatory cytokines and extracellular stresses (PMID: 11163770) and functions as a regulator of cellular proliferation, apoptosis and morphogenesis (PMID: 9561845). Through the leucine/isoleucine zipper domain, MAP3K13 forms dimers or oligomers with other proteins, such as JNK interacting protein (JIP-1), an interaction that is essential for the activation of MKK7 in the JNK signaling cascade (PMID: 9353328, 11163770, 11726227). In addition, MAP3K13 has been found to interact with PRDX3 and regulates the activation of NF-κB in the cytosol (PMID: 12492477). MAP3K13 mRNA is found primarily in the pancreas, with lower levels of expression in the brain, liver and placenta (PMID: 9353328). Amplification and loss-of-function mutations in MAP3K13 are found in various solid tumors, including breast, lung cancer, and melanoma (PMID: 22722201, 22817889, 28760853). False +ENST00000344686 NM_003954.3 9020 MAP3K14 True MAP3K14, a serine/threonine kinase, is infrequently altered in cancer. MAP3K14 (also NIK) is a serine/threonine kinase which is an important signaling molecule in the noncanonical NF-kB pathway (PMID: 15485626). Following ligand stimulation, the TRAFT2/3 ubiquitin ligase complex releases MAP3K14, which then phosphorylates and activates IKK-α. IKK-α homodimers phosphorylate and activate a precursor protein of the NF-kB complex, p100, triggering its cleavage and ultimately activation of the NF-kB cascade (PMID: 11520989, 11239468, 22435551). Through its role in NF-kB signaling, MAP3K14 influences a wide range of cellular processes, including regulation of B- and T-cells (PMID: 14764671, 16034105, 18799149, 10878354, 10637282), production of inflammatory cytokines and chemokines (PMID: 18997792, 18997794), formation of osteoclasts (PMID: 12939342) and response to viral infection (PMID: 9182687, 20685151, 18550535). Mice lacking MAP3K14 are immunodeficient, with a reduced B-cell population and a lack of lymph nodes (PMID: 11069060, 10878354, 8605936, 25406581), highlighting the importance of MAP3K14 in immune regulation. Overexpression of MAP3K14 has been linked to lethal liver inflammation and fibrosis. In obese mice, high levels of MAP3K14 result in hyperglycemia and glucose intolerance (PMID: 22581287, 25088600). MAP3K14 overexpression caused by amplification or translocation has been observed in various hematological malignancies, including multiple myeloma, splenic marginal zone lymphoma and Hodgkin lymphoma (PMID: 17692804, 17692805, 21881048, 22469134). Although less common, aberrant expression of MAP3K14 has been observed in some solid tumor models, including pancreatic cancer, lung cancer and melanoma (PMID: 19646419, 20338663). False +ENST00000366624 NM_032435 84451 MAP3K21 True MAP3K21, a serine/threonine kinase, is altered by amplification and mutation in various cancers. MAP3K21 encodes for a serine/threonine kinase that functions primarily in the negative regulation of the TLR4 signaling pathway (PMID: 21602844). There are conflicting reports of the role MAP3K21 plays in the JNK, ERK and p38 signaling pathways. MAP3K21 has been identified to mediate both negative and positive regulation of MAPK signaling pathways (PMID: 21602844, 23552557, 28757353, 23319808). Overexpression of MAP3K21 in various cancer cell lines and models induces cellular proliferation, migration and invasion, suggesting that MAP3K21 functions predominantly as an oncogene (PMID: 30552384, 23319808, 34839359). MAP3K21 amplification and mutations have been identified in various cancers, including breast cancer and melanoma (PMID: 30552384, 24849047). False +ENST00000369329 NM_145331 6885 MAP3K7 True MAP3K7, a serine/threonine protein kinase, is infrequently altered in cancer. MAP3K7 encodes for a serine/threonine protein kinase that functions in the MAP kinase signaling pathway to regulate various physiological cellular processes (PMID: 9079627, 8663074). MAP3K7 mediates signal transduction from various cytokines, including TGF-β, TLR and IL-1, to regulate transcription and apoptosis (PMID: 24801688, 10094049, 16845370, 16893890). MAP3K7 functions upstream of the MKK/JNK signal transduction cascade, which in turn activates MAP kinases that control various transcription factors (PMID: 11460167, 8663074). Knockdown of MAP3K7 in various cancer cell lines and models attenuates tumor formation and cellular proliferation, suggesting that MAP3K7 functions predominantly as an oncogene (PMID: 31214512, 28194669, 21834757, 21743023, 32523651). Amplification of MAP3K7 has been identified in various types of cancer, including breast cancer and hepatocellular carcinoma (PMID: 28820959, 35053591). Clinical trials have investigated the efficacy of MAP3K7 inhibitors to trigger cell death in the context of various cancers (PMID: 28820959, 34676048, 32273474). False +ENST00000347699 NM_001242559 9448 MAP4K4 True MAP4K4, a serine/threonine kinase, is infrequently altered in cancer. MAP4K4, a member of the mammalian sterile 20 protein kinase family, is a serine/threonine kinase that regulates activation of the JNK signaling pathway (PMID: 10021364). TNFa upregulates the expression of MAP4K4 through a TNFR1-dependent mechanism (PMID: 17500068). MAP4K4 has been implicated in various physiological processes including embryonic development, inflammation, cell migration, cell proliferation and cell adhesion through activation of the JNK pathway (PMID: 11290295, 19407801, 35941177, 25490267). MAP3K11 (or MLK3) is an activator of the JNK pathway and is a direct downstream target of MAP4K4 phosphorylation (PMID: 34511598, 10232608). Inhibition of MAP4K4 in pancreatic cancer cell lines reduces cancer cell growth and migration, suggesting that MAP4K4 functions predominantly as an oncogene (PMID: 34511598). Overexpression of MAP4K4 has been identified in various cancers, including hepatocellular carcinoma, pancreatic cancer and lung adenocarcinoma (PMID: 27010469, 18981001, 22824148). Alternative splice variants of MAP4K4 that retain the N-terminal kinase domain have been identified in various different human tissues with unknown biological significance (PMID: 12612079). False +ENST00000215832 NM_002745.4 5594 MAPK1 True MAPK1 (ERK2), a serine/threonine kinase, is altered by mutation or amplification in various cancer types including head and neck, cervical and ovarian cancer. MAPK1 (also known as ERK2) is a serine/threonine kinase that functions as an effector protein in the mitogen-activated protein kinase (MAPK) signaling cascade (PMID: 25435214, 17496922). The MAPK signaling pathway is involved in the regulation of diverse cellular processes including proliferation, differentiation, cell adhesion and transcription (PMID: 25435214, 17496922). As a component of a three-tiered MAPK cascade, ERK2 activity is dependent on phosphorylation by upstream MEK1/2 kinases (PMID: 22177953). Activated ERK2 homodimerizes and phosphorylates downstream targets, including transcription factors with central roles in cell proliferation and survival such as RSK (ribosomal S6 kinase), MSK (mitogen- and stress-activated protein kinases) and MYC (PMID: 25320010, 22569528). However, ERK2 targets also include upstream MAPK pathway effectors, highlighting the role ERK2 plays in negative feedback on the MAPK pathway (PMID: 15664191, 8816480). ERK2 targets also include cytoskeletal molecules and nucleoporins (PMID: 25320010, 22569528). These signaling events are triggered by growth factors, cytokines and hormones that activate upstream receptor tyrosine kinases, ultimately leading to altered expression of key regulators of cell growth, differentiation, proliferation and survival (PMID: 9069255, 11242034). ERK2 and its homolog, ERK1 (MAPK3), are essential for cell proliferation; they are ubiquitously and often simultaneously expressed, but evidence suggests they may have some distinct functions in specialized contexts (PMID: 23482492, 21248139, 17496918). ERK2 is infrequently mutated in human cancers; however, a recurrent ERK2 mutation is found in cervical and head and neck cancers and amplification is observed in ovarian cancer (PMID: 25631445, 21720365, 23820584). Inhibitors of ERK1/2 are being explored as complementary and alternative options to RAF and MEK inhibition in cases of resistance or partial response (PMID: 25435214). False +ENST00000263025 NM_002746.2 5595 MAPK3 True MAPK3 (ERK1), a serine/threonine kinase, is infrequently altered in cancer. MAPK3 (also known as ERK1) is a serine/threonine kinase that functions as an effector protein in the mitogen-activated protein kinase (MAPK) signaling cascade (PMID: 25435214, 17496922). The MAPK signaling pathway is involved in the regulation of diverse cellular processes including proliferation, differentiation, cell adhesion and transcription (PMID: 25435214, 17496922). As a component of a three-tiered MAPK cascade, ERK1 activity is dependent on phosphorylation by upstream MEK1/2 kinases (PMID: 22177953). Activated ERK1 homodimerizes and phosphorylates downstream targets, including transcription factors with central roles in cell proliferation and survival such as RSK (ribosomal S6 kinase), MSK ( mitogen- and stress-activated protein kinases) and MYC (PMID: 25320010, 22569528). However, ERK1 targets also include upstream MAPK pathway effectors, highlighting the role ERK1 plays in negative feedback on the MAPK pathway (PMID: 15664191, 8816480). ERK1 targets also include cytoskeletal molecules and nucleoporins (PMID: 25320010, 22569528). These signaling events are triggered by growth factors, cytokines and hormones that activate upstream receptor tyrosine kinases, ultimately leading to altered expression of key regulators of cell growth, differentiation, proliferation and survival (PMID: 9069255, 11242034). ERK1 and its homolog, ERK2 (MAPK1), are essential for cell proliferation; they are ubiquitously and often simultaneously expressed, but evidence suggests they may have some distinct functions in specialized contexts (PMID: 23482492, 21248139, 17496918). ERK1 is infrequently mutated in human cancers; however, inhibitors of ERK1/2 are being explored as complementary and alternative options to RAF and MEK inhibition in cases of resistance or partial response (PMID: 25435214). False +ENST00000265960 NM_001006617.1 79109 MAPKAP1 False MAPKAP1, a component of the mTORC2 complex, is mutated or amplified at low frequencies in various cancers. MAPKAP1 (also SIN1) is a component of the mTORC2 complex, which is involved in cell growth and cytoskeletal organization (PMID: 19339977). MAPKAP1 not only acts as a scaffold protein for mTORC2 complex formation but also as a key factor in mTORC2-mediated phosphorylation of AKT (PMID: 24795562, 16962653, 17043309). Functional experiments have demonstrated that knockdown of MAPKAP1 activity results in reduced invasion and migration (PMID: 27993679). In addition, MAPKAP1 can bind RAS and suppress the mitogen-activated protein kinase (MAPK) signaling pathway (PMID: 17303383). Somatic mutations in MAPKAP1 are infrequent in human cancers; however, MAPKAP1 expression levels are elevated in a subset of patients with breast cancer (PMID: 27780891). False +ENST00000358664 NM_002382.4 4149 MAX False MAX, a transcription factor, is altered by mutation and deletion in various cancer types including small-cell lung cancer. Germline mutations of MAX are associated with hereditary pheochromocytoma. "MAX (Myc-associated factor X) is a transcription factor that is a member of the basic helix-loop-helix leucine zipper (bHLHZ) family (PMID: 8479534, 2006410). MAX functions at the center of a transcription factor network that governs many aspects of cell behavior, inducing cell proliferation, by binding to enhancer-boxes containing the CANNTG sequence (PMID: 16908182, 1557420). MAX lacks a transactivation domain, and thus MAX homodimers act as transcriptional repressors (PMID: 9824157). However, MAX also dimerizes with other bHLHZs such as MYC, MAD or MXL1 (PMID: 12553908). Heterodimers of MYC/MAX can bind and transactivate gene expression and promote cell proliferation and apoptosis. MAX is expressed in different splice-isoforms, each having different functions (PMID: 10229200, 1566084, 8426752). A ""delta MAX"" isoform, truncated at its C-terminus, appears to enhance MYC-driven tumorigenesis, whereas full-length MAX suppresses MYC-driven tumorigenesis (PMID: 1566084). Chromosomal rearrangements involving the MAX gene location at 14q22-q24 are common in several malignancies such as malignant lymphoma, chronic lymphocytic leukemia and uterine leiomyomas (PMID:1594250). Germline loss-of-function mutations in the MAX gene are found in patients with hereditary pheochromocytoma and paragangliomas (PMID: 21685915, 22452945). Other studies, however, were not able to reproduce these findings in a separate cohort (PMID: 23743562). MAX is recurrently inactivated through somatic mutations in small-cell lung cancer (SCLC) (PMID: 24362264)." True +ENST00000249910 NM_003925 8930 MBD4 False MBD4, a DNA glycosylase, is infrequently altered in cancer. MBD4 encodes a DNA glycosylase that functions in the detection and repair of deamination of methyl-cytosines (PMID: 10499592, 30049810). The methyl-CpG domain at the N-terminus of the protein functions in binding methylated DNA and repressing transcription from methylated gene promoters (PMID: 10930409). The mismatch-specific glycosylase domain at the C-terminus of the protein functions in DNA mismatch repair in CpG methylation regions (PMID: 10930409, 10499592). MBD4-deficient mice demonstrate accelerated tumor formation in cancer-predisposing backgrounds and increased CpG mutation burden, suggesting that MBD4 functions primarily as a tumor suppressor gene (PMID: 12130785, 12417741). Loss of MBD4 has been identified in colorectal cancer, acute myeloid leukemia and uveal melanoma (PMID: 17285135, 35460607, 32421892, 30049810). True +ENST00000355673 NM_052897.3 114785 MBD6 False MBD6, a chromatin-associated protein, is infrequently mutated in various cancer types. MBD6 (also KIAA1887) is a chromatin-associated protein that is a member of the methyl-binding domain (MBD) protein family (PMID: 20700456, 12529184). Expression of MDB6 is most predominant in the brain and testes (PMID: 20700456, 16713569). MBD6 localizes to heterochromatin regions of DNA; however, this interaction is independent of DNA methylation (PMID: 20700456). MBD6 interacts with the Polycomb Repressive-Deubiquitinase Complex (PR-DUB), which removes monoubiquitin at lysine 119 on histone H2A, a critical protein complex involved in gene repression (PMID: 20436459, 24634419). The interaction of MBD6 with PR-DUB is mutually exclusive with family member MBD5, suggesting functional redundancies (PMID: 24634419). In addition, MBD6 binds to sites of DNA damage independent of PR-DUB (PMID: 24634419). MBD6 was also found to interact with the RNA binding protein ATXN1 in neuronal cells, and the protein has been implicated in self-renewal and cellular proliferation (PMID: 16713569, 23052207). Germline mutations in MBD6 are found in patients with autism and Wilson’s disease, a metabolic disorder which stems from accumulation of copper in tissues due to defective biliary excretion (PMID: 30230192, 23055267). Somatic mutations in MBD6 are infrequent in human cancers and their function has not yet been characterized. True +ENST00000369026 NM_021960.4 4170 MCL1 True MCL1, an anti-apoptotic protein, is amplified in various cancer types. MCL1 (Myeloid cell leukemia 1) is a member of the BCL2 pro-survival protein family (PMID: 11960321, 18955968, 23478333). The BCL2 family is defined by the presence of BCL2 homology (BH) domains. MCL1, similar to BCL2, confers cell survival through inhibition of apoptosis. Together with BCL2, MCL1 regulates mitochondrial outer membrane permeabilization, release of pro-apoptotic factors such as cytochrome c and activation of caspases (PMID: 21763611, 20683470). Genome-wide studies have identified increased gene copy numbers of MCL1 across many cancer entities (PMID: 20164920). Focal amplifications of MCL1 were found in over 10% of cancers and were even higher in lung and breast cancers (PMID: 20164920). MCL1 expression can drive lymphomagenesis (PMID: 9787159) and is required for lung adenocarcinoma formation (PMID: 21406400), possibly through interaction with AKT (PMID: 31662324). Through inhibition of apoptosis, MCL1 leads to increased survival of cancer cells and resistance to pro-apoptotic stimuli (PMID: 23478333). Therapies targeting MCL1 and other BCL2 family members are being developed and are currently under investigation (PMID: 26045609). False +ENST00000376406 NM_014641.2 9656 MDC1 False MDC1 is a regulator of the cell cycle response to DNA damage. It has tumor suppressor functions in the context of cancer. Mediator of DNA damage check point protein 1 (MDC1) is a key regulator of the cell cycle in response to DNA damage (PMID: 12607005, 14519663). MDC1 binds to sites of DNA double-stranded breaks through its SDT domain, which binds to the MRN complex, and its BRCT domain which binds to phospho-H2AX (PMID: 16377563, 11741547, 16618811, 15201865). The main functions of MDC1 are to regulate the cell cycle check points in S and G2/M phase through Chk1/2 and to regulate TP53 apoptotic response to DNA damage (PMID: 12607005, 11100718, 12607004, 12607003, 16427009). MDC1 binds TP53 through its BRC1 domain which inhibits TP53 transactivation domain (PMID: 17535811, 24194938). Loss of MDC1 results in genomic instability and promotes oncogenesis in a variety of cancer entities (PMID: 17546051). In some cancers, however, oncogenic functions of MDC1 have been observed (PMID: 21853275). False +ENST00000462284 NM_002392.5 4193 MDM2 True 3A MDM2, a ubiquitin ligase and p53 inhibitor, is amplified in a diverse range of cancers including well-differentiated liposarcomas. The MDM2 gene encodes an E3 ubiquitin ligase that negatively regulates the p53 tumor suppressor protein (PMID: 8875929, 1535557, 25550083). The MDM2-p53 interaction blocks the activation domain of p53, inhibiting its transcriptional activity (PMID: 8875929, 25550083, 7686617). Additionally, the MDM2-p53 interaction results in increased proteasomal degradation of the p53 protein (PMID: 8653711, 9153396, 9153395, 9382809). Transcription of the MDM2 gene is directly activated by p53, and levels of both p53 and MDM2 are maintained at low levels in unstressed cells (PMID: 8265599, 8440237, 8319905). Cells may acquire oncogenic potential from p53 loss (50% of tumors) or MDM2 amplification, which cripple the p53 pathway in tumor cells (PMID: 10549356, 23161690, 9671804, 20025780). Recently, numerous studies targeting the interaction between p53 and MDM2 have resulted in the development of therapeutic strategies aimed at normalizing p53 levels in tumor cells (PMID: 14704432, 15715460, 16759082, 15956260, 17126603, 14704432, 15715460, 16759082, 15956260, 17126603). False +ENST00000367182 NM_002393.4 4194 MDM4 True MDM4, a negative regulator of the p53 tumor suppressor, is altered by amplification and overexpression in various cancer types including breast cancer. MDM4 is a negative regulator of the p53 tumor suppressor, the most frequently inactivated gene in human cancer (PMID: 25960041, 22154076). The two major negative regulators of p53, MDM2 and MDM4, function by blocking its N-terminal transactivation domain (PMID: 21730163). In addition, MDM4 stimulates the MDM2-catalysed ubiquitination of p53 which leads to its degradation (PMID: 14507994, 12162806). Similar to MDM2, MDM4 is deregulated in several tumor types such as cutaneous melanoma, primary breast tumors, retinoblastomas (PMID: 17080083), Ewing sarcomas (PMID: 21098696) and gliomas (PMID: 22820643, 15199139, 12640683, 11280734). In the overwhelming majority of cases, cells with deregulated MDM2 or MDM4 retain wild-type p53 (PMID: 23303139). Thus, inhibition of the p53 interaction with MDM2 or MDM4 is an attractive candidate strategy for the treatment of cancer via the reactivation of p53 (PMID: 25621298, 21098696, 20080970, 14704432, 25201201, 23374098, 16905541, 16540668). False +ENST00000468789 NM_001105078.3 2122 MECOM True MECOM, a transcription factor expressed in hematopoietic stem cells, is recurrently altered by chromosomal rearrangement in hematologic malignancies. MECOM (also EVI1) is a transcription factor that is encoded by the MDS1 and EVI1 complex (MECOM) gene locus (PMID: 26729571). MECOM expression is restricted to long and short term hematopoietic stem cells and is transcriptionally silent during hematopoietic differentiation (PMID: 21666053). MECOM functions as a DNA binding protein that regulates the expression of many hematopoietic genes, including SPI1, a master regulator of myelopoiesis (PMID: 30315161). In addition, MECOM activity regulates additional cellular functions including proliferation, apoptosis, and chromatin state (PMID: 28538183). MECOM was identified as an oncogene in retroviral integration assays, which revealed that MECOM could transform murine hematopoietic cells (PMID: 2542863, 2827004). Increased expression of MECOM in hematopoietic assays and murine models leads to ineffective differentiation and skewing towards the expansion of myeloid populations (PMID: 1370341, 8321231). Recurrent MECOM rearrangements are found in patients with myelodysplastic syndromes and acute myeloid leukemia (AML) (PMID: 19016745, 15156182), resulting in increased EVI1 activity. Overexpression of MECOM is also common in myeloid malignancies and breast cancers, suggesting that MECOM functions predominantly as an oncogene (PMID: 18272813, 28209621). EVI1 alterations may require cooperation with other genetic events to drive transformation to acute myeloid leukemia (PMID: 17227832). False +ENST00000374080 NM_005120.2 9968 MED12 True MED12 is a component of CDK8, a subcomplex involved in transcription initiation. MED12 plays a role in the genesis of benign tumors such as uterine leiomyoma and breast fibroadenoma and is altered in a variety of estrogen-dependent tumors. MED12 is a component of the CDK8 subcomplex that is involved in transcription initiation. The MED12 protein is essential for activating CDK8 kinase. The CDK8 subcomplex which includes MED13, CDK8 kinase and cyclin C, modulates mediator-polymerase II interactions thereby regulating transcription initiation and reinitiation rates (RefSeq August 2009). The most commonly seen mutations in MED12 are in exon 2. Mutations in this domain have been described in uterine leiomyomas (PMID: 25108465, 24980722, 23443020, 23738515), breast fibroadenomas (PMID: 25038752), and Phyllodes tumors of the breast (PMID: 25593300). In benign breast tumors, MED12 hotspot mutations are thought to be early events that lead to deregulation of estrogen signaling (PMID: 25593300). MED12 is the most frequently mutated gene in uterine leiomyomas, suggesting it has a major role in the development of these lesions (PMID: 25108465). MED12 somatic exon 2 mutations have also been described in uterine leiomyosarcoma (uLMS) and colorectal cancer (CRC) (PMID: 23132392). The presence of the same MED12 mutations in uLMS as in uterine leiomyomas suggests that a subgroup of the malignant tumors may develop from a leiomyoma precursor. Leucine (L) to Phenylalanine (F) mutations at amino acid 1224 have been described in prostate cancer. These mutations are thought to play a role in tumorigenesis via perturbation of transcriptional programs linked to p53 and androgen signaling (PMID: 22610119). True +ENST00000162023 NM_001145785.1 100271849 MEF2B True MEF2B, a transcriptional activator, is altered by mutation in various hematological malignancies including follicular lymphoma. MEF2B is a transcription factor that has a role in mediating differentiation in heart and skeletal muscle (PMID: 17959722). MEF2B regulates transcriptional programs that facilitate cell migration and epithelial-mesenchymal transition as well as the cancer genes MYC, TGFB1, CARD11, RHOB and NDRG1 (PMID: 26245647). Consistent with a role in epithelial-mesenchymal transition, overexpression of MEF2B in human cell lines results in increased cell migration (PMID: 26506234). MEF2B has been found to be amplified in several cancer types including ovarian serous cystadenocarcinomas, adrenocortical carcinomas and esophageal carcinomas (PMID: 26506234). Recurrent somatic mutations in MEF2B have been identified in diffuse large B-cell lymphoma (DLBCL) (PMID: 21796119, 22343534, 21804550, 23292937), follicular lymphoma (FL) (PMID: 21796119) and mantle cell lymphoma (MCL) (PMID: 24145436). The recurrence of MEF2B mutations at particular residues is consistent with the notion that MEF2B mutations have either gain-of-function or dominant negative effects on MEF2B activity. Mutations in MEF2B in DLBCL lead to increased transcription of BCL6, a proto-oncogene essential for DLBCL germinal center proliferation and decreased association with the co-repressor CABIN1 (PMID: 23974956). However, other data suggest that MEF2B mutations lead to loss of DNA binding and decreased DLBCL cell chemotaxis (PMID: 26245647). False +ENST00000437473 NM_001193350 4208 MEF2C True MEF2C, a transcription factor important for muscle development, is infrequently altered in cancer. MEF2C, a Myocyte Enhancer Factor 2 family transcription factor, is an early expressed gene that is a direct transcriptional target of ETS transcription factors and which binds to the MEF2 element in muscle-specific genes to promote muscle differentiation. In addition to its role in myogenesis, MEF2C expression is critical for the development of the neural system, vascular endothelium, heart and bone (PMID: 15501228, 29340119). MEF2C has been shown to have a role in hematopoietic cell differentiation, particularly germinal center formation in B-cells (PMID: 18955699). Germline haploinsufficiency of MEF2C has been linked to neurodevelopmental disorders associated with cognitive disability and epilepsy, highlighting its importance in neural differentiation (PMID: 23389741). In cancer, MEF2C contributes to oncogenicity by enhancing the invasion and stemness of cancer cells, and may act as a tumor suppressor or oncogene depending on the cancer context (PMID: 16862118, 23435431, 21481790, 25328135, 24043307, 25404735). True +ENST00000348159 NM_005920.3 4209 MEF2D True MEF2D, a transcriptional activator, is altered by rearrangement in acute lymphoblastic leukemia. MEF2D is a transcription factor that is a member of the myocyte-specific enhancer factor 2 (MEF2) protein family (PMID: 29879430). Gene expression programs necessary for muscle, neuronal, and B-cell differentiation, among other cell types, are modulated by MEF2D activity (PMID: 20716948, 26660426). MEF2D predominantly functions as a transcriptional activator and interacts with other co-activators and chromatin-modifying proteins (e.g. MYOD, p300 and PCAF) to regulate context-specific target gene expression (PMID: 20716948, 32512162, 32512162, 31722213). However, MEF transcription factors can also function as transcriptional repressors (PMID: 28419090). MEF2D expression is important for a variety of cellular activities including proliferation, DNA damage response and cell cycle progression (PMID: 29879430, 24672010, 26506234). The activity of MEF2D has also been linked to the regulation of oxidative stress and pro-survival gene programs (PMID: 2512162). Aberrant MEF2D localization and activity have been linked to cancer progression in a variety of cancer types (PMID: 28419090, 29218083, 25814384). In B-cell precursor acute lymphoblastic leukemia (B-ALL), MEF2D translocations occur between recurrent partner proteins including DAZAP1, FOXJ2, SS18 and BCL9 (PMID: 28778863, 30630978) and are associated with poor patient outcome (PMID: 27824051). MEF2D fusion proteins demonstrate oncogenic activity by increasing MEF2D transcriptional activity, HDAC9 expression, and cellular transformation (PMID: 27507882, 27824051). HDAC inhibition may be efficacious in patients with MEF2D translocations (PMID: 27507882). False +ENST00000312049 NM_130799.2 4221 MEN1 False MEN1, a transcriptional repressor, is altered by mutation and deletion in various cancer types including parathyroid and endocrine cancers. Germline mutations of MEN1 are associated with Multiple Endocrine Neoplasia Syndrome and predispose to certain cancers. MEN1 is a putative tumor suppressor gene that localizes to the nucleus (PMID: 19068082). The function of MEN1 is not well-understood as MEN1 does not share sequence homology with any other known proteins (PMID: 19068082). MEN1 interacts with multiple proteins that play critical roles in the regulation of cell proliferation, including JunD, SMAD, and activator of S-phase kinase (PMID:16740708, 9103196, 9215690). In addition, MEN1 binds several histone regulatory proteins and is predicted to be a transcriptional regulator (PMID: 19068082). Germline loss-of-function mutations in MEN1 are associated with MEN1 syndrome, a disease that causes tumors in the pituitary, parathyroid, lung, and enteropancreatic endocrine tissues (PMID: 14992727). Somatic mutations and deletions in MEN1 have been identified in a variety of sporadic endocrine tumors, thyroid tumors, and a subset of pancreatic neuroendocrine tumors (PMID: 9361035, 9241276, 9766672, 21252315). True +ENST00000295408 NM_006343.2 10461 MERTK True MERTK, a transmembrane tyrosine kinase, is infrequently altered in cancer. MERTK encodes for a TYRO3/AXL/MER (TAM) receptor kinase family transmembrane tyrosine kinase that functions in transducing extracellular matrix signals into the cytoplasm through binding several ligands, including Gas6 and ProS1 (PMID: 35636929). MERTK regulates various physiological functions including cellular survival, efferocytosis, cytokine secretion and cellular differentiation (PMID: 19386698, 19301199). Overexpression of MERTK in various cancer cells induces cell motility, chemoresistance, cell growth and tumor growth, suggesting that MERTK functions primarily as an oncogene (PMID: 25074939, 35728303, 36939040). Amplification and point mutations of MERTK have been identified in various cancers, including breast cancer and hepatocellular carcinoma (PMID: 33239426, 35728303). False +ENST00000397752 NM_000245.2 4233 MET True 1 R2 MET, a receptor tyrosine kinase, is recurrently altered by mutation or amplification in various cancer types. The MET (Mesenchymal Epithelial Transition) proto-oncogene is a receptor tyrosine kinase, also called c-MET or hepatocyte growth factor (HGF) receptor. MET is a ubiquitously expressed cell surface receptor that binds to extracellular HGF, leading to the activation of several downstream intracellular pathways. These include the PI3K/AKT and RAS/RAF/MEK pathways, which promote cellular growth and proliferation, motility, migration and angiogenesis (PMID: 25770121, 23867513). Dysregulation of MET via gene amplification, germline or somatic mutations or receptor overexpression has been observed in a variety of epithelial cancers, including breast (PMID: 15455388), prostate cancer (PMID 10454259), non-small cell lung cancer (PMID: 9699182), renal papillary carcinoma (PMID: 24812413), hepatocellular (PMID: 24222167) and gastric carcinomas (PMID: 9759658). R2 False +ENST00000219905 NM_001164273.1 23269 MGA False MGA, a tumor suppressor and transcription factor, is altered by mutation, deletion or chromosomal translocation in a diverse range of cancers. MGA (MAX-gene associated protein) is a dual-specificity transcription factor that regulates the expression of MAX-target genes and T-box family target genes. MAX is a transcription factor that heterodimerizes with other basic helix-loop-helix leucine zipper (bHLHZ) family members, including MYC and MXI1, to regulate the expression of genes involved in cellular proliferation. As part of this network, MGA contains a MYC-like bHLHZip motif and heterodimerize with MAX to bind to MYC-MAX DNA binding sites (PMID: 10601024). MGA contains a second DNA-binding domain, known as the T-domain, that binds to genes containing Brachyury-binding sites. In vitro studies demonstrated that MGA can function as a transcriptional activator or repressor, and transcriptional activation is dependent on MAX (PMID: 10601024). MGA loss of function mutations have been observed in lung cancer, leukemia and lymphoma, and are mutually exclusive with MYC amplifications (PMID: 25079552, 26192917, 23039309, 23047824). True +ENST00000549489 NM_004668.2 8972 MGAM True MGAM, an intestinal glucosidase, is infrequently altered in various cancer types. MGAM (also MGA) is a glucosidase that regulates the digestion of starch to glucose (PMID: 17592362). MGAM and a second glucosidase, sucrose isomaltase (SI), are responsible for the last enzymatic step that results in the release of glucose during starch digestion (PMID: 18036614, 21924903). Starch digestion initially involves breakdown by α-amylases into small malto-oligosaccharides, which then are hydrolyzed by glucosidases (PMID: 22851177, 23838818). The main enzymatic activity of MGAM is to hydrolyze short, linear alpha-1,4-oligosaccharides, resulting in the production of glucose to the lumen (PMID: 20356844, 22058037). Dietary restriction alters chromatin modifications at the MGAM promoter, suggesting that gene expression is regulated by diet (PMID: 22819554). MGAM expression is localized to gastric tissues and is predominantly found anchored to the brush border membrane of the intestinal mucosa (PMID: 3143729, 18036614). Loss of MGAM expression in mice results in the inability to increase intestinal alpha-glucosidic activities in response to a starch-based diet, implicating MGAM in glucose homeostasis (PMID: 19193815). Somatic mutations in MGAM are rare; however, overexpression and amplification of MGAM have been found in several tumor types including gastric and oral cancers, among others (PMID: 17611641, 23405089). In addition, MGAM has been identified as a possible serum biomarker in intestinal cancer (PMID: 23924158) and a proposed drug target for type 2 diabetes (PMID: 22058037). False +ENST00000286523 NM_001043318.2 91748 MIDEAS False MIDEAS, a chromatin-associated protein that mediates histone deaceylation, is recurrently altered by mutation in a variety of cancers. MIDEAS is a chromatin-associated protein that shares sequence homology with the REST co-repressor (PMID: 21258344). MIDEAS was identified in a proteomic study to identify interactions of proteins with histone deacetylase (HDAC) inhibitors (PMID: 21258344). HDAC complexes remove acetyl groups from histone molecules, typically leading to gene repression and compacted chromatin (PMID: 17694093, 26908329). MIDEAS functions in the mitotic deacetylase complex (MiDAC) in association with class I HDACs (HDAC1 and HDAC2) and DNTTIP1, a DNA polymerase involved in the generation of diverse immunoglobulin genes (PMID: 21258344); however, several non-canonical MiDAC complexes have also been elucidated (PMID: 21258344). Biochemical studies have demonstrated that the MiDAC complex has increased HDAC activity in arrested cells (PMID: 21258344). In addition, MIDEAS associates with HDAC1 in mouse embryonic stem cells and controls the expression of neurodevelopmental gene programs via deacetylation of lysine 20 on histone 4 (PMID: 21258344). MIDEAS has been associated with histone acetylation at lysine 27 on histone H3, suggesting a role in active transcription (PMID: 25755260). True +ENST00000394351 NM_000248.3 4286 MITF True MITF, a transcription factor involved in melanocyte differentiation, is altered by amplification and mutation in melanomas. Germline mutations of MITF predispose to various cancer types, including melanoma and renal cell cancers. Microphthalmia associated transcription factor (MITF) is a master regulator of melanocyte lineage (PMID: 14597395, 12789276, 12789278, 10898786). MITF regulates the proliferation and differentiation of neural crest melanocyte progenitor cells (PMID: 16862190). It cooperates with BRAF mutations in the transformation process of melanocytes to malignant melanoma. MITF is amplified in >15% of metastatic melanoma (PMID: 12789286). The proliferative activity seems to be mediated by Ink4a, RB1 and CDK2, and MITF has anti-apoptotic activity mediated by BCL2 (PMID: 12086670,15607961, 15623583, 15716956). True +ENST00000368654 NM_002417 4288 MKI67 True MKI67, a non-histone nuclear protein only expressed in proliferating cells, is rarely altered in cancer. MKI67 (Ki-67) is a non-histone nuclear protein involved in the formation of the perichromosomal layer that helps chromosome organization during mitosis by preventing chromosomal aggregation (PMID: 24867636). Levels of Ki-67 protein are regulated by the cell cycle (PMID: 28283655). Thus, as Ki-67 is only expressed in proliferating cells, it is commonly used as an immunohistochemical marker of cell proliferation in vitro and in tumor samples (PMID: 10837136). While early studies investigated the requirement of Ki-67 for cell proliferation (PMID: 12740923) and ribosomal RNA synthesis (PMID: 17531085) more recent studies have demonstrated that it is not essential for either (PMID: 26823390, 26949251). Ki-67 is rarely overexpressed or mutated in cancer; however, it is critical for tumor formation, tumor growth, regulation of global transcription, promotion of stemness, and metastasis (PMID: 33658388). False +ENST00000231790 NM_000249.3 4292 MLH1 False 1 MLH1, a tumor suppressor involved in DNA mismatch repair, is recurrently altered by deletion and mutation in various cancer types. Germline mutations of MLH1 are associated with Lynch syndrome and predispose to colorectal cancer. The MLH1 gene encodes a DNA mismatch repair protein. MLH1 functions to correct mismatched nucleotides and insertion/deletion loops that are erroneously incorporated into the newly synthesized strand of DNA during replication, using the parental strand of DNA as a template. As part of this pathway, MLH1 heterodimerizes with PMS2 (most commonly), PMS1 or MLH3 to form an endonuclease complex that incises the damaged strand, leading to its local excision (PMID: 10037723, 10542278, 10615123). Mutations in MLH1 lead to an inability to correctly repair mismatches and insertion/deletion loops, which are most frequently associated with microsatellite repeat sequences. Tumors with inactivating MLH1 mutations are likely to exhibit a microsatellite instability-high phenotype (PMID: 9823339, 12454837). Mutations in MLH1 occur in multiple tissue types, but are most common in a specific subset of sporadic colon, gastric and endometrial cancers (PMID: 8484122, 8040889). Germline heterozygous mutations in MLH1 similarly predispose patients to colorectal, endometrial, ovarian, urothelial, and other cancers as part of Lynch syndrome, also known as hereditary non-polyposis colon cancer (HNPCC) (PMID: 8261393, 30627969, 31171120), whereas biallelic mutations cause constitutional mismatch repair deficiency (CMMRD) (PMID: 24737826). Defects in the MMR pathway have been associated with improved response to radiotherapy, chemotherapy and immunotherapy (PMID: 20153885, 26028255), and the FDA has approved the immunotherapy pembrolizumab for all mismatch repair deficient (dMMR) and MSI tumors, irrespective of specific tumor etiology. True +ENST00000355774 NM_001040108 27030 MLH3 False MLH3, a DNA mismatch repair protein, is infrequently altered in cancer. MLH3, a member of MLH family, encodes for a DNA mismatch repair protein that functions in preventing microsatellite instability (MSI) and promoting meiotic crossover (PMID: 10615123, 23316435). MLH3 heterodimerizes with MLH1 to form an endonuclease complex that incises damaged DNA strands leading to local excision (PMID: 34088835, 10615123). Knockdown of MLH3 in various cancer cell lines and models induces MSI, impairs DNA damage response, and increases susceptibility to tumors such as gastrointestinal tumors, suggesting that MLH3 functions predominantly as a tumor suppressor gene (PMID: 16204034). Inactivating mutations of MLH3 have been identified in various types of cancer, including hereditary nonpolyposis colorectal cancer, endometrial cancer and gastric cancer (PMID: 18521850, 16885347, 18551179). True +ENST00000252674 NM_005934.3 4298 MLLT1 False MLLT1, a scaffolding protein involved in transcriptional elongation, is recurrently altered by translocation in hematologic malignancies. MLLT1 (also ENL) is a transcriptional adaptor protein that is a member of the eleven-nineteen leukemia (ENL) family (PMID: 17855633, 20153263, 28241139). MLLT1 associates with the super elongation transcription complex composed of p-TEFb (Positive Transcription Elongation Factor b), a protein complex implicated in the phosphorylation of RNA pol II (PMID: 20153263), and other KMT2A-associated adaptor proteins involved in transactivation (PMID: 17855633). The super elongation complex targets KMT2A, a hematopoietic transcriptional coactivator, to hematopoietic genes to initiate transcription (PMID: 20153263). MLLT1 interacts with a variety of proteins involved in chromatin regulation, such as the histone H3 K79 methyltransferase DOT1L, and other KMT2A-related adaptor proteins (PMID: 17855633, 17957188, 15856011). Activating mutations in MLLT1 have been identified in patients with Wilm's tumor and these alterations impact the binding of MLLT1 to histone tails (PMID: 26635203). MLLT1 is the third most common fusion partner of KMT2A, a commonly rearranged gene in hematopoietic malignancies such as acute myeloid leukemia and acute lymphoblastic leukemia (PMID: 23628958). Mouse and human hematopoietic stem cells engineered to express MLLT1 fusion proteins exhibit altered hematopoietic lineage identity, clonal expansion and transformation in functional assays (PMID: 28572162, 28572162, 17957188, 28068328). MLLT1-rearranged proteins are aberrantly targeted to KMT2A target genes, leading to activation of gene expression programs that promote transformation (PMID: 20153263, 27050521). DOT1L inhibitors or therapeutics targeting transcriptional elongation, such as BRD4 inhibitors, may be efficacious in patients with MLLT1 rearrangements (PMID: 31157223). False +ENST00000307729 NM_001195626.1 8028 MLLT10 True MLLT10, a histone methyltransferase cofactor, is recurrently altered by chromosomal rearrangement in hematologic malignancies. MLLT10 (also AF10) is a histone methyltransferase cofactor that is a member of the MLL family of PHD finger proteins (PMID: 7888665). MLLT10 regulates the methylation of H3K79 on histone H3, a histone mark that is predominantly found within gene bodies (PMID: 21724828). Histone proteins are an essential component of the nucleosome, which consists of DNA wrapped around eight histone protein molecules (two sets of each H2A, H2B, H3 and H4 histones) and histone methylation results in the activation or repression of gene expression in different contexts (PMID: 11498575). Methylation of H3K79 has been implicated in a variety of cellular functions including DNA repair, cellular differentiation, splicing, cell cycle, and regulation of transcription, among others (PMID: 27234562). Binding of MLLT10 to chromatin, in collaboration with the histone methyltransferase DOT1L, mediates the conversion of H3K79me1 to H3K79me2, which serves as a signal for gene expression changes important in several differentiation programs including at the HOXA locus (PMID: 25464900, 21724828). Reduced expression of MLLT10 results in weakened transforming ability in hematopoietic assays, suggesting that MLLT10 functions predominantly as an oncogene (PMID: 25464900). Recurrent fusion proteins containing MLLT10 have been identified in patients with hematopoietic malignancies including acute myeloid leukemia and T-ALL (PMID: 23673860, 28242784, 23673860). MLLT10-rearrangements are predicted to bind chromatin and activate DOT1L H3K79-methyltransferase activity (PMID: 28242784, 15851025). Hematopoietic malignancies with aberrant MLLT10 activity may be sensitive to DOT1L inhibitors, as demonstrated in functional assays (PMID: 25464900). False +ENST00000380338 NM_004529 4300 MLLT3 True MLLT3, a subunit of the super elongation complex, is recurrently altered by rearrangement in cancer. MLLT3, or A9, is a subunit of the super elongation complex, which plays a key role in the regulation of the transcriptional elongation checkpoint of transcription (PMID: 20159561). MLLT3 is a key regulator of the self-renewal of human hematopoietic stem cells through the maintenance of their transcriptional program (PMID: 31776511). In coordination with the histone methyltransferase DOT1L, MLLT3 localizes to active transcription start sites through its YEATS domain (PMID: 31776511). The YEATS domain of MLLT3 recognizes crotonylated histone H3 and links crotonylation to active transcription (PMID: 27105114). Knocked-down expression of MLLT3 in cell lines results in suppressed cell proliferation and JNK signaling (PMID: 31966817). MLLT3 rearrangements that result in truncation and loss of the YEATS domain promote tumorigenesis through aberrant gene transcription (PMID: 31776511). MLLT3 fusion proteins have been identified in a variety of tumor types including osteosarcoma, acute myeloid leukemia and acute lymphoblastic leukemia (PMID: 31966817, 20844554). MLLT3 rearrangements may be sensitive to DOT1L inhibitors, as demonstrated in functional assays (PMID: 25464900). False +ENST00000302326 NM_002430 4330 MN1 True MN1, a transcriptional coregulator, is altered by amplification and chromosomal translocation in acute myeloid leukemia. MN1 encodes for a transcriptional coregulator which primarily functions in mediating activation of nuclear hormone receptors to regulate cellular proliferation and differentiation (PMID: 12569362, 15890672). MN1 synergistically induces transcriptional activity when co-expressed with RAC3 or EP300 in RAR-RXR-mediated transcription or steroid receptor coactivators in vitamin D receptor-mediated transcription (PMID: 12569362, 15890672). Inactivation of MN1 has been identified in meningioma through a balanced translocation (4;22) (PMID: 7731706). Mutations in the C-terminal region of MN1 have been implicated in the neurodevelopmental and craniofacial disorder MN1 C-terminal truncation (MCTT) syndrome (PMID: 31834374). Overexpression of MN1 in acute myeloid leukemia mouse models induces lethal acute myeloid leukemia, suggesting that MN1 functions predominantly as an oncogene (PMID: 17494859, 22905229). Amplification of MN1 and chromosomal translocations have been identified in acute myeloid leukemia, and are associated with poor patient prognosis (PMID: 35483876, 28440611, 28892045, 33974912). Preclinical studies suggest that MN1 overexpression may confer resistance to all-trans retinoic acid (ATRA) treatment and chemotherapy in the context of acute myeloid leukemia (PMID: 17494859, 22905229). False +ENST00000262244 NM_024761.4 79817 MOB3B False MOB3B, a kinase activator likely involved in the Hippo signaling pathway, is recurrently deleted in mantle cell lymphomas. MOB3B (also MOBKL2B) is a kinase activator that shares homology with the MOB family of proteins (PMID: 28792927). While the function of MOB3B is unknown, MOB3B is a paralog of MOB1A/B, components of the Hippo signaling pathway (PMID: 28792927). MOB proteins bind activated Hippo, resulting in the recruitment and activation of the signaling factor LATS (PMID: 30183404). The MOB-LATS complex recruits additional signaling proteins and controls the activity of the downstream transcription factors YAP and TAZ (PMID: 30183404). In addition, MOB proteins have been implicated in the regulation of mitotic checkpoint regulation, cellular proliferation and spindle pole body duplication (PMID: 18328423, 9436989). Deletions in MOB3B are found in patients with mantle cell lymphoma and these alterations are associated with poorer patient outcome (PMID: 20421449, 18984860). In addition, MOB3B overexpression has been implicated in resistance to the tyrosine kinase inhibitors vemurafenib and cetuximab (PMID: 28792927, 29802456), likely due to altered Hippo signaling (PMID: 28792927). True +ENST00000361050 NM_001039396.1 219972 MPEG1 False MPEG1, a pore forming protein involved in innate immunity, is infrequently altered in various cancer types. MPEG1 (also Perforin-2) is a pore forming protein that perforates target cell membranes or bacterial envelopes (PMID: 27857713, 7888681, 23257510). MPEG1 is a membrane protein that is most highly expressed in macrophages and is involved in the host defense against intracellular and extracellular bacteria (PMID: 7888681, 25717326, 28705375). Pore-forming proteins, such as MPEG1, homopolymerize resulting in a hollow hydrophobic cylinder that allows for insertion into the membrane or bacterial cell walls (PMID: 27857713, 20860583). Following the MPEG1-mediated immune attack, pore clusters render bacteria susceptible to secondary attack by antimicrobial effectors including reactive oxygen species, the lysozyme and proteases (PMID: 26402460, 26402460). MPEG1 is a largely unspecific effector in innate immunity and is conserved across multicellular organisms (PMID: 26307549). The unspecific mechanism of MPEG1 allows for the clearance of Gram-negative, Gram-positive, and acid-fast bacteria (PMID: 27857713). Expression of MPEG1 in mouse embryonic fibroblasts results in the ability to clear bacteria from the culture, unlike wildtype cells (PMID: 23257510). Loss of MPEG1 expression in model organisms results in an abnormal immune response and the inability to effectively combat bacterial infection (PMID: 25247677, 28422754, 30249808, 26831467). Mutations in MPEG1 are found in patients with persistent nontuberculous mycobacterial infections and immune cells isolated from these patients are unable to kill bacteria in functional assays (PMID: 28422754). Somatic mutations in MPEG1 are infrequent in human cancers. False +ENST00000372470 NM_005373.2 4352 MPL True MPL, a transmembrane protein receptor, is frequently mutated in myeloproliferative neoplasms including essential thrombocytosis and myelofibrosis. MPL encodes for the myeloproliferative leukemia proto-oncogene, thrombopoietin receptor. The gene was first identified in as the oncogene v-mpl, from the murine myeloproliferative leukemia virus that transformed hematopoietic cells from the bone marrow in mice (PMID: 7836743). The normal receptor protein is critical in growth and regulation of megakaryocytes and platelet production (PMID: 8202154). The gene is a transmembrane protein with an extracellular cytokine binding domain and intracellular cytokine signaling domains. Binding of its ligand, thrombopoietin (TPO), results in receptor dimerization and activation of the JAK family of tyrosine kinases; this leads to activation of the STAT family of transcription factors (PMID: 7796811). The MAPK pathway can also be activated as a result of receptor activation (PMID: 10438715). The most common mutations, W515L and W515K, which activate receptor signaling are found in myeloproliferative neoplasms such as essential thrombocytosis and myelofibrosis (PMID: 16834459). Aberrant expression of MPL has been reported in some solid tumors. In a study of 128 colorectal cancer cases, higher MPL expression was associated with metastasis to liver and lung (PMID:23747337). However, in a study of 118 breast tumors and 29 lung tumors, MPL mRNA was either not detectable or at very low levels (PMID: 22967017). The thromobopoietin receptor can be activated by administration of drug agonists such as eltrombopag and romiplostim. These therapies have been approved for the treatment of idiopathic thrombocytopenic purpura (ITP) (PMID:18046028,7050891). False +ENST00000323929 NM_005591.3 4361 MRE11 False 1 MRE11 is a tumor suppressor involved in DNA repair. Germline mutations of MRE11 are associated with ataxia-telangiectasia-like disorder and predispose to breast and ovarian cancers. MRE11 is a member of the Mre11-Rad50-Nbs (MRN) complex involved in sensing and repairing DNA double strand breaks (PMID:10523656, 11430828). The complex activates the kinases ATM (ataxia telangiectasia mutated) and ATR (ATM- and RAD3-related) to initiate DNA damage responses and is itself phosphorylated by ATM (PMID: 23525106, 23582259, 26512707). MRE11 has DNA nuclease activity important for stimulating repair (PMID:18854157). Activation of the MRN complex enables the G2/M cell cycle checkpoint in response to DNA damage (PMID:14657032). The complex is also important for genomic integrity at telomeres, replication forks, immunoglobulin gene loci during rearrangements, and DNA breaks formed in meiosis (PMID:19667071, 21565612, 16285919, 17291760). Activation of repair mechanisms include non-homologous end joining and homologous recombination repair (PMID:12422221, 24316220). Mutations in MRE11 are associated with an ataxia-telangiectasia-like disorder, resulting in chromosomal instability and sensitivity to ionizing radiation (PMID:10612394). MRE11 is also a familial breast and ovarian cancer susceptibility gene and mutations have also been identified in endometrial, colorectal, and lymphoid cancers (PMID:19383352, 24549055, 24894818, 23755103, 11196167, 11850399, 16959974). MRE11 polymorphisms and mutations affect response to chemotherapy, radiotherapy, and Poly(ADP-ribose) polymerases (PARP) inhibitors (PMID:24623370, 25310185, 24927325, 24215868, 25324139, 24240112). True +ENST00000345732 NM_021950 931 MS4A1 False MS4A1, a B-cell membrane protein, is infrequently altered in cancer. MS4A1, which encodes the B-cell surface marker CD20, is a member of the MS4A (membrane-spanning 4-domains family, subfamily A) family that is comprised of proteins that span the cellular membrane four times (PMID: 25835430, 35091527). MS4A1 functions in B-cell activation, proliferation, and differentiation (PMID: 33352466, 35091527). MS4A1 can associate with a variety of membrane proteins, including major histocompatibility complex (MHC) class I, MHC class II, tetraspanins (CD53, CD81, and CD82), and CD40; however the exact nature of these associations are still unknown (PMID: 25835430, 32482755). MS4A1 is involved in calcium conductance, as it functions as a store-operated calcium (SOC) channel that promotes calcium influx through physical association with the B-cell receptor (BCR) (PMID: 25835430). MS4A1 is required for optimal humoral immunity, as MS4A1 deficiency in both humans and mice results in impaired immune responses (PMID: 25835430, 32482755). In colorectal cancer, MS4A1 is significantly downregulated and CD20 expression is positively correlated with the patient survival rate (PMID: 33352466). In ovarian cancer, CD20-positive T-cells were shown to be elevated in ascites fluid of patients and were associated with a positive prognosis, as these cells mediate antitumor immunity (PMID: 26137418, 34654826). In breast cancer, patients who demonstrated higher MS4A1 expression also had a better prognosis (PMID: 35091527). CD20 expression is a clinically useful biomarker for B-cell targeted monoclonal antibody therapies, including rituximab, ofatumumab and obinutuzumab (PMID: 34654826, 25835430, 32482755). False +ENST00000233146 NM_000251.2 4436 MSH2 False MSH2 is a tumor suppressor involved in DNA mismatch repair. Select mutations of MSH2 are associated with Lynch syndrome and can lead to genomic instability in tumors. The MSH2 (MutS protein homolog 2) protein is a tumor suppressor involved in the mismatch repair process. MSH2 forms heterodimers with other MutS proteins, MSH6 and MSH3, to form the MutS-alpha and MutS-beta mismatch repair (MMR) complexes, respectively (PMID: 8252616, 7973733). Both complexes are involved in the recognition of a mismatched base pair, forming a DNA-MutS complex that signals other components of the MMR machinery to excise the aberrant nucleotide. MSH2 and other MMR genes are most notably implicated in Lynch syndrome, also known as hereditary non-polyposis colon cancer (HNPCC), which predisposes individuals to colorectal, endometrial, ovarian, urothelial, and other cancers (PMID: 428275, 1648437, 30627969, 31171120). Biallelic mutations in MSH2 also result in constitutional mismatch repair deficiency (CMMRD) (PMID: 24737826). Loss of function mutations or epigenetic silencing both in the germline and somatic context lead to an increased mutation rate that drives carcinogenesis as well as microsatellite instability (MSI). MSH2 mutations represent approximately 40% of all HNPCC cases (PMID: 11852992) and are associated with the MSI-high phenotype, along with mutations in MLH1 (PMID: 9823339, 9354436). Although most commonly seen in colon cancer, MSH2 mutations have also been reported in a diverse range of other cancer types and syndromes, including endometrial and uterine cancers, and sebaceous gland tumors (PMID: 19078925,16826164). Tumors with a large number of somatic mutations due to mismatch-repair defects have been predictive of clinical benefit to certain immune checkpoint blockade therapies (PMID:26028255, 25409260). Recently, the FDA approved pembrolizumab (PD-1 blockade) for all mismatch repair deficient and microsatellite unstable (MSI-high) tumors, irrespective of specific tumor etiology. True +ENST00000265081 NM_002439.4 4437 MSH3 False MSH3, a protein that participates in mismatch DNA repair pathway, is frequently lost in colorectal cancers. The MSH3 gene encodes the protein MutS Homolog 3 (MSH3), the human homolog of the bacterial MutS protein, which functions in the mismatch repair (MMR) pathway of DNA repair. MSH3 partners with MSH2 to form the heterodimer MutS-beta, which is important for recognition and repair of mismatched base pairs, forming a DNA-MutS complex that signals other components of the MMR machinery to excise the aberrant nucleotide (PMID: 22179786, 8942985, 9679053). MSH3 deletion or loss-of-function mutations can result in MMR deficiency, leading to an increased mutation rate and increased tumorigenesis in cooperation with loss of MSH6 (PMID: 10706084). Unlike other MMR genes, germline mutations in MSH3 are associated with autosomal recessive familial adenomatous polyposis (PMID: 27476653, 34250384, 35675019, 37402566, 38243056), and there is minimal evidence for an association with Lynch syndrome (PMID: 21128252, 34250384). MSH3 is altered in nearly 50% of MMR-deficient colorectal cancers by somatic frameshift mutations (PMID: 23724141, 18922920, 14871813, 9331106). Tumors with a large number of somatic mutations due to mismatch-repair defects have been predictive of clinical benefit to certain immune checkpoint blockade therapies (PMID: 26028255, 25409260). Recently, the FDA approved pembrolizumab (PD-1 blockade) for all mismatch repair deficient and microsatellite unstable (MSI-high) tumors, irrespective of specific tumor etiology. True +ENST00000234420 NM_000179.2 2956 MSH6 False MSH6 is a tumor suppressor involved in post-replication DNA mismatch repair. Select mutations of MSH6 are associated with Lynch syndrome and can lead to genomic instability via microsatellite instability in tumors. The MSH6 (mutS homolog 6) gene encodes the DNA repair mismatch protein MSH6. MSH6 is a tumor suppressor which heterodimerizes with MSH2 to form MutS-alpha. This complex recognizes single base pair mismatches and dinucleotide insertion-deletion loops, initiating the mismatch repair (MMR) process (PMID: 8816473). MSH6 and other MMR genes are most notably implicated in Lynch syndrome, also known as hereditary non-polyposis colon cancer (HNPCC), which predisposes individuals to colorectal, endometrial, ovarian, urothelial, and other cancers (PMID: 428275, 1648437, 30627969, 31171120). Biallelic mutations in MSH6 also result in constitutional mismatch repair deficiency (CMMRD) (PMID: 24737826). Loss of function mutations or epigenetic silencing both in the germline and somatic context lead to an increased mutation rate that drives carcinogenesis as well as microsatellite instability (MSI). Although most commonly seen in colon cancer, MSH6 mutations have also been reported in a wide range of other cancer types and syndromes, including endometrial and uterine cancers (PMID: 19078925,16106253). Tumors with a large number of somatic mutations due to mismatch-repair defects have been predictive of clinical benefit to certain immune checkpoint blockade therapies (PMID: 26028255, 25409260, 29489427). Recently, the FDA approved pembrolizumab (PD-1 blockade) for all mismatch repair deficient and microsatellite unstable (MSI-high) tumors, irrespective of specific tumor etiology. True +ENST00000257552 NM_002442.3 4440 MSI1 True MSI1, an RNA-binding protein expressed in stem cells of neural and intestinal origin, is overexpressed in various cancer types. MSI1 (Musashi1) is an RNA-binding protein which binds to the consensus RNA sequence GU3-5(G/AG) on specific mRNAs and controls their expression by translational repression (PMID: 22201732). The Musashi family of RNA-binding proteins is known to be important for cell fate determination, neural development and maintenance of stem-cell state, differentiation and tumorigenesis. Musashi1 is selectively expressed in neural progenitor cells, including neural stem cells (PMID: 9790759). Musashi1, in cooperation with Musashi2, activates Notch signaling through translational repression of Numb mRNA, an intracellular Notch signal repressor, and maintains the self-renewing ability of neural stem cells (NSCs) (PMID: 15925591). Musashi1 also activates the WNT pathway and serves to sustain mammary gland stem cell pools (PMID: 18362162). In addition, Musashi1 is a selective marker for intestinal stem or early lineage cells (PMID: 12924647, 15925591). Elevated Musashi1 expression is found in gliomas and glioblastomas and correlates with tumor proliferation (PMID: 11284014, 11896183), however, Musashi1 is infrequently mutated in human cancers. False +ENST00000284073 NM_138962.2 124540 MSI2 True MSI2, an RNA-binding protein expressed in stem cells of neural and hematopoietic origin, is over-expressed in myeloid leukemias. MSI2 (Musashi2) is an RNA-binding protein which binds to the consensus RNA sequences on specific mRNAs and controls their expression in part by translational repression (PMID: 28143872). The Musashi family of RNA-binding proteins is known to be important for cell fate determination, neural development and maintenance of stem-cell state, differentiation and tumorigenesis. Musashi2, like Musashi1, activates Notch signaling through translational repression of Numb mRNA, an intracellular Notch signal repressor, and maintains the self-renewing ability of neural stem cells (NSCs) (PMID: 15925591). In addition, Musashi2 expression is required for self-renewal and pluripotency of embryonic stem cells in early stages of differentiation (PMID: 22496868). Musashi2 is highly expressed in hematopoietic stem cells (HSCs) and is important in the maintenance of the stem cell compartment and proliferation of hematopoietic progenitor cells (PMID: 21613258). Overexpression of Musashi2 in mouse models cooperates with the BCR-ABL1 oncoprotein to drive aggressive leukemia (PMID: 20616797). Musashi2 is overexpressed in human myeloid leukemias and increased expression directly correlates with survival of patients with the disease (PMID: 20616797, 20639863); however, Musashi2 is infrequently mutated in human cancers. False +ENST00000449682 NM_020998.3 4485 MST1 False MST1, an intracellular kinase, is infrequently altered in various cancer types. MST1 (mammalian sterile 20-like kinase 1) is an intracellular kinase and key component of the Hippo signaling pathway. The Hippo signaling cascade is a critical regulator for controlling cell growth, differentiation and organ size control (PMID: 22683405, 22898666). MST1 is proteolyticaly activated by caspases during apoptosis; activation is mediated by apoptotic stimuli and other stress signals. Full activation of MST1 kinase requires autophosphorylation at Thr-183 and caspase-mediated cleavage. Once activated, MST1 phosphorylates Lats1/2 (large tumor suppressor 1/2), which then phosphorylates and inhibits two transcriptional coactivators in the Hippo pathway, YAP and TAZ (PMID:17889654). Phosphorylated YAP and TAZ remain in the cytoplasm and cannot induce the expression of genes that promote cell growth and proliferation (PMID: 17889654). Hence, MST1 negatively regulates YAP and TAZ and acts as a tumor suppressor. Reduced expression of MST1 has been observed in gastric cancer, liver cancer, prostate cancer and soft tissue sarcoma (PMID: 21940329, 17538946, 18381433). True +ENST00000296474 NM_002447.2 4486 MST1R True MST1R, a receptor tyrosine kinase, is altered by overexpression and mutation in various cancer types. MST1R (Macrophage Stimulating 1 Receptor) is a cell surface receptor for macrophage-stimulating protein (MSP). The MST1R protein is one of two members of the MET receptor tyrosine kinase family, along with parent receptor MET. Activation of MST1R triggers downstream signaling cascades, including RAS, PI3-kinase (PI3-K), and mitogen-activated protein kinases (MAPK) to induce cell scattering, migration, survival and invasion (PMID: 12807733,18836480, 25997828). MST1R is expressed in various cell types including macrophages, epithelial and hematopoietic cells. MST1R is overexpressed in pancreatic and epithelial cancers of the breast, colon, lung, and prostate (PMID: 22834780, 17616662, 17311308, 26477314, 15289319), and is involved in tumor progression and metastasis (PMID: 15289319, 10910951, 19956854). MST1R is rarely mutated, but alternative splicing events are common as the gene transcript is increasingly overexpressed. Approximately eight different MST1R isoforms have been described in various epithelial cancer types (PMID: 23792360). In breast cancer, short-form MST1R overexpression specifically activates the PI3K signaling pathway, resulting in increased tumor growth, epithelial to mesenchymal transition and metastasis (PMID: 22207901). In prostate cancer cells, MST1R has been shown to regulate angiogenic chemokine production (PMID: 19838218). Additionally, one study using gastroesophageal carcinoma (GEC) samples reported increased MST1R gene copy number in 35.5% (16/45) of cases and a novel somatic MST1R juxtamembrane mutation (R1018G) in 11% of samples, making MST1R an important prognostic marker in this GEC cohort (PMID: 21543897). False +ENST00000380172 NM_002451.3 4507 MTAP False 3A MTAP, a phosphorylase involved in methionine salvage pathways, is recurrently altered by deletion in various cancer types. MTAP is a methylthioadenosine phosphorylase that is a regulator of polyamine metabolism (PMID: 27068473, 26912360). MTAP metabolizes 2-methylthiosdenosine (MTA), a byproduct of polyamine synthesis, for the salvage of methionine amino acids and adenine nucleotides (PMID: 21301207). Loss of MTAP results in increased sensitivity to purine starvation and has been linked to regulation of stemness, apoptosis, and inflammation (PMID: 31040154, 30854099). The MTAP gene resides within the 9p21 chromosomal region, which is deleted in 15% of all cancers (PMID: 27068473). The 9p21 region includes the tumor suppressors CDKN2A, p16-INK4A, and p19-ARF; MTAP co-deletion with these genes occurs in a majority of 9p21 deletions (PMID: 27068473, 26912360). Deletion of MTAP in cancer cell lines results in the accumulation of MTA, a metabolic inhibitor of the arginine methyltransferase PRMT5, due to reduced MTAP-mediated byproduct cleavage (PMID: 27068473, 26912360). PRMT5 activity and expression of PRMT5 binding partners are downregulated in MTAP-deleted cancer cells, including RIOK1 and WDR77 (PMID: 27068473, 26912360). Functional studies demonstrated that MTAP-deleted cancer cell lines have an increased sensitivity to PRMT5 inhibitors, and PRMT5 inhibitors may be an efficacious therapeutic strategy in 9p21-deleted cancers (PMID: 27068473, 26912360, 31257072). In addition, MAT2A, a methionine adenosyltransferase that produces a byproduct that also inhibits PRMT5, was identified as an additional vulnerability in MTAP-deleted cancers (PMID: 27068473). True +ENST00000394053 NM_006636 10797 MTHFD2 True MTHFD2, a mitochondrial folate metabolism enzyme, is frequently overexpressed in various cancer types. MTHFD2 is a mitochondrial folate metabolism enzyme that functions in one-carbon folate metabolism, a process that provides precursor molecules for nucleic acid synthesis. MTHFD2 also helps regenerate the cofactor NADP(H) through its action as a dehydrogenase (PMID: 38422037, 27641100, 35693982). Under normal conditions, MTHFD2 is active only during early embryogenesis and supports rapid cell proliferation by supplying nucleotides (PMID: 35228749, 33782411). In cancer cells, MTHFD2 expression promotes tumor cell proliferation, migration, and invasion by multiple mechanisms including immune evasion via the upregulation of PD-L1 (PMID: 26461067, 23295955, 33782411). Increased MTHFD2 expression has been observed in many cancer types, and may be indicative of poor prognosis (PMID: 24451681, 30466107, 24870594, 38422037, 30534944). Inhibition of MTHFD2 in various cancer lines and models impairs cell proliferation and increases chemosensitivity in hepatocellular carcinoma cells (PMID: 24451681, 32411609, 38287824). False +ENST00000361445 NM_004958.3 2475 MTOR True 3A MTOR, an intracellular kinase that regulates cell growth and metabolism, is infrequently mutated in various cancer types. The MTOR protein is a serine-threonine kinase that coordinates cell growth, protein synthesis and metabolic signaling (PMID: 22500797, 21157483). MTOR activity is mediated through two distinct multi-protein complexes, mTORC1 and mTORC2 (PMID: 22500797, 21157483) which are composed of common subunits (mTOR, mLST8, DEPTOR) (PMID: 12718876, 19446321) and uniquely defined by specific subunits. mTORC1 is defined by the PRAS40 and RAPTOR subunits (PMID: 12150926, 12150925, 17386266, 17510057), while mTORC2 is defined by RICTOR, mSIN1 and PROTOR1/2 (PMID: 15268862, 15718470, 16919458). The two best characterized downstream targets of mTORC1, S6K and 4EBP1, dictate the rate of protein synthesis, nutrient response and many additional features required for rapid tumor growth (PMID: 15314020). Consequently, inhibition of mTORC1 has been therapeutically exploited across a variety of malignancies. mTORC2 coordinates with PDK1 to phosphorylate and activate AKT. mTORC2 is known to regulate the actin cytoskeleton, cell cycle progression and cellular survival (PMID: 18566586). Missense mutations of the MTOR gene occur in many tumors, notably in approximately 6% of clear cell renal cell carcinoma, 7.5% of lung adenocarcinomas, 5% of endometrial carcinomas and 4% of colon and rectal carcinomas (PMID: 24132290). Furthermore, various mTOR mutations have been characterized that cause increased MTOR pathway activation and increased sensitivity to rapamycin (PMID: 24631838, 24625776). Several case reports in the literature have reported extreme durable responses to rapamycin-analogue (rapalogue) therapies in patients with heavily pre-treated metastatic cancer and activating mTOR mutations (PMID: 24622468, 24625776). Additionally, two rapalogue mTOR inhibitors, everolimus and temsirolimus, are FDA-approved for the treatment of human cancer, and numerous compounds with alternative mechanisms of action are in various stages of development (PMID: 26299952). False +ENST00000372115 NM_001048171.1 4595 MUTYH False MUTYH is a tumor suppressor involved in DNA repair. Germline mutations of MUTYH are associated with MUTYH-associated Polyposis syndrome. MUTYH is a DNA glycosylase that mediates base excision repair. MUTYH can repair DNA lesions in which oxidized guanine is mispaired with adenine due to oxidative damage (PMID: 23507534, 1495996). Repair of these lesions prevents GC to TA transversions (PMID: 17581577). Germline mutations in MUTYH lead to colorectal polyposis and adenomas and are inherited in a recessive fashion (PMID: 12606733, 19506731, 31171120); risks for cancer in heterozygous carriers is controversial (PMID: 21063410, 21171015, 34244858, 38394468). MUTYH alterations result in increased TA transversions in colon cancer patients, suggesting that these are loss-of-function alterations (PMID: 12393807). Somatic allelic loss and rare mutations of MUTYH have been identified in colon cancer, however, these alterations did not lead to increased transversions (PMID:22641385). Further functional studies are required to determine if somatic MUTYH mutations are drivers of human cancer. True +ENST00000367814 NM_005375 4602 MYB True MYB, a transcription factor, is altered by chromosomal rearrangement in cancer. MYB encodes for a transcription factor that functions primarily in fetal hematopoiesis and lymphocyte development (PMID: 10323859, 16169500, 19843942). MYB can function as both a transcriptional repressor and transcriptional activator for genes essential to cellular proliferation, such as RUNX1 and CEBPB, and can either suppress differentiation or promote cellular proliferation (PMID: 21317192). The C-terminal region of MYB contains a negative regulatory domain and mutations or deletion of this region can promote cellular transformation (PMID: 2670562). Ectopic expression of MYB in various types of cancer cell lines and models induces cellular growth and increased cell survival, suggesting that MYB functions predominantly as an oncogene (PMID: 21948968, 11290547). Amplification and rearrangements of MYB have been identified in various types of cancer, such as breast cancer, acute myelogenous leukemia and salivary gland adenoid cystic carcinoma (PMID: 11034064, 3281804, 25963073). False +ENST00000522677 NM_001080416 4603 MYBL1 True MYBL1, a transcription factor involved in male-specific meiosis, is infrequently altered by amplification and translocation in cancer. MYBL1 is a transcription factor that regulates spermatogenesis in the pachynema stage of male-specific meiosis. The conserved N-terminal helix-turn-helix DNA binding domain and the trans-activating domain located at the central portion of the protein allow for binding to specific DNA sequences and subsequent meiotic gene transcription, respectively (PMID: 8058310). The conserved C-terminal negative regulatory domain regulates the expression of MYBL1 (PMID: 33637673). MYBL1 serves as the master regulator of meiotic genes involved in multiple meiotic processes such as DNA double-strand break repair, synapsis, crossing over, pachynema cell cycle progression and postmeiotic transcription (PMID: 21750041). Alterations of MYBL1 have been identified to truncate the C-terminal negative regulatory domain, leading to the activation of MYBL1 (PMID: 33637673). Overexpression of MYBL1 promotes tumorigenesis due to aberrant meiotic gene transcription causing angiogenesis (PMID: 35987690). MYBL1 alterations have been identified in a variety of tumor types including adenoid cystic carcinoma, low-grade glioma and hepatocellular carcinoma (PMID: 26631609, 29410490, 33637673, 32637581, 35987690). False +ENST00000377970 NM_002467.4 4609 MYC True MYC, a transcription factor, is altered by chromosomal rearrangement, amplification and overexpression in a variety of cancer types. "MYC is a transcription factor in the MYC family of proteins (c-MYC, n-MYC and l-MYC) that heterodimerizes with the protein MAX to control the transcription of thousands of genes. MYC promotes tumorigenesis by inducing cell proliferation, inhibiting exit from the cell cycle, stimulating vascularization and enhancing genomic instability (PMID: 22464321,10378696,16934487,19029958). The MYC gene contains several distinct structural domains, including five ""Myc-boxes"", which are highly conserved in MYC family proteins across multiple species (PMID: 19029958). Mutations of known function reside near residue T58, which is a phosphorylation site on MYC critical for ubiquitination and subsequent degradation of the MYC protein (PMID: 10706881, 22464321). Mutations in the MYC gene occur but are less frequent than amplification and translocation." False +ENST00000397332 NM_001033082.2 4610 MYCL True MYCL, a transcription factor, is altered by overexpression and amplification in various cancer types including small cell lung cancer. MYCL is a transcription factor and member of the MYC oncoprotein family (PMID: 3322939). The architecture of the MYCL gene shows substantial homology with the other members of the human MYC gene family (MYC and MYCN) (PMID:10378696). Unlike MYC, which is expressed ubiquitously, MYCL is preferentially expressed in the developing kidney and lung (PMID: 8657155), and appears to be less potent in terms of transformation potential (PMID: 2457153). Reports of cancer-associated genomic alterations of MYCL are predominantly limited to small cell lung carcinomas, where MYCL is found amplified in approximately 5-10% of samples (PMID: 2997622,1327035). Amplification of other MYC family members also occurs in small cell lung cancer, and in some cases these amplifications may co-occur with amplifications of MYCL (PMID:10378696,1327035). False +ENST00000281043 NM_005378.4 4613 MYCN True MYCN, a transcription factor, is altered by amplification and overexpression in a variety of cancer types including in neuroblastoma. MYCN is a MYC-family transcription factor with high homology to the commonly amplified transcription factor c-MYC (encoded by the gene MYC) (PMID: 20399964). MYCN has been shown to function both as a transcriptional activator and repressor, regulating the expression of genes involved in the cell cycle, proliferation, apoptosis, metabolism and regulation of the tumor microenvironment, among other processes (PMID: 16934487, 20399964). The MYCN gene is organized into an N-terminal transcriptional activation domain and a C-terminal basic helix-loop-helix leucine zipper DNA-binding domain. Unlike c-MYC, which is ubiquitously expressed, expression of n-MYC is temporally restricted to embryonic development and spatially restricted to cells of the nervous system, kidney, lung and spleen. Amplification of MYCN is predominantly associated with cancers of neural origin (e.g. neuroblastoma, medulloblastoma, glioblastoma), but has been observed in other solid tumors including prostate, breast and small cell lung cancers (PMID: 24589438, 16934487,15013217). Targeting MYCN directly has been challenging, and therefore therapeutic strategies have focused on targeting MYCN downstream targets, factors involved in MYCN transcriptional activity or MYCN stability (PMID: 24857145, 24086065). False +ENST00000396334 NM_002468.4 4615 MYD88 True MYD88, an adaptor protein, is frequently altered in hematologic malignancies including Waldenström's macroglobulinemia. MYD88 encodes for the signaling adaptor protein Myeloid differentiation primary response 88. It functions to transduce signaling from Toll-like receptors and the Interleukin-1 receptor important for innate immunity (PMID: 16413925, 12467250, 11544529). Signaling through MYD88 activates the NFkB pathway (PMID: 9734363). Patients with MYD88 loss of function mutations are more susceptible to bacterial infections due to immune dysfunction (PMID:18669862). Activating mutations of MYD88, particularly the L265P mutation, are frequently identified in Waldenström's macroglobulinemia patients (PMID: 22931316). The same mutation is also found in lymphomas, including chronic lymphocytic leukemia and the Activated B-cell type Diffuse Large B-cell Lymphomas (DLBCL) (PMID: 21179087, 22150006). False +ENST00000300036 NM_002474 4629 MYH11 False MYH11, a smooth muscle myosin protein, is altered at low frequencies in various cancer types. MYH11 is a smooth muscle myosin protein belonging to the myosin heavy chain family (PMID: 32382337). MYH11 functions as a contractile protein involved in inducing muscle contraction via ATP hydrolysis, but may also be able to regulate gene expression patterns of the cell by binding DNA as a transcription factor (PMID: 34380460). Pathogenic germline alterations in MYH11 predispose to familial thoracic aortic aneurysm and aortic dissection (TAAD), and individuals with these mutations show smooth muscle cell disarray and hyperplasia (PMID: 17666408). Meanwhile, in vitro overexpression of MYH11 inhibits cell migration, proliferation and invasion suggesting it acts as a tumor suppressor (PMID: 34380460). Inversion of chromosome 16 can result in the CBFB-MYH11 fusion, which is found in the M4 type of acute myeloid leukemia with associated eosinophilia (PMID: 23160462). This fusion protein disrupts the CBF complex and results in a block in proper hematopoiesis (PMID: 20007544). True +ENST00000399231 NM_000259 4644 MYO5A True MYO5A, a myosin motor protein, is infrequently altered in various cancer types. MYO5A encodes for myosin Va (5a), a motor protein that is part of the myosin protein superfamily. The myosin protein superfamily consists of actin-based motors that play critical roles in normal cell motility and migration through interaction with actin in the cytoskeleton (PMID: 16904206, 27757761). Myosin proteins are responsible for forming transport vesicles such as insulin granules and melanosomes, cell polarization, and cytokinesis during mitosis and meiosis (PMID: 29898384, 21151132, 28903372, 12382324). MYO5A is involved in cell and organelle motility, spindle formation, nuclear morphogenesis and transport of molecules to the cell membrane such as cell-surface receptors, pigments and RNA (PMID: 23176491, 21151132, 28903372). In cancer cells, MYO5A enhances tumor cell motility and viability enabling tumor progression and migration (PMID: 28903372). Upregulation of MYO5A promotes cell invasion and metastasis in colorectal cancer cells and head and neck squamous cell carcinoma cells, while MYO5A knockout decreases cell migration in lung cancer cells, suggesting MYO5A functions primarily as an oncogene (PMID: 28903372, 38129784). MYO5A is frequently overexpressed in multiple cancers including head and neck squamous cell carcinoma, metastatic colorectal cancer, melanoma, breast, prostate and bladder cancers (PMID: 38129784, 19521958, 23652798). It has also been shown to be overexpressed in metastatic lung, breast, prostate and colon cancer-derived cell lines (PMID: 19521958). False +ENST00000250003 NM_002478.4 4654 MYOD1 False MYOD1, a transcription factor involved in muscle differentiation, is recurrently altered by mutation in rhabdomyosarcoma. MYOD1 is a transcription factor that is a member of the bHLH protein family. MYOD1, together with the closely related regulatory transcription factors MYF5, MRF4 and MYOGENIN, control myogenic differentiation. MYOD1 commits mesoderm cells to a skeletal myoblast lineage, regulates their continued state and can also regulate muscle repair (PMID:16099183). MYOD1 removes cells from the cell cycle by increasing the transcription of p21 and myogenin, which is important for the switch from cellular proliferation to differentiation. Loss of this control can lead to the formation of rhabdomyosarcoma (PMID:16099183, 12783965). MYOD1 is infrequently mutated in embryonal rhabdomyosarcoma (PMID:25295632, 24824843, 24793135, 24272621). True +ENST00000341426 NM_001198993.1 65220 NADK True NADK, a metabolic enzyme involved in the conversion of NAD+ to NADPH, is altered by overexpression and mutation in pancreatic and colon cancers. NADK is a kinase involved in the regulation of several metabolic and biosynthetic pathways (PMID: 27582489, 21526340, 17855339). NADK is localized to the cytoplasm and catalyzes the phosphorylation of nicotinamide adenine dinucleotide (NAD+) to NADP+ (PMID 27582489, 21526340, 17855339). NADK-dependent phosphorylation requires ATP and magnesium cofactors for this conversion (PMID: 21526340, 17855339). NADP+ is then reduced to NADPH by dehydrogenases, such as glucose-6-phosphate dehydrogenase and malic enzymes (PMID: 27582489, 21526340). NADPH is an important cofactor involved in several protein, nucleotide and lipid biosynthesis pathways (PMID: 27582489). Proliferating cancer cells are increasingly dependent on these biosynthetic pathways during growth (PMID: 27582489). In addition, NADPH is necessary for maintenance of the cellular redox state and neutralizes reactive oxygen species (ROS) during cancer cell proliferation (PMID: 22550069, 18020963). Additional roles of NADPH include antioxidant host defense and regulation of glucose-mediated insulin secretion (PMID: 22550069). Somatic gain-of-function mutations in NADK have been identified in patients with pancreatic and colorectal cancer (PMID: 28954733, 26806015). Overexpression of NADK has also been found in patients with various cancers, suggesting that NADK may predominantly function as an oncogene (PMID: 27582489). Suppression of the NADPH pool has been proposed as a therapeutic strategy in cancer patients (PMID: 26219913). False +ENST00000265433 NM_002485.4 4683 NBN False 1 NBN is a tumor suppressor involved in DNA double-strand break repair. Germline mutations of NBN are associated with Nijmegen breakage syndrome and a predisposition to cancer. NBN is a component of the Mre11-Rad50-Nbs (MRN) complex involved in DNA double-strand break sensing and repair (PMID: 9590181). The complex activates the kinases ATM (ataxia telangiectasia mutated) and ATR (ATM- and RAD3-related) to initiate DNA damage response and is itself phosphorylated by ATM (PMID: 23525106, 23582259, 26512707, 10802669). The complex has DNA nuclease activity important for stimulating repair (PMID: 18854157). Activation of the MRN complex enables the G2/M cell cycle checkpoint response to DNA damage (PMID: 14657032). The complex is also important for genomic integrity at telomeres, replication forks, immunoglobulin gene loci during rearrangements and DNA breaks formed in meiosis (PMID: 19667071, 21565612, 16285919, 17291760). Activation of repair mechanisms includes non-homologous end joining and homologous recombination repair (PMID: 12422221, 24316220). Germline NBN mutations are associated with the Nijmegen breakage syndrome, characterized by increased cancer incidence, microcephaly, growth retardation, immunodeficiency and sensitivity to ionizing radiation (PMID: 9590180, 9590181). Mutations have been found in cholangiocarcinoma, liver, prostate cancer, lymphoma, leukemia, medulloblastoma and other cancers (PMID: 24349281, 22864661, 21923652, 18593981,18056440). Mutations and copy number alterations in NBN may lead to susceptibility to radiation and specific inhibitors related to DNA damage including Poly(ADP-ribose) polymerases (PARP) inhibitors (PMID: 22396666, 25324139, 25415046, 24240112). True +ENST00000371998 NM_181659.2 8202 NCOA3 True NCOA3, a nuclear hormone receptor co-activator, is altered by amplification and mutation in various cancer types. NCOA3 (also known as pCIP, SRC3) is a nuclear receptor co-activator involved in the regulation of transcription. It interacts with nuclear hormone receptors to enhance transcription (PMID:23850489, 15383283). NCOA3 has histone acetyltransferase activity and can recruit other histone acetyltransferase enzymes to the complex (PMID:9296499, 9192892). It acts to regulate pluripotency in stem cells, mammary gland development and response to TNF alpha (PMID: 10823921, 23019124, 15383283). It is expressed in various cancer cells and affects processes including cancer metabolism, anti-apoptosis, and cell growth (PMID:24584933, 23388826, 20663904). Its overexpression is associated with poor prognosis in various tumor types including gastric and non-small cell lung cancer (PMID: 25970779, 20064830). The gene has been found to be amplified in breast, ovarian, and colorectal cancer (PMID:9252329, 22371647). Inhibitors of NCOA3 are in development for anti-tumor therapy (PMID:24743578, 24390736). False +ENST00000268712 NM_006311.3 9611 NCOR1 False NCOR1, a transcriptional co-repressor, is altered by chromosomal translocation and mutation in various cancer types. NCOR1 is a nuclear transcriptional co-repressor that represses transcription mainly by recruiting histone deacetylase HDAC3 to DNA promoter regions (PMID: 20084085). Physiologically, NCOR1 is involved in the control of metabolism and inflammation as well as embryonal development (PMID: 20084085). NCOR1 is involved in the regulation of S-phase progression and genomic stability. It does so by maintaining acetylation and methylation patterns during S phase, which are essential for DNA repair and genomic stability (PMID: 21075309). NCOR1 has previously been linked to several kinds of cancers such as leukemia, glioblastoma multiforme, colorectal as well as endometrial carcinoma and prostate cancer (PMID: 17190815, 17630505, 17694085, 17312396, 19414341, 19269830, 12441355, 16373395, 22695118). Some leukemias are caused by translocation events that pair co-repressor-interacting proteins with proteins that are not regulated by NCOR1. This results in aberrant gene repression, which in some cases can be overcome by HDAC inhibitors (PMID: 9462740). NCOR is dramatically increased in glioblastoma multiforme, which correlates with de-differentiated phenotype and progression of the tumors (PMID: 16479164, 16534112). In these cases, preclinical evidence has shown that inhibition of the NCOR1 pathway can be achieved by simultaneous administration of Retinoic Acid and the protein phosphatase 1 (PP1) inhibitors which led to dramatic increase in differentiation and inhibition (PMID: 17312396). True +ENST00000405201 NM_006312.6 9612 NCOR2 False NCOR2, a nuclear hormone transcriptional co-repressor, is altered by mutation in a range of human cancers. NCOR2 (also SMRT) is a nuclear hormone transcriptional co-repressor that is a member of the NCOR protein family (PMID: 20084085). NCOR2 represses transcription mainly by recruiting the histone deacetylase HDAC3 to DNA promoter regions (PMID: 20084085, 11509652). Histone deacetylases predominantly function to add repressive marks to chromatin, resulting in chromatin compaction and reduced gene expression (PMID: 17694085). NCOR2 is homologous to NCOR1 and both corepressors bind similar substrates, namely the HDAC3 complex, which includes TBL1, TBLR1 and GPS2 (PMID: 20084085). In addition, NCOR2 associates with additional DNA binding proteins that regulate actin binding, kinase inhibition, histone binding and scaffolding, p53-dependent DNA damage and ubiquitination (PMID: 20084085). While NCOR1 and NCOR2 have some overlapping functions, non-redundant upstream kinases regulate their activation and differential expression patterns contribute to their context-specificity (PMID: 15491994, 17928865). In addition, NCOR2 preferentially regulates the activity of the retinoic acid receptor (PMID: 11435607). In addition, NCOR2 has been implicated in the regulation of neural stem cell proliferation, lineage commitment, metabolism, and inflammation (PMID: 19066220). Somatic mutations in NCOR2 are rare; however, aberrant NCOR2 activity is predicted to aberrantly regulate histone deacetylation and gene repression in human cancers (PMID: 17694085). In leukemias, NCOR2 mediates the binding of fusion proteins to DNA, such as PML/RARα, to coordinate gene regulation (PMID: 15729358). Additional mutations in NCOR2 binding partners lead to abnormal NCOR2/HDAC3 activity in cancers; however, NCOR2 mutations have not been extensively characterized (PMID: 27733359). False +ENST00000294785 NM_015331.2 23385 NCSTN True NCSTN, an endoprotease, is infrequently altered by mutation and amplification in a diverse range of cancers. NCSTN is a protease that serves as an essential component of the gamma-secretase complex (PMID: 25565961). NCSTN catalyzes the cleavage of membrane proteins, including Notch receptors 1-4, in order to release a processed intracellular NOTCH domain that can then activate gene expression in the nucleus (PMID: 22547652). The NOTCH signaling pathway regulates various aspects of cell differentiation, growth, proliferation, survival, and metabolism (PMID: 27507209). Deletion of NCSTN in the hematopoietic system in murine models results in increased numbers of thymic dendritic cells and T regulatory cells, implicating NCSTN in immune homeostasis (PMID: 22547652). In addition, NCSTN functions as a protease in other contexts, including in the cleavage of APP (amyloid-beta precursor protein) into amyloid-beta peptides, which compose plaques in the brains of Alzheimer’s patients (PMID: 12297508). Germline and somatic NCSTN alterations have been identified in patients with Alzheimer’s disease as well as in dermatological disorders (PMID: 11992262, 12419494, 25211177, 26224166). Somatic mutations in NCSTN are rare in human cancers; however, amplifications in NCSTN may lead to increased NOTCH signaling (PMID: 26109346, cbioportal accessed August 2018). Inhibitors targeting gamma-secretase are currently in clinical trials and may have activity in patients with aberrant NCSTN activity (PMID: 28539479). False +ENST00000357731 NM_173808.2 257194 NEGR1 False NEGR1, a cell adhesion protein, is altered by deletion and mutation in various cancer types. NEGR1 is a cell adhesion protein that is primarily localized to cell membrane rafts, especially in regions of cell-to-cell contact. NEGR1 is extracellularly tethered to the membrane using a specialized lipid moiety termed a GPI-anchor. NEGR1 and other GPI-anchored proteins are highly enriched in lipid raft domains and are involved in a number of important cellular activities including signaling processes and cell adhesion (PMID: 12440695). Genetic alterations of NEGR1 have been implicated in human obesity and dyslexia (PMID: 19079261). NEGR1 is downregulated in several cancers types (PMID: 21624008) and reintroduction of NEGR1 into a human cancer cell line results in reduced cell proliferation (PMID: 21624008, 25057311). These data suggest that NEGR1 functions as a putative tumor suppressor, however, pro-tumorigenic roles have been assigned to NEGR1 in the maintenance of tumorigenic activity in metastatic breast cancer cells (PMID: 24648515). In addition, a study aimed at identifying protein biomarkers in urine for early detection of invasive breast cancer found NEGR1 as a protein that was significantly upregulated in patients with metastatic breast cancer compared to the normal control subjects (PMID: 26544852). False +ENST00000356175 NM_000267.3 4763 NF1 False 1 NF1, a negative regulator of RAS, is inactivated by mutation or deletion in various solid and hematologic malignancies. The NF1 gene encodes a GTPase activating protein (GAP) for the small GTPases HRAS, KRAS and NRAS (PMID: 2121370,1946382). When bound to RAS, the NF1 protein stabilizes the GTPase activity of the RAS proteins, which switches RAS from its active, GTP-bound state to its inactive, GDP-bound state (PMID: 9219684, 9302992). The GAP-related domain (GRD) is the catalytic domain of NF1, which is directly responsible for its GAP activity but only encompasses approximately 10% of the protein. NF1 is congenitally altered in the cancer-predisposing syndrome Neurofibromatosis Type 1 and is somatically altered in many tumor types including breast cancer, melanoma, and glioma (PMID: 2134734, 1946382, 18772890, 23000897, 9639526, 18948947, 22817889). Inactivation of NF1 due to gene deletion, gene mutation, or protein degradation results in elevated levels of active, GTP-bound RAS and activation of downstream pathways such as the MAPK/ERK pathway and the PI3K pathway (PMID: 19573811, 24576830, 8563751, 7542586, 8052307, 12509763). Missense and truncating mutations occur across the entire gene and do not localize to hotspots. Alterations occurring on one allele of NF1 likely lead to haploinsufficiency of the protein (PMID: 7920653,18089636) as many patients with Neurofibromatosis Type 1 have an unaltered second allele despite exhibiting symptoms of the syndrome. Additionally, functional loss of heterozygosity likely occurs on the second NF1 allele, as tumors with NF1 point mutations have lower levels of mRNA than wildtype tumors (cBioPortal, MSKCC, May 2015). True +ENST00000338641 NM_000268.3 4771 NF2 False NF2 is a tumor suppressor involved in the regulation of downstream signaling pathways. Germline mutations of NF2 are associated with Neurofibromatosis Type 2 and predispose to certain cancers. NF2, also known as Merlin, is a membrane-cytoskeleton scaffolding protein that is expressed predominantly in nervous tissues (PMID:25893302). NF2 is important in indirectly linking actin-transmembrane receptors and intracellular effectors to modulate signaling pathways controlling cell proliferation and survival. These include downstream signaling pathways of receptor tyrosine kinases (RTKs), cell adhesion, small GTPases, mTOR, PI3K/Akt and hippo pathways (PMID: 20491622). NF2 is a tumor suppressor. Germline inactivation of NF2 by mutation or deletion results in the autosomal dominant tumor syndrome Neurofibromatosis Type 2, which is associated with the development of benign central nervous system (CNS) tumors such as vestibular schwannomas (PMID: 7911002). NF2 is found to be somatically mutated in other types of cancers. True +ENST00000312156 NM_001136023.2 4778 NFE2 True NFE2, a hematopoietic transcription factor, is infrequently altered by mutation in hematopoietic malignancies. NFE2 is a transcription factor that regulates erythroid and megakaryocytic gene expression (PMID: 11154691, 8469283). The NFE2 transcription factor complex consists of two subunits: p45, a hematopoietic-specific subunit and the smaller Maf protein subunit, which is more ubiquitously expressed (PMID: 11154691). NFE2, in collaboration with the chromatin regulatory protein CBP, binds erythroid and megakaryocytic promoters to regulate gene expression and epigenetic state (PMID: 11154691). In addition, NFE2 co-binds with the transcription factor AP-1 to modulate the expression of the erythroid globin genes (PMID: 12920035). NFE2 expression is regulated by JAK2 in myeloproliferative neoplasms, a malignancy that is dependent on JAK-STAT pathway activity (PMID: 29519804). Overexpression of NFE2 results in leukemic transformation in murine models, likely due to the upregulation of a chronic inflammatory response and subsequent clonal evolution (PMID: 23932394, 22231305). Somatic NFE2 mutations in human cancers are rare; however, NFE2 is overexpressed in myeloproliferative neoplasms and polycythemias (PMID: 16572198, 24297870). In addition, rare truncating gain-of-function mutations have been identified in myeloproliferative neoplasms (PMID: 23589569), suggesting the NFE2 predominantly functions as an oncogene. False +ENST00000397062 NM_006164.4 4780 NFE2L2 True NFE2L2, a transcription factor involved in oxidative stress response, is recurrently altered by mutation in lung cancer. NFE2L2 (Nuclear factor-erythroid 2-related factor 2), also known as NRF2, is a transcription factor that is important in activating antioxidant proteins to protect against certain environmental and oxidative stresses (PMID: 16968214). Under normal cellular conditions, the interaction of NRF2 with KEAP1 retains the protein in the cytoplasm and promotes its proteasomal degradation via ubiquitination (PMID: 9887101). Upon sensing stress signals, KEAP1 undergoes a conformational change, preventing it from interacting with NRF2 and allowing NRF2 to translocate to the nucleus and drive the expression of specific genes (PMID:12359864). NRF2 can have a protective role in cancer formation from certain chemical carcinogens (PMID: 11248092). However, chronic activation of NRF2 can also support the development of chemo- and radio-resistance (PMID: 24142871). Tumor-associated NRF2 activation can result from inactivation of KEAP1 through mutation, loss of heterozygosity or epigenetic silencing (PMID: 19321346). NRF2 activation can also arise directly from mutations in NFE2L2 in the KEAP1-binding domains (PMID: 18757741, 19967722). False +ENST00000216797 NM_020529.2 4792 NFKBIA False NFκBIα, a negative regulator of NF-κB, is altered by mutation and deletion in various cancer types. NFκBIα (NF-κB inhibitor α) is a protein that represses signaling of NF-κB, a family of transcription factors activated by the epidermal growth factor receptor (EGFR) pathway. NFκBIα helps keep NFκB in an inactive state by supporting its interaction with inhibitory molecules in the cell cytoplasm. A range of external stimuli, including pro-inflammatory cytokines, growth factors or stress, can lead to phosphorylation of NFκBIα and subsequently the release and nuclear translocation of NFκB; this results in the transcriptional activation of hundreds of genes that regulate the immune response, protect against apoptosis and signaling pathways critical to the formation of ectodermal tissues. Lack of NFκB is often due to loss-of-function mutations (small insertions, deletions, or missense) in one allele of NFκBIα coupled with deletion or inactivation of the second allele (PMID: 9572494). Constitutive expression of NF-κB signaling results in overexpression of several target genes encoding anti-apoptotic proteins and growth-promoting proteins (PMID: 11313274). Deletion of NFκBIA has demonstrated an effect similar to EGFR amplification in glioblastomas (GBM) and is associated with relatively reduced survival (PMID: 21175304). Further, enrichment of single-nucleotide polymorphisms (SNPs) and mutations in NFκBIA have been observed in Hodgkin’s lymphoma (PMID: 10023670, 19507254), colorectal cancer (PMID: 17354114), melanoma (PMID: 17492467), hepatocellular carcinoma (PMID: 19797428), breast cancer (PMID: 16959974) and multiple myeloma (PMID: 16540234). True +ENST00000262613 NM_004252 9368 NHERF1 True NHERF1, a scaffold protein, is infrequently altered in cancer. NHERF1 (NHERF family PDZ scaffold protein 1) encodes for sodium-hydrogen antiporter 3 regulator 1, also known as ERM Binding Protein 50 (EBP50) or Na+/H+ Exchanger Regulatory Factor 1 (NHERF1) (PMID: 28068322). NHERF1 is expressed abundantly in the plasma membrane of polarized epithelial cells and functions as a scaffold protein by stabilizing macromolecule signaling complexes linking extracellular signals with cytoskeleton machinery. Major signaling pathways that are regulated by NHERF1 include the PI3K/AKT pathway as well as PDGFR, EGFR, and Wnt/ꞵ-catenin signaling (PMID: 33965858, 29846905, 28684865, 28068322). NHERF1 regulates transporters and channels through actin-binding ERM (ezrin-radixin-moesin) proteins (PMID: 28068322). The role of NHERF1 in cancer depends on its cellular location, acting as a tumor suppressor when localized in the cell membrane and as an oncogene when expressed in the cytoplasm or nucleus of cancer cells, where it participates in the epithelial-to-mesenchymal transition process (PMID: 33965858, 29846905, 28684865). NHERF1 expression in the nucleus has been observed in renal, breast, liver, colon, and ovarian cancer cells (PMID: 33965858, 28011475). Cytoplasmic expression of NHERF1 has been observed in head and neck squamous cell carcinoma and melanoma (PMID: 29846905, 25897829). True +ENST00000354822 NM_001079668.2 7080 NKX2-1 True NKX2-1, a transcription factor expressed in lung and thyroid lineages, is altered by mutation, amplification, and rearrangement in lung and thyroid cancers. NKX2-1 is a homeobox-containing transcription factor essential for the development of the lung, thyroid and ventral forebrain (PMID: 16405855). Expression of NKX2-1 is restricted to specific cell types in these lineages and NKX2-1 has a role in the regulation of cell-type specific transcriptional programs. In the lung, NKX2-1 is a critical regulator of the expression of surfactants, which are proteins important for reducing surface tension in the lung and play a critical role in host defense against infection and inflammation (PMID: 15173172). Thyroid precursor cells express NKX2-1 in order to regulate thyroid-specific genes and maintenance of NKX2-1 expression is important in adult tissues for the regulation of thyroid hormones (PMID: 25350068). In thyroid carcinomas, NKX2-1 is primarily expressed in follicular neoplasm and papillary carcinoma but not in anaplastic carcinoma (PMID: 12023581). Germline mutations in NKX2-1 have been identified in families affected by multinodular goiter and papillary thyroid carcinoma (PMID: 19176457). In lung adenocarcinoma, somatic mutations of NKX2-1 are rare but sustained expression of NKX2-1 is frequently associated with gene amplification (PMID: 17925434, 18212743, 17616654, 17982442). Loss of NKX2-1 expression is also associated with favorable prognosis and reduced metastasis in murine models and humans (PMID: 21471965, 23125078), likely due to altered differentiation programs controlled by NKX2-1 (PMID: 23523371). Rearrangements of NKX2-1 with T-cell receptor or immunoglobulin heavy chain loci have also been identified in T-cell acute lymphoblastic leukemia (PMID: 21481790). False +ENST00000380871 NM_006167.3 4824 NKX3-1 False NKX3-1, a transcription factor expressed in prostate lineages, is altered by deletion and mutation including in prostate cancer. NKX3-1 (NK3 homeobox 1, also known as NKX3.1) is a homeobox-contiaing transcription factor and prostate-specific tumor suppressor that is under tight androgenic control (PMID: 11839815, 19886863, 11085535, 9226374). NKX3-1 is expressed at high levels in the prostate where it plays a role in tissue differentiation and homeostasis (PMID: 11839815, 8943214, 10215624), and is proposed to be a marker of prostate-specific stem cells (PMID: 19741607). Loss of heterozygosity of the 8p21 genomic locus, which includes NKX3-1, is associated with tissue dedifferentiation and lost of androgen response in prostate cancer (PMID: 9226374). Loss of NKX3-1 expression is found in prostate tumors of different stages, from benign prostate hyperplasia to castrate-resistant and metastatic prostate cancer (PMID: 11085535, TCGA PRAD paper, no PMID yet). True +ENST00000277541 NM_017617.3 4851 NOTCH1 True NOTCH1, a transmembrane receptor and transcription factor, can function as both an oncogene and tumor suppressor. NOTCH1 is a transmembrane receptor that participates in an evolutionarily conserved cell-to-cell signal transduction pathway (PMID: 24651013). Interaction of the NOTCH1 receptor with ligand molecules on adjacent cells results in the proteolytic cleavage of NOTCH1 by gamma-secretase (PMID: 24651013). The cleaved intracellular NOTCH1 domain can then activate gene expression in the nucleus and regulate various aspects of cell differentiation, growth, proliferation, survival, and metabolism (PMID: 27507209). The specific effects of NOTCH1 signaling vary depending on the cellular context (PMID: 21508972, 24651013). NOTCH family members are frequently mutated in a variety of cancers, and these mutations can be either gain- or loss-of-function mutations (PMID: 21948802). Translocations and activating mutations in NOTCH1 have been identified in T-cell acute lymphoblastic leukemia (T-ALL), chronic lymphocytic leukemia, and adenoid cystic carcinoma (PMID: 15472075, 24170027, 27870570). These NOTCH1 activating mutations either enhance the cleavage of NOTCH1 by gamma-secretase or extend the half-life of intracellular NOTCH1 (PMID: 15472075). NOTCH1 loss-of-function mutations are most common in solid tumors, namely squamous cell carcinomas, and occur as missense, frameshift or nonsense mutations in important NOTCH1 functional domains (PMID: 28154375, 30087145). Inhibitors targeting gamma-secretase are currently in clinical trials and may have activity in patients with activating NOTCH1 mutations (PMID: 28539479). True +ENST00000256646 NM_024408.3 4853 NOTCH2 True NOTCH2 encodes a transmembrane receptor that regulates many aspects of development by affecting cell-fate determination. NOTCH2 is a transmembrane receptor that participates in an evolutionarily conserved cell-to-cell signal transduction pathway (PMID: 24651013). Interaction of the NOTCH2 receptor with ligand molecules on adjacent cells results in the proteolytic cleavage of NOTCH2 by the protease termed gamma-secretase (PMID: 24651013). The cleaved intracellular NOTCH2 domain can then activate gene expression in the nucleus and regulate various aspects of cell differentiation, growth, proliferation, survival and metabolism (PMID: 27507209). The specific effects of NOTCH2 signaling vary depending on the cellular context (PMID: 21508972, 24651013). Truncating mutations in NOTCH2, known to cause Hajdu-Cheney syndrome, interrupt the regulation of the protein degradation process, leading to activation of the NOTCH2 intracellular domain (PMID: 15284851, 21378989). NOTCH family members are frequently mutated in a variety of cancers, and these mutations can be either gain- or loss-of-function mutations (PMID: 21948802). Truncating mutations and focal amplifications of NOTCH2 have been observed in diffuse large B-cell lymphoma (DLBCL) and triple negative breast cancer, leading to stabilization and activation of intracellular NOTCH2 (PMID: 25314575, 19445024, 25564152). NOTCH2 inactivating mutations are most common in solid tumors, namely squamous cell carcinomas, and occur as missense, frameshift or nonsense mutations in important NOTCH2 functional domains (PMID: 28154375). Inhibitors targeting gamma-secretase are currently in clinical trials and may have activity in patients with activating NOTCH2 mutations (PMID: 28539479). True +ENST00000263388 NM_000435.2 4854 NOTCH3 True NOTCH3 encodes a Type I transmembrane protein of the Notch family. Missense and nonsense mutations in NOTCH3 have been identified in various cancers. NOTCH3 is a transmembrane receptor that participates in an evolutionarily conserved cell-to-cell signal transduction pathway (PMID: 24651013, 19165418). Interaction of the NOTCH3 receptor with ligand molecules on adjacent cells results in the proteolytic cleavage of NOTCH3 by gamma-secretase (PMID: 24651013). The cleaved intracellular NOTCH3 domain can then activate gene expression in the nucleus and regulate various aspects of cell differentiation, growth, proliferation, survival, and metabolism (PMID: 27507209). The specific effects of NOTCH3 signaling vary depending on the cellular context (PMID: 21508972, 24651013). NOTCH3 mutations were initially identified in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) (PMID: 26715087). Activating mutations and focal amplifications of NOTCH3 have been identified in T-cell acute lymphoblastic leukemia (T-ALL), and triple negative breast cancer (PMID: 27157619, 25564152). These NOTCH3 activating mutations either enhance the cleavage of NOTCH3 by gamma-secretase or extend the half-life of intracellular NOTCH3 (PMID: 15472075). NOTCH3 inactivating mutations are most common in solid tumors, namely squamous cell carcinomas, and occur as missense, frameshift or nonsense mutations in important NOTCH3 functional domains (PMID: 28154375). Inhibitors targeting gamma-secretase are currently in clinical trials and may have activity in patients with activating NOTCH2 mutations (PMID: 28539479). True +ENST00000375023 NM_004557.3 4855 NOTCH4 True NOTCH4, a transmembrane receptor, can function as both an oncogene and tumor suppressor. NOTCH4 is a transmembrane receptor that participates in an evolutionarily conserved cell-to-cell signal transduction pathway (PMID: 24651013, 19165418). Interaction of the NOTCH4 receptor with ligand molecules on adjacent cells results in the proteolytic cleavage of NOTCH4 by gamma-secretase (PMID: 24651013). The cleaved intracellular NOTCH4 domain can then activate gene expression in the nucleus and regulate various aspects of cell differentiation, growth, proliferation, survival, and metabolism (PMID: 27507209). The specific effects of NOTCH4 signaling vary depending on the cellular context (PMID: 21508972, 24651013). NOTCH4 was first identified as oncogenic following truncation in a retrovirus-induced murine mammary cancer (PMID: 19165418). These NOTCH4 oncoproteins either enhance the cleavage of NOTCH4 by gamma-secretase or extend the half-life of intracellular NOTCH4. Expression of activated NOTCH4 disrupts mammary gland morphogenesis and promotes carcinomas in different cancer types (PMID: 11344305, 8620493, 10797286, 26323259, 25511451). NOTCH4 inactivating mutations have been identified in gliomas and neuroendocrine cancers and occur as missense, frameshift or nonsense mutations in important NOTCH4 functional domains (PMID: 28154375, 26061751, 26960398). Inhibitors targeting gamma-secretase are currently in clinical trials and may have activity in patients with activating NOTCH4 mutations (PMID: 28539479). True +ENST00000296930 NM_002520.6 4869 NPM1 False 3A NPM1, a nucleolar phosphoprotein, is frequently altered in hematologic malignancies. NPM1, also known as nucleophosmin, is a nucleolar phosphoprotein that has diverse cellular functions including regulation of ribosome biogenesis, mRNA processing, chromatin remodeling, apoptosis and DNA damage repair (PMID: 16007073). NPM1 has been implicated in the regulation of several DNA repair processes including homologous recombination, translesion synthesis, and repair of lesions created by UV light (PMID: 27553022). Loss of NPM1 has also been associated with increased genome instability (PMID: 16007073). In addition, NPM1 plays an important role in the regulation of the TP53 tumor suppressor pathway. The TP53-stabilizing protein ARF binds NPM1, sequestering ARF and NPM1 from binding the ubiquitin ligase MDM2 that is responsible for degrading TP53. Disruption of the NPM1-ARF interaction allows NPM1 and ARF to inhibit MDM2-mediated degradation of p53 leading to apoptosis (PMID: 15144954,15684379). Translocations and loss-of-function mutations have been identified in various human lymphomas and leukemias (PMID: 15659725, 8122112, 17488663). Mutations in NPM1 commonly result in a cytoplasmic form, NPM1c, which functions as a dominant negative and excludes NPM1 from the nucleus. NPM1c mutations in acute myeloid leukemia have been associated with a more favorable patient prognosis (PMID: 15659725). Murine models engineered to express NPM1 mutations develop hematopoietic disease and cooperate with other oncogenes to induce leukemias (PMID: 26559910). In solid tumors, NPM1 is commonly overexpressed leading to mislocalization of NPM1 (PMID: 26559910, 21258971,18037965, 26559910). True +ENST00000320623 NM_000903 1728 NQO1 True NQO1, a quinone oxidoreductase, is altered by amplification in various cancers. NQO1, a member of the NAD(P)H dehydrogenase (quinone) family, encodes for a cytoplasmic 2-electron reductase and functions in reducing quinones to hydroquinones (PMID: 22687461). NQO1 has been identified to regulate various cellular processes such as cellular homeostasis and cell cycle progression through redox reactions (PMID: 33298924, 36793872). NQO1 protects against oxidative stress through the generation of antioxidative agents such as α-tocopherol hydroquinone and long-chain CoQ derivatives (PMID: 9271353, 8637908). There is conflicting evidence on the oncogenic effect of NQO1 depending on the tissue context. Overexpression of NQO1 in various cancer cell lines and models induces HIF-1α signaling and tumor growth, suggesting that NQO1 functions predominantly as an oncogene (PMID: 27966538, 24499631). Amplification of NQO1 has been identified in various cancers, including gastric cancer, breast cancer and colon cancer (PMID: 34168410, 27966538, 25885439). Knockdown of NQO1 in prostate cancer cells and models induces increased cellular migration and sensitivity to oxidative stress, suggesting that NQO1 may function as a tumor suppressor gene in this context (PMID: 31909204). False +ENST00000395097 NM_006981.3 8013 NR4A3 True NR4A3, a hormone receptor transcription factor, is rarely altered by chromosomal rearrangement in extraskeletal myxoid chondrosarcoma. NR4A3 (NOR-1) is a member of the steroid-thyroid hormone-retinoid receptor superfamily that acts as a transcriptional activator in a ligand-independent manner (PMID: 16604165). NOR-1 is expressed in a limited number of adult tissues and has been shown to be involved in the cellular response to a variety of stimuli, including TLR-mediated activation of dendritic cells, IFN-γ and LPS-induced activation and proliferation of macrophages, development of dopaminergic neurons, induction of adipocyte differentiation, and cAMP response in vascular smooth muscle cells (PMID:8961274,15964844,16051664,16051663,14962944). Gene expression resulting from the binding of NR4A3 to DNA leads to proliferation, differentiation, or apoptosis, depending on the stimuli and cell type. False +ENST00000369535 NM_002524.4 4893 NRAS True 1 R1 NRAS, a GTPase, is mutated in a diverse range of cancers, most frequently in melanoma and thyroid cancer. The NRAS gene encodes a membrane-associated GTPase that controls intracellular oncogenic MAPK and PI3K signaling pathways. Activating NRAS mutations lock the enzyme in an active state causing increased cellular proliferation via hyperactivating these downstream pathways (PMID: 20194776, 21993244). NRAS mutations are common in thyroid cancer, ovarian cancers, melanoma and hematological cancers (PMID: 21993244, 22589270, 24651010). NRAS is also important during development with germline mutations enhancing stimulus-dependent MAPK activation and accounting for some cases of Noonan syndrome (PMID: 19966803). NRAS mutations and upregulation can also provide resistance to cancer therapies, including epidermal growth factor receptor (EGFR) and BRAF inhibitors (PMID: 22389471, 20619739, 25110411, 24024839). R1 False +ENST00000405005 NM_013964.3 3084 NRG1 True 1 NRG1, a ligand that binds HER3, is recurrently altered by fusions in lung, pancreatic, and other cancers. NRG1 is a cell adhesion protein that is a member of the neuregulin protein family (PMID: 18478032, 25501131). The NRG1 gene encodes six types of proteins with distinct N-terminal domains and at least 31 different isoforms, which all contain an EGF-binding domain (PMID: 18478032, 11042203). NRG1 growth factors are predominantly synthesized as membrane-bound proteins that are cleaved and released into the extracellular space; however, type III NRG1 isoforms have transmembrane and intracellular activities (PMID: 18478032, 9789034). NRG1 functions as a ligand for the HER receptor tyrosine kinases, with specificity for HER3 and HER4 (PMID: 11042203, 17250808). Binding of NRG1 via the EGF-domain initiates HER dimerization, leading to the activation of downstream signaling pathways including the MAPK and PI3K pathways (PMID: 18478032, 25501131). NRG1-mediated signaling regulates a variety of cellular functions including neuronal survival, migration, differentiation, and cellular proliferation, among others (PMID: 12821646, 18478032, 25501131). The expression and processing of the differential NRG1 proteins are highly cell-type specific, leading to the activation of specialized cellular programs (PMID: 27989735, 24237343). Germline NRG1 variants are found in developmental disorders and schizophrenia (PMID: 30180823, 30180823). Overexpression of NRG1 has been implicated in tumor progression in a variety of cancer types including ovarian cancer and gastric cancer, among others (PMID: 20227043, 28573357). NRG1 rearrangements are also found in patients with non-small cell lung cancer and pancreatic cancer, resulting in increased NRG1 expression, suggesting that NRG1 functions as an oncogene (PMID: 25501131, 24469108, 27626312, 29802158). False +ENST00000439151 NM_022455.4 64324 NSD1 True NSD1 encodes a nuclear receptor that can both positively and negatively regulate transcription. Translocations involving NSD1 and the NUP98 gene are highly recurrent in pediatric acute myeloid leukemia. NSD1 is a ligand-regulated nuclear transcription factor that is activated by steroid hormones (PMID: 11733144). NSD1 has a unique role as a bifunctional cofactor that can both positively and negatively regulate transcription (PMID: 12805229, 9628876, 11733144). Additionally, NSD1 recognizes histone lysines and contains histone methyltransferase activity with specificity for H3K36 and H4K20 (PMID: 12805229, 21972110). H3K36 methylation is most commonly associated with activation of gene transcription, but may also affect other processes such as DNA repair or RNA splicing (PMID: 22266761). Germline mutations of NSD1 are associated with Sotos syndrome, characterized by overgrowth, distinctive appearance, and developmental delay (PMID: 11896389). Translocations involving NSD1 and the NUP98 gene are highly prevalent in pediatric acute myeloid leukemia and are associated with a poor prognosis (PMID:11895789, 23630019, PMID: 24951466 ). Loss-of-function NSD1 mutations have also been identified in head and neck squamous cell carcinomas and leukemias (PMID: 25631445, 26438511, 25056374, 22976956). NUP98-NSD1 fusions and NSD1 loss-of-function mutations result in global genomic histone methylation changes leading to altered gene expression (PMID: 17589499, 26690673, 28067913). True +ENST00000382891 NM_001042424.2 7468 NSD2 True NSD2, a histone methyltransferase, is altered by translocation in hematologic malignancies. The NSD2 gene encodes the NSD2 histone lysine methyltransferase. NSD2 specifically methylates the H3K36 residue of histones and promotes an open chromatin state that favors gene transcription (PMID: 22099308, 20974671, 19808676). Activation of NSD2 enhances an oncogenic H3K36me2-dependent transcriptional program that includes genes such as MET, PAK1 and PRKCA, and activates tumorigenesis in in vitro and in vivo cancer models (PMID: 19808676, 24076604, 37463241). NSD2 is mutated in acute lymphoblastic leukemia and Mantle cell lymphoma (PMID: 24076604, 24145436). False +ENST00000317025 NM_023034.1 54904 NSD3 False NSD3, a histone methyltransferase, is altered by amplification in various cancers. The NSD3 gene encodes the NSD3 histone lysine methyltransferase. NSD3 methylates both the H3K4 residue, which constitutes an epigenetic mark for transcriptional activation, and the H3K27 residue, which acts as a repressive mark (PMID: 16682010). Thus, it is controversial whether this gene acts as an oncogene or a tumor suppressor (PMID: 20599755). NSD3 is altered by amplification in a subset of various cancers, including breast and lung tumors (PMID: 20940404, 25942451; cBioPortal, MSKCC, Dec. 2016). False +ENST00000343289 NM_001134373.2 22978 NT5C2 True NT5C2, a 5' nucleotidase, is frequently altered by mutation in relapsed hematopoietic malignancies. NT5C2 (also CN-II) is a 5’ nucleotidase that catalyzes the hydrolysis of nucleotides (PMID: 29990496, 30201983). Activity of NT5C2 is important for the maintenance of nucleotide pools and the export of excess purine nucleotides out of the cell (PMID: 29990496). NT5C2 functions as a dimer of dimers to dephosphorylate purine substrates including inosine monophosphate (IMP), xanthine monophosphate (XMP), and guanosine monophosphate (GMP), resulting in the clearance of purine nucleosides (PMID: 30201983). Nucleotide analog chemotherapies that disrupt DNA synthesis, such as cytarabine and thiopurines, are also targets of dephosphorylation by NT5C2, ultimately leading to their inactivation (PMID: 30201983). High expression of NT5C2 in patients with myelodysplastic syndromes and acute myeloid leukemia correlates with drug resistance and poor outcome (PMID: 16330448, 17350683, 26294725). Activating NT5C2 mutations are found in patients with hematopoietic malignancies, including childhood and adult acute lymphoblastic leukemia (ALL) and B-lymphoblastic leukemia, predominantly after relapse to nucleotide analog chemotherapies (PMID: 29990496, 23377183, 23377281, 25790293, 28253933). Gain-of-function NT5C2 mutations can activate NT5C2 by several distinct mechanisms: locking the enzymatic complex in an activate state, disrupting the NT5C2 off-switch, or loss of the negative regulation at the C-terminal (PMID: 29535428, 29990496). Germline NT5C2 variants have also been linked to relapse in hematopoietic and non-small cell lung cancers (PMID: 30201983, 22173087, 28573946). Expression of activating NT5C2 mutations in murine models results in impaired leukemia growth and tumor-initiating capacity due to the excessive export of purines, suggesting that NT5C2 functions as an oncogene at relapse but not at tumor initiation (PMID: 29342136). In preclinical studies, NT5C2-mutant leukemia cells were sensitive to blocking guanosine synthesis by inhibiting inosine-5'-monophosphate dehydrogenase (IMPDH) (PMID: 29342136). False +ENST00000219066 NM_002528.5 4913 NTHL1 False NTHL1, a DNA damage repair protein, is mutated in the germline of families with hereditary cancer syndromes. The NTHL1 gene encodes a protein involved in the repair of oxidative DNA damage. NTHL1 localizes in the nucleus, where it catalyzes the N-glycosylation of damaged DNA and subsequent cleavage of the resulting modified bond, constituting the first steps towards DNA repair in the base excision repair (BER) pathway (PMID: 10882850, 18166975, 21930793, 9890904, 17923696). Low NTHL1 expression has been associated with a decreased capacity for DNA repair in gastric cancer (PMID: 19414504). However, a dual role for NTHL1 has been described in irradiated cells; it both repairs potentially lethal DNA lesions and generates lethal double-strand breaks at radiation-induced sites (PMID: 16111924). NTHL1 interacts with PCNA and p53 proteins (PMID: 15358233). Germline truncating mutations of NTHL1 have been identified as the causal alteration in families with hereditary colorectal tumors and other neoplasias (PMID: 25938944, 26559593). Paradoxically, NTHL1 is somatically amplified in a subset of breast and pancreatic tumors (cBioPortal, MSKCC, Dec. 2016). True +ENST00000524377 NM_002529.3 4914 NTRK1 True 1 R1 NTRK1, a receptor tyrosine kinase, is altered by gene fusions in various cancer types. The NTRK1 (neurotrophic receptor tyrosine kinase 1) protein is a transmembrane neurotrophic receptor that is found in neural cells and is triggered via the binding of its main ligand, nerve growth factor (NGF). NTRK1 consists of an extracellular ligand-binding domain, a transmembrane domain and an intracellular region harboring the tyrosine kinase domain. Oncogenic activation of NTRK1 leads to autophosphorylation and activation of the MAP-kinase, PI3-kinase and PLC-γ pathways, mediating cell proliferation, survival and differentiation (PMID: 10851172, 12652644). NTRK1 mutations and fusions are found in various cancers. Treatment strategies for NTRK1-altered cells include broad inhibitors of receptor tyrosine kinases as well as more specific inhibitors of the NTRK-family of kinases. R1 False +ENST00000277120 NM_006180.3 4915 NTRK2 True 1 NTRK2, a receptor tyrosine kinase, is altered by mutation or chromosomal rearrangement in a diverse range of cancers. The NTRK2 gene (neurotrophic receptor tyrosine kinase 2) encodes a transmembrane neurotrophic receptor involved in signaling that is important for normal neurologic development (PMID: 8402890, 8145823). NTRK2 consists of an extracellular ligand-binding domain, a transmembrane domain and an intracellular region harboring the tyrosine kinase domain. Normal activation in neural cells occurs upon binding one of its three ligands, the nerve growth factor (NGF), the brain-derived neurotrophic factor (BDNF) or neurotrophin-3 (NT-3), leading to autophosphorylation and activation of downstream signaling pathways controlling and promoting cell proliferation, survival and differentiation via MAPK, PI3K and PLC-γ (PMID: 1649702, 1649703, 10851172). NTRK2 alterations, especially fusions, are found in several human cancers, such as lung cancer, pilocytic astrocytoma, and neuroblastoma (PMID: 25204415, 21242122, 23817572, 8264643, 9049830). False +ENST00000360948 NM_001012338.2 4916 NTRK3 True 1 R1 NTRK3, a receptor tyrosine kinase, is altered by gene fusion in various cancer types. The NTRK3 (neurotrophic receptor tyrosine kinase 3) gene encodes a transmembrane neurotrophic receptor normally activated in neural cells upon binding of its main ligand, the neurotrophin-3 (NT-3). NTRK3 consists of an extracellular ligand-binding domain, a transmembrane domain and an intracellular region harboring the tyrosine kinase domain. Activation of NTRK3 leads to autophosphorylation and subsequent activation of a downstream signaling pathway controlling cell proliferation, survival and differentiation via MAPK, PI3K and PLC-γ (PMID: 10851172). NTRK3 has been found altered, mainly in the form of oncogenic fusions, in several human cancers (PMID: 9462753, 11801301, 10895816, 12450792, 9823307, 25207766, 21401966, 24327398, 24135138, 23583981, 24705251). While NTRK3 is overexpressed in some leukemias (PMID: 23832765) it has been found inactivated and transcriptionally downregulated in breast and colon cancer (PMID: 25520870, 23341610, 23874207) showing that NTRK3 may have dual context-dependent roles as both a tumor suppressor and an oncogene. Treatment strategies for NTRK3-altered cells include broad inhibitors of receptor tyrosine kinases as well as more specific inhibitors of the NTRK-family of kinases. R1 False +ENST00000271452 NM_031423.3 83540 NUF2 True NUF2, a protein involved in mitosis, is altered by amplification in various cancers. The NUF2 gene encodes a protein involved in chromosome segregation during meiosis and mitosis. NUF2 is essential for kinetochore-microtubule interactions and spindle checkpoint activity (PMID: 15358233, 15239953, 15548592, 17535814, 15062103). Silencing of NUF2 inhibits cell proliferation and induces apoptosis in normal and cancer cells (PMID: 12438418, 19878654, 25481014, 25370920, 25374179). The NUF2 gene is amplified in various tumors, including breast, prostate, bladder and liver (cBioPortal, MSKCC, Dec. 2016). NUF2 overexpression has been associated with poor prognosis in colorectal cancers (PMID: 24247253), and RNA interference screens have implicated NUF2 as a therapeutic target in ovarian cancers (PMID: 23056589). False +ENST00000359428 NM_005085 8021 NUP214 True NUP214, a nucleoporin protein, is altered by translocation in leukemia. NUP214 is a nucleoporin found on the cytoplasmic side of the nuclear pore complex (PMID: 8108440). NUP214, a phenylalanine-glycine (FG)-repeat-containing nucleoporin, is responsible for nucleocytoplasmic transport of proteins and mRNA across the nuclear envelope in conjunction with NUP88 and the nuclear export receptor XPO1 (PMID: 7878057, 9488438, 8896451, 16943420). The FG-repeat of NUP214 is a disordered domain that contributes to selective transport while also acting as a selective barrier to specific proteins and RNAs, and mutations that alter this domain affect the movement of molecules between the cytoplasm and the nucleus (PMID: 16769882). Because NUP214 regulates the proteins and mRNA that cross the nuclear envelope, it plays a role in the regulation of cell cycle, mitosis and gene expression (PMID: 30669574, 9488438). NUP214 fusions such as SET-NUP214 and DEK-NUP214, which may arise de novo or due to prior treatment, have been identified in liquid tumors such as AML and ALL (PMID: 30669574) and are associated with disease that is characterized as more aggressive, with poor prognosis, higher risk of relapse, etc. (PMID: 24441146, 16628187, 30669574). False +ENST00000308159 NM_014669.4 9688 NUP93 False NUP93 encodes subunit of the nucleoporin complex that controls the transport of molecules across the nuclear envelope. NUP93 is a subunit of the nuclear pore complex that is essential for the exchange of macromolecules across the nuclear envelope (PMID: 24572986). NUP93 activity promotes and maintains the correct assembly of the nuclear pore complex (PMID: 15229283, 22171326). Functional studies have suggested that NUP93 plays a role in gene regulation by tethering chromatin at superenhancer sites to generate the necessary structural environment for transcriptional repression or activation (PMID: 26341556, 27807035). Expression of NUP93, along with other members of the nucleoporin complex, is increased in cardiac tissue of patients with heart failure and decreased in the thymus of patients with Down syndrome (PMID: 23152829, 21856934). While NUP93 copy number alterations are observed in a variety of solid cancers (cBioPortal, MSKCC, Nov. 2017), NUP93 mutations in human cancers are not common. However, a recent analysis identified the NUP93 E14K mutation as a hotspot mutation with unknown function in multiple cancers (PMID: 26619011). False +ENST00000359171 XM_005252950.1 4928 NUP98 True NUP98, a protein involved in the nuclear pore and nuclear-cytoplasmic trafficking, is altered by chromosomal rearrangements in hematologic malignancies. NUP98 is a scaffold component of the nuclear pore complex, a large multi-protein structure embedded in the nuclear membrane that is required for nuclear-cytoplasmic trafficking. Localization studies have shown that NUP98 is located on the nucleoplasmic side of the NPC and facilitates docking of proteins being imported into the nucleus from the cytoplasm (PMID: 7736573). During mitosis, the NPC disassembles along with the nuclear membrane, which is initiated by phosphorylation of proteins in the NPC. Studies have shown that hyperphosphorylation of NUP98 by CDK1 and Neks is an early and required step in the NPC disassembly and is proposed to be a rate-limiting step in the process (PMID: 21335236). NUP98 is fused to a variety of partner genes in hematologic malignancies (PMID: 21948299). False +ENST00000333756 XM_011521429.1 256646 NUTM1 False NUTM1, a gene of unknown function, is recurrently altered by chromosomal rearrangement in NUT midline carcinoma. NUTM1 encodes the nuclear protein in testis (NUT), which is expressed in normal spermatocytes. NUTM1 is a novel gene located on chromosome 15; not much is known about its function, except that the protein harbors an acidic binding domain for the acetyltransferase p300 (PMID: 20676058). Most of the current knowledge on NUTM1 is focused on alterations involved in cancer (PMID: 17934517). More specifically, chromosomal translocations involving NUT and BRD proteins—in particular BRD4, but also BRD3—are found in NUT midline carcinoma (NMC), a rare, aggressive, and lethal genetically defined epithelial cancer syndrome, characterized by the insurgence of carcinomas in various tissues along the upper midline of the body, that mainly affects young individuals (PMID: 17934517, 26551281, 24655834,12543779, 25675182). Approximately 75% of NMC cases feature BRD4-NUT translocation, where the fusion oncogene is expressed under the BRD4 promoter and consists of the first half of the BRD4 protein (which contains all of the functional domain of BRD4) and all of the coding region of NUT. Translocation leading to the fusion protein BRD3-NUT is less common. A novel translocation that results in the fusion protein NSD3-NUT has been observed in NMC of the lung (PMID: 25466466). In a small number of cases involving NUT rearrangements, called NUT variants, the partner of the translocation is unknown. These NUT variants are associated with longer survival, compared with BRD4-NUT carcinomas (PMID: 15483023). NUT rearrangements are found in 18% of cases of undifferentiated carcinoma of the upper aerodigestive tract (PMID: 18391746). Missense mutations and copy number alterations, although rare, are found in some solid cancers (cBioPortal, MSKCC, Nov. 2015). False +ENST00000491143 NM_004852 9480 ONECUT2 True ONECUT2, a transcription factor, is recurrently altered by amplification in lung adenocarcinoma. ONECUT2, a member of the ONECUT transcription factor family, encodes for a transcription factor that functions in the regulation of various cellular functions such as development, proliferation and differentiation (PMID: 20354101, 16950765, 16103213). ONECUT2 has a redundant role in the regulation of cellular development with ONECUT1 (PMID: 25228773). Overexpression of ONECUT2 in various types of cancer cell lines and models induces cellular proliferation, invasion, tumor growth and metastasis, suggesting that ONECUT2 functions predominantly as an oncogene (PMID: 31882655, 14656735, 29737581). Amplification of ONECUT2 has been identified in various cancers, including prostate cancer, hepatocellular carcinoma and small cell lung cancer (PMID: 25788493, 26547929, 34155000). Upregulation of ONECUT2 has been observed in lung adenocarcinoma cell lines following treatment with osimertinib (PMID: 34155000). False + -2 Other Biomarkers False 1 False +ENST00000381297 NM_178129.4 286530 P2RY8 False P2RY8, a member of the G-protein coupled receptor family, is altered by mutation or fusion in lymphomas. P2RY8 is an orphan receptor that is a member of the G-protein coupled receptor family (GPCRs). GPCRs signal by association with heterotrimeric G proteins at the plasma membrane and function as exchange factors leading to G-protein activation (PMID: 30262890). P2RY8 signals via the G-protein GNA13 and the downstream effector ARHGEF1, leading to activation of signaling pathways (PMID: 26573295). P2RY8 is highly expressed in germinal center B cells; functional studies in murine B cells demonstrate that P2RY8 suppresses B cell growth and mediates B cell positioning in the germinal center in a GNA13-dependent manner (PMID: 25274307, 26573295). In addition, P2RY8 is required to promote the clustering of activated B cells within follicles in collaboration with follicular dendritic cells (PMID: 26573295). P2RY8 fusions are found in patients with B-progenitor acute lymphoblastic leukemia (ALL) and ALL-associated Down Syndrome (PMID: 19838194). P2RY8 predominantly fuses with CRLF2, and P2RY8-CRLF2 rearrangements are associated with relapse and poor prognosis in ALL (PMID: 20139093, 22484421). In addition, loss-of-function P2RY8 mutations have been identified in diffuse large B cell lymphomas (DBLCL) and follicular lymphomas; however, the function of these mutations have yet to be determined (PMID: 22343534, 27959929). True +ENST00000356341 NM_002576.4 5058 PAK1 True PAK1 encodes a serine/threonine kinase involved in cytoskeletal remodeling and cellular motility, adhesion and survival. Amplifications and overexpression of PAK1 are found in a variety of cancers. PAK1 is serine/threonine protein kinase that in physiologic states is expressed in a wide variety of tissue types and plays important roles in cytoskeletal remodeling, cell motility, adhesion and survival (PMID: 21653999). PAK1 is overexpressed in several cancer types, through amplification of the PAK1 gene on chromosome 11q13, a feature most commonly described in estrogen receptor (ER) positive breast carcinomas (PMID: 9533029) or through other mechanisms. PAK1 plays several roles in oncogenesis, including increasing cancer proliferation through activation of MAPK signaling (PMID: 7592806), mediation of the oncogenic transformation caused by ErbB2 overexpression (PMID: 23576562), activation of the Wnt pathway (PMID: 21822311), inhibition of apoptosis through activation of BAD (PMID: 15849194, 10611223) and promotion of cancer cell metastasis through direct action on the cytoskeleton (PMID: 21196207). False +ENST00000353224 NM_177990.2 57144 PAK5 True PAK5, a serine/threonine kinase, is altered by mutation in various cancer types, including melanoma and lung cancers. PAK5 (also PAK7) is a serine/threonine kinase and member of the PAK family of proteins, which function as downstream effectors of Rho GTPases (PMID: 24869804). PAK5 is predominantly expressed in neuronal cell types and functions as a target of the Rho GTPases Cdc42 and RAC (PMID: 11756552, 12860998). Cdc42 cycles between a GDP-bound inactive state and a GTP-bound active state, in which PAK5 binds activated Cdc42 to initiate downstream signaling pathways (PMID: 24869804). PAK5 mediates a variety of cellular functions including regulation of MAPK and JNK signaling, as well as cell motility and survival (PMID: 12032833, 11756552, 18199048), apoptosis via phosphorylation of the pro-apoptotic protein BAD (PMID: 12897128, 20567954), and cytoskeletal stability (PMID: 16014608, 20564219). In neuronal cell types, PAK5 is predominantly localized in the mitochondria (PMID: 12897128) and expression of PAK5 leads to the induction of neurite formation via downstream activity of Cdc42 and Rac (PMID: 11756552, 15322108). Loss of PAK5 expression in mice results in defects in memory and learning and variants in PAK5 have been associated with the risk of psychosis in humans (PMID: 24474471). PAK5 overexpression has been identified in a variety of human tumor types including lung cancer, gastric cancer and melanoma, among others (PMID: 19415746, 16845324, 20564219, 23685956, 23106939, 25052921, 26116538). Expression of PAK5 in preclinical studies has been associated with increased invasion and migration and cellular protection from apoptosis (PMID: 25726523, 19415746, 20567954). Somatic variants in PAK5 are rare in human cancers; however, mutations in PAK5 have been identified in melanoma and lung cancer and are predicted to result in gain-of-function activity (PMID: 29875996, 23836671, 17344846). False +ENST00000261584 NM_024675.3 79728 PALB2 False 1 PALB2 is a component of the Fanconi anemia complementation (FANCC) group involved in DNA double-strand break repair. Germline mutations of PALB2 are associated with Fanconi anemia and predispose to breast cancer. PALB2 (Partner and localizer of BRCA2, also known as FANCN) encodes a DNA-repair factor and BRCA2 binding protein (PMID: 16793542). PALB2 acts as a scaffold protein in the homologous recombination (HR) pathway for the repair of double-stranded DNA breaks, likely mediating recruitment of BRCA2 and RAD51 at damaged loci (PMID: 19423707). PALB2 also interacts with BRCA1, possibly functioning as an intermediary factor between BRCA1 and BRCA2 in the HR pathway (PMID: 19268590, 19584259). Preclinical data show that mutations in BRCA1 and BRCA2 can abrogate interaction with PALB2 and disrupt HR-mediated DNA repair (PMID: 19369211, 16793542). Germline heterozygous mutations in PALB2 increase susceptibility to breast cancer with possible lesser effects in ovarian, pancreatic, prostate cancer and melanoma (PMID: 17200668, 17287723, 17420451, 18053174, 19264984, 20858716, 24448499, 25099575). Biallelic mutations of PALB2 are implicated in Fanconi anemia complementation group N (PMID: 17200671, 17200672, 20858716). Although rare, deleterious somatic variants in PALB2 are observed across various tumor types. True +ENST00000366794 NM_001618.3 142 PARP1 False PARP1 encodes a nuclear protein modifier enzyme involved in the DNA repair pathway. PARP1 inhibition has been shown to be effective in germline BRCA-deficient tumors, triple-negative breast cancer (TNBC), chronic lymphocytic leukemia, and ovarian serous papillary carcinoma. PARP1 encodes a nuclear localized poly(ADP-ribose) polymerase that transfers an ADP-ribose group to target proteins. PARP1 activity has been implicated in several biological processes including DNA repair, DNA replication, transcription, and chromatin remodeling (PMID: 9315851, 26184161). After induction of DNA damage, PARP1 binds to sites of single-strand breaks and recruits DNA repair proteins to the site of damage (PMID: 9315851, 26184161). PARP1 is also a key factor in regulating other biological and oncogenic processes, including maintenance of pluripotency in embryonic development, cell reprogramming and transcriptional regulation (PMID: 17286852, 22902501, 23939864, 21095583, 19262751, 26184161). Functional studies have demonstrated that PARP1 loss leads to genomic instability and resistance to DNA damage-induced cell death (PMID: 24916104). PARP1 is highly expressed in several human cancers, however, PARP1 mutations are rare (PMID: 25528020). In the absence of PARP1, single-strand breaks cause replication fork collapse resulting in double-stranded breaks and ultimately triggering DNA repair by homologous recombination pathways involving DNA repair genes such as BRCA1/2 (PMID: 24916104, 25286972). PARP1 inhibitors have been developed to leverage the ability of PARP1 to induce double-strand breaks in cancers with mutations in DNA repair genes, such as BRCA1/2, resulting in inefficient repair and cell death (PMID: 15829967, 19351835, 20858840, 25286972). PARP inhibitors have also been shown to be efficacious in other tumor types that share clinicopathological characteristics with BRCA-mutant tumors (‘BRCAness’), such as triple-negative breast cancer (TNBC), chronic lymphocytic leukemia, and ovarian serous papillary carcinoma (PMID: 16912188). The PARP1 inhibitor rucaparib has been approved for the treatment of BRCA-mutated ovarian cancer (PMID: 28751443). True +ENST00000350526 NM_181457 5077 PAX3 True PAX3, a transcription factor, is altered by chromosomal translocation in rhabdomyosarcoma. PAX3, a member of the paired-box (PAX) family, encodes for a transcription factor that regulates expression of target genes involved in cellular proliferation, survival and differentiation (PMID: 22532290). All PAX proteins contain a paired box DNA-binding domain, a homeobox DNA-binding domain and a transactivation domain (PMID: 24496612). The expression of PAX genes is temporally and spatially restricted during organogenesis and these genes play a key role in controlling cell fate during early development (PMID: 24496612). There are seven human isoforms of PAX3, with each isoform regulating intersecting target genes (PMID: 17187370). Knockdown of PAX3 in melanoma, glioblastoma and rhabdomyosarcoma cell models suppresses cellular proliferation, migration and invasion, suggesting that PAX3 functions predominantly as an oncogene in these contexts (PMID: 36057879, 10871843, 23701726). PAX3 chromosomal rearrangements have been identified in rhabdomyosarcoma and gastric cancer (PMID: 18457914, 25653235, 12039929). False +ENST00000358127 NM_016734.2 5079 PAX5 True PAX5 encodes a transcription factor involved in B-cell development. Translocations of PAX5 are found in lymphomas and leukemias. PAX5 is a protein in the paired-box family of transcription factors that is important in early B-cell development and differentiation (PMID:10524622). PAX5 plays a key role in the commitment of bone marrow multipotent progenitors to the B-lymphoid lineage by favoring VDJ gene rearrangement and activating the expression of B-cell-specific genes (PMID: 9442394) while simultaneously repressing genes involved in other hematopoietic differentiation programs (PMID: 12479824). The oncogenic function of PAX5 is likely tissue specific. PAX5 deficiency in B-cell acute lymphoblastic leukemia cell lines and models induces leukemia development and aberrant B-cell development and differentiation, suggesting that PAX5 functions predominantly as a tumor suppressor gene in this context (PMID: 25855603, 24939936, 30643249). Inactivating mutations, hypermethylation, translocations and deletions of PAX5 have been found in B-ALL, pediatric acute lymphoblastic leukemia and breast cancer (PMID: 17344859, 8943844, 25855603, 19020546, 37403081). A germline susceptibility mutation in PAX5 for development of B-ALL has also been identified (PMID: 24013638). Conversely, expression of PAX5 in other cancer cell models induces increased cancer cell viability, promotion of c-Met transcription and confers cisplatin resistance, suggesting that PAX5 functions predominantly as an oncogene in these tissue contexts (PMID: 19139719, 9815975, 29964012). Amplification of PAX5 has been identified in neuroblastoma and B-ALL (PMID: 29296789, 15155532). True +ENST00000420770 NM_001135254 5081 PAX7 True PAX7, a transcription factor, is altered by chromosomal translocation in rhabdomyosarcoma. PAX7, a member of the paired-box (PAX) family, encodes for a transcription factor that regulates expression of target genes involved in cellular proliferation, survival and differentiation (PMID: 34571854, 31534153, 17548510). All PAX proteins contain a paired box DNA-binding domain, a homeobox DNA-binding domain and a transactivation domain (PMID: 24496612). The expression of PAX genes is temporally and spatially restricted during organogenesis and these genes play a key role in controlling cell fate during early development (PMID: 24496612). Overexpression of PAX7 in rhabdomyosarcoma models induces cellular migration and invasion, suggesting that PAX7 functions predominantly as an oncogene (PMID: 25123133). PAX7 chromosomal rearrangements have been identified in rhabdomyosarcoma (PMID: 12039929, 22089931). False +ENST00000263334 NM_003466.3 7849 PAX8 True PAX8, a transcription factor, is overexpressed in various cancer types and chromosomal rearrangements involving this gene are found in thyroid cancers. PAX8 is a protein in the paired-box (PAX) family of transcription factors that plays a key role in controlling cell fate during early development and organogenesis (PMID: 24496612). All PAX proteins contain a paired box DNA-binding domain, a homeo box DNA-binding domain and a transactivation domain (PMID: 24496612). The expression of PAX genes is temporally and spatially restricted during organogenesis and these genes play a key role in controlling cell fate during early development (PMID: 24496612). PAX8 is the only member of the family expressed in the thyroid tissue; it is involved in thyroid follicular cell development and expression of thyroid-specific genes, and also functions in very early stages organogenesis of the kidney, the gynecologic tract and the thymus (PMID: 1337742). A fusion protein, PAX8-PPARγ, is implicated in some follicular thyroid carcinomas and follicular-variant papillary thyroid carcinomas (PMID: 10958784). An array of heterogenous mutations of PAX8 have been seen in thyroid dysgenesis, which causes congenital hypothyroidism (PMID: 25231445). False +ENST00000394830 NM_018313.4 55193 PBRM1 False PBRM1 encodes a tumor suppressor and component of the SWI/SNF chromatin-remodeling complex. Inactivating mutations of PBRM1 are frequently found in renal carcinoma. The PBRM1 gene encodes the protein BAF180, which is a component of the nucleosome-remodeling complex switching defective/sucrose non-fermenting (SWI/SNF) (PMID: 21248752). Nucleosomes are histone octamers around which DNA is wrapped in order to regulate its exposure to transcription factors and RNA polymerases (PMID: 23113498). Remodeling complexes such as the SWI/SNF family serve to loosen, reposition and break DNA/histone contacts ultimately rendering the DNA accessible to modulation (PMID: 21654818). BAF180 contains 6 bromodomains, which bind to lysine residues in histone tails (PMID:19084573, PMID:22435813). Aberrations of each individual bromodomain are sufficient to disrupt the protein's function as a tumor suppressor (PMID: 22435813, PMID:24613357). Specifically, one study demonstrated that BAF180 is among the key components required for p53-dependent cellular senescence (PMID:20660729). Additional work focusing on breast cancer cell lines identified BAF180 as a critical promoter in the induction of p21 activity, which functions as a key component of cell cycle regulatory functions (PMID:18339845). PBRM1 truncation mutants can no longer bind and remodel the p21 locus leading to cell cycle defects and aberrant cell proliferation (PMID: 18339845, 22949125). Loss of PBRM1 activity is also associated with chromosomal instability due to its inability to promote cohesion (PMID: 24613357). True +ENST00000303577 NM_006196.3 5093 PCBP1 False PCBP1, an RNA binding protein, is recurrently altered by mutation in Burkitt's lymphoma and gastrointestinal adenocarcinomas. PCBP1 (also alpha-CP1 and HNRNP E1) is an RNA binding protein that mediates transcription, translation and alternative splicing of mRNA molecules in a variety of contexts (PMID: 17389360). PCBP1 functions as a poly(rc)-binding protein (PMID: 7607214) that binds cloverleaf and large stem-loop IV mRNA structures (PMID: 10608888). The proteins PCBP1 and PCBP2 are translated from the same intronless gene and can cooperate to regulate RNA binding in collaboration with other components, including the hnRNPK ribonucleoparticle (PMID: 7607214, 9257647, 10455157). PCBP1 has been implicated in the stability of a variety of mRNA substrates including alpha-globin (PMID: 9234743), the androgen receptor (PMID: 12011088), EPO (PMID: 10068686), p21(WAF1) (PMID: 12431987), the folate receptor (PMID: 14722620), histone molecules (PMID: 18656558) and STAT3 (PMID: 14722620), among others. PCBP1 activity regulates a variety of cellular processes including cell cycle progression (PMID: 19211566), metastasis (PMID: 20154680, 26096938), and alternative splicing in both normal and malignant cells (PMID: 20361869, 27746021). For example, TGF-β activity promotes PCBP1 regulation of SMAD3, a critical mediator of metastasis (PMID: 27746021, 20154680, 26096938). Somatic mutations in PCBP1 are found in Burkitt’s lymphoma and gastrointestinal adenocarcinomas and these alterations are predicted to disrupt mRNA stability and alternative splicing (PMID: 29622466, 26173642). PCBP1 regulates a diverse range of substrates implicated in oncogenesis and therefore can function as either a tumor suppressor or oncogene (PMID: 18656558). False +ENST00000334409 NM_005018.2 5133 PDCD1 True PDCD1 is a key mediator of immune self tolerance and several cancer entities highly express PDCD1 to evade anti-tumoral immune response. Anti-PD1 therapy has been successful in PD1 expressing cancer. PDCD1 (Programmed cell death protein 1) encodes the protein PD1, which is a coinhibitory receptor expressed on T-cells and pro-B cells that belongs to the immunoglobulin superfamily (PMID: 20636820, 12421930). PD1 acts to inhibit an immune response by binding to the ligands PD-L1 and PD-L2, which are expressed on other normal or malignant cells (PMID: 17629517). PD-L1 binding to PD1 leads to programmed cell death in antigen-specific T-cells and reduced apoptosis in regulatory T-cells, which results in an overall decrease in immune response (PMID: 11857337, 16382236, 20208540). Amplification or overexpression of PD1 has been identified in some tumor types and can be predictive of responses to immunotherapy (PMID: 22437870, 26918453, 28652380, 27620277). Antibodies targeting PD1 have been developed and assessed in clinical trials that block the immune evasive PD-L1/PD1 interaction. Atezolizumab, a monoclonal antibody targeting PD-L1, is FDA approved for the treatment of patients with locally advanced or metastatic urothelial carcinoma (PMID: 28424325) and metastatic non-small cell lung cancer (NSCLC) whose disease progressed during or following platinum-containing chemotherapy (PMID: 28611199). Pembrolizumab, an anti-PD-1 antibody, is considered first-line therapy for patients with non-small cell lung cancer and metastatic melanomas that express PD-L1 and may be efficacious in other tumors that express PD-L1 (PMID: 28806116). Nivolumab, an FDA-approved monoclonal antibody that targets PD-1, is also effective in tumors with high PD-L1 expression due to the blockade of the PD-1/PD-L1 interaction and activation of a robust immune response (PMID: 28806116). Tumors with defects in mismatch-repair and overexpression of PD-L1 should be considered for PD-1 blockade (PMID: 26028255). False +ENST00000397747 NM_025239.3 80380 PDCD1LG2 True PDCD1LG2, a ligand of T-cell receptors involved in immune suppression, is overexpressed in various cancer types. "The PDCD1LG2 gene encodes the ""programmed cell death 1 ligand 2"" (PD-L2) protein. PD-L2 is highly similar to PD-L1, a protein whose overexpression by tumor cells and antigen presenting cells (APC) leads to negative regulation of T-cell receptor (TCR) signaling and subsequent tumor immune evasion (PMID: 15599732, 22437870, 16864790). PD-L2 binding affinity for PD-1 is higher than PD-L1, although the biological consequences of this are unknown (PMID: 12893276). PD-L2 is also expressed in activated T-helper cells type 2 (Th2), inhibiting its function and regulating IFN-γ production (PMID: 21752471). Impaired tumor growth has been observed in several in vitro and in vivo cancer models upon dual PD-L1/PD-L2 inhibition, but the specific additive role for the latter remains elusive (PMID: 22611421). PDCD1LG2 overexpression or amplification has been reported in renal, cervical and breast cancers, among others, and in some cases predicts poor prognosis (PMID: 26464193, 26913631, 26424759, 26752545, 26317899, 24270737, 15837746). PDCD1LG2 is a putative target for cancer immunotherapy (PMID: 22658128, 22611421)." False +ENST00000331163 NM_002608.2 5155 PDGFB True 1 PDGFB, a growth factor that activates PDGFR signaling, is recurrently altered by rearrangement in dermatofibrosarcoma protuberans (DFSP), a sarcoma of the skin, and related diseases. PDGFB is a signaling ligand that is a member of the platelet-derived growth factor family (PMID: 7073684, 18483217). PDGFB encodes a precursor peptide that requires intracellular, proteolytic processing to initiate receptor binding (PMID: 16007151). Receptor binding activity of PDGFB is also dependent on ligand dimerization, either as a homodimer or a heterodimer with family member PDGFRA, to form PDGF-BB or PDGF-AB (PMID: 2836952, 18483217). PDGF dimers activate PDGF receptor kinases in a context-specific manner, dependent on ligand configuration and receptor expression (PMID: 28267575). PDGFR signaling mediates a variety of downstream signaling effectors including PI3K, MAPK, and PLC-γ, among others (PMID: 18483217). These signaling pathways regulate a variety of cellular processes including cell proliferation, cell cycle progression, differentiation, and invasion (PMID: 18483217). Overexpression of PDGFB is implicated in several cancer types and promotes tumor progression in preclinical studies (PMID: 18478301). Rearrangements involving PDGFB are found in patients with dermatofibrosarcoma protuberans, a sarcoma of the skin (PMID: 17431412, 12131162). These translocations result in enhanced expression of PDGFB and increased PDGFR signaling activity, suggesting that PDGFRB functions as an oncogene (PMID: 17431412, 12131162). Several small molecule inhibitors targeting PDGFR may be efficacious in patients with increased PDGFB signaling (PMID: 26261104, 26261104). False +ENST00000257290 NM_006206.4 5156 PDGFRA True 1 R1 PDGFRA, a receptor tyrosine kinase, is altered by mutation, chromosomal rearrangement or amplification in a diverse range of cancers. The PDGFRA gene encodes for the protein Platelet-derived growth factor alpha (PDGFRA). Binding of ligand to the extracellular domain of PDGFRA, which contains immunoglobulin (Ig)-like domains, causes dimerization followed by autophosphorylation of the receptor and activation of downstream pathways such as RAS-MAPK, PI3K and PLC-γ that are involved in developmental and cellular responses. The catalytic activity of PDGFRA is mediated through the split intracellular tyrosine kinase domain; PDGFRA binds to all PDGF ligand isoforms except PDGF-DD (PMID:18483217, 24703957). Mutations, insertions, deletions, fusions and genomic amplification of PDGFRA lead to its activation in several tumor types: ~7% of gastrointestinal stromal tumors (GISTs) have PDGFRA activating mutations and these mutations are mutually exclusive from KIT mutations (PMID: 20023271); activating mutations in PDGFRA have been been reported in ~5% of Chinese melanoma patients (PMID:24132921); amplification of PDGFRA is the second most frequent receptor tyrosine kinase amplification in glioblastoma (GBM), is found in ~7-15% of GBM tumors and is often associated with in-frame deletions (PMID:18772890,19915670, 22323597, 20129251, 20889717); amplification of the PDGFRA locus has been reported in more than 80% of intimal sarcomas (PMID:20685895), ~19% of malignant peripheral nerve sheath tumors (PMID:16357008), 3-7% of non-small cell lung adenocarcinomas and 8-10% non-small cell lung squamous cell carcinomas (PMID:19755855); activating mutations have been found in ~5% of diffuse intrinsic pontine gliomas and in ~14% of non-brain stem pediatric high-grade gliomas, around 40% of these occurring in the context of PDGFRA amplification (PMID:23970477); chimeric fusion transcripts to the catalytic domain of PDGFRA have been reported in select cases of GBM (PMID:20889717), chronic myeloid leukemia (PMID:12023981,12944919, 15034867) and hypereosinophilic syndrome (HES)/chronic eosinophilic leukemia (CEL) (PMID:12660384, 19187542, 16498388, 16845659, 17555450). PDGFRA mutations have also been reported in inflammatory fibroid polyps (PMID: 22394371), and these mutations have been characterized as activating in other disease types. R1 False +ENST00000261799 NM_002609.3 5159 PDGFRB True 1 PDGFRB, a receptor tyrosine kinase, is infrequently mutated in solid tumors. PDGFRB (platelet-derived growth factor receptor beta), is a transmembrane receptor-tyrosine kinase whose ligands are the homodimers PDGF-BB and PDGF-DD (PMID: 18483217, 20581310). Upon binding to PDGF ligand, the receptor undergoes homodimerization (or heterodimerization with PDGFRα), bringing the intracellular kinase domains into proximity and triggering kinase activation. Downstream signaling pathways include JAK/STAT, PI3K/AKT, MAPK/ERK, PLCγ, and NF-κB (PMID: 18483217, 20581310). PDGFRB is primarily expressed on cells of mesenchymal origin (e.g. fibroblasts, endothelium) and is involved in organ development, angiogenesis and wound repair (PMID: 7958864, 10375497, 18483217, 20581310). Although PDGFRB plays a role in early hematopoiesis, its role in adult hematopoietic cells is less clear (PMID: 7958864, 11264163). Pathologic overexpression of PDGFRB in hematopoietic cells contributes to neoplastic growth and progression (PMID: 20581310). Although PDGF/PDGFR signaling appears to play an important role in numerous types of solid tumors, mutations, amplifications or translocations/fusions of PDGFRB are relatively rare in most solid tumors (PMID: 18483217). False +ENST00000282077 NM_002610 5163 PDK1 True PDK1, a serine/threonine kinase, is altered by amplification in various cancer types. PDK1 encodes for a master serine/threonine kinase which functions in the regulation the activation of at least 23 other kinases, including the AKT serine/threonine kinase family and AGC serine/threonine kinase family (PMID: 24352480, 9368760, 20027184, 23448267). PDK1 can activate and control the expression of various downstream substrates, including CDKN1B, CCND1 and PI3K, to regulate critical cellular processes such as proliferation, cell cycle control and survival (PMID: 18430722, 23893244, 34646383). Overexpression of PDK1 in various types of cancer cell lines and models induces aberrant cellular proliferation, adhesion, invasion and tumor growth, suggesting that PDK1 functions predominantly as an oncogene (PMID: 31646108, 32071289, 27878287, 36474273). Amplification of PDK1 has been identified in various types of cancer, including breast cancer, prostate cancer and ovarian cancer (PMID: 21542898, 23401739, 33403023). Aberrant PDK1 expression has been implicated in conferring chemoresistance in various cancer cell models through hyperactivation of PI3K/AKT/mTOR downstream signaling (PMID: 24044505, 36474273, 37169941). False +ENST00000342085 NM_002613.4 5170 PDPK1 False PDPK1 encodes a serine/threonine kinase involved in the PI3K signaling pathway. Amplifications of PDPK1 are found in breast and thyroid cancers. PDPK1 (also known as PDK1) encodes for 3-phosphoinositide-dependent protein kinase 1 that mediates downstream signaling from phosphoinositide 3-kinase (PI3K). It is a serine-threonine kinase that responds to mitogenic and insulin signals to phosphorylate targets including the AGC family of kinases such as p70 S6K and AKT (PMID:10801415, 9094314, 9427642). Breast cancer and multiple myeloma cells have shown dependency on PDPK1 for survival and tumor progression (PMID:19573809, 25269480). In pancreatic cancer, PDPK1 signaling can contribute to Kras oncogenic activity (PMID:23453624). The PDPK1 gene has been found to be amplified in breast and thyroid cancers (PMID:19602588, 18492751). Inhibitors are in development for different tumor types, particularly in breast cancer (PMID:22491800, 24039447, 21568903, 24037523). False +ENST00000315596 NM_015032.3 23047 PDS5B False PDS5B, a cohesin regulatory protein, is recurrently altered by mutation and deletion in hematologic malignancies and solid tumors. PDS5B (also AS3 and APRIN) is a protein that binds cohesin, a ring-like structure that regulates sister chromatid segregation during cell division (PMID: 15855230). PDS5B mediates cohesin-dependent sister chromatid cohesion during mitosis or meiosis to ensure proper chromosome-spindle attachments (PMID: 26903600). In addition, PDS5B activity is important for the maintenance of the curved interface of the cohesin ring and for the dissolution of the cohesin complex during mitosis to allow for appropriate chromosome segregation (PMID: 15855230, 27549742). PDS5B mediates additional cellular functions including regulation of stem cell function (PMID: 20383194) and chromatin looping (PMID: 29217591). PDS5B also interacts with BRCA2 to mediate DNA repair and is located on a chromosomal region that contains BRCA2 that is commonly lost in breast cancer (PMID: 22293751). Loss of PDS5B expression results in chromosome missegregation, aneuploidy and developmental defects in mice (PMID: 17652350, 24141881). PDS5B also mediates androgen-dependent signals that are required for growth arrest in prostate cells (PMID: 18499069, 10215036, 10963680). Germline mutations in PDS5B are found in patients with cohesinopathies, such as Cornelia de Lange syndrome (PMID: 19412548). Somatic loss-of-function mutations in PDS5B are found in patients with myelodysplastic syndrome and acute myeloid leukemia as well as some solid tumors (PMID: 26492932, 23850494, 19737411), suggesting that PDS5B functions as a tumor suppressor. PDS5B expression is also correlated with improved patient survival and sensitivity to DNA damaging agents (PMID: 27924011, 22293751). True +ENST00000525115 NM_001258311.1 79605 PGBD5 True PGBD5, a DNA transposase that mediates transposon movement in the genome, is involved in the initiation of chromosomal rearrangements in childhood cancers. PGBD5 is a DNA transposase that is a member of the piggyBac transposase family (PMID: 24180413, 26406119). piggyBac transposases mediate the mobility of genetic elements flanked by inverted terminal repeats (ITR) and reintegrate these elements, termed transposons, into another location in the genome via a “cut and paste” mechanism (PMID: 24180413, 26406119). Transposons mediate genetic evolution and comprise half of the human genome, with PGDB5 functioning as the most conserved transposase in humans (PMID: 26406119). PGBD5 is predominantly expressed in the brain and in the central nervous system during development (PMID: 24180413). Increased expression of PGBD5 in cell lines and murine models results in transformation, suggesting that PGBD5 functions as an oncogene (PMID: 28504702). Overexpression of PGBD5 is found in childhood cancers including rhabdoid tumors, neuroblastoma, medulloblastoma and Ewing sarcoma (PMID: 28504702, 30333322). PGBD5 promotes the formation of chromosomal rearrangements by binding site-specific sequences and disrupting the expression of tumor suppressor genes (PMID: 30333322). Oncogenic PGBD5 activity requires DNA end-joining repair and is sensitive to ATM and ATR inhibition (PMID: 29093183). False +ENST00000325455 NM_000926.4 5241 PGR True PGR encodes the progesterone receptor which mediates the effects of progesterone, playing a central role in reproductive events. PGR expression is common in breast and endometrial tumors and is predictive for response to endocrine therapy. PGR encodes the progesterone receptor (PR) which is a nuclear hormone receptor. It bind to progesterone in the cytoplasm and dimerizes. The complex then enters the nucleus and binds to DNA. PR then modulates transcription depending on its isoform and on the pattern of phosphorylation at a large number of possible sites (PMID: 11110801). PR is essential in the coordination of the reproductive cycle and is especially associated with the establishment and maintenance of pregnancy. PR has been shown to interact with STAT3 (PMID: 21184768) and the SP1 transcription factor (PMID: 21184768).The PR protein is commonly expressed in breast and endometrial tumors (cBioPortal, MSKCC, Mar. 2016; PMID: 11041059, 8319181) and provides a key prognostic indicator alongside the presence and absence of estrogen receptor (ER) (PMID: 1634918). PGR can be involved in other tumor types (PMID: 26892043, 26976979) and is mutated in a range of solid tumors especially at the R740 codon in the ligand binding domain (cBioPortal, MSKCC, Mar. 2016). Germline mutations in PGR are associated with endometrial cancer (PMID: 26881523). PR is targeted to some extent by endocrine therapy, PGR expression has been associated with response to tamoxifen in ER- patients (PMID: 16497822). False +ENST00000373896 NM_015651 26147 PHF19 True PHF19, a Polycomb-group cofactor of PRC2, is infrequently altered in cancer. PHF19 encodes for a cofactor that recruits the PRC2 complex and binds histone H3K36me3 to regulate embryonic stem cell differentiation and self-renewal (PMID: 31959557, 23160351, 23104054). PHF19 binding to H3K36me3 is a mark of transcriptional activation and leads to the association of H3K36me3 demethylases and recruitment of the PRC2 complex (PMID: 23160351, 23228662). Recruiting the PRC2 complex causes PRC2-mediated H3K27 trimethylation and the demethylation of H3K36 and subsequent transcriptional silencing (PMID: 23160351). Overexpression of PHF19 in multiple myeloma and prostate cancer cell lines induces cellular proliferation, growth and metastasis, suggesting that PHF19 functions primarily as an oncogene (PMID: 32155117, 31383640). PHF19 amplification has been identified in various cancers, including multiple myeloma, plasma cell leukemia and glioblastoma, and these cancers may also be sensitive to PRC2 inhibition (PMID: 31383640, 30323224). False +ENST00000332070 NM_001015877.1 84295 PHF6 False PHF6, a chromatin binding protein, is frequently altered by mutation and deletion in a range of hematologic malignancies. PHF6 is a DNA binding protein that functions as an epigenetic remodeler (PMID: 28607179). PHF6 binds chromatin via two imperfect zinc finger domains and mediates transcription by functioning as an epigenetic reader protein (PMID: 20228800). Expression of PHF6 is highest in the thymus, ovary, and thyroid (PMID: 20228800) and PHF6 is associated with lineage-specific roles in hematopoietic differentiation (PMID: 25737277, 28607179). In biochemical experiments, PHF6 associated with the NuRD complex, an epigenetic complex involved in histone deacetylation (PMID: 22720776). Loss of PHF6 resulted in increased gamma-H2AX, a histone mark implicated in DNA repair (PMID: 20228800). PHF6 also regulates the cell cycle by mediating ribosomal RNA synthesis (PMID: 23229552). Germline PHF6 mutations have been identified in Börieson-Forssman-Lehmann syndrome (BFLS), a developmental disorder associated with severe mental retardation and epilepsy (PMID: 12415272). Somatic mutations in PHF6 are found in patients with hematopoietic malignancies, including acute myeloid leukemia and T-cell acute lymphoblastic leukemia, among others (PMID: 20228800, 21736506). PHF6 mutations are predominantly missense and truncating, resulting in loss of protein, suggesting that PHF6 is a tumor suppressor (PMID: 20228800, 21030981, 21736506, 22928734). Loss-of-function mutations in PHF6 have been associated with poorer outcome in patients with acute myeloid leukemia (PMID: 22417203). True +ENST00000262719 NM_194449 23239 PHLPP1 False PHLPP1, a protein phosphatase, is recurrently altered by deletion in cancer. PHLPP1, a member of the metal-dependent protein phosphatase family, encodes for a phosphatase which functions in regulating Akt and PKC signaling (PMID: 15808505, 18162466). PHLPP1 dephosphorylates the hydrophobic motifs of Akt and PKC isoforms to mediate increased apoptosis and inhibition of cellular proliferation (PMID: 15808505, 18162466, 17386267). Knockdown of PHLPP1 in various cancer cell lines and models induces tumorigenesis, increased metastasis and increased Akt signaling, suggesting that PHLPP1 functions predominantly as a tumor suppressor gene (PMID: 21840483, 29391600, 22044669). Downregulation of PHLPP1 has been identified in various types of cancer, including melanoma, colon cancer and prostate cancer (PMID: 29391600, 19079341, 21840483). True +ENST00000568954 NM_015020 23035 PHLPP2 False PHLPP2, a protein phosphatase, is recurrently altered by deletion in cancer. PHLPP2, a member of the metal-dependent protein phosphatase family, encodes for a phosphatase that functions in regulating AKT and PKC signaling (PMID: 15808505, 18162466). PHLPP2 dephosphorylates the hydrophobic motifs of AKT and PKC isoforms to mediate increased apoptosis and inhibition of cellular proliferation (PMID: 15808505, 18162466, 17386267). Knockdown of PHLPP2 in various cancer cell lines and models induces cellular proliferation and transformation and increases eIF2α phosphorylation, suggesting that PHLPP2 functions predominantly as a tumor suppressor gene (PMID: 32319585, 34663797, 25977341, 19079341). Loss of PHLPP2 has been identified in various types of cancer, including esophageal squamous cell carcinoma, hypopharyngeal squamous cell carcinoma and colon cancer (PMID: 26245343, 25793736, 19079341). True +ENST00000226382 NM_003924.3 8929 PHOX2B False PHOX2B encodes a transcription factor involved in neural development. Germline mutations of PHOX2B are associated with congenital central hypoventilation syndrome and Hirschprung's disease and predispose to neuroblastomas. PHOX2B (Paired-like homeobox 2b) is a homeobox transcription factor that physiologically regulates the specification of sympathic neuron neurotransmitter identity (PMID: 7910552, 10230790). It does so by regulating the transcriptional expression of important genes for the production of neurotransmitters such as tyrosin hydroxylase (TH) and others (PMID: 10230790). PHOX2B mutations can lead to congenital central hypo-ventilation syndrome (CCHS) and Hirschprung's disease (PMID: 12640453, 12631670). Patients with PHOX2B mutant CCHS have a higher incidence of neuroblastoma and a subset of hereditary as well as sporadic neuroblastoma show PHOX2B mutations (PMID: 15516980, 10360575, 15024693). In neuroblastoma PHOX2B mutations lead to impaired neuroblast differentiation, but the exact mechanisms are not yet clear (PMID: 25124476, 12612655). True +ENST00000333590 NM_002641.3 5277 PIGA False PIGA, an enzyme involved in the synthesis of GPI membrane attachments, is recurrently altered in hematologic malignancies. PIGA (also PIG-A) is an enzyme involved in the first step of the GPI anchor biosynthesis pathway (PMID: 8500164). Glycosylphosphatidylinositol (GPI) anchors are post-translational modifications that attach the C-terminal of extracellular proteins to the cellular membrane (PMID: 8500164, 22265715). Cell surface proteins require GPI anchors for attachment at the membrane as well as for protein sorting, signal transduction, and immune regulation (PMID: 25885527). GPI anchors are added to proteins in the endoplasmic reticulum (ER) prior to protein sorting (PMID: 8500164, 9463366). PIGA is the catalytic enzyme in the GPI-N-acetylglucosamine transferase (GlcNAc) complex that is responsible for the first step in GPI synthesis (PMID: 8500164, 9463366). PIG-A initiates the formation of the intermediate N-acetylglucosaminyl phosphatidylinositol by transferring GlcNAc to phosphatidylinsositol (PI) (PMID: 8500164). GPI anchoring is required during embryogenesis and loss of PIGA in mice results in embryonic lethality (PMID: 7851884). Somatic loss-of-function mutations in PIGA are found in patients with paroxysmal nocturnal hemoglobinuria (PNH), a clonal hematopoietic malignancy that leads to anemia and a predisposition for leukemia (PMID: 10220445, 10627475, 10048414). Patients with PNH present with red blood cells that cannot express proteins at the membrane that require GPI anchoring, including the complement proteins CD55 and CD59 (PMID: 10220445, 8946596). Because PIGA loss results in depletion of important cell surface proteins from the membrane, a PIG-A assay has been developed to test for mutations in response to genotoxic stress (PMID: 24798381, 27637482, 20034593). True +ENST00000367187 NM_002646 5287 PIK3C2B True PIK3C2B, a lipid phosphoinositide, is infrequently altered in cancer. PIK3C2B, a member of the phosphoinositide 3-kinase (PI3K) family, encodes for a lipid phosphoinositide which functions in regulating various cellular processes including cytoskeleton organization, cell morphology and cell survival (PMID: 16775008, 22984590). The C2 domain of PIK3C2B is a lipid-binding domain which allows for phosphorylation of lipids and lipid signaling to regulate cellular processes (PMID: 20713135). Overexpression of PIK3C2B in various cancer cell lines and models induces fibrosis and cellular invasion and migration, suggesting that PIK3C2B functions predominantly as an oncogene (PMID: 31513749, 32903879). Amplification and mutations of PIK3C2B have been identified in various cancers, including glioblastoma and non-small cell lung cancer (PMID: 14655756, 22510280). False +ENST00000266497 NM_004570.4 5288 PIK3C2G False PIK3C2G encodes a kinase involved in cell proliferation, oncogenic transformation and protein trafficking signaling pathways. Inactivating mutations of PIK3C2G are found in melanomas and lung and gastrointestinal cancers. PIK3C2G is a class II catalytic subunit of PI3-Kinase (PMID: 25785104). PIK3C2G acts as a lipid kinase to create phosphatidylinositol-3,4-bisphosphate (PtdIns(3,4)P2), which acts as a secondary messenger in key signaling pathways involved in cell cycle, motility, differentiation and transformation (PMID: 10209156). Class II PI3Ks are the least studied, however, they are defined by the presence of a carboxyl-terminal calcium-dependent phospholipid-binding motif (PMID: 22507127). PIK3C2G is mutated in a number of cancers, and a large proportion of these mutations are predicted to be inactivating mutations. False +ENST00000262039 NM_002647.2 5289 PIK3C3 False PIK3C3 encodes a kinase involved in maturation of autophagosomes and lysosomes. Inactivating mutations or deletions of PIK3C3 are found in melanoma, uterine, lung, gastrointestinal, urothelial and pancreatic cancers. PIK3C3, also known as VPS34, is a class III catalytic subunit of PI3K and is important in creating phosphatidylinositol 3-phosphate (PtdIns3P). PIK3C3 plays an important role in the maturation of autophagosomes and the transport of lysosomal enzyme precursors to lysosomes (PMID: 20562532, 22498475). PIK3C3 is also involved in mTOR signaling, which regulates autophagy in response to nutrient sensing in the cell (PMID: 24013218). Inactivating mutations of PIK3C3 are seen in multiple cancer types. False +ENST00000263967 NM_006218.2 5290 PIK3CA True 1 PIK3CA, the catalytic subunit of PI3-kinase, is frequently mutated in a diverse range of cancers including breast, endometrial and cervical cancers. Phosphatidylinositol-3-kinase (PI3K) is comprised of a regulatory subunit (p85α) as well as a catalytic subunit (p110α) and it is the catalytic subunit that is encoded by the PIK3CA gene. PIK3CA is among the most commonly mutated genes in cancer and aberrant activation of PI3K is a transforming event (PMID: 17376864). Multiple receptor tyrosine kinases, including EGFR, ERBB2 (HER2), RET, MET, and VEGFR, among others, convert extracellular cues into intracellular signals and recruit PI3K to the plasma membrane via scaffold proteins such as IRS1 or by activating RAS. Upon stimulation, PI3K-110α converts its lipid substrate PIP2 (phosphatidylinositol - 4,5 - bisphosphate) to PIP3 (phosphatidylinositol - 3,4,5 - bisphosphate), which activates several signaling cascades, including the well-characterized AKT-mTOR pathway. Once activated, AKT-mTOR downstream signaling promotes cell survival, proliferation, growth and motility (PMID: 16341083). Adding to this complexity, exposure to some PI3K/mTOR pathway-targeted drugs relieves cancer cells of self-regulatory properties inherent in the PI3K-AKT-mTOR pathway thereby promoting tumor resistance to these agents (PMID: 22576208). False +ENST00000289153 NM_006219.2 5291 PIK3CB True PIK3CB, a catalytic subunit of PI3-kinase, is altered by amplification or mutation in various cancer types. PIK3CB, also known as p110-β, is a catalytic subunit of PI3K that is important in creating phosphoinositol 3,4,5-trisphosphate (PIP3), which acts as a secondary messenger in key cellular signaling pathways such as AKT-mTOR. PIK3CB plays a critical role in tumorigenesis driven by loss of PTEN (PMID: 18755892, 18594509) and drives PI3K signaling. Roles other than oncogenic activation of PI3K/AKT pathway have also been described for PIK3CB, including effects on growth and cell metabolism, including insulin signaling (PMID: 18594509, 18780892, 26132308). In HER2-amplified and PIK3CA-mutant cancers, inhibition of PIK3CA can lead to reactivation of PI3K signaling through PIK3CB (PMID: 25544637). Hence, combined inhibition of both isoforms is a promising therapeutic strategy that blocks pathway activation and leads to successful tumor regression (PMID: 25544636, 25544637, 25409150). False +ENST00000377346 NM_005026.3 5293 PIK3CD True PIK3CD encodes a kinase involved in immune cell regulation. Inactivating mutations of PIK3CD are found in uterine, endometrial and colorectal cancers, among others. PIK3CD, also known as p110-ẟ, is a catalytic subunit of PI3K that is important in creating phosphoinositol 3,4,5-trisphosphate (PIP3), which acts as a secondary messenger in key cellular signaling pathways such as AKT-mTOR. PIK3CD primarily functions in immune cells through AKT signaling. It is required for T-cell receptor activation (PMID: 12130661), and it is also necessary for a full antibody response in B-cells (PMID: 12235209). Germline mutations in PIK3CD likely causes both immunodeficiency and lymphoproliferative disease as a result of hyperactivation of AKT-mTOR signaling, which forces the differentiation of naive CD8+ T-cells into short-lived effector cells and reduces long-term memory T- and B-cells (PMID: 24165795). Idelalisib, a specific inhibitor of PIK3CD, has been used with Rituximab (a CD20 antibody) in the treatment of chronic lymphocytic leukemia (CLL) and has been associated with significant increase in progression-free survival (PMID: 24450857). False +ENST00000359195 NM_002649.2 5294 PIK3CG True PIK3CG encodes a kinase involved in modulation of the extracellular signal. Inactivating mutations of PIK3CG are found in uterine, endometrial, skin and lung cancers, among others. PIK3CG (phosphatidelinositol-4,5-bisphophsphate3-kinase catalytic subunit gamma), also known as p110-gamma, is a class I catalytic subunit of PI3-kinase and acts as a lipid and protein kinase that phosphorylates phosphoinositides (PMID: 17290298). PIK3CG is involved in extracellular signaling and linking cell-surface receptors to intracellular signaling networks, such as the PI3-kinase/AKT pathway (PMID:12040186). Once activated, AKT-mTOR downstream signaling promotes cell survival, proliferation, growth and motility (PMID: 16341083). PIK3CG is primarily expressed in white blood cells, and through its direct interactions with RAS and G-protein coupled receptors (GPCRs) (PMID:12507995) is important in immune cell responses and inflammatory stimuli (PMID:10669418). While deletions of PIK3CG are often found in myeloid malignancies in conjunction with broad 7q22 deletion, PIK3CG is not likely a tumor suppressor in these settings (PMID: 11756194). False +ENST00000274335 NM_181523.2 5295 PIK3R1 False PIK3R1, the regulatory subunit of PI3-kinase, is mutated in various cancers, most frequently in glioma, endometrial and colorectal cancers. PIK3R1 encodes p85α, the regulatory subunit of phosphatidylinositol-3-kinase (PI3K)(PMID: 12040186). In the absence of upstream receptor tyrosine kinase (RTK) activation, p85α both stabilizes and inhibits the activity of p110α, the catalytic subunit of PI3K. Upon RTK activation, p85α binds to phosphorylated tyrosine residues on the cytoplasmic tails of RTKs. Subsequently, this recruits the PI3K enzymatic complex to the cell membrane and allows the p110α catalytic subunit to generate phosphatidylinositol-3,4,5-trisphosphate (PIP3) (PMID: 12040186, 1707345, 2833705). The production of PIP3 results in recruitment and activation of the serine/threonine kinase, AKT, which in turn activates numerous downstream targets (e.g. mTOR) involved in cell growth, proliferation and survival (PMID: 12094235). PIK3R1 mutations occur most frequently in its two SRC Homology 2 (SH2) domains, nSH2 and iSH2 (PMID: 21478295, 19962665). These mutations disrupt the ability of p85α to inhibit the PI3K catalytic subunit, thus resulting in aberrant activation of AKT-mTOR signaling (PMID: 9450999, 11606375, 15932879, 17626883, 18079394, 19962665). Across all tumor types, PIK3R1 mutations tend to be mutually exclusive with alterations in TP53, PIK3CA, SETD2 and WT1 (PMID: 24132290). PIK3R1 mutations are prevalent in glioblastoma and to a lesser extent in endometrial, breast and colorectal cancers (PMID: 23636398, 24120142, 17932254, 22810696). True +ENST00000222254 NM_005027.3 5296 PIK3R2 False PIK3R2 encodes a regulatory subunit of PI3-kinase, a component of the pro-oncogenic PI3-kinase/AKT/mTOR signaling pathway. PIK3R2 is mutated at low frequencies in a diverse range of cancer. PIK3R2, also known as p55-β, is a regulatory subunit of PI3K and functions to regulate activated receptor tyrosine kinases (RTKs) via direct interaction (PMID: 12094235). It is thus important in regulating various downstream activities in the cell, such as growth, proliferation and motility. Upon RTK activation, PIK3R2 helps recruit the PI3K enzymatic complex to the cell membrane and allows the PI3K catalytic subunit to generate phosphatidylinositol-3,4,5-trisphosphate (PIP3), which is important in activating downstream signaling pathways such as AKT-mTOR (PMID:12040186). PIK3R2 mutations are often found in endometrial cancers with wildtype PTEN, and allow for increased PI3K and downstream AKT signaling (PMID: 21984976). True +ENST00000262741 NM_003629.3 8503 PIK3R3 False PIK3R3 encodes a kinase involved in insulin-like growth factor 1 receptor signaling. Inactivating mutations of PIK3R3 are found in stomach and uterine cancers. The PIK3R3 (phosphatidylinositol 3-kinase regulatory subunit gamma) protein, also known as p55-gamma, is a regulatory subunit of PI3K and functions to regulate activated receptor tyrosine kinases (RTKs) via direct interaction (PMID: 12094235). It is thus important in regulating various downstream activities in the cell, such as growth, proliferation and motility. Upon RTK activation, PIK3R3 helps recruit the PI3K enzymatic complex to the cell membrane and allows the PI3K catalytic subunit to generate phosphatidylinositol-3,4,5-trisphosphate (PIP3), which is important in activating downstream signaling pathways such as AKT-mTOR (PMID:12040186). PIK3R3 has been shown to directly modulate IGF2 signaling in glioblastoma and is amplified in some cases (PMID: 17360667, 16530701). True +ENST00000373509 NM_002648.3 5292 PIM1 False PIM1 encodes a serine/threonine kinase involved in cell survival and proliferation. Mutations of PIM1 are found in lymphomas. The PIM1 gene encodes a serine/threonine protein kinase that is constitutively active and signals survival and growth pathways (PMID:10435626,19276681, 23712827). PIM1 cooperates with the MYC oncogene and can lead to genomic instability (PMID:21860423, 14678956). It targets many important proteins involved in cell proliferation and survival including MYC, nitric oxide synthase and Bad (PMID:18438430, 15280015, 26598507). Its expression is upregulated in multiple tumor types including leukemias, glioblastoma, pancreatic and prostate cancers (PIMD:15498859, 25155357,18708761). PIM1 expression is associated with prostate and gastric cancer prognosis (PMID:11518967, 21993851). PIM1 mutations are found in lymphomas (PMID:11460166, 24970810, 26773040). Inhibitors of PIM1 kinase are being developed for anti-tumor therapy (PMID:25505253, 17218638, 26643319). False +ENST00000373271 NM_182811.1 5335 PLCG1 True PLCG1, a phospholipase-C signaling molecule, is recurrently mutated in hematologic malignancies. PLCG1 is a membrane-associated enzyme that is a member of the phospholipase-C (PLC) family (PMID: 19665973). PLC proteins cleave phospholipid phosphatidylinositol 4,5-bisphosphate (PIP2) into the products diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3) (PMID: 25456276, 29174396, 23140367). DAG and IP3 are secondary messengers that mediate cellular signaling pathways (PMID: 29174396, 23140367). IP3 binds calcium-mediated receptors resulting in an increase in cytosolic calcium concentrations and activation of protein kinase C (PKC) (PMID: 9096335, 10373546, 19179337). PLCG1 activity is regulated by receptor tyrosine kinases, such as PDGFR, VEGFR, and EGFR, in response to hormones and growth factors (PMID: 9096335). PLCG1-regulated signal transduction pathways, such as the MAPK and JNK pathways, regulate a variety of cellular processes including migration, proliferation, oxidative stress, angiogenesis and transformation (PMID: 11931670, 15944397). Somatic mutations in PLCG1 have been identified in T-cell lymphomas (PMID: 24497536, 25304611, 26415585, 26437031), Sezary syndrome (a leukemic variant of cutaneous T-cell lymphomas) (PMID: 27121473, 26415585) and angiosarcomas (PMID: 24633157, 25252913). PLCG1 mutations typically occur in the catalytic domain of PLCG1 and are predicted to be gain-of-function alterations resulting in activation of downstream oncogenic signaling pathways (PMID: 24497536). False +ENST00000359376 NM_002661.3 5336 PLCG2 True PLCG2 encodes an enzyme involved in transmembrane signaling. Mutations of PLCG2 are associated with autoimmunity and immune dysregulation and resistance to Ibrutinib therapy in patients with CLL. PLCG2 encodes for the gene phospholipase C gamma 2, a calcium dependent enzyme that cleaves phospholipids (phosphatidylinositol 4,5-bisphosphate (PIP2)) into diacylglycerol (DAG) and inositol 1,4,5-triphosphate (IP3) (PMID:20870410). The enzyme is autoinhibited by a C-terminal SH2 domain and activated by phosphorylation (PMID:20807769). It is expressed mainly in B-cells and Natural Killer cells where it acts to transduce signals from the immunglobulin family of receptors (PMID:10933392, 16002670). It is also involved in regulating osteoclast development (PMID:17053833). Mutations and deletions have been associated with autoimmunity and immune dysregulation (PMID:22236196, 23000145). Mutations in PLCG2 are found as resistance mechanisms to Ibruitinib therapy in CLL patients (PMID:24869598). These activating mutations result in Btk independent signaling from the B-cell receptor (PMID:25972157). Polymorphisms in PLCG2 have also been associated with cancer development risk (PMID:24080446, 23874846). False +ENST00000274289 NM_006622.3 10769 PLK2 False PLK2 encodes a tumor suppressor involved in cell cycle progression. PLK2 mediates chemotherapy sensitivity and resistance, apoptosis, and proliferation in cancer cells. PLK2 encodes polo-like kinase 2 a serine/threonine kinase that controls cell cycle progression (PMID:16627997). PLK2 is involved in regulating many pathways including angiogenesis, skeletal development, neuronal differentiation, synapse formation, centrosome duplication, and mitochondrial respiration response (PMID:26004360, 12972611, 25590559, 19706541,18498738, 19700763). PLK2 also phosphorylates alpha-synuclein that may have a role in Parkinsons disease (PMID:19004816, 23983262). In cancer cells PLK2 mediates chemotherapy sensitivity and resistance, apoptosis, and proliferation (PMID:21402713,19764992,25501818,16160013, 12897130, 26640387, 23703673). Inhibitors of polo-like kinases are in development (mainly against PLK1) although their effects on each family member may bring varying responses (PMID:25263688). False +ENST00000316660 NM_021127.2 5366 PMAIP1 False PMAIP1 is involved in promoting cell death (apoptosis). Mutations and deletions of PMAIP1 are found in lymphomas and leukemias. PMAIP1, also known as NOXA, encodes for phorbol-12-myristate-13-acetate-induced protein 1, a gene involved in regulating apoptosis (PMID:15694340). PMAIP1 contains a Bcl2 homology 3 (BH3) domain that mediates interactions with Bcl-2 family member proteins to alter the balance towards pro-apoptosis (PMID:15901672). Specifically, inhibition of Mcl-1 by PMAIP1 can lead to mitochondrial cytochrome c release and cell death (PMID:17115033). PMAIP1 is induced by TP53 as a consequence of DNA damage and other death signals such as c-Myc induction (PMID:10807576, 18042711, 23948298, 23153536, 19647221). PMAIP1 function is important for the sensitivity of tumors to anti-cancer therapy (PMID: 24525728, 24030633, 23302226, 22693249, 17038534). Its expression may also determine the efficacy of BH3 mimetics in development for cancer therapy (PMID:22128299,21628457). Mutations have been identified in lymphomas but are rare in solid tumors (PMID: 16960149, 12969015, 18231856). PMAIP1 expression is frequently down-regulated in pancreatic cancer, and in Panc-1 pancreatic cancer cell line, PMAIP1 expression is negatively correlated with proliferation rate and tumorigenic potential (PMID:18231856). True +ENST00000268058 NM_033238 5371 PML False PML, a transcription factor, is recurrently altered by chromosomal rearrangement in acute promyelocytic leukemia. PML, a member of the tripartite motif (TRIM) family, encodes for a phosphoprotein transcription factor which functions primarily in regulating cell cycle processes (PMID: 10574707, 25412268). PML is interspersed between chromatin and is the core component of the subnuclear multiprotein PML nuclear bodies complex (PML-NBs) (PMID: 9448006, 1999457). Within PML-NBs, PML activates caspases and Fas to induce Fas-dependent and caspase-dependent DNA-damage-induced apoptosis (PMID: 9806545). Knockout of PML in acute promyelocytic leukemia models induces tumor formation and impairs apoptosis, suggesting that PML functions predominantly as a tumor suppressor gene (PMID: 9806545, 11181703). Translocations between RARA and PML are implicated in the pathogenesis of acute promyelocytic leukemia (PMID: 23841729). The PML-RARA fusion protein confers sensitivity to targeted treatment with all-trans retinoic acid and arsenic trioxide (PMID: 20378816). True +ENST00000441310 NM_000534.4 5378 PMS1 False PMS1 is involved in DNA mismatch repair. PMS1 is one of four MutL homologs that functions in the DNA mismatch repair (MMR) system, which is important in detecting and repairing nucleotide base mismatches. Within the MMR system, PMS1 forms a heterodimer with MLH1 (known as the MutLβ complex); in humans the specific function of this complex is unknown (PMID: 24614649, 16136382). The MMR system primarily acts as a sensory system that scans newly synthesized DNA for base pair mismatches caused by DNA polymerase strand slippage. Upon recognition of DNA mismatches, the MMR system recruits repair enzymes that excise mismatched bases and initiates resynthesis along the parental template by DNA polymerase. Loss of function of the MMR system leads to an accumulation of distinct single nucleotide mutations and alterations known as microsatellite instability (MSI), which can cause frameshift mutations or protein truncations, potentially increasing the risk of tumorigenesis (PMID: 24614649). Germline mutations in PMS1 have been shown to be involved in Lynch syndrome, which can cause a predisposition to certain types of cancer, including colorectal cancer and endometrial cancer (PMID: 15528792). Patients who are MMR-deficient have also been shown to respond well to PD-1 blockade immunotherapies, hence the FDA-approval of pembrolizumab for patients with MSI-high or MMR-deficient tumors regardless of tumor etiology (PMID: 26028255). True +ENST00000265849 NM_000535.5 5395 PMS2 False PMS2 encodes a tumor suppressor involved in DNA mismatch repair. Germline mutations of PMS2 are associated with Lynch Syndrome and predispose to colorectal cancer. PMS2 is an endonuclease that plays an essential role in the mismatch repair (MMR) pathway. Specifically, PMS2 nicks DNA to initiate excision of a mismatched strand (PMID: 20624957). Mutations in PMS2 lead to an inability to correctly repair mismatches and insertion/deletion loops in the DNA, which results in increased tumor hypermutation and a microsatellite instability-high (MSI-H) phenotype (PMID: 14871975). Germline mutations of PMS2 can cause Lynch syndrome, also known as hereditary non-polyposis colon cancer (HNPCC), which predisposes individuals to colorectal, endometrial, ovarian, urothelial, and other cancers (PMID: 428275, 1648437, 30627969, 31171120). Biallelic mutations in MSH6 also result in constitutional mismatch repair deficiency (CMMRD) (PMID: 24737826). Sporadic PMS2 mutations have also been reported in cancers from numerous tissue types (PMID: 16472587). Tumor hypermutation has been associated with response to certain immunotherapies. Specifically, pembrolizumab has been FDA-approved for all MMR-deficient and MSI tumors, irrespective of specific tumor etiology (PMID: 25409260, 26028255). True +ENST00000336032 NM_006813.2 10957 PNRC1 False PNRC1 is a nuclear receptor activator that modulates transcription of a variety of nuclear receptors. It is widely expressed in normal tissue, whereas downregulation and, in some cases, upregulation have been observed in solid cancers, including breast, gastric, hepatocellular and colorectal carcinomas. PNRC1 is a nuclear receptor coactivator that modulates the transcriptional activation of a variety of nuclear receptors. Among these, the nuclear receptors (e.g. estrogen receptor α and β, progesterone receptor, androgen receptor, glucocorticoid receptor, thyroid hormone receptor, retinoic acid receptor and retinoid X receptor) bind PNRC1 in a ligand-dependent manner, whereas the orphan receptors (e.g. steroidogenic factor 1 and estrogen-related receptor α 1) interact with PNRC1 in a ligand-independent manner (PMID: 23925889, 17068076, 15604093). PNRC1 also stimulates transcription by RNA polymerase III through direct binding of its subunit RPC39 (PMID: 7578250, 10894149, 17612402). In addition to its function as a modulator of transcription, PNRC1 plays an important role in the Ras-MAPK pathway, where it downregulates the signaling cascade through its interaction with Grb2 (PMID: 15122321). Downregulation of PNRC1 has been observed in various tumor types including breast, gastric, hepatocellular and colorectal carcinomas; however, somatic mutations in PNRC1 are infrequent in human cancers (PMID: 15122321, 11768609). False +ENST00000440232 NM_002691.3 5424 POLD1 False 2 POLD1 encodes an enzyme involved in DNA replication and repair. Germline mutations of POLD1 predispose to colorectal and endometrial cancers. POLD1 is the catalytic subunit of the DNA polymerase δ complex p125. The p125 subunit contains both polymerase and 3ꞌ to 5ꞌ exonuclease activity (PMID: 7490075, 9030545). POLD1 is involved in DNA synthesis of the lagging strand during DNA replication, proofreading activity during polymerization and DNA repair (PMID: 18439893, 10781066, 11027336). In functional studies, reduced expression of POLD1 was shown to cause genomic instability resulting from the accrual of errors during DNA replication. Furthermore, reduced expression of POLD1 was associated with fragile site instability and a high frequency of chromosomal aberrations (PMID: 11003646, 18591249). Recent studies have demonstrated that levels of POLD1 protein decrease with age, resulting in reduced DNA repair capacity (PMID: 22915169, 21556771). Alterations within the exonuclease domains of POLD1 and POLE, another proofreading protein that contributes to DNA replication fidelity, result in the accumulation of single nucleotide variants and an ultra-mutated phenotype, similar to the ultra-mutated phenotype seen in dMMR/MSI-H tumors (PMID: 35398880). Germline heterozygous loss-of-function mutations in the exonuclease domain of POLD1 cause polyposis and predispose individuals to colorectal, endometrial, and possibly brain cancers (PMID: 23263490, 23528559, 24501277, 26133394, 26493165). Note that somatic variants of POLD1 are extremely rare (PMID: 35398880, 37848928, 31479159). POLD1 mutations have been identified as drivers of hypermutation, and therefore, cancers with POLD1 variants may be increasingly sensitive to immunotherapy (PMID: 29056344). Several studies have demonstrated clinical benefit to immune checkpoint inhibitors in patients with tumors harboring POLE or POLD1 proofreading deficiency mutations (PMID: 38777726, 35780178, 35817971, 35398880). True +ENST00000320574 NM_006231.2 5426 POLE False 2 POLE, the catalytic subunit of DNA polymerase epsilon, is an enzyme involved in DNA replication and repair. Select POLE mutations lead to ultra-high mutation rates, most frequently in endometrial and colorectal cancer. "POLE is the catalytic subunit of DNA polymerase ε, the replicative DNA polymerase that extends the leading strand during DNA replication (PMID: 24861832). POLE contains an exonuclease ""proofreading"" domain, which replaces incorrectly incorporated nucleotides spontaneously during faithful replication (PMID: 24861832). Alterations within the exonuclease domains of POLE and POLD1, another proofreading protein that contributes to DNA replication fidelity, result in the accumulation of single nucleotide variants and an ultra-mutated phenotype, similar to the ultra-mutated phenotype seen in dMMR/MSI-H tumors (PMID: 35398880). Germline heterozygous loss-of-function mutations in the exonuclease domain of POLE cause polyposis and predispose individuals to colorectal cancer (PMID: 23263490, 23528559, 24501277, 26133394, 26493165). Several recurrent mutation hotspots in the exonuclease domain of POLE have been identified as impacting its proofreading capability and leading to ultra-high mutation rates, primarily in cancers of the colon, rectum and endometrium. Somatic mutations in the proofreading domain of POLE have been reported in endometrial cancers (PMID: 23636398, 25505230) and colorectal cancers (PMID: 25228659). In some contexts, POLE mutations have been associated with hypermutation, increased mutation load and better response to checkpoint inhibition in human cancers (PMID: 29056344, 29489427, 27159395, 28188185, 27486176, 31415061). Patients with mutated, proofreading-deficient POLE in endometrial cancer have been shown to have better outcomes (PMID: 25505230, 23636398). Several studies have demonstrated clinical benefit to immune checkpoint inhibitors in patients with tumors harboring POLE or POLD1 proofreading deficiency mutations (PMID: 38777726, 35780178, 35817971, 35398880)." True +ENST00000268124 NM_001126131 5428 POLG False POLG, a mitochondrial DNA polymerase, is infrequently altered in cancers. Mutations in POLG are associated with inherited mitochondrial disorders, including Alpers-Huttenlocher syndrome. POLG (DNA polymerase gamma) is a mitochondrial DNA polymerase involved in the replication and maintenance of the mitochondrial genome (PMID: 10827171). POLG contains a catalytic subunit with both polymerase and 3'-5' proofreading exonuclease domains, as well as an accessory subunit involved in maintaining processivity (PMID: 19837034, 10827171). Mutations in the polymerase domain of POLG lead to reduction in the mitochondrial DNA (mtDNA) content, decreased oxidative phosphorylation and increased cell migration in breast cancer cell lines (PMID: 19629138). Furthermore, mice with POLG mutations affecting the exonuclease domain exhibit accumulation of mtDNA mutations, earlier onset of aging phenotypes and increased apoptotic markers compared to wildtype (PMID: 16020738). Autosomal dominant or recessive mutations in POLG, mostly in the polymerase domain, are associated with mitochondrial diseases such as Alpers-Huttenlocher syndrome and progressive external ophthalmoplegia (PMID: 23545419, 11431686). POLG is mutated by missense mutations in patients with breast cancer (PMID: 19629138). False +ENST00000357628 NM_015450.2 25913 POT1 False POT1, a tumor suppressor that functions as a telomere binding protein, is altered by mutation in hematologic malignancies. POT1 is a telomere binding protein that is a component of shelterin (PMID: 29149597, 30208292). Shelterin is a protein complex that protects the ends of chromosomes, or telomeres, from inappropriate DNA repair mechanisms (PMID: 27218840). Telomeres are repetitive sequences at the end of chromosomes that prevent fusion with other chromosomes, maintain chromosome integrity, and are implicated in aging and cancer (PMID: 15181449). POT1 is an oligonucleotide binding protein that interacts with single-stranded DNA on telomeres and controls telomerase-mediated telomere elongation (PMID: 12768206). In addition, POT1 binds other telomere regulatory proteins including TRF1 (Telomere Repeat Factor 1), which inhibits unnecessary telomere extension (PMID: 15231715). POT1 also interacts with other telomere interacting proteins including PIP1 (POT-interacting protein), TIN2 (TRF1-interacting factor) and TPP1, among others, to maintain telomere stability and to recruit telomerase (PMID: 15231715, 15181449). Disruption of these protein interactions with POT1 results in aberrant mutagenic alternative non-homologous end joining (A-NHEJ) leading to genomic instability and chromosome fusions (PMID: 28393832, 27869160). Inhibition of POT1 expression also results in the activation of ATR-dependent DNA damage resulting in replication stress (PMID: 27239034). Germline loss-of-function mutations in POT1 are found in familial cutaneous melanoma, lymphoma and glioma (PMID: 24686849, 25482530, 29693246). Somatic loss-of-function POT1 mutations are found in chronic lymphocytic leukemia and disrupt oligonucleotide binding activity (PMID: 23502782). POT1 mutations are predicted to promote genome instability due to the inability of POT1 to protect telomeres from DNA repair mechanisms (PMID: 28393832). True +ENST00000526816 NM_001207025 5452 POU2F2 True POU2F2, a homeobox-containing transcription factor, is altered by amplification in various cancers. POU2F2, a member of the POU domain family, encodes for a homeobox-containing transcription factor that binds to the octamer motif (5’-ATTTGCAT-3’) found in immunoglobulin gene promoters (PMID: 2904654). POU2F2 regulates the transcriptional activation of immunoglobulin genes primarily in B lineage cells (PMID: 23045607). POU2F2 mediates B cell development, differentiation and survival by promoting transactivation of genes such as STAT3, IL-10 and MYC (PMID: 26993806). The transactivation activity of POU2F2 is enhanced through the transcriptional coactivator Obf1, which is encoded by POU2AF1 (PMID: 24688485). Overexpression of POU2F2 in various cancer cell lines and models induces cellular proliferation, migration and invasion, suggesting that POU2F2 functions predominantly as an oncogene (PMID: 33832481, 26019213, 33931589). POU2F2 amplification has been identified in various cancers including lung cancer, gastric cancer and liver cancer (PMID: 33832481, 26019213, 14576340). False +ENST00000328345 NM_005604 5454 POU3F2 True POU3F2, a transcription factor, is recurrently altered by amplification in lung adenocarcinoma. POU3F2 encodes for a class III POU-homeodomain transcription factor that functions primarily in neuronal differentiation (PMID: 8543155, 10842361). POU3F2 is a core regulator of neural gene networks that have been implicated in risk for schizophrenia and bipolar disorder (PMID: 30545964, 32929213). POU3F2 is required for the generation of tuft cells, which are chemosensory cells found in gastrointestinal and respiratory tracts that respond to external stimuli by releasing bioactive material to regulate immune cell function (PMID: 26675736, 29216297). Overexpression of POU3F2 in various types of cancer cell lines and models induces cellular proliferation, invasion and migration and confers radioresistance, suggesting that POU3F2 functions predominantly as an oncogene (PMID: 36797433, 32169117, 23358112, 27784708, 31920461). POU3F2 amplification has been identified in various types of cancer, including glioblastoma, small cell lung cancer and melanoma (PMID: 2216722, 23530560, 32632141, 7478537). False +ENST00000373200 NM_000307 5456 POU3F4 True POU3F4, a neural transcription factor, is infrequently altered in cancer. POU3F4, a member of the POU-III family, encodes for a transcription factor that functions primarily in early neural development, including neural tube and hypothalamic patterning (PMID: 1628619). POU3F4 is located on the X chromosome, and mutations in this gene have been associated with X chromosome-linked hearing loss due to its function in middle and inner ear development (PMID: 33919129, 36000053). Overexpression of POU3F4 in various cancer cell lines and models induces increased cellular proliferation, migration and viability, suggesting that POU3F4 functions predominantly as an oncogene (PMID: 31371344, 25243889, 25343275, 19307926). Amplification of POU3F4 has been identified in various cancers, including pancreatic neuroendocrine tumors and neuroendocrine prostate cancer (PMID: 19307926, 31371344). False +ENST00000287820 NM_015869.4 5468 PPARG True PPARG, a nuclear receptor, is known to behave as an oncoprotein when fused with with PAX8 in thyroid cancer. PPARG encodes the Peroxisome Proliferator-Activated Receptor- gamma (PPAR- γ) subfamily of nuclear receptors. PPAR-γ forms a heterodimer with Retinoid X Receptor-α in response to peroxisome proliferators such as clofibric acid or to RXR-α agonists such as 9-cis-retinoic acid and activates the expression of various genes involved in the regulation of adipogenesis, lipid metabolism, glucose homeostasis, atherogenesis, inflammation and tumor susceptibility (PMID: 1324435, 8536636). Chromosomal translocation (2;3)(q13;p25) resulting in a fusion between DNA binding domains of thyroid transcription factor Paired box gene 8 (PAX8) and PPAR- γ1 has been identified in a subset of thyroid follicular carcinomas (PMID: 10958784). PAX8-PPAR-γ behaves like an oncoprotein, and its transforming properties can be attributed at least in part to a dominant negative inhibition of wildtype PPAR-γ (PMID: 15077183). Ligands that activate PPAR-γ, typically thiazolidinediones, are known to sensitize a wide array of cancer cells to death receptor (DR)-mediated apoptosis, owing to de novo expression of proteins involved in regulating the cell cycle and cell survival/death, and also act as inhibitors of angiogenesis (PMID: 18615184,15041792). On the contrary, PPAR-γ agonists have also been reported to increase the frequency and size of colon tumors in APCMin/+ mouse models of colon cancer (PMID: 9734399, 9734400). False +ENST00000305921 NM_003620.3 8493 PPM1D True PPM1D, a protein phosphatase, is altered by mutation in various solid and hematologic malignancies including in therapy-related hematopoietic disorders. PPM1D (Protein Phosphatase, Mg2+/Mn2+ dependent, 1D) is a member of the protein phosphatase 2C (PP2C) family of Ser/Thr protein phosphatases. PPM1D is induced by p53 following activation in response to various environmental stresses such as radiation, H2O2, and anisomycin (PMID: 19015127, 22201816). PPM1D is emerging as an important oncogene by virtue of its negative control on several key tumor suppressor pathways including ATM, CHK2, p38 MAPK, and p53 (PMID: 19879149). PPM1D is overexpressed and/or mutated in various human primary cancers, including breast cancer, hepatocellular carcinoma, pancreatic adenocarcinoma, ovarian carcinoma and neuroblastoma (PMID: 19879149, 23242139, 17233815, 19293255). High PPM1D expression has been associated with tumor progression and poor prognosis in non-small cell lung cancer, nasopharyngeal carcinoma and prostate cancer (PMID: 25412952, 25060857, 26714478). Finally, various PPM1D inhibitors, including peptidic inhibitors derived from substrate sequences and small chemical inhibitors, were reported that suppress cancer cell growth and could be useful in the development of effective anti-cancer agents (PMID: 18845566, 21528848, 17073441, 24390428, 22115592, 25466181, 26358280). False +ENST00000322088 NM_014225.5 5518 PPP2R1A False 3A PPP2R1A encodes a serine/threonine phosphatase that regulates cell growth and division. PPP2R1A is frequently mutated in endometrial and ovarian cancers. The PPP2R1A gene encodes protein phosphatase 2A (PP2A) a serine/threonine phosphatase involved in cell growth and division (PMID: 11171037). PP2A activity has long been considered an important tumor suppressor (PMID: 2153055), although recent evidence suggests that it may function as an oncogene in some context (PMID: 27272709). The PPP2R1A gene encodes the 'scaffolding' subunit of the PP2A trimeric holoenzyme, so named because it bridges PP2A's catalytic subunit to a myriad of targeting subunits (PMID: 17055435). Targeting subunits confer specificity for substrate selection and enzyme localization in the cell. PPP2R1A mutations have recently been found to positively correlate with whole-genome doublings in human cancers (PMID: 24071852). These mutations have been identified in uterine (endometrial) carcinomas (PMID: 23636398, 21435433, 21381030, 21435433), uterine (serous) carcinomas (PMID: 21435433) , ovarian low-grade serous, low-grade endometrioid, clear cell, and mucinous carcinomas (PMID: 21435433, 20826764, 21381030). The functional impact of these mutations during tumorigenesis is limited, however, the available studies describing these mutations indicate that normal function of PPP2R1A is tumor suppressive (PMID: 22262169, PMID: 21791616). True +ENST00000380737 NM_002717.3 5520 PPP2R2A False PPP2R2A, a subunit of the PP2A phosphatase, is altered by mutation and deletion in various cancer types. PPP2R2A (also PR55α) is a subunit of the protein phosphatase 2 (PP2A) that is a member of the PP2A regulatory B subunit family (PMID: 18588945). PP2A is a trimeric enzyme, which is composed of a catalytic subunit, a scaffold subunit, and one of 18 regulatory subunits, such as PPP2R2A, functioning as the predominant serine/threonine phosphatase (PMID: 18588945). PPP2R2A binding contributes to the selectivity of the PP2A phosphatase for substrates (PMID: 18588945, 18042541). Oncogenes, such as MYC and AKT, are negatively regulated by PPP2R2A activity (PMID: 32522823). Dephosphorylation of these targets results in altered cellular functions including reduced proliferation and cellular survival (PMID: 18042541, 12932319). In addition, PPP2R2A regulates ATM dephosphorylation, leading to homologous recombination at sites of DNA damage in the genome (PMID: 23087057). PPP2R2A has additional protein targets including AP-1, HDAC4, and TFGBR1, among others (PMID: 18158287, 12912990, 18045992, 12932319, 14712210, 9774674). Somatic PPP2R2A loss-of-function mutations and deletions have been reported in many cancer types, including prostate, ovarian and non-small cell lung cancers (PMID: 21872824, 23087057, 25879784, 31349904, 27531894), and are predictive or poor survival (PMID: 32522823, 25879784, 31822657, 26893480, 25879784). In loss-of-function preclinical studies, PPP2R2A deletion corresponded to increased sensitivity to DNA damaging agents, such as ATR, CHK1, and PARP1 inhibitors, due to elevation of replication stress pathways (PMID: 32522823, 23087057). True +ENST00000356692 NM_174907.2 151987 PPP4R2 False PPP4R2, a regulatory subunit of a protein phosphatase, plays a vital role in DNA double strand break repair. PPP4R2 encodes a regulatory subunit of the protein phosphatase 4 (PPP4C), a protein serine/threonine phosphatase that has been implicated in microtubule organization at centrosomes. PPP4R2 may be instrumental in targeting PPP4 catalytic subunit (PPP4c) to the centrosomes, and may also regulate (inhibit) the activity of PPP4c at centrosomal microtubule organizing centers (PMID: 10769191). PPP4R2 interacts with Survival of Motor Neurons (SMN) protein complex and is essential for differentiation of neuronal cells (PMID: 22559936) as well as for temporal localization of small nuclear ribonucleoproteins (snRNPs), suggesting a role in maturation of spliceosomal snRNPs (PMID: 12668731). PPP4R2 is part of a conserved ternary complex including PPP4R3 and PPP4c that mediates dephosphorylation of RPA2 and γH2AX, and is required for DNA double strand break repair (PMID: 18614045, 20154705). False +ENST00000373547 NM_002721.4 5537 PPP6C False PPP6C encodes a serine/threonine phosphatase involved in cell cycle progression and DNA double-strand break repair. Aberrant expression of PPP6C is found in melanomas, hepatocellular carcinomas, mesotheliomas and glioblastomas. The PPP6C gene encodes the catalytic subunit of serine/threonine phosphatase 6 (PP6) (PMID: 9143513), which integrates signaling from multiple pathways. In normal cells, PP6 regulates cell cycle progression, and hence restricts G1 to S phase progression in cancer cells (PMID: 9013334, 21187329, 10227379). PP6 plays an important role in oocyte meiosis, and loss of PP6 protein is associated with female infertility (PMID: 26349807). In addition, PP6 is involved in the homology-directed repair of DNA double-strand breaks induced by ionizing radiation; it also plays an important role in inflammatory responses by IL-1 via dephosphorylation of Thr-187 in the activation loop of TAK1 (PMID: 21451261, 17079228). PP6 has been shown to promote replication of influenza A virus (PMID: 25187537). PP6’s involvement in cancer has been largely established. Somatic mutations that lead to inactivation of the protein, loss of heterozygosity and nonsense mutations are observed in approximately 10% of melanomas harboring NRAS or BRAF mutations; these mutations are associated with poor prognosis (PMID: 24336958, 22842228, 24755198, 23729733, 22817889). Overexpression of PPP6C in glioblastoma is associated with worse overall survival (PMID: 25332711, 22395973); downregulation of PP6, which is dependent on miR-373, is observed in hepatocellular carcinoma and mesothelioma (PMID: 21481188, 20463022). PPP6C mutations play a role in the progression of thyroid cancer (PMID: 24718460). True +ENST00000271526 NM_005973 5546 PRCC True PRCC, a proline-rich splicing protein, is altered by chromosomal rearrangement in renal cell carcinomas. PRCC encodes for a proline-rich protein that functions primarily in pre-mRNA splicing. Phosphorylated PRCC is recruited to precursor mRNA to activate the human spliceosome B complex (PMID: 21536652). PRCC can interact with the mitotic checkpoint protein MAD2B and regulates various processes, such as checkpoint control, colony formation and cell apoptosis (PMID: 34715922, 11717438). Overexpression of PRCC in non-small cell lung cancer cell lines induces cellular proliferation, migration and invasion, suggesting that PRCC functions predominantly as an oncogene (PMID: 30900418). Amplification of PRCC has been identified in non-small cell lung cancer (PMID: 16322280). PRCC has been identified as a common translocation partner for the transcription factor TFE3 in papillary renal cell carcinoma (PMID: 8872474, 12459622, 11313942, 38740306). The PRCC-TFE3 fusion is suggested to enhance the transcription factor activity of TFE3 through the N-terminal proline-rich transcriptional activation domain of PRCC (PMID: 8872474). False +ENST00000369096 NM_001198.3 639 PRDM1 False PRDM1 encodes a transcriptional repressor involved in the cellular response to viral infection and B-cell differentiation. Deletions of PRDM1 are found in diffuse large B-cell lymphomas and prostate cancer. PRDM1, also known as BLIMP-1 and PRDI-BF1, encodes PR domain zinc finger 1 (PRDM1), a DNA-binding protein with five zinc fingers (PMID: 1851123). PRDM1 was initially described as a transcriptional repressor of interferon ß, and as an essential component of B cell differentiation, wherein it represses MYC (PMID: 1851123, 9887105, 8168136, 9110979. It has been shown to function by interaction with the Groucho family of transcriptional co-repressors as well histone-modifying factors (PMID: 9887105, 14985713, 19124609). More recent results from animal studies indicate PRDM1 as an important factor in establishment in the germ cell lineage, T cell differentiation and homeostasis and heart function (PMID: 15937476, 16565720, 24821700). Two single-nucleotide polymorphisms (SNPs) located intergenic to PRDM1 and ATG5 have been associated with increased risk for radiation therapy-induced second malignant neoplasms after radiotherapy for pediatric Hodgkin's lymphoma (PMID: 21785431). True +ENST00000276594 NM_024504.3 63978 PRDM14 False PRDM14, a transcriptional regulator, is amplified and overexpressed in breast cancer. The PRDM14 gene encodes a zinc-finger protein that acts as a transcriptional regulator. It belongs to the PRDM family of genes, which exert both positive and negative roles in the transcription of genes involved in development, and either possess or enhance histone methyltransferase activity (PMID: 22669819, 22028065). PRDM14 plays an important role in the establishment of germ cell lineage in mice (PMID: 18665129, 18622394). Additionally, PRDM14 is required for the maintenance of human embryonic stem cell (hESC) identity, and enhances the reprogramming of human fibroblasts into hESC by co-regulating the expression of key genes (PMID: 20953172, 24268575). PRDM14 overexpression in breast cancer cells leads to increased growth and colony formation capabilities and decreased apoptosis (PMID: 17942894). PRDM14 is overexpressed or amplified in a subset of breast and prostate cancers (PMID: 17942894; cBioPortal, MSKCC, Dec. 2016). False +ENST00000288368 NM_024870.2 80243 PREX2 False PREX2, a positive mediator of RAC1 GTPase, is predominantly mutated in melanomas. The PREX2 gene encodes a protein that facilitates the exchange of GDP to GTP on RAC1, leading to the activation of its downstream effectors. PREX2 is activated by phosphatidylinositol 3,4,5-trisphosphate (PIP3) and G-protein coupled receptors and mediates the PI3K pathway-dependent activation of RAC1 (PMID: 15304343, 15304342, 15897194). PREX2 can activate the PI3-Kinase (PI3K) pathway by antagonizing PTEN inhibitory effects (PMID: 19729658); conversely, PTEN negatively regulates PREX2-mediated oncogenic effects (PMID: 25829446). PREX2 activation increases cell proliferation, activates PI3K signaling and downregulates tumor suppressors such as CDKN1C in NRAS-mutant melanoma (PMID: 25829446, 26884185). Oncogenic effects of PREX2 have also been described in other cancers (PMID: 26718453), as well as a role for PREX2 in the insulin signaling pathway (PMID: 26438819). PREX2 is mutated in melanomas and other skin cancers, as well as in pancreatic tumors (PMID: 22622578, 25719666; cBioPortal, MSKCC, Dec. 2016). False +ENST00000308677 NM_002730.3 5566 PRKACA True PRKACA, a catalytic subunit of protein kinase A, is predominately altered by chromosomal rearrangement in various types of hepatocellular carcinoma. PRKACA, a catalytic subunit of protein kinase A (PKA), is involved in the phosphorylation of many cellular proteins important for cell proliferation, maturation, and apoptosis. Cyclic-AMP (cAMP)-dependent activation of PKA leads to the release of PKA regulatory subunits and subsequent phosphorylation of a number of downstream substrates. Cellular substrates of PKA, including transcription factors such as cAMP response element binding protein (CREB), are involved in the activation of multiple downstream processes, typically those involved in cellular metabolism. Fusions of PRKACA to DNAJB1 are the defining oncogenic alteration in fibrolamellar hepatocellular carcinoma (FL-HCC) (PMID: 25557953, 25698061, 25605237, 25122662, 24578576, 26489647). PRKACA overexpression has been identified in HER2-targeted breast carcinoma (PMID: 24909179), and an activating hotspot mutation (L205R) in PRKACA has been frequently identified in patients with adrenal Cushing's syndrome (PMID: 24700472). False +ENST00000358598 NM_212471.2 5573 PRKAR1A False PRKAR1A, a regulatory subunit of protein kinase A, is altered by mutation or translocation in various cancers. PRKAR1A is a cyclic adenosine monophosphate (cAMP)-dependent regulatory subunit that inhibits the catalytic subunits of protein kinase A (PKA) (PMID: 15331577). Binding of cAMP to the regulatory subunit PRKAR1A releases the catalytic subunits of PKA to phosphorylate target proteins, resulting in the activation of signaling pathways that promote cell proliferation, cell division and invasion (PMID: 26042218, 27995993). Germline mutations in PRKAR1A are responsible for the Carney complex disorder characterized by skin pigmented lesions, myxomas, collagenomas and fibromas (PMID: 10973256) and for primary pigmented nodular adrenocortical disease leading to Cushing's syndrome (PMID: 17036196, 12424709). Deletions and loss-of-function mutations in PRKAR1A have been identified in adrenocortical tumors (PMID: 14500362). Missense and nonsense mutations result in decreased cAMP-dependent dissociation of PKA catalytic subunits, suggesting that PRKAR1A functions as a tumor suppressor. PRKAR1A has been identified as a translocation partner for RARA in acute promyelocytic leukemia (PMID: 17712046) and for RET in papillary thyroid carcinoma (PMID: 7678053). True +ENST00000303531 NM_002738.6 5579 PRKCB True PRKCB, a serine/threonine protein kinase, is altered by amplification in various cancers. PRKCB, protein kinase C beta, encodes for a calcium and diacylglycerol (DAG)-dependent serine/threonine protein kinase that plays an important role in angiogenesis, immunity via NF-κB signaling, apoptosis and cellular proliferation (PMID: 24795864, 9935234, 35567329). It is a member of the protein kinase C (PKC) family of proteins, which serve as major receptors of phorbol esters, a class of natural compounds that can promote tumors and are involved in the phosphorylation of various transduction pathways, including the Wnt pathway (PMID: 37505453, 28422739, 35567329). Alternative splicing of the PRKCB gene produces two isoforms, PCKβI and PCKβII, which exhibit distinct functional properties that contribute to the tissue-type specific oncogenic role of PRKCB (PMID: 24795864, 9935234, 17145886). Overexpression of both isoforms in breast and colon cancer cells increases cellular proliferation and TGF-alpha levels, suggesting that PRKCB functions as an oncogene in these contexts (PMID: 17145886, 9935234). Furthermore, PRKCB is upregulated in breast cancer and Ewing sarcoma tumors and its loss in Ewing sarcoma models, both in vitro and in vivo, induces apoptosis and prevents tumor growth (PMID: 19324060, 22930730). However, promoter methylation leading to loss of PRKCB expression is associated with worse survival in diffuse large B-cell lymphoma (DLCBL), non-small cell lung cancer (NSCLC) and prostate cancer, and patients with glioblastoma multiforme with undermethylated PRKCB show higher rates of survival, suggesting that PRKCB may function as a tumor suppressor gene in these cancer types (PMID: 35567329, 37505453, 34198725, 38606198). True +ENST00000295797 NM_002740.5 5584 PRKCI True PRKCI, a serine/threonine kinase, is frequently altered by amplification across various cancers. The PRKCI gene encodes the protein kinase C iota, an atypical serine/threonine kinase involved in multiple cellular processes. PRKCI protects BCR-ABL leukemia cells from undergoing apoptosis (PMID: 9346882). It also enhances cell proliferation and survival via NF-KB pathway activation (PMID: 10467349, 10356400). PRKCI promotes colony formation and tumor growth in vivo (PMID: 15994303) and cooperates with SOX2 to activate the Hedgehog signaling pathway in lung cancers (PMID: 24525231). PRKCI phosphorylates BAD in glioma cells, thus allowing them to evade apoptosis (PMID: 21419810). PRKCI is frequently altered by amplification in several cancers, including lung, ovarian, esophageal and head and neck carcinomas (cBioPortal, MSKCC, Dec. 2016). False +ENST00000331968 NM_002742.2 5587 PRKD1 False PRKD1, a serine/threonine kinase, is mutated in salivary gland carcinomas. The PRKD1 gene encodes the serine/threonine protein kinase D1, which is involved in a variety of cellular processes. PRKD1 is activated by diacylglycerol (DAG) and is able to phosphorylate EGFR, among other targets, leading to signaling suppression (PMID: 17703233, 10523301, 21209314). PRKD1 plays a role in apoptosis and NF-kB-mediated response to oxidative stress (PMID: 10764790, 12505989). PRKD1 has also been implicated in VEGF-induced angiogenesis in endothelial cells (PMID: 18332134) and in the KRAS-mediated methylator phenotype of colorectal cancers (PMID: 24623306). The PRKD1 gene is mutated in cutaneous squamous cell carcinomas and salivary gland adenocarcinomas (PMID: 25240283, 25303977). Small molecule inhibitors against PRKD1 and other protein kinase D isoforms are available (PMID: 20442301). False +ENST00000314191 NM_006904.6 5591 PRKDC True PRKDC, a catalytic subunit of the DNA-dependent serine/threonine protein kinase, is recurrently altered by mutation in various cancers. PRKDC, a member of the phosphatidylinositol 3-kinase-related kinase (PIKK) protein family, encodes for a catalytic subunit of the DNA-dependent serine/threonine protein kinase (DNA-PK), which functions in the non-homologous end joining pathway of DNA repair and V(D)J recombination (PMID: 31189537, 22813740, 19535303, 9398855). DNA-PK is activated by the DNA-Ku70/80 protein dimer complex, which also mediates DNA binding for DNA repair (PMID: 20023628, 18334221). DNA-PK maintains chromosome stability and telomere length by preventing end joining through interaction with Ku (PMID: 12954774, 11090128). The oncogenic function of PRKDC is likely tissue-specific. Knockdown of PRKDC in lung cancer and colorectal cancer cell lines and models induces increased DNA damage and malignant transformation, suggesting that PRKDC functions predominantly as a tumor suppressor gene in these contexts (PMID: 31055244, 26175416). Conversely, overexpression of PRKDC in breast cancer and gastric cancer cell lines and models induces cell cycle progression and cellular proliferation and migration, suggesting that PRKDC functions predominantly as an oncogene in this context (PMID: 31513357, 31255330). Mutations of PRKDC have been identified in various cancers, including lung cancer, breast cancer, liver cancer, colorectal cancer and skin cancer (PMID: 32238472, 35801800). True +ENST00000366898 NM_004562.2 5071 PRKN False PRKN encodes a tumor suppressor invovled in tagging cellular proteins for degradation. PRKN is inactivated in various cancer types, and its dysfunction is associated with hereditary Parkinson's disease. PRKN encodes the parkin protein, which is a component of an E3-ubiquitin ligase complex that serves to mark proteins for proteasomal degradation (PMID: 19946270, 24793136). The PRKN protein functions through physical interaction with ubiquitin-conjugating enzymes, including UBCH7 and UBCH7 (PMID:19946270). Through regulation of protein stability, PRKN plays a role in several molecular processes which contribute to oncogenesis, including but not limited to cell cycle progression (PMID:24793136), mitochondrial homeostasis (PMID: 25815004, 24149988) and apoptosis (PMID: 19679562). PRKN is frequently deleted across a variety of cancer types (PMID: 24793136, 24297497, 19946270); however, other forms of PRKN inactivation, including somatic mutation and promoter hypermethylation/down-regulation of expression, have also been observed (PMID: 24297497; cBioPortal, MSKCC, Nov. 2015). Recently, germline mutation in PRKN has been associated with familial lung cancer (PMID: 25640678). True +ENST00000304992 NM_006445 10594 PRPF8 False PRPF8, a core component of spliceosome complexes, is infrequently altered in cancer. PRPF8 encodes the core component of the catalytic U2- and U12-dependent spliceosome complexes. PRPF8 contains several WD domains throughout the protein that allow for protein-protein interactions to mediate the assembly of spliceosomal proteins, snRNAs and pre-mRNA splicing (PMID: 9774689). Alternative splicing of PRPF8 has been identified in various different cancers and results in dysfunction of the proofreading function when assembling spliceosome complexes (PMID: 24781015, 32547101, 35124606). PRPF8 is located close to the TP53 locus on chromosome 17p, and alternative splicing mutations of PRPF8 have been identified in cancer concomitantly with TP53 loss-of-function mutations (PMID: 24781015). True +ENST00000311737 NM_002769.4 5644 PRSS1 False PRSS1 encodes the digestive pro-enzyme trypsinogen, which is activated in the small intestine. Mutations in PRSS1 are associated with pancreatitis and increased risk of pancreatic cancer. PRSS1 encodes cationic trypsinogen which is secreted in the pancreas, making up about two-thirds of the trypsin content in normal pancreatic juice. Cationic trypsinogen is typically activated in the small intestine to become the digestive enzyme trypsin-1. Trypsin-1 cleaves peptide linkages involving the carboxyl group of lysine or arginine (PMID: 16791840, 7845208, 25010489). It is part of a family of serine protease enzymes that perform a wide variety of functions including immune response, digestion, blood coagulation and reproduction (PMID 12475199). Germline mutations in PRSS1 are associated with premature activation of trypsin-1 causing pancreatic self-digestion that results in pancreatitis and an increased risk of pancreatic cancer (PMID: 23187834, 25479140). Missense mutations in PRSS1 are relatively common in some other solid tumors, including melanoma and lung adenocarcinoma (cBioPortal, MSKCC, Mar. 2016). False +ENST00000373237 NM_002794 5690 PSMB2 True PSMB2, a subunit of the 20S core proteasome complex, is infrequently overexpressed in cancer. PSMB2 is a non-catalytic beta subunit of the 20S core proteasome complex (PMID: 15244466). The proteasome complex maintains protein homeostasis through the degradation of intracellular proteins (PMID: 15244466). PSMB2, along with the other six beta subunits, form the proteasome complex's proteolytic chamber through the assembly of two heptameric rings (PMID: 12015144). Overexpression of PSMB2 promotes tumorigenesis through decreasing homologous recombination, impairing DNA double-strand break repair, promoting cell proliferation and inhibiting apoptosis (PMID: 21660142, 36110152). In vitro knockdown of PSMB2 in cell lines suppresses proteasome complex activity and cell proliferation, and promotes apoptosis (PMID: 36110152). High levels of PSMB2 have been identified in a variety of tumor types including chronic leukemia, liver cancer and hepatocellular carcinoma (PMID: 32933107, 29780166). False +ENST00000331920 NM_000264.3 5727 PTCH1 False 3A PTCH1, a tumor suppressor and inhibitor of the hedgehog pathway, is recurrently mutated in basal cell carcinoma. PTCH1 (protein patched homolog 1) encodes a transmembrane protein that is a component of the oncogenic Hedgehog (HH) signaling pathway. PTCH1 functions as the primary receptor for sonic hedgehog (SHH), a secreted protein involved in embryonic development (PMID: 11001584, 8906787). In response to SHH, PTCH1 binds and inhibits Smoothened (SMO), a G protein-coupled receptor; this results in decreased signaling via the HH pathway (PMID: 14737121). Thus, PTCH1 functions as a classic tumor suppressor by inhibiting SMO-mediated oncogenic signaling. Germline PTCH1 mutations are associated with the nevoid basal cell carcinoma syndrome (NBCCS, Gorlin syndrome), which predisposes patients to basal cell carcinoma as well as medulloblastoma (PMID: 8658145). Recurrent somatic inactivating PTCH1 mutations have been identified in basal cell carcinoma (PMID: 26950094) and medulloblastoma, suggesting that mutant PTCH1 is a primary driver of these diseases (PMID: 21107850, 22832583, 24651015, 22820256, 21163964, 22832581). As inactivating PTCH1 mutations lead to increased SMO activity recently developed SMO inhibitors show promising responses in PTCH1 mutant tumors (PMID: 24651015, 26169613). True +ENST00000371953 NM_000314.4 5728 PTEN False 1 PTEN, a lipid and protein phosphatase, is one of the most frequently mutated genes in cancer. PTEN is a tumor suppressor that is one of the most frequently mutated genes in human cancer (PMID: 9072974, 9090379, 22473468). PTEN has several physiological functions, most notably operating as a phosphatase that converts phosphatidylinositol (3,4,5)-triphosphate (PIP3) to phosphatidylinositol (4,5)-diphosphate (PIP2) at the cell membrane (PMID: 18767981). Impairment of PTEN function through multiple mechanisms, including through non-synonymous mutations, results in PIP3 accumulation and constitutive activation of catabolic downstream AKT/mTOR signaling. Therefore, PTEN inactivation promotes cell growth, proliferation and survival (PMID: 12040186). Additionally, nuclear PTEN is thought to regulate RAD51 expression, and in this way is also associated with homologous recombination and repair of DNA strand breaks (PMID: 17218262, 23888040). Thus, loss of PTEN may also lead to greater genomic instability and provide a setting for the accumulation of other deleterious mutations. PTEN is frequently mutated in many types of human cancers (PMID: 15254063). Germline loss-of-function PTEN mutations occur in approximately 80% of patients with the cancer predisposition syndrome Cowden disease, which is associated with high-penetrance breast and thyroid cancer (PMID: 9467011, 24136893, 21430697). True +ENST00000370651 NM_003463.4 7803 PTP4A1 False PTP4A1, a protein tyrosine phosphatase, is altered by amplification at low frequencies in various cancers. The PTP4A1 gene encodes a protein tyrosine phosphatase (PTP) with a characteristic PTP domain that is necessary to dephosphorylate its substrates, and a prenylation domain that allows the protein to bind the plasma membrane (PMID: 9018080, 15571731). PRP4A1 forms part of the mitotic spindle and stimulates progression from G1 to S phases during mitosis, probably via negative regulation of the p21 tumor suppressor (PMID: 12235145, 14643450). PTP4A1 enhances cell migration, invasion and metastasis by activating SRC and ERK pathways (PMID: 12782572, 19199380,). THE PTP4A1 gene is rarely altered in human tumors, only being amplified in a small subset of tumors such as prostate cancers (cBioPortal, MSKCC, Dec. 2016). False +ENST00000371621 NM_001278618.1 5770 PTPN1 True PTPN1, a tyrosine phosphatase, is recurrently altered by mutation, fusion, deletion, and amplification in a variety of cancer types. PTPN1 (also PTP1B) is a tyrosine phosphatase that functions as a signaling protein. PTPN1 is implicated as a negative regulator of the insulin pathway and removes phosphat molecules from activated insulin receptor kinase (PMID: 11884589). In addition, PTPN1 regulates the activity of a variety of other kinases implicated in a variety of cellular contexts including EGFR (PMID: 9050838), JAK2 (PMID: 11694501), TYK2 (PMID: 11694501), and FAK (PMID: 16291744), among others. PTPN1 activity has been associated with the regulation of several cellular processes including invasion (PMID: 18332219), cytokine sensitivity (PMID: 26817397), cell adhesion (PMID: 10409197), and proliferation (PMID: 14766979). Loss of PTPN1 in preclinical studies leads to increased JAK-STAT pathway activity in hematopoietic cells (PMID: 24531327) and deletion of PTPN1 in mice results in a hematopoietic malignancy (PMID: 28111468). Somatic mutations in PTPN1 have been identified in lymphomas including B-cell acute lymphoblastic leukemia (B-ALL), primary mediastinal B cell lymphoma (PMBCL), and Hodgkin’s lymphoma (PMID: 29650799, 24531327). PTPN1 alterations are largely loss-of-function mutations that are associated with reduced PTPN1 protein expression and phosphatase activity, suggesting that PTPN1 functions as a tumor suppressor (PMID: 24531327). However, overexpression of PTPN1 truncation and splice mutations in cell lines results in transformation, implicating some alterations as dominant negative mutations (PMID: 27855221). In addition, the PTPN1 gene lies within the 20q region that is frequently deleted in myeloproliferative disorders and myelodysplastic syndromes (PMID: 7949181) and amplified in breast and ovarian cancers (PMID: 8758909, 10815905). PTPN1 fusion proteins have also been identified in non-Hodgkin lymphomas (PMID: 27268263). True +ENST00000351677 NM_002834.3 5781 PTPN11 True PTPN11, a protein tyrosine phosphatase, is altered in various solid and hematologic malignancies. PTPN11 (also known as SHP2) is a protein tyrosine phosphatase that removes phosphate groups from signaling molecules (PMID: 18286234). In its resting inactive state, PTPN11 maintains a conformation that inhibits phosphatase activity (PMID: 18286234). After growth factor or cytokine stimulation of a receptor tyrosine kinase (RTK), such as the platelet-derived growth factor receptor alpha (PDGFRA), PTPN11 is recruited to the phosphorylated tyrosine residue on the RTK leading to a conformational change and activation of phosphatase activity (PMID: 18286234, 21575863). PTPN11 regulates multiple signaling cascades and is involved in the negative regulation of the PI3K/AKT (PMID: 14644997), STAT5 (PMID: 23103841) and RAS/RAF/MEK/ERK signaling pathways (PMID: 25026279, 24618081). Germline mutations in PTPN11 have been identified in Noonan syndrome and LEOPARD syndrome, while somatic PTPN11 mutations have been identified in several cancers and are prevalent in juvenile myelomonocytic leukemia (JMML) (PMID: 11704759,16358218). PTPN11 mutations typically occur as missense mutations that disrupt phosphatase activity or have dominant negative function, leading to the activation of signaling pathways that regulate growth (PMID: 21575863). However, both gain-of-function and loss-of-function mutations can lead to pathway activation, as the open conformation of PTPN11 resulting from mutation matters more for its interaction with other proteins than does its catalytic activity (PMID: 29559584). KRAS-mediated tumorigenesis has been shown to depend on functional PTPN11 protein (PMID: 29808010, 29808006, 29808009).While PTPN11-specific therapies have not yet been developed, small molecule inhibitors targeting members of the RAF and PI3K signaling pathways have been found to be therapeutically effective in the context of PTPN11 loss (PMID: 26365186). False +ENST00000411767 NM_080683 5783 PTPN13 False PTPN13, a tyrosine phosphatase, is infrequently altered in cancer. PTPN13, a member of the PTP family, encodes for a tyrosine phosphatase that functions in apoptotic regulation (PMID: 15611135). PTPN13 interacts with FAS and NGFR through its phosphotyrosine substrate recognition pocket to negatively regulate pro-apoptotic signaling (PMID: 7536343, 20620960). PTPN13 functions in the regulation of various other cellular physiological processes, including cell-cell adhesion and cellular proliferation, by regulating phosphorylation levels of signaling pathways such as Akt and PI3K (PMID: 32919955, 23604317). Knockdown of PTPN13 in various cancer cell lines and models reduces cell-cell junction stability and cell-cell adhesion, tumor growth and invasiveness, and colony formation and invasion, suggesting that PTPN13 functions predominantly as a tumor suppressor gene (PMID: 31938048, 20501847, 17982484). Downregulation of PTPN13 has been identified in various types of cancer, including breast cancer, non-small cell lung cancer and clear cell renal cell carcinoma (PMID: 20501847, 22245727, 32919955). Hypermethylation of the PTPN13 promoter region has also been identified in lymphoma, breast cancer, liver cancer and gastric cancer (PMID: 16572203). True +ENST00000366956 NM_005401 5784 PTPN14 False PTPN14, a tyrosine phosphatase, is infrequently altered in cancer. PTPN14, a member of the PTP family, encodes for a tyrosine phosphatase that functions in development and the regulation of various cellular processes including cellular proliferation, cellular adhesion and cytoskeleton organization (PMID: 10212280, 10934049). PTPN14 modulates angiogenesis and organogenesis through the TGF-β/BMP pathway and Hippo-YAP pathway (PMID: 22233626, 17893246, 26950094). Knockdown of PTPN14 in various cancer cell lines and models induces cellular proliferation and invasion, suggesting that PTPN14 functions predominantly as a tumor suppressor gene (PMID: 29017057, 32141101, 32645410). Loss of PTPN14 has been identified in various types of cancer, including prostate cancer, pancreatic cancer and basal cell carcinoma (PMID: 32645410, 29017057, 33602785). True +ENST00000309660 NM_002828.3 5771 PTPN2 False PTPN2, a tyrosine phosphatase, is recurrently altered by mutation and deletion in lymphomas. PTPN2 (also TC-PTP) is a tyrosine phosphatase that functions as a signaling protein. PTPN2 is highly expressed in immune cells and functions to remove phosphate molecules from proteins, namely protein tyrosine kinases (PMID: 19290937). Many substrates of PTPN2 have been identified including JAK1 (PMID: 11909529), JAK3 (PMID: 11909529), STAT1/6 (PMID: 12138178, 17210636), EGFR (PMID: 11514572, 9488479), and the oncogenic fusion BCR-ABL (PMID: 14966296), among others. Predominantly, PTPN2-mediated dephosphorylation of protein tyrosine kinases results in negative regulation of downstream signaling pathways (PMID: 11514572). PTPN2 can shuttle between the nucleus and cytoplasm, which is dependent on numerous factors including the presence of cellular stress (PMID: 11479308). Activity of PTPN2 is required for a variety of cellular processes including cell cycle control (PMID: 11498795), lymphocytic proliferation (PMID: 12847239), lymphocytic lineage specification (PMID: 28798028), insulin signaling (PMID: 20484139), apoptosis (PMID: 21984578) and cytokine sensitivity (PMID: 21115548). PTPN2 also negatively regulates T cell receptor signaling, leading to attenuation of immune responses (PMID: 22080863). Loss of PTPN2 expression in mice results in hematopoietic deficiencies and dysregulation of inflammatory responses (PMID: 9271584, 29444435). Polymorphisms in PTPN2 are associated with autoimmune disorders such as Crohn’s disease, type I diabetes and ulcerative colitis (PMID: 22080863, 22457781, 24445916). Deletions and somatic loss-of-function mutations in PTPN2 have been identified in T-cell acute lymphoblastic leukemia and peripheral T-cell lymphomas (PMID: 20473312, 21551237, 21791476). In contrast, PTPN2 expression has been associated with colon cancer promotion due to reduced inflammasome activity (PMID: 29444435). Consistent with this result, deletion of PTPN2 leads to enhanced efficacy of immunotherapies as evidenced in preclinical studies by an activated inflammatory response (PMID: 28723893). True +ENST00000356435 NM_002839.3 5789 PTPRD False PTPRD, a tumor suppressor and receptor protein tyrosine phosphatase, is altered by mutation or deletion in various cancer types including skin and lung cancers. PTPRD encodes the enzyme Receptor-type tyrosine-protein phosphatase delta (PTPδ), which is a member of the family of protein tyrosine phosphatases (PTPs) that are involved in various cellular processes. Specifically, PTPRD contains extracellular, transmembrane and intracellular domains thus constituting a receptor-like PTP with a role in cell-cell adhesion (PMID: 16557282, 22977525). Identified targets for dephosphorylation by PTPRD include STAT3 and AURKA (PMID: 19478061, 22305495). PTPRD is inactivated in a large number of glioblastomas and is mutated, deleted or promoter methylated in multiple other human cancers, ranging from neuroblastomas to endometrial, lung and colon cancers and has a putative tumor suppressor function (PMID: 25263441, 19478061). True +ENST00000357368 NM_002850.3 5802 PTPRS False PTPRS encodes a tyrosine phosphatase involved in regulation of synapse structure, function and plasticity in the central nervous system. Mutations, altered expression and microdeletions of PTPRS are found in colorectal, head and neck and ovarian cancers, among others. The PTPRS gene encodes the enzyme receptor-type tyrosine-protein phosphatase T (PTPσ), which is a member of the family of protein tyrosine phosphatases (PTPs) that are involved in various cellular processes. Specifically, PTPRS contains extracellular, transmembrane and intracellular domains thus constituting a receptor-like PTP. Additionally, PTPRS is considered a member of the leukocyte common antigen-related (LAR) subfamily of PTPs, due to its role in development of the nervous system and evolutionary conservation (PMID: 15674434). PTPRS is seldom altered in cancer but its deregulation has been observed in several cancers, such as colorectal, head and neck and ovarian tumors, and it might act as a tumor suppressor through regulation of angiogenic and EMT processes (PMID: 16557282, 25998839, 26308964, 22065749). True +ENST00000373198 NM_133170.3 11122 PTPRT False PTPRT encodes a tyrosine phosphatase involved in cell adhesion. Mutations of PTPRT are found in colon, lung, skin and head and neck cancers, among others. The PTPRT gene encodes the enzyme receptor-type tyrosine-protein phosphatase T, which is a member of the protein tyrosine phosphatases (PTPs) family. PTPRT contains extracellular, transmembrane and intracellular domains, thus constituting a receptor-like PTP with a role in cell-cell adhesion (PMID: 16973135, 16557282). Identified targets for dephosphorylation by PTPRT include cadherins E, N and VE, STAT3, PXN and BCR (PMID: 16973135, 22767509, 20133777). Mutations in PTPRT are found specifically in colon cancer but also in a wide range of other human cancers, including both solid and blood tumors. PTPRT is characterized as a tumor suppressor, as PTPRT mutations in cancer are predominantly loss of function, and PTPRT knock-out mice are hypersensitive to AOM (azoxymethane)-induced colon cancer (PMID: 17223850, 25982282, 15155950, 21517784). True +ENST00000257075 NM_014676 9698 PUM1 False PUM1, an RNA binding protein involved in post-translational gene regulation, is infrequently altered in cancer. PUM1 is an RNA-binding Pumilio protein of the highly conserved PUF family of proteins, which are important mediators of post-translational gene regulation. These proteins bind to the 3’UTR of target mRNAs, promoting their degradation and thereby controlling their translation (PMID: 18411299, 28232582, 31395860). However, PUM1 has also been shown to mediate transcript-specific post-translational gene activation in certain contexts (PMID: 28232582). Due to its role in regulating gene expression, PUM1 is known to be involved in tumorigenesis, as dysregulated expression of PUM1 can lead to DNA repair damage, chromosomal instability (PMID: 29428722) and may inhibit apoptosis (PMID: 18166083). PUM1 may also regulate innate immunity (PMID: 28760986). In leukemia, PUM1 is known to promote and maintain hematopoietic stem and myeloid leukemia cell growth (PMID: 28232582). False +ENST00000361752 NM_006775 9444 QKI False QKI, an RNA-binding protein, is altered by deletion in various cancers. QKI, a member of the signal transduction and activation of RNA (STAR) family, is an RNA-binding protein which regulates cellular differentiation through control of mRNA transport, stability and splicing (PMID: 33397958, 27029405). QKI regulates myelination and oligodendrocyte differentiation, and downregulation of QKI has been implicated in schizophrenia (PMID: 16641098). QKI encodes for three major alternatively spliced transcripts, QKI-5, QKI-6 and QKI-7, that are developmentally regulated and vary in RNA processing roles in the brain (PMID: 19727426, 23319046, 11917126). Knockdown of QKI in various cancer cell lines and models induces cellular proliferation, migration and invasion, suggesting that QKI functions predominantly as a tumor suppressor gene (PMID: 33569406, 35600368, 33196842). Downregulation of QKI has been identified in various types of cancer, including colorectal cancer, prostate cancer and oral cancer (PMID: 19686745, 24153116, 24918581). True +ENST00000229340 NM_006861.6 11021 RAB35 True RAB35 encodes a member of the Ras superfamily of small GTPases that signals through the pro-oncogenic PI3-kinase pathway. RAB35 is a member of the Ras superfamily of small GTPases that collectively function in regulating the myriad of membrane transport processes in eukaryotic cells (PMID: 19931531, 20937701, 23060965). RAB35 (also named Ray or Rab1c), interacts with p53-related protein kinase and distributes in the nucleus, cytosol, and cell membrane (PMID: 16600182). RAB35 is an interacting partner for nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) in human lymphoma cells (PMID:14968112) and mediates Wnt5a-induced migration of breast cancer cells (PMID:23353182). Through mutual antagonism, RAB35 and ARF6 are geared to reciprocally balance the recycling of integrins and cadherins in order to tune cell adhesive behavior towards cell migration or intercellular contact. Consistent with that, there is a strong reduction in RAB35 expression levels in brain, breast and squamous tumors, which are all associated with EGF receptor overexpression and enhanced ARF6 activity (PMID: 23264734). A clinical investigation demonstrates a significant positive correlation between RAB35 and androgen receptor (AR) expression in ovarian cancer, making RAB35 attractive as a candidate for biomarker of AR function in ovarian cancer (PMID:19623182). Importantly, RAB35 is a critical regulator of PI3K-AKT signaling that acts upstream of PDK1 and mTORC2 and downstream of growth factor receptors (PMID:26338797). Expression of two known cancer-related RAB35 missense mutations, RAB35-A151T or RAB35-F161L, resulted in increased AKT phosphorylation, enhanced cell viability, resistance to apoptosis under growth-factor deprivation, and PI3K-dependent transformation, indicative of a gain-of-function effect (PMID: 26338797). Searches of existing human tumor sequencing databases reveal that RAB35 mutations are rare and are therefore unlikely to appear on current lists of human cancer genes that rely solely on statistical methods to distinguish between driver and passenger mutations (PMID: 26338797). Finally, RAB35 is a target gene of miR-720 in HEK293T and HeLa cells, a nonclassical miRNA involved in the initiation and progression of several tumors (PMID:26413265). False +ENST00000356142 NM_018890.3 5879 RAC1 True RAC1 encodes a RAS superfamily small GTPase involved in the regulation of cell adhesion, differentiation and migration. RAC1 is predominantly mutated in melanoma and has several well-defined hotspot mutations. The RAC1 (ras-related C3 botulinum toxin substrate 1) gene encodes a member of the Rho family of GTPases, which includes RHO, RAC1 and CDC42. Rho GTPases regulate the assembly and disassembly of the cytoskeleton; in this regard, RAC1 plays a role in cell adhesion, differentiation and migration (PMID: 24072884, 17373658). Additionally, RAC1 is involved in pathways governing proliferation (MAPK pathway), the inflammatory response (NFkB pathway) and regulation of the cell cycle (PMID: 24072884, 10816416, 17373658). The activity of RAC1 is controlled by guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs), which switch GDP for GTP and trigger catalysis of GTP to GDP, respectively (PMID: 10816416). RAC1 is ubiquitously expressed, and gain-of-function mutations are implicated in processes underlying metastasis and drug-resistance; therefore, RAC1 is a putative drug target (PMID: 22407364, 25056119, 19509242, 24072884, 25594058, 24750242). RAC1 mutations are found predominantly in melanoma, but have also been identified in other cancer types (PMID: 22817889, 22842228, 17904119, 22786680). An alternatively spliced and constitutively active version of RAC1, named RAC1B, has been detected in colon and lung cancer (PMID: 11062023, 10597294, 15516977, 22786680). False +ENST00000249071 NM_002872.4 5880 RAC2 True RAC2 is a small GTPase that is implicated in promoting tumor growth, angiogenesis and metastasis. RAC2 encodes a small signaling GTPase protein Rac2 (Ras-relatedC3 botulinum toxin substrate 2) belonging to the Rac sub-family of Rho family of GTPases. RAC2 regulates various cellular processes such as secretion, cytoskeletal reorganization, cell polarization (specifically lamellipodial extension and membrane ruffling), and phagocytosis (PMID: 16949823). RAC2 has been identified as a component of the phagocytic oxidase complex in neutrophils, and a dominant negative mutation (D57N) in RAC2is associated with phagocyte immunodeficiency in humans (PMID: 10961859, 15814684, 21167572). In addition, RAC2 is involved in multiple kinase-mediated signal transduction pathways, including the mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3-K) signaling networks (PMID: 7664330, 9042860, 10843388). Unlike RAC1 and RAC3, RAC2 is expressed specifically in cells of hematopoietic lineages (PMID: 23850828, 12370311), and RAC2-deficient mice demonstrate cellular defects in multiple hematopoietic lineages, including stem and progenitor cells, neutrophils, mast cells, T and B cells (PMID:12370311, 11057896, 11320224). Mouse models have revealed a distinct role for RAC2 in promoting tumor growth, angiogenesis and metastasis (PMID: 24770346) and loss of RAC2 causes a significant delay in the development of BCR-ABL-driven myeloproliferative disorders (PMID: 17996650). False +ENST00000380774 NM_133339 5884 RAD17 False RAD17, a cell cycle checkpoint chromatin-binding protein, is frequently altered by loss-of-function in various cancers. RAD17 is a cell cycle checkpoint chromatin-binding protein that functions as a regulator of cell cycle arrest and DNA damage repair in response to DNA damage (PMID: 20424596). When DNA damage occurs in cells, RAD17 is phosphorylated at two conserved serine motifs on its C-terminus by ATM and ATR checkpoint kinases (PMID: 11418864). Phosphorylated RAD17 in turn recruits and activates Claspin to phosphorylate CHK1 to halt mitotic entry and mediate DNA repair and replication (PMID: 16885023, 11090622, 11390642). Loss of RAD17 function promotes tumorigenesis through increased chromosomal aberrations, DNA double-strand breaks and endoreduplication, significantly reducing cell viability (PMID: 12672690). Loss of RAD17 has been frequently identified in various cancer types, including head and neck squamous cell carcinoma, adenoid cystic carcinoma and prostate adenocarcinoma (PMID: 17657792, 26437225). True +ENST00000297338 NM_006265.2 5885 RAD21 False RAD21 encodes a protein involved in DNA repair and chromosome segregation. Germline mutations of RAD21 are associated with an increased risk of developing breast cancer. RAD21 is a subunit of the cohesin complex that aligns and stabilizes sister chromatids during metaphase (PMID: 24854081). The cohesin ring is comprised of two large structural proteins, SMC1a and SMC3, and this ring opens and closes through the binding of alpha-kleisin subunits to the RAD21 adapter protein (PMID: 24854081). The cohesin complex also functions to maintain chromatin looping structures, or 3D arrangements of DNA that allow for regulatory control of gene expression (PMID: 28985562). RAD21 has been implicated as a double-stranded break DNA repair protein (PMID: 20711430). Germline mutations in RAD21 have been identified in patients with cohesinopathies leading to a spectrum of developmental defects (PMID: 22633399). Somatic RAD21 mutations have been identified in patients with acute myeloid leukemia and myelodysplastic syndromes (PMID: 24335498, 23955599, 25006131). RAD21 mutations are predominantly missense and predicted to lead to loss of function activity, however, it remains unclear if RAD21 mutations lead to aneuploidy as predicted (PMID: 25006131). True +ENST00000265335 NM_005732.3 10111 RAD50 False RAD50 encodes a component of protein complex critical to DNA double-stranded-break end processing. Select germline mutations of RAD50 predispose to breast cancer. RAD50 is a subunit of the MRE11/RAD50/NBS1 (MRN) complex. The MRN complex is recruited to the site of DNA double-strand breaks (DSBs) as part of the DNA damage response (DDR) and plays a pivotal role in the repair of damage via either the homologous recombination (HR) or non-homologous end-joining (NHEJ) pathways (PMID: 2659437, 15309560). Within this complex, RAD50 functions as a flexible and dynamic dimer with ATPase activity. Biochemical studies have demonstrated that RAD50 functions in the maintenance of genomic integrity via the bridging of multiple RAD50 molecules to DNA and subsequent recruitment of the MRN complex to damaged chromatin (PMID: 21458667, 21511873, 21441914, 12152085, 25576492). RAD50 also has a direct function in bridging the ends of DNA that are to be repaired via NHEJ (PMID: 15309560). Germline mutations in RAD50 have been identified in patients with Nijmegen breakage syndrome-like disorder, characterized by progressive microcephaly, short stature and increased risk of cancer (PMID: 19409520). Mutations in RAD50 increase tumor susceptibility, similar to mutations in other DNA repair enzymes, and RAD50 somatic mutations have been identified in several human cancers (PMID: 16385572, 24894818). RAD50 mutations are predicted to be loss-of-function leading to the reduced ability for DNA damage-induced MRN foci to form (PMID: 19409520). True +ENST00000267868 NM_002875.4 5888 RAD51 False RAD51 encodes a protein involved in DNA double-strand break repair. Germline mutations or overexpression of RAD51 are associated with an increased risk of developing breast cancer. RAD51 is a member of the RAD51 recombinase family that functions in homologous recombination (HR)-mediated repair of double-stranded DNA breaks (DSBs). RAD51 acts at an early step in the DSB pathway: the 5’ended DNA strands flanking the DSB break site are resected and the single-stranded overhangs are coated by RAD51 forming a nucleo-protein filament (PMID: 25833843). RAD51 then probes for homologous DNA and initiates the process of strand invasion and exchange between homologous DNA (PMID: 19122145, 20930833). RAD51 forms protein complexes with known tumor suppressors including BRCA1, BRCA2 and PALB2; specifically, BRCA2 loads RAD51 monomers at sites of DNA double-strand breaks (PMID: 14636569, 20729832, 20930833, 20871615, 20729858). RAD51 germline mutations may increase breast cancer risk in certain populations (PMID: 10807537, 26108708), while other studies suggest the RAD51 135 G/C single nucleotide polymorphism may increase breast cancer risk in BRCA2 mutation carriers (PMID: 11248061, 17999359). RAD51 is infrequently mutated in human cancer; however, RAD51 overexpression has been linked to increased oncogenic potential in several tumor types, including pancreatic and breast (PMID: 18243065, 24811120, 26317153, 21807066, 10851081). True +ENST00000487270 NM_133509.3 5890 RAD51B False 1 RAD51B, a DNA repair protein involved in homologous recombination, is altered by mutation in various cancer types. RAD51B (also known as RAD51L1) is a member of the RAD51 recombinase family that functions in homologous recombination (HR)-mediated repair of double-stranded DNA breaks (DSBs). RAD51B, in complex with the central homologous repair protein RAD51, acts at an early step in the DSB pathway: the 5’ ended DNA strands flanking the DSB break site are resected and the single-stranded overhangs are coated by RAD51 forming a nucleo-protein filament (PMID: 25833843). RAD51 then probes for homologous DNA and initiates the process of strand invasion and exchange between homologous DNA (PMID: 19122145, 20930833). RAD51B expression is upregulated following ionizing radiation (PMID: 9788630) and RAD51B function is required for the formation of repair complexes including RAD51 paralogs, XRCC2 and XRCC3 (PMID:11751635, 11283264, 10938124). In addition to the DNA damage repair pathway, RAD51B has been shown to influence cell cycle regulation through phosphorylation of p53, CDK2 and cyclin E, resulting in G1 cell cycle delay (PMID: 10623463). Germline RAD51B variants have been identified as risk factors in familial breast cancer (PMID: 24139550, 26261251, 27149063, 34021944, 34635660). Loss of RAD51B expression results in loss of DNA repair functions and may promote oncogenesis via genome instability (PMID: 25313082, 24390348, 19330030). True +ENST00000337432 NM_058216.2 5889 RAD51C False 1 RAD51C is a protein involved in DNA double-strand break repair. Germline mutations of RAD51C are associated with an increased risk of breast and ovarian cancer. RAD51C is infrequently mutated in human cancers; however, RAD51C gene expression was reduced in a subset of breast cancer tumor samples (PMID: 23512992). RAD51C (also known as RAD51L2) is a member of the RAD51 recombinase family that functions in homologous recombination (HR)-mediated repair of double-stranded DNA breaks (DSBs). RAD51C, in complex with RAD51, acts at an early step in the DSB pathway: the 5’ended DNA strands flanking the DSB break site are resected and the single-stranded overhangs are coated by RAD51 forming a nucleo-protein filament (PMID: 25833843). RAD51 then probes for homologous DNA and initiates the process of strand invasion and exchange between homologous DNA (PMID: 19122145, 20930833). RAD51C is a component of two DSB repair complexes, BCDX2 (including RAD51B, RAD51C, RAD51D, and XRCC2) and CX3 (including XRCC3), which have roles in damage-stabilization and assembly of RAD51 filaments, respectively (PMID: 16093548, 23149936). RAD51C activity is also important for resolving Holliday junctions (PMID: 17114795, 14716019). Germline heterozygous mutations in RAD51C increase susceptibility to ovarian cancer and possibly breast cancer (PMID: 22415235, 32107557, 32235514, 33471991, 36411032). In addition, biallelic mutations of RAD51C are implicated in Fanconi anemia complementation group O (PMID: 20400963, 20952512, 29278735, 37031326). True +ENST00000345365 NM_002878.3 5892 RAD51D False 1 RAD51D encodes a protein involved in DNA double-strand break repair. Germline mutations of RAD51D are associated with an increased risk of developing breast and ovarian cancer. RAD51D (also known as RAD51L3) is a member of the RAD51 recombinase family that functions in homologous recombination (HR)-mediated repair of double-stranded DNA breaks (DSBs). RAD51D, in complex with RAD51, acts at an early step in the DSB pathway: the 5’ended DNA strands flanking the DSB break site are resected and the single-stranded overhangs are coated by RAD51 forming a nucleo-protein filament (PMID: 25833843). RAD51 then probes for homologous DNA and initiates the process of strand invasion and exchange between homologous DNA (PMID: 19122145, 20930833). Biochemical studies demonstrate that RAD51D forms a complex with three other RAD51 paralogs: XRCC2, RAD51B and RAD51C (known as the BCDX2 complex) (PMID: 10871607, 11751635, 16236763). This complex plays a role in the early stages of HR, prior to recruitment of RAD51 to damaged DNA foci (PMID: 11751635, 21821141). RAD51D also interacts with DNA binding and replication proteins including SFPQ, NONO, MCM2, and MSH2 (PMID: 19658102) and has a role in the telomere maintenance (PMID: 15109494). RAD51D-deficient cells develop spontaneous chromosomal aberrations and exhibit G2 arrest (PMID: 11283264, 21205838, 15781618). Germline, heterozygous mutations in RAD51D increase susceptibility to ovarian cancer and possibly breast cancer (PMID: 22415235, 32107557, 33471991, 36411032). RAD51D somatic mutations are rare in human cancers; however, RAD51D variants have been associated with increased chemoresistance (PMID: 19033885). True +ENST00000358495 NM_134424.2 5893 RAD52 False RAD52, a DNA repair protein, is inactivated by mutation in hereditary breast and ovarian cancers. RAD52 is a recombinase protein involved in RAD51-mediated DNA recombination and repair (PMID: 27649245). RAD52 binds to RAD51, promoting strand exchange during homologous recombination (HR) by pairing of homologous single- and double-stranded DNA (PMID: 27649245). Biochemical studies suggest RAD52 may help recruit RAD51 to double-stranded break (DSB) loci or form RAD51 nucleoprotein filaments (PMID: 10212258, 8550550, 9450758, 8370524). Whereas RAD51 knockout is embryonic lethal in mice, depletion of RAD52 in mice or human cell lines does not render a lethal or DSB-sensitive phenotype (PMID: 9774659, 8943369, 8692798). However, preclinical studies show that inactivation of RAD52 in cells lacking BRCA2, BRCA1, RAD51 paralogs or PALB2 results in synthetic lethality (PMID: 9774659, 22964643, 23071261) indicating that RAD52 has redundant function in RAD51-mediated HR repair pathways (PMID: 22964643, 23071261). Rare germline RAD52 variants have been found in familial breast and ovarian cancer (PMID: 12883740, 10463575, 23188672), however somatic RAD52 mutations in human cancers are infrequent. False +ENST00000371975 NM_001142548.1 8438 RAD54L False 1 RAD54L encodes a protein involved in DNA double-strand break repair. Mutations of RAD54L are found in non-Hodgkin lymphoma and chronic lymphocytic leukemia, among other cancers. RAD54L is a member of the SNF2-family of helicases that functions as a chromatin remodeling protein for the repair of double-stranded breaks during homologous recombination and repair (PMID: 17417655, 19671661). RAD54L binds to RAD51, the central homologous repair protein, and facilities a topological change in the DNA leading to DNA pairing and recombination (PMID: 11030338, 12359723). The RAD54L-RAD51 interaction results in supercoiling ahead of replication factor complex movement and the stabilization of the D loops during DNA repair (PMID: 11459989, 16818238). RAD51 binding to single and double-stranded DNA is stabilized by RAD54L during recombination initiation (PMID: 12566442). There is additional evidence that RAD54L can disassociate RAD51 from duplex DNA after recombination has been initiated (PMID: 12453424). Mutations in RAD54L have been identified in breast cancers, colon cancers, and lymphomas, however, somatic alterations of RAD54L in human cancers are infrequent (PMID: 10362365). False +ENST00000251849 NM_002880.3 5894 RAF1 True 2 RAF1 (CRAF), an intracellular kinase and component of the pro-oncogenic MAP-kinase signaling pathway, is infrequently mutated in cancer. Germline mutations of RAF1 are associated with Noonan and LEOPARD syndrome. RAF1, or CRAF, is one of three RAF serine/threonine kinases that signal in the mitogen-activated protein kinase (MAPK) pathway (PMID: 17555829). In response to extracellular stimuli, RAS-mediated signaling induces the formation of CRAF homodimers or CRAF/BRAF heterodimers leading to phosphorylation of MEK and subsequently ERK, which are signaling effectors in the MAPK pathway. Activation of MAPK signaling stimulates a wide range of cellular functions such as proliferation, differentiation and migration (PMID: 21779496). CRAF is ubiquitously expressed and is necessary for normal physiology in several tissues despite partially overlapping functions with ARAF and BRAF (PMID: 9767153). Somatic mutations in RAF1 occur at a low frequency in different cancers, including uterine, stomach, colorectal and malignant melanoma (PMID: 27273450, 24957944). Several RAF1 missense mutations have been shown to be oncogenic, leading to increased MAPK signaling and oncogenic transformation in vitro (PMID: 24569458). Additionally, rare oncogenic RAF1 fusions have been found in different types of cancer (PMID: 19363522, 20526349, 25266736). CRAF-activated MAPK signaling has also been associated with resistance to the BRAF inhibitor vermurafenib in melanoma (PMID: 27327499). False +ENST00000283195 NM_006267 5903 RANBP2 True RANBP2, a RAN-binding protein, is altered by mutation and chromosomal rearrangement in various cancers. RANBP2 encodes for a RAN-binding protein which functions as a component of the nuclear pore complex and regulates the RAN-GTPase cycle (PMID: 19118815, 26251516, 9480752). RAN, a small GTP-binding protein of the RAS superfamily, functions in the regulation of nuclear protein import and export, RNA processing and cell cycle progression, and is sumoylated by RANBP2 (PMID: 17287812, 26251516). RANBP2 interacts with the E2 enzyme UBC9 and enhances SUMO1 transfer from UBC9 to SUMO1 target SP100 to regulate protein localization and stability at the nuclear pore complex (PMID: 11792325). RANBP2 mutations are implicated in the development of the neurological disorder acute-necrotizing encephalopathy type 1 (PMID: 19118815, 26923722). Knockdown of RANBP2 in various cancer cell lines and models suppresses cellular proliferation, migration and invasion, suggesting that RANBP2 functions predominantly as an oncogene (PMID: 33816306, 34298689). Conversely, downregulation of RANBP2 in HeLa cells and colorectal cancer cells induces chromosomal misalignment, improper mitotic progression and mitotic cell death, suggesting that there may be tumor suppressive roles for RANBP2 (PMID: 24113188, 27058664). RANBP2 has been identified as a recurrent fusion partner of ALK in inflammatory myofibroblastic tumors (PMID: 12661011, 25028698, 26893756). False +ENST00000254066 NM_000964.3 5914 RARA False 1 RARA, a transcription factor, is altered by mutation or amplification in various solid tumors and is recurrently altered by chromosomal rearrangement in acute promyelocytic leukemia. RARA (retinoic acid receptor alpha) is a transcription factor that plays a role in the differentiation of white blood cells. RARA heterodimerizes with the RXR nuclear receptor and is activated by binding retinoid ligands (PMID: 1310350). Binding of the ligand results in a conformational change and recruits histone acetyltransferases and chromatin remodeling ATPases that activate transcription (PMID: 8274399, 11106744). RARA signaling is involved in the development of multiple tissue types, hematopoiesis, and stem cell specification (PMID: 9053308, 10529422, 24074870). Translocations between RARA and PML is implicated in the pathogenesis of acute promyelocytic leukemia (APL) (PMID: 23841729). The fusion protein confers sensitivity to targeted treatment with all-trans retinoic acid and arsenic trioxide (PMID: 20378816). Other rarer translocations partners with RARA have also been observed in APL (PMID: 25583766, 25629986, 23287866, 26414475, 20807888, 9288109). The RARA gene can also be methylated and reduced in expression other leukemias (PMID: 17993618). RARA mutations have been observed in breast fibroepithelial tumors (PMID: 26437033). The gene is also amplified in a subset of breast cancers and can interact with the estrogen receptor (PMID: 23830798, 20080953). False +ENST00000274376 NM_002890.2 5921 RASA1 False RASA1, a GTPase-activating protein (GAP) and negative regulator of RAS, is deleted or mutated in a number of cancers. RASA1 (Ras p21 protein activator 1) encodes a RAS GAP also known as p120RasGAP (PMID: 3201259). It accelerates the conversion of Ras-GTP to Ras-GDP to terminate Ras signaling (PMID: 17540168, 18568040). The absence of RASA1 activity leads to accumulation of GTP-bound RAS and persistent MAP kinase signaling following growth factor stimulation (PMID: 9121432). Somatic alterations in RASA1 map to all regions of the gene, including the C-terminal GAP catalytic domain and the N-terminal tandem SH2-SH3-SH2-PH-C2 domains. The SH2 and SH3 domains have been shown to interact with signaling proteins, including RhoGaps. Statistical analysis of mutational profiles of more than 8,200 tumor data sets identified RASA1 as a candidate driver and a putative tumor-suppressor gene based on a high ratio of inactivating to benign mutations (PMID: 24183448). RASA1 has also been implicated as a potential tumor suppressor in aggressive cutaneous squamous cell carcinoma and several subtypes of breast cancer (PMID: 25303977, 16570289, 19372580). The highest rates of RASA1 mutations have been reported for prostate adenocarcinoma (13.1%) and cutaneous squamous cell carcinoma (13%) (PMID: 22722839, 25303977). In most cancers somatic alterations in RASA1 are infrequent (e.g. 1.6% across 21 tumor types) (PMID: 24390350). RASA1 plays an essential role in vascular system development, as loss-of-function mutations cause capillary ‘malformation-arteriovenous’ malformation syndrome (CM-AVM) (PMID: 24038909, 22913934). True +ENST00000267163 NM_000321.2 5925 RB1 False RB1, a regulator of the cell cycle, is inactivated by mutation, deletion or allelic loss in various cancer types, including retinoblastoma and lung cancer. RB1, also known as RB, is involved in the cell-cycle checkpoint and in its active form inhibits the transition from G1 to S phase of the cell cycle until the cell is ready to divide. RB is active in its unphosphorylated form where it binds to E2F family of transcription factors, which together with the E2F Dimerization Partner (E2F-DP), inhibits the transcription of S-phase promoting factors by recruiting histone deacetylases (HDACs) and induce heterochromatin formation (PMID: 1655277). At the end of G1, cyclin-dependent kinases (CDKs) phosphorylate RB to pRB which leads to its dissociation from the E2F-DP complex, thereby allowing entry into S-phase. RB remains phosphorylated until the end of mitosis at which point it is dephosphorylated by protein phosphatase 1 (PP1) to activate the G1-S-phase checkpoint (PMID: 20694007). In addition to its role in G1 cell cycle arrest, RB1 has also been shown to play a role in safeguarding genome stability and mediating apoptosis, senescence and differentiation in response to various stimuli (PMID: 22293180). As a result of its role in these essential cellular functions, loss of function of RB1 not only leads to unregulated cell division and growth but also to the abrogation of multiple mechanisms that safeguard against cellular transformation and tumorigenesis. Loss-of-function and deletions of RB1 have been associated with many human cancers including lung, breast, prostate and bladder cancers, and concomitant loss of RB1 and p53 are thought to constitute a tumor-initiating event (PMID: 12204530). Homozygous loss or inactivation of the RB1 gene is a hallmark of retinoblastoma (PMID: 22293180), and heterozygous germline mutations in RB1 predispose children to retinoblastoma (PMID: 10502774, 24688104, 27068507) and adults to sarcoma and other tumors (PMID: 16269091, 22205104). True +ENST00000329236 NM_001204468.1 8241 RBM10 False RBM10 encodes a member of the RNA-binding motif gene family that is implicated in regulating mRNA alternative splicing. RBM10 is mutated in various human cancers, and also identified as a susceptibility gene in TARP syndrome. RBM10 encodes a nuclear protein that belongs to a family of proteins with RNA-binding motif. RBM10 is located on the X chromosome and therefore subject to X-inactivation whereby the remaining active allele is widely expressed in human cell lines and tissues (PMID: 11944989, 15514923). Mutations that result in a truncated RBM10 protein are identified as the causes of TARP (Talipes equinovarus, Atrial septal defect, Robin sequence, and Persistent left superior vena cava) syndrome, which has been reported to cause pre- or postnatal death in affected males (PMID: 20451169, 21910224, 24000153). RBM10 was discovered to be among the most frequently mutated genes in lung adenocarcinoma samples (PMID: 22980975, 25079552); mutations in this gene have also been observed in breast, colon, ovary, pancreas and prostate cancers (PMID: 20668451, 16959974). RBM10 has been characterized as an RNA-binding protein both in vitro and in vivo, and identified as an important regulator of alternative splicing (PMID: 24000153, 24332178). Recently, RBM10 has been shown to regulate alternative splicing of FAS and Bcl-X, two genes involved in apoptosis (PMID: 24530524). True +ENST00000369784 NM_022768.4 64783 RBM15 True RBM15, an RNA binding protein, is altered by chromosomal rearrangement in hematologic malignancies. RBM15 (also OTT) is an RNA binding protein that is a member of the SHARP family of proteins (PMID: 17376872). RBM15 is a regulator of N6-methyladenosine methylation of RNA, an RNA modification that impacts gene expression (PMID: 17376872). RBM15 binds pre-messenger RNA at introns of important hematopoietic genes, including GATA1, MPL, and RUNX1, and recruits splicing factors to mediate alternative splicing (PMID: 26575292, 25468569). In addition, RBM15 is important in the nuclear export of mRNA via binding to the nuclear receptor NFX1, leading to nuclear envelope localization in order to coordinate messenger ribonucleoprotein binding (PMID: 17001072, 18981216, 19586903, 19786495). RBM15 is also important in the regulation of several cellular functions including X chromosome inactivation, cell fate specification, DNA damage and cellular proliferation (PMID: 26190105). RBM15 is highly expressed in hematopoietic stem cells and RBM15 expression restricts the development of myeloid and megakaryocytic cell types (PMID: 17283045). In addition, RBM15 coordinately regulates differentiation in a cell-type specific manner with NOTCH transcriptional activity (PMID: 17283045). Loss of RBM15 expression in murine models results in hematopoietic abnormalities including loss of peripheral B cells and a shift towards myeloid progenitor fate (PMID: 17376872). Recurrent RBM15 translocations are found in patients with acute megakaryocytic leukemia (PMID: 11344311). In addition, somatic loss-of-function mutations in RBM15 have been identified in phyllodes tumors, a benign fibroepithelial neoplasm of the breast (PMID: 29315289). True +ENST00000421138 NM_002907.3 5965 RECQL False RECQL, a DNA helicase, is a germline breast cancer susceptibility gene. The RECQL gene encodes a DNA helicase that localizes to sites of DNA damage where mismatch repair factors are also recruited and unwinds the DNA (PMID: 7961977, 8056767, 15886194). The precise mechanisms of action of RECQL are largely unknown, but it is thought to be required for proper DNA replication, DNA repair and genome homeostasis (PMID: 18074021, 20065033, 15886194, 23095637). Alternative functions for RECQL include a role in telomere maintenance (PMID: 24623817). RECQL has been described to regulate genes that promote cell migration and invasion and inhibit apoptosis (PMID: 25424877, 25483193). The RECQL gene is rarely altered in tumors (cBioPortal, MSKCC, Dec. 2016). Germline mutations in RECQL have been associated with breast cancer susceptibility (PMID: 25915596, 25945795). True +ENST00000428558 NM_004260.3 9401 RECQL4 False RECQL4 encodes a DNA helicase that is involved in DNA replication and repair. Germline mutations of RECQL4 are associated with Rothmund-Thomson, RAPADILINO and Baller-Gerold syndromes and predispose to osteosarcomas, among other cancers. RECQL4 appears to function both in single-stranded DNA annealing and double-stranded DNA unwinding and is involved in DNA replication and various types of DNA repair, including double-strand break repair, nucleotide excision repair, base excision repair and single strand repair (PMID: 20065033, 20222902, 17320201, 18693251, 16949575, 22508716, 19567405). RECQL4 functions as a tumor suppressor. Inheritance of two compromised alleles leads to Rothmund-Thomson Syndrome (RTS), Baller-Gerold Syndrome (BGS), or RAPADILINO syndrome, each a rare syndrome with many overlapping phenotypic features. It has been suggested that the different syndromes are a result of mutations with different effects on the protein product, with certain domains involved in specific pathways (PMID: 20301383, 20113479, 17364146). RTS and RAPADILINO have a cancer predisposition, particularly osteosarcoma. RECQL4 somatic mutations, reported in tumors of numerous tissue types, are found across the gene without any specific hotspot. There is currently no therapy targeted at RECQL4 mutations. Missense mutations make up approximately 69% of all point mutations in RECQL4 in reported tumor samples. These mutations are scattered throughout the gene, include the Sld2 (DNA replicative factor) domain and the conserved RecQ-family helicase domain (PMID: 23238538, 23899764, 20668451, 24332040). Mutations in the Sld2 domain have the potential to affect the initiation of DNA replication (PMID: 25336622). Mutations within the helicase domain may affect the ability of RECQL4 to carry out strand annealing/unwinding functions (PMID: 25336622). True +ENST00000295025 NM_002908.2 5966 REL True REL, a transcription factor, is most frequently altered by mutation or amplification in B-cell lymphomas. REL encodes a transcription factor in the NF-kappa B family of transcription factors regulating immune function (PMID:22405852). It is important for the development of regulatory T-cells, B-cell proliferation and survival, and cytokine production (PMID:19995950,10049356,12646638, 12426000). While normally expressed mainly in lymphocytes, it has also been found expressed in various solid cancer types in an oncogenic role (PMID:18037997, 21933882). Polymorphisms in REL are associated with autoimmune disease such as rheumatoid arthritis, psoriasis, and gastrointestinal autoimmune disorders (PMID:19503088, 20953190, 21425313). REL is most frequently altered by amplifications seen in both Hodgkins and non-Hodgkins lymphomas (PMID: 11433522, 12511414, 11830502). It can also be over expressed in lymphomas through translocation with the immunglobulin loci (PMID:17079453). Mutations that alter REL transactivation activity are rare but have been seen in lymphomas (PMID:17072339,1650444, 11921291). REL promotes lymphoma proliferation and cell survival and inhibitors are in development for lymphoma therapy (PMID:17567982, 26744524). False +ENST00000428762 NM_005045.3 5649 RELN False RELN, an extracellular glycoprotein involved in neuronal migration, is altered by mutation in neurological disorders and in solid and hematologic malignancies. RELN (also Reelin) is a secreted extracellular matrix glycoprotein important in neuronal function (PMID: 27303269). Expression of RELN is highest during brain development and is predominantly secreted from Cajal-Retzius neurons and regions of hypothalamic differentiation (PMID: 9182958). In addition, expression of RELN shifts dramatically postnatally, suggesting different roles of RELN during development and adulthood (PMID: 18477607). Activity of RELN is required for appropriate cell migration, aggregation, synaptic function and dendrite formation (PMID: 27803648). RELN acts as an exogenous ligand that binds the receptors VLDLR and ApoER2, resulting in the phosphorylation of DAB1, a signaling effector molecule (PMID: 27803648). Activation of DAB1 initiates the activity of downstream signaling proteins including PI3K and the Src-family protein Crk (PMID: 18477607). RELN signaling mediates the activity of RAP1-GTP and cofilin, proteins involved in cell adhesion and actin cytoskeleton (PMID: 27803648). Loss of RELN in mouse models results in central nervous system defects including aberrant motor coordination, tremors, and altered gait (PMID: 7972007, 7715726). Reduced RELN expression has been implicated in a variety of neurological diseases including schizophrenia, bipolar disorder and autism, among others (PMID: 27092053). Germline RELN mutations are found in patients with neurodevelopmental disorder autosomal recessive lissencephaly with cerebellar hypoplasia (PMID: 10973257). Somatic mutations in RELN were identified in patients with T-cell precursor acute lymphoblastic leukemia, adult T-ALL and lung cancers (PMID: 22237106, 25595890, 22980976). Epigenetic silencing of RELN expression via methylation occurs in several cancer types including gastric and hepatocellular cancer (PMID: 19956836, 20734148, 29222813), suggesting that RELN likely functions as a tumor suppressor. False +ENST00000309042 NM_001193508.1 5978 REST False REST, a transcriptional repressor, is altered by mutation in various cancer types. Germline mutations of REST are associated with Wilm's tumor. REST (also NRSF or RE-1 silencing transcription factor) is a transcriptional repressor that is a member of the Krüppel-type zinc-finger transcription factor protein family (PMID: 23414932, 15907476). REST functions to suppress the expression of neuronal genes by binding to neuron-restrictive silencer elements (NRSE) (PMID: 15907476). Epigenetic modifying proteins that facilitate gene repression are recruited to chromatin by REST, including CDYL1, EHMT2, HDACs, and SIN3a, among others, to inhibit neuronal gene expression (PMID: 10491605, 15200951, 28286748, 10734093). REST activity has been implicated in the restriction of neuroendocrine cell fate, including in neuroendocrine tumor types such as small cell lung and prostate cancer (PMID: 28489825, 28256535, 24163104). REST also regulates various cellular functions including stemness, invasion, proliferation, hypoxia, neuronal function and embryonic development (PMID: 28256535, 27531581, 28286748). Germline mutations in REST are associated with Wilm’s tumor, a pediatric cancer that affects the kidney (PMID: 26551668). Epigenetic silencing of REST expression is implicated in neurodegenerative disease and in cancer (PMID: 29351877). Somatic truncating mutations and deletions in REST have been identified in several cancer types, including colorectal cancer, suggesting that REST predominantly functions as a tumor suppressor (PMID: 15960972, 23414932). However, increased REST activity is found in neuronal cancers, such as glioblastomas, medulloblastomas and neuroblastomas, suggesting that REST activity may be context-dependent (PMID: 23414932). True +ENST00000355710 NM_020975.4 5979 RET True 1 RET, a receptor tyrosine kinase, is altered by mutation in medullary thyroid cancers and by chromosomal rearrangement in lung cancers, papillary thyroid cancers, and rarely, other solid tumors. RET is a receptor tyrosine kinase that binds ligands of the glial cell line-derived neurotrophic factor (GDNF) family and transmits intracellular signals via the pro-oncogenic mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) pathways (PMID: 24561444). RET is normally expressed in the developing embryo, playing a particularly important role in neural and neuroendocrine lineages (PMID: 8306871). In cancer, RET can be activated either through point mutations or gene rearrangements with a variety of translocation partners resulting in constitutively active cytosolic oncoproteins (PMID: 24561444). Germline heterozygous, activating mutations in RET lead to the highly penetrant familial cancer syndromes multiple endocrine neoplasia type 2A (MEN2A: medullary thyroid carcinoma, pheochromocytoma, hyperparathyroidism), multiple endocrine neoplasia type 2B (MEN2B: medullary thyroid carcinoma, pheochromocytoma, multiple mucosal neuromas and intestinal ganglioneuromas, marfanoid habitus), and familial medullary thyroid carcinoma (FMTC) (PMID: 15322516, 19469690, 25810047). Oncogenic somatic mutations include point mutations and genomic rearrangements of the RET locus leading to inversions or translocations. These have been identified in various cancers including papillary thyroid cancer, lung adenocarcinoma and chronic myelomonocytic leukemia (CMML). In addition, aberrant expression or activation of wildtype RET correlates with tumor invasion and metastasis in pancreatic cancer and endocrine therapy resistance in breast cancer (PMID: 24561444). False +ENST00000358835 NM_002912 5980 REV3L True REV3L, a catalytic component of DNA polymerase zeta involved in translesion DNA synthesis, is frequently altered in cancer. REV3L, also known as POLZ, encodes the catalytic subunit of DNA polymerase zeta and functions in translesion DNA synthesis (PMID: 9618506). The catalytic activity of REV3L requires interaction with the non-catalytic subunit of polymerase zeta, REV7, and the scaffolding protein, REV1, to allow assembly of translesion DNA polymerases at sites of DNA damage (PMID: 22859296). REV3L maintains genomic stability and proliferation of cells in response to DNA damage, however, accumulation of DNA damage occurs as a result of REV3L-mediated proliferation (PMID: 11050391, 12805232). The expression level of REV3L varies in a variety of cancer tissues (PMID: 11115544) and cell lineage plays a large role in dictating the oncogenic function of REV3L alterations. Amplification of REV3L has been identified in various cancers, including glioma, esophageal squamous cell carcinoma and cervical cancer (PMID: 19289490, 26752104, 18593951). Overexpression of REV3L in cervical cancer cells promotes tumorigenesis as measured by increased cell growth and tumor colony formation (PMID: 25781640). Loss of REV3L has been identified in various cancers, including colon cancer, non-small cell lung cancer and gastric cancer (PMID: 18622427, 15617831). In vitro studies examining the deletion of REV3L have had conflicting results on the effects on cancer cell growth. REV3L inhibition in HeLa cells demonstrated no effect on tumorigenesis as measured by no alteration in colony growth or survival, however other studies using cervical cancer, lung, breast, mesothelioma and colon tumor cells demonstrated suppressed colony growth (PMID: 20028736, 22028621). Polymorphisms of REV3L resulting in loss of REV3L function have been identified in non-small cell lung cancer, breast cancer and mesothelioma (PMID: 22349819, 21455670, 24956248). False +ENST00000262187 NM_005614.3 6009 RHEB True RHEB encodes the protein Ras homolog enriched in brain (RHEB), a GTPase that is a direct upstream activator of the mTOR pathway. While RHEB is infrequently mutated in human cancer, it has been shown to be overexpressed in many cancer types, likely due to amplifications and/or post-transcriptional regulation. RHEB encodes a small GTPase within the RAS superfamily that functions as a molecular switch by activating the mTOR pathway (specifically, mTORC1) when bound to GTP (PMID: 24863881). Specifically, RHEB is thought to enact its activation upon mTORC1 via affecting the substrate affinity of mTORC1 for 4EBP1, a downstream effector of the mTOR pathway, resulting in protein synthesis activation (PMID: 19299511). RHEB is negatively regulated by the tuberous sclerosis complex (TSC1/TSC2) which functionally activates the GTPase activity of RHEB causing exchange of the RHEB-bound GTP for GDP thus preventing RHEB from activating mTORC1 (PMID: 18708577). The TSC1/TSC2 complex is frequently mutated in human cancers, which allows for RHEB-associated upregulation of the mTOR pathway (PMID: 18708577, 15240005). RHEB is ubiquitously expressed in human cells and is localized to the lysosomal membrane along with mTORC1 and the TSC1/TSC2 complex (PMID: 24863881, 14614311). Beyond its role in the regulation and activation of the mTORC1 complex, RHEB has been suggested to have multiple other non-canonical functions, including regulation of BRAF, as well as being important in developmental functions (PMID: 24863881, 21412983). RHEB has also been postulated to play a context-dependent role in the regulation of apoptosis and autophagy (PMID: 24216995). RHEB is not a commonly mutated gene in human cancer, although hotspot, activating mutations have been discovered within the effector domain in a small number of renal cell carcinomas and endometrial cancers (PMID: 24390350, 24631838, cbioportal March, 2015). RHEB has, however, been shown to be overexpressed in multiple cancer types, including liver, lung, prostate, lymphoma and bladder cancer, and RHEB overexpression has been postulated to be associated with poor outcomes in breast cancers and head and neck squamous cell carcinomas (PMID: 18708577, 18708578, 20388784). This overexpression may result in part from copy number gains (RHEB is located at 7q36) or focal amplifications, which occur in numerous cancer types including ovarian (12%, cbioportal March, 2015). RHEB overexpression has been proposed to be a biomarker for response to mTOR pathway inhibitors (rapalogs), although clinical evidence for this is lacking at this time (PMID: 18708578, 24631838). False +ENST00000418115 NM_001664.2 387 RHOA True RHOA, a GTPase, is altered in various solid and hematologic malignancies. The RHOA gene encodes a ubiquitously expressed small GTPase protein that primarily localizes to the cytoplasm. RHOA cycles between an active, guanosine triphosphate (GTP) bound, and an inactive, guanosine diphosphate (GDP) bound state. Proteins known as guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs) facilitate activation and inactivation of RHOA respectively. RHOA mediates several cellular functions by activating a number of downstream effectors, including the ROCK-cofilin pathway which stimulates cell motility by causing actin stress fiber formation and contractility (PMID: 25660168). RHOA plays an important role in tumorigenesis and metastasis by mediating invasion of tumor cells, and inhibition of RHOA signaling has shown anti-tumor effect in preclinical models (PMID: 21622195, 25728708, 20364104, 25333508). On the contrary, recent studies have shown that several oncogenic RHOA mutations lead to inactivation of the protein, and RHOA deletion is more common than RHOA amplification in some tumors, suggesting a complex and potentially context-dependent role of RHOA in cancer (cBioPortal, MSKCC, April. 2015; PMID: 24413737, 24816253). False +ENST00000357387 NM_152756.3 253260 RICTOR True RICTOR, a core component of the oncogenic mTOR2 complex, is altered by amplification or mutation in various cancer types. The RICTOR (rapamycin-insensitive companion of mTOR) gene encodes a core component of the mTOR complex-2 (mTOR2), which also includes mTOR, mLST8, DEPTOR, PRAS40, SIN1, and PROTOR1/2 (PMID: 20418915 ). RICTOR is an upstream kinase for several AGC kinase family members, including AKT/PKB, PKC (protein kinase C) and SGK1 (serum-glucocorticoid-induced protein kinase-1). In response to growth factors, mTOR2 phosphorylates and activates these kinases to regulate cytoskeletal organization, cell proliferation and survival (PMID: 22350330, 15268862, 15718470, 18566586, 18925875, 17141160, 18566587). Included in the mTORC2 targets is AKT, a key component in the pro-oncogenic PI3-kinase signaling pathway that regulates various cellular functions including cell survival, proliferation and apoptosis (PMID: 25505994, 15718470). RICTOR also associates with factors independent of mTOR (PMID: 20832730, 18339839, 18426911), and some of the less well-characterized mTOR-independent functions of RICTOR include regulation of cell morphology, migration and protein degradation (PMID: 21670596). Overexpression of RICTOR is positively associated with tumor progression and poor survival in hepatocellular carcinoma (PMID: 25371154), endometrial carcinoma (PMID: 24966915), pituitary adenoma (PMID: 23898069) and gastric cancer (PMID: 26159923). Upregulation of RICTOR is associated with renal cell carcinoma (RCC) metastasis, suggesting RICTOR as a potential biomarker for prognosis and stratification of patients with RCC (PMID:26500094). The RICTOR locus is amplified in melanoma (PMID: 26356562) and lung cancer (PMID: 26370156). False +ENST00000283109 NM_018343.2 55781 RIOK2 True RIOK2, a transcription factor and atypical kinase, is altered in various cancers. Right open-reading-frame kinase 2 (RIOK2), also known as Rio2, is an ATPase required for ribosome subunit maturation and is also a master transcription factor that regulates hematopoietic differentiation through control of GATA1, GATA2, SPI1, RUNX3 and KLF1 (PMID: 34359076, 34937919). This atypical kinase belongs to the RIO protein family, which comprises proteins that function in ribosome biogenesis, cell cycle progression and chromosome maintenance (PMID: 36518977, 16182620). RIOK2 assists in the maturation of the pre-40S ribosomal complex by facilitating subunit export from the nucleus to the cytoplasm (PMID: 33753942, 34359076). Additionally, RIOK2 plays a regulatory role in the metaphase-anaphase transition during mitosis. When RIOK2 is overexpressed, cells remain in metaphase for longer, and when RIOK2 is knocked down, the duration of mitosis is extended (PMID: 21880710). The role of RIOK2 in ribosome maturation and protein synthesis suggests that it functions as an oncogene. RIOK2 overexpression is implicated in the development of multiple cancers, including non-small cell lung cancer (NSCLC), glioblastoma, prostate cancer and acute myeloid leukemia (PMID: 36518977, 29749434, 23459592). However, RIOK2 loss is common in myelodysplastic syndromes, which results in decreased erythroid differentiation, anemia, increased megakaryopoiesis and myelopoiesis (PMID: 33753942, 34937919). Preclinical research into RIOK2 inhibitors such as ERGi-USU and NSC139021 is ongoing and has shown efficacy in vitro and in vivo (PMID: 29712692, 36518977, 34572430). False +ENST00000368323 NM_006912.5 6016 RIT1 True RIT1 encodes a RAS-related GTPase that plays a role in neuronal development and differentiation. Activating mutations in RIT1 are frequent in Noonan syndrome and are found in a variety of cancers, including lung adenocarcinoma, hepatocellular carcinoma and myeloid malignancies. RIT1 encodes a RAS-related small GTP-binding protein that belongs to the RAS subfamily of small GTPases (PMID: 8824319, 10545207). These proteins function as binary molecular switches; in response to external stimuli, they exchange GDP with GTP, thereby triggering several intracellular signaling networks. RIT1 is widely expressed in adult and embryonic tissue, including primary neurons and the developing brain. It plays a central role in the induction of neuronal differentiation through activation of both the BRAF/ERK and the p38 MAP kinase signaling pathways (PMID: 15632082, 11914372). Additionally, RIT1 plays a role in regulating axonal versus dendritic growth, and it contributes to IFNγ-induced dendritic retraction (PMID: 17460085, 12668729, 18957053). RIT1 has been identified as a regulator of a p38/MAPK-dependent cascade that functions as a prosurvival mechanism in response to oxidative stress (PMID: 21737674, 21444726, 23123784). RIT1 gain-of-function mutations are associated with Noonan syndrome (PMID: 25049390, 24939608, 23791108); activating mutations in the Switch II domain of RIT1 have been observed in lung adenocarcinoma and myeloid malignancies (PMID: 25079552, 24469055, 23765226). The transforming potential of RIT1 is associated with the activation of a p38γ-dependent signaling pathway (PMID: 11821041, 15831491). False +ENST00000221486 NM_006397 10535 RNASEH2A True RNAseH2A, a subunit of ribonuclease RNAse H2, is frequently altered by amplification in cancer. RNAseH2A encodes the catalytic A subunit of the trimeric endoribonuclease RNAse H2 and functions in DNA replication through the degradation of RNA in RNA/DNA hybrids (PMID: 19015152). RNAseH2A interfaces with the non-catalytic C subunit, RNAseH2C, through interaction on its C-terminus, and this interaction is required for the catalytic activity of the RNAse H2 complex (PMID: 21454563). Alterations of RNAseH2A that appear on this interface disrupt interaction and enzymatic activity and have been implicated in the human auto-inflammatory disease Aicardi-Goutières syndrome (PMID: 21177854). Overexpression of RNAseH2A is associated with poor patient prognosis and has been frequently identified in various cancers (PMID: 27176716, 32509219, 29843367). RNAseH2A amplification promotes tumorigenesis through the upregulation of cell cycle progression and survival and the downregulation of apoptosis in DNA-damaged cells (PMID: 29843367, 32509219). False +ENST00000336617 NM_024570 79621 RNASEH2B False RNAseH2B, a subunit of ribonuclease RNase H2, is frequently altered by deletion in cancer. RNAseH2B encodes the non-catalytic B subunit of the trimeric endoribonuclease RNAse H2 and functions in DNA replication through the degradation of RNA in RNA/DNA hybrids (PMID: 19015152). The conserved PCNA interacting protein-box sequence located on the C-terminus of RNAseH2B allows for PCNA binding to RNAseH2B to promote hydrolyzation of ribonucleotides misincorporated during replication (PMID: 19015152). Loss of RNAseH2B is associated with poor patient prognosis and has been frequently identified in various cancers including cervical cancer, intestinal carcinoma and prostate cancer (PMID: 29642758, 30273559, 35179959). RNAseH2B loss causes impairment in nucleotide excision repair and PARP trapping, leading to significant accumulation of DNA damage, genomic instability and tumorigenesis (PMID: 35179959). RB1 and BRCA2 are physically close to RNAseH2b on chromosome 13q and both genes are frequently co-deleted with RNAseH2B (PMID: 35179959). True +ENST00000407977 NM_017763.4 54894 RNF43 False RNF43, a ubiquitin ligase, is mutated in various cancers including gastrointestinal and gynecological cancers. RNF43 encodes for ring finger protein 43 is a transmembrane protein that has ubiquitin ligase activity (PMID: 24532711). It inhibits the Wnt pathway signaling by controlling Frizzled receptor expression through ubiquitination and protein degradation (PMID:26863187, 25891077). It binds to the ligand R-spondin which inhibits its activity (PMID:22575959). RNF43 is expressed in LGR5 positive colonic stem cells and regulates their growth and differentiation through Wnt signaling (PMID:22895187). Mutations are found in colorectal, endometrial, ovarian, gastric, cholangiocarcinoma, and pancreatic neoplasms (PMID:26257827, 25344691, 24816253, 22561520, 26505881, 23847203, 24293293, 26924569). Mutations have been characterized as loss of function and may lead to susceptibility to treatment with Wnt pathway inhibitors (PMID:25901018). RNF43 truncating mutations and loss-of-function mutations have been associated with increased sensitivity and clinical benefit in patients with microsatellite stable BRAF V600E-mutant colorectal cancer treated with anti-BRAF/EGFR therapies (PMID: 38394466, 36779536, 36097219). True +ENST00000464233 NM_002941.3 6091 ROBO1 False ROBO1, a signaling protein and axon guidance receptor, is recurrently altered by mutation and deletion in a range of hematopoietic and solid tumors. Germline mutations in ROBO1 are also found in families with a predisposition for both breast and colon cancer risk. ROBO1 is an axon guidance receptor that is a member of the immunoglobulin superfamily of proteins (PMID: 9458045, 27578174). ROBO1 is expressed on axon growth cones and controls midline axon crossing between the left and right half of the central nervous system (PMID: 16254601). Slit, an extracellular matrix protein, functions as a chemorepulsive signal at the midline and is a ligand for ROBO1 (PMID: 10102267). ROBO1 signaling also mediates a variety of other cellular functions including angiogenesis, migration, cell polarity, cell proliferation and mammary gland development (PMID: 27578174). SLIT2 and ROBO1 are implicated in a signaling pathway that regulates endothelial cell polarity and migration involving the effector proteins VEGFR, CDC42, NCK, and PAK2 (PMID: 26659946). Heterozygous loss of ROBO1 expression in murine models results in tumor formation, suggesting a role of ROBO1-SLIT2 signaling in cancer (PMID: 15374951). Germline ROBO1 variants are associated with neurodevelopmental disorders including craniofacial microsomia and dyslexia, among others (PMID: 16254601, 28402530, 28286008). In addition, germline ROBO1 mutations are found in families with a predisposition for familial breast and colon cancer (PMID: 29698419, 26427657). Somatic loss-of-function mutations in ROBO1 have been identified in patients with hematopoietic malignancies including myelodysplastic syndromes and multiple myeloma (PMID: 26608094, 24429703). Deletions and hypermethylation of ROBO1 are also found in a range of cancer types including lung cancer, colorectal cancer and cholangiocarcinomas, among others (PMID: 12615722, 21603610, 19104841, 24500968, 27009864), suggesting that ROBO1 predominantly functions as a tumor suppressor. Several studies, however, propose that ROBO-SLIT signaling may also promote cancer progression in some contexts dependent on the availability of SLIT2 ligand (PMID: 12892710). True +ENST00000368508 NM_002944.2 6098 ROS1 True 1 R2 ROS1, a receptor tyrosine kinase, is altered by mutation or chromosomal rearrangement in a diverse range of cancers, including lung cancer. The ROS1 gene encodes a transmembrane protein with intracellular tyrosine kinase activity (PMID: 18778756). ROS1 is a member of the sevenless subfamily of tyrosine kinase insulin receptor genes (PMID: 27256160). The normal physiological role and ligand of this protein in humans is currently unknown (PMID: 23814043). ROS1 rearrangements where the kinase domain is retained (PMID: 22327623) are implicated in a range of human epithelial cancers including cholangiocarcinoma (PMID: 21253578), ovarian carcinoma (PMID: 22163003), gastric carcinoma (PMID: 23400546), angiosarcoma (PMID: 23637631) and most commonly non-small cell lung cancer (PMID: 22215748). Although ROS1 rearrangements were first discovered in a human glioblastoma cell line (PMID: 2827175), there is a paucity of ROS1 rearrangements in human gliomas (PMID: 24999209). The mechanism by which ROS1 rearrangements leads to dysregulated kinase activity is not clear, as its ligand has not yet been deciphered; however, it is hypothesized to occur through constitutive kinase activation (PMID: 18083107). R2 False +ENST00000370321 NM_000969 6125 RPL5 False RPL5, a ribosomal protein, is infrequently altered in cancer. RPL5 encodes for the 60S ribosomal protein L5, a component of the ribosome (PMID: 7937132, 7772601). RPL5 interacts with MDM2 to mediate protein ubiquitination and degradation in response to ribosomal stress (PMID: 16803902). RPL5 also functions as a component of the 5S RNA-protein complex through binding to 5S rRNA (PMID: 11410658). Knockdown of RPL5 in various cancer cell lines and models induces increased cellular proliferation, tumor growth and increased inflammation suggesting that RPL5 functions predominantly as a tumor suppressor gene (PMID: 28147343, 33348919). Downregulation of RPL5 has been identified in various types of cancer, including glioblastoma, breast cancer and multiple myeloma (PMID: 28147343, 27909306). RPL5 mRNA expression has been suggested as a predictive biomarker for initial response to bortezomib for newly diagnosed and relapsed patients with multiple myeloma (PMID: 27909306). True +ENST00000592588 NM_001018 6209 RPS15 True RPS15, a ribosomal protein, is altered by mutation in chronic lymphocytic leukemia. RPS15 encodes for a ribosomal protein that is a component of the 40S ribosomal subunit (PMID: 35438042). RPS15 is essential for mRNA translation and ribosomal biogenesis as the protein mediates interaction between the 40S and 60S ribosomal subunits, facilitates binding of mRNA and tRNA during translation and mediates nuclear export and cytoplasmic processing of rRNA (PMID: 32583822, 16037817). Overexpression of RPS15 in esophageal squamous cell carcinoma cancer cell lines and models induces cellular proliferation, migration and invasion, suggesting that RPS15 functions predominantly as an oncogene (PMID: 37264021). RPS15 mutations have been identified in chronic lymphocytic leukemia (PMID: 30498067, 34251413). False +ENST00000334205 NM_003942.2 8986 RPS6KA4 True RPS6KA4 encodes a serine/threonine kinase involved in the MAPK signaling pathway. RPS6KA4 regulates several oncogenes and is a potential chemotherapeutic target. The ribosomal protein S6 kinase, 90 kDa, polypeptide 4 (RPS6KA4, also known as MSK2 or RSK-B), is a serine/threonine protein kinase, composed of two kinase domains, the N and C-terminal kinase domains and acts as an important downstream effector of mitogen-activated protein kinase (MAPK) (PMID:9003374,7498520). Many growth factors, peptide hormones, and neurotransmitters regulate RPS6KA4 through Erk1/2 signaling (PMID: 10411321,10610536). Knockdown of RPS6KA4 gene expression leads to upregulation of p53 transcriptional activity and its overexpression results in the inhibition of p53 target promoters and p53-mediated apoptosis, indicating that RPS6KA4 has a p53-inhibiting function (PMID:16929179, 19797274). Moreover, the antitumoral effect of α-Lipoic acid (α-LA) on colorectal cancer cells stems, at least partially, from its property to prevent RPS6KA4-mediated p53 inhibition (PMID:23599020). MAPKs play a major role in UV-induced skin cancer development and a phospho-MAPK array analysis indicated that p38α and its downstream target proteins, MSK2 and HSP27, were strongly activated by UVB and SUV (PMID:23382047). RPS6KA4 is also known as MSK2 (human mitogen- and stress-activated protein kinase 2) and shares 64% homology with MSK1. Activated MSK1/2 is known to induce cellular transformation in various cell lines; for instance, following induction by EGF and TPA, MSK1/2 activation leads to cellular transformation of mouse epidermal cells (JB6 cells) (PMID:18381464). The role of MSK1/2 in cellular transformation also involves its ability to activate various transcription factors such as CREB, ATF1, ER81, and the p65 subunit of NFκB, which in turn activate the transcription of genes involved in tumorigenic and metastatic progression (PMID:22983151). MSK1/2 also mediate chromatin remodeling that is required at the enhancer and upstream promoter element for TPA-induced initiation of TFF1 expression in MCF-7 breast cancer epithelial cells (PMID:23675462). Finally, an exciting new study reported that MSK1/2 is involved in an in vivo model of skin tumor development (PMID: 21314333). Mice lacking MSK1 and 2 exhibit reduced skin tumor formation by tumor promoting agents 7,12-dimethylbenz[a]anthracene (DMBA) and TPA in a multistage skin carcinogenesis model compared to wild-type mice. As such, MSK1/2 as a key regulator of expression of several oncogenes presents a potential target in chemotherapeutic development (PMID:21314333). Inhibition of MSK1/2 can be achieved by cell permeable molecules that have varying degrees of potency and selectivity. The two most common inhibitors used to study the effects of MSK in vitro are H89 and Ro 318220 (PMID:10998351,22983151). False +ENST00000312629 NM_003952.2 6199 RPS6KB2 True RPS6KB2 encodes a serine/threonine kinase involved in protein translation, cell proliferation and survival. Copy number alterations and mutations of RPS6KB2 are found in various cancers and are associated with poor prognosis. RPS6KB2 encodes the ribosomal protein S6 kinase β-2 (S6K2), a serine/threonine kinase involved in the control of cap-independent translation of a subset of proteins, in proliferation and in cell survival (PMID: 10490847, 22431522, 17786541, 16810323). In addition, S6K2 plays a role in learning, memory and synaptic plasticity (PMID: 18174371). S6K2 is activated upon stimulation of cells with insulin, serum or phorbol 12-myristate 13-acetate by effectors of the PI3K signaling pathway, such as Rac, CDC42, PDK1 and PKC-ζ (PMID: 9804755, 10490846, 11108711, 8653792, 9445476, 10082559, 12529391). Genetic variations in RPS6KB2 are associated with Alzheimer disease (PMID: 21811019). S6K2 is ubiquitously expressed, with the highest levels found in the gastrointestinal tract, lungs and central nervous system; levels in normal tissues are relatively low, compared with levels in corresponding tumor samples (PMID: 21444676, 16810323). High levels of S6K2 are found in adenocarcinoma, breast cancer, endometrial cancer, lung cancer and gastric cancer (PMID: 15627062, 21748818, 15995633, 15627061, 20953835, 16810323, 23393338). Expression and localization of RPS6KB2 are distinguishing features of cancer cells (PMID: 15627062). Amplification of RPS6KB2 has prognostic value and can help predict treatment success in breast cancer. In endometrial and gastric cancers, the level of nuclear expression of RPS6KB2 correlates with tumor grade and decreased overall survival. In lung cancer, increased expression of S6K2 is correlated with drug resistance (PMID: 15627062, 21748818, 15995633, 15627061, 20953835, 16810323). Somatic mutations are found in lung adenocarcinomas in nonsmokers and are associated with worse survival (PMID: 24894543). Polymorphisms in RPS6KB2 are associated with a risk of developing colon cancer and rectal cancer (PMID: 21035469). False +ENST00000306801 NM_020761.2 57521 RPTOR True RPTOR encodes a scaffolding protein in the mTORC1 complex that regulates protein synthesis. RPTOR (regulatory-associated protein of mTOR) encodes a scaffolding protein that regulates the assembly, localization and substrate binding of mTORC1. mTOR (mechanistic target of rapamycin) is an atypical serine-threonine protein kinase that belongs to the phosphoinositide 3-kinase (PI3K)-related kinase family (PMID: 19339977). It interacts with several proteins to form two distinct complexes named mTOR complex 1 and 2 (mTORC1 and mTORC2). RPTOR/raptor is a unique member of the mTRORC1 complex and serves as a scaffolding protein and is essential for mTORC1 complex activity (PMID: 25450580, 14684181, 26159692). mTORC1 is a key regulator of protein synthesis (PMID: 19339977). RPTOR binds to the translational regulator 4E-BP1 and mTORC1 then directly phosphorylates 4E-BP1, which, in turn, promotes protein synthesis (PMID: 19339977, 15718470). mTORC1 also controls the synthesis of lipids required for proliferating cells to generate membranes (PMID: 19948145). The mTOR pathway is of great importance in cancer pathogenesis (PMID: 25450580). Many components of the pathway upstream of mTORC1 are mutated in human cancers (PMID: 22500797). Derivatives of rapamycin (rapalogs) that potently inhibit mTOR activity are tested in different cancer types some of which are clinically approved (PMID: 21490404). False +ENST00000373001 NM_022157.3 64121 RRAGC True RRAGC, an mTORC1 activator, is mutated in follicular lymphomas. The RRAGC gene encodes a guanine-binding protein of the RAG family of GTPases; it acts as a heterodimer with RRAGCA or RRAGCB (PMID: 24095279). RRAGC targets mTORC1, a complex that responds to growth factors and various other stimuli to positively regulate cell growth that is frequently deregulated in cancer. Specifically, RRAGC regulates the intracellular localization of mTORC1 and facilitates its RHEB-dependent activation (PMID: 20381137, 27234373). RRAGC missense mutations are found in follicular lymphomas (PMID: 26691987). False +ENST00000246792 NM_006270.3 6237 RRAS True "RRAS is a small GTPase, and mutations in this gene are found in disorders termed ""RASopathies"" as well as in hematologic and pediatric cancers." "RRAS (also R-Ras) is a small GTPase protein belonging to the RRAS subfamily of Ras-like GTPases. RRAS regulates diverse cellular processes including angiogenesis, vascular homeostasis, vascular regeneration, cell adhesion and neuronal axon guidance (PMID: 28610953). In addition, RRAS regulates the organization of the actin cytoskeleton and promotes the formation of ruffling lamellipodia via its activation of phospholipase Cε (PMID: 16537651). RRAS mediates cell adhesion, cell spreading, cell polarization and phagocytosis via Integrin β1 activity (PMID: 8620538,18270267, 11257001). Loss of RRAS expression in mice results in vasculature defects, highlighting the importance of RRAS in the hematopoietic system (PMID: 27029009). Germline mutations in RRAS are found in disorders related to Noonan Syndrome collectively called ""RASopathies"" and rare somatic alterations have been associated with hematologic and pediatric cancers (PMID: 24705357)." False +ENST00000256196 NM_012250.5 22800 RRAS2 True RRAS2, a small GTPase, is altered frequently by amplification or missense mutations in various cancers. RRAS2 (also TC21) is a small GTPase protein belonging to the RRAS subfamily of Ras-like GTPases. RRAS2 primarily localizes to the plasma membrane and activates the MAPK (mitogen-activated protein kinase), PI3K (phosphatidylinositol 3-kinase), and JNK signaling cascades (PMID: 10557073,11850823). Interaction of RRAS2 with c-Raf initiates these downstream signaling pathways and mediates transformation and differentiation of diverse cell types (PMID: 10557073,11850823). Functional experiments have demonstrated that RRAS2 can function as an oncogene, as engineered gain-of-function mutations have high levels of transforming activity and induce transcriptional activation from Ras-responsive promoter elements (PMID: 8196649). Oncogenic mutations in RRAS2 are occasionally found in tumor cell lines (PMID: 8052619, 7478545) and RRAS2 amplification is found in many cell lines derived from breast cancer (PMID: 8552388); however, RRAS2 alterations are relatively rare in human cancers. False +ENST00000360203 NM_001283009.1 51750 RTEL1 False RTEL1 is a helicase important for regulating telomere length in which germline mutations are associated with dyskeratosis congenital and Hoyerall-Hreidarsson syndrome. RTEL1 (Regulator of telomere length1) encodes a DNA helicase implicated in telomere length regulation, DNA repair, and maintaining genomic stability. The helicase activity of RTEL1 is essential in disassembling telomere loops and suppressing telomere fragility to maintain the integrity of chromosome ends (PMID: 24115439). In addition, it interacts with proteins in the shelterin complex known to protect telomeres during DNA replication (PMID:23959892). It also acts as an anti-recombinase to affect the disassembly of toxic DNA recombination intermediates, and thus regulates meiotic recombination and crossover homeostasis (PMID: 18957201). Germline mutations in this gene have been associated with dyskeratosis congenital (PMID: 23329068) and Hoyerall-Hreidarssonsyndrome (PMID: 23959892). True +ENST00000300305 NM_001754.4 861 RUNX1 False RUNX1, a transcription factor involved in hematopoietic differentiation, is altered by mutation or chromosomal rearrangement in various hematologic malignancies. RUNX1, also known as AML1 or CBFA2, is a transcription factor that is a master regulator of hematopoietic differentiation. It interacts with a diverse subset of transcriptional complexes and can act as a transcriptional activator via recruitment of histone acetyltransferases or methyltransferases (PMID: 18695000, 22012064), or a repressor via recruitment of histone deacetylases or Polycomb-repressive complex 1 (PRC1) (PMID: 21059642, 22325351). Due to its important role in hematopoiesis, conditional deletion of RUNX1 in mice results in an expansion of the hematopoietic stem and progenitor population, and defective T- and B-lymphocyte development (PMID: 14966519). RUNX1 is highly regulated via alternative splicing, ubiquitination, phosphorylation, acetylation, and methylation, which has important regulatory consequences in cancer (PMID: 19386523). RUNX1 is frequently translocated and altered in acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), acute lymphoid leukemia (ALL), and Familial platelet disorder with predisposition for acute myeloid leukemia (FPD/AML) (PMID: 17290219, 15156185, 21174539). Many translocations involving RUNX1 lack the activation domain, and have a leukemogenic effect by acting as a dominant negative inhibitor of wild-type RUNX1 in transcription activation (PMID: 15156182). True +ENST00000265814 NM_001198626.1 862 RUNX1T1 True RUNX1T1, a transcriptional repressor, is recurrently altered by fusion in acute myeloid leukemias. RUNX1T1 (also ETO, MTG8, CBFA2T1) is a transcription factor that is a member of ETO/MTG family of proteins (PMID: 15649458). RUNX1T1 functions as a transcriptional repressor and interacts with several complexes involved in silencing of gene expression, including the nuclear receptor corepressor (NCoR), silencing-mediator for retinoid/thyroid hormone receptors (SMRT), mSin3a, and histone deacetylases (PMID: 9724795, 9819404, 9819405, 9724795). In addition, RUNX1T1 co-binds CEBPA, a transcription factor associated with tissue-specific differentiation programs (PMID: 19811452). RUNX1T1 is expressed in normal heart and brain tissues and is not highly expressed in hematopoietic lineages (PMID: 9661669, 9209371). Functional studies of RUNX1T1 activity have been predominantly completed in the context of leukemic fusion proteins; therefore, further work is necessary to study the cellular functions of wildtype RUNX1T1. The RUNX1-RUNX1T1 or t(8;21) fusion (most commonly termed AML-ETO fusion) is the most frequent translocation in acute myeloid leukemia (PMID: 8338940). In this fusion protein, the RUNT homology domain of the RUNX1 gene on chromosome 21 is fused to the entirety of the RUNX1T1 gene on chromosome 8 (PMID: 11607817). The AML-ETO fusion protein is insufficient to drive leukemia in murine models and human leukemias, suggesting that a second mutational hit is required for leukemogenesis (PMID: 22875638, 26666262). This translocation functions as an oncogene by enhancing self-renewal in hematopoietic stem cells and mediating transcriptional activity via the recruitment of epigenetic complexes to target genes (PMID: 28299657, 11607817). False +ENST00000481739 NM_002957.4 6256 RXRA False RXRA is a nuclear receptor and a transcriptional regulator, and deficiency of RXRA cause hyperplasia and aberrant differentiation in skin and prostate. RXRA encodes the Retinoid X Receptor Alpha, which is a member of the steroid and thyroid hormone receptor superfamily of transcriptional regulators. RXRA functions either as a homodimer or as a heterodimeric partner for a number of nuclear receptors. RXRA/PPARA (Peroxisome Proliferator-activated Receptor- alpha) heterodimers regulate PPARA-mediated transcriptional activity on genes involved with fatty acid oxidation, such as the cytochrome P450 system genes (PMID: 10195690). RXRA also heterodimerizes with the thyroid hormone receptor (T3R), Vitamin D3 receptor (VD3R) and Retinoic Acid Receptors (RARs). RXRA is required for forming stable complexes of these receptors with their cognate DNA response elements and for transactivation of genes regulating growth, differentiation, metabolism, homeostasis and neoplasia (PMID: 1314167, 1310351). In acute promyelocytic leukemia (APL) driven by PML/RARA fusion protein, RXRA is deemed essential for APL pathogenesis in vivo, even though PML/RARA can complex with DNA and transform primary hematopoietic progenitors ex vivo (PMID: 17613434). RXRA deficiency causes hyperplasia and aberrant differentiation of skin epidermis and prostate epithelium (PMID: 11171393, 12183441). False +ENST00000477973 NM_012234.5 23429 RYBP False RYBP is a transcriptional repressor with a possible tumor-suppressor function. It is frequently lost in prostate cancer. The RYBP (RING1 and YY1 binding protein) protein is a Polycomb group protein that is involved in transcriptional regulation. RYBP is part of the Polycomb-repressive complex 1 (PRC1) and interacts directly with RING1, RNF2, and YY1, to mediate H2A ubiquitylation at specific polycomb target sites to repress these genes (PMID: 22325148). It has been show to play an important role in development and stem cell programming through its role in transcriptional repression (PMID: 10369680). RYBP also has polycomb-independent roles, and can act as a tumor suppressor through interaction with MDM2 and subsequent stabilization of TP53 (PMID: 19098711). The genetic locus of RYBP is frequently deleted in prostate cancers and loss of RYBP expression has been detected in hepatocellular carcinoma and non-small cell lung cancer and is associated with poor outcome (PMID: 20579941, 25344099, 26404750). True +ENST00000379958 NM_017654.3 54809 SAMD9 False SAMD9, a cytoplasmic nuclease, is infrequently altered in various cancers. SAMD9 encodes a multi-domain, cytoplasmic anticodon nuclease that plays a role in many cell functions including immune response to viral infection, protein translation and endosome fusion (PMID: 37285440, 28545555, 28157624). An effector domain in SAMD9 preferentially binds to double-stranded nucleic acids and is crucial in its antiviral and antiproliferative functions (PMID: 35046037, 25428864). Additionally, the SAM domain located at the N-terminus of SAMD9 is able to polymerize and facilitate protein-protein interactions (PMID: 21805519). Key functions of SAMD9 include binding and cleaving the phenylalanine tRNA molecule, effectively decreasing protein translation, and binding endosome protein RGI2 to regulate endosome function (PMID: 38848876). SAMD9 expression is regulated by interferon and tumor necrosis factor-α, and activation of SAMD9 downregulates MYC and E2F targets (PMID: 33731850, 38848876). SAMD9 is implicated in the development of myeloid lineage malignancies via dysregulation of cell cycle control and endocytosis, including those characterized by deletions of chromosome 7q (PMID: 27259050, 35046037, 24029230). Knockdown of SAMD9 increases the invasion, migration and proliferation of non-small cell lung cancer (NSCLC) cells in vitro, while overexpression of SAMD9 suppresses proliferation and invasion in NSCLC cells (PMID: 25450373). However, SAMD9 silencing and knockdown in vivo reduces esophageal squamous cell carcinoma formation and metastasis and reduces migration and invasion of glioma and lung cancer cell lines in vitro (PMID: 36757050, 31646435). Gain-of-function mutations in SAMD9 that inhibit cell proliferation cause the autosomal recessive disorder normophosphatemic familiar tumoral calcinosis and the autosomal dominant disorder MIRAGE syndrome (myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes, and enteropathy) (PMID: 35046037, 16960814, 27182967). False +ENST00000318238 NM_152703.2 219285 SAMD9L False SAMD9L, a cytoplasmic nuclease, is infrequently altered in various cancers. SAMD9-like (SAMD9L) encodes a multi-domain, cytoplasmic anticodon nuclease that plays a role in many cell functions including immune response to viral infection, protein translation and endosome fusion (PMID: 37285440, 28545555, 28157624). An effector domain in SAMD9L preferentially binds to double-stranded nucleic acids and is crucial in its antiviral and antiproliferative functions (PMID: 35046037, 25428864). Additionally, the SAM domain located at the N-terminus of SAMD9L is able to polymerize and facilitate protein-protein interactions (PMID: 21805519). Key functions of SAMD9L include binding and cleaving the phenylalanine tRNA molecule, effectively decreasing protein translation, and binding endosome protein RGI2 to regulate endosome function (PMID: 38848876, 33731850). SAMD9L expression is regulated by interferon and tumor necrosis factor-α, and activation of SAMD9L downregulates MYC and E2F targets (PMID: 33731850, 38848876). Disruption of SAMD9L is associated with the development of myelodysplastic syndromes and acute myeloid leukemia, including those characterized by deletions of chromosome 7q, via dysregulation of endocytosis, hematopoietic cell proliferation and differentiation (PMID: 28346228, 24029230, 28202457, 27259050, 35046037). Knockdown of SAMD9L increases cell proliferation and colony formation in hepatocellular carcinoma cell lines and increases tumorigenicity in nude mice (PMID: 27259050). Gain-of-functions in SAMD9L that inhibit cell proliferation cause ataxia-pancytopenia and other immunodeficiency disorders with variable neurological presentations (PMID: 35046037, 28202457). False +ENST00000262878 NM_015474.3 25939 SAMHD1 False SAMHD1, a deoxynucleoside triphosphate triphosphohydrolase involved in cellular dNTP homeostasis, is recurrently altered by mutation in chronic lymphocytic leukemia. SAMHD1 (also AGS5 and Mg11) is a deoxynucleoside triphosphate triphosphohydrolase involved in cellular dNTP homeostasis (PMID: 28502830). SAMHD1 converts dNTPs, the nitrogenous bases that are required for DNA synthesis, into deoxynucleosides after stimulation by dGTP, leading to depletion of the dNTP pool (PMID: 28502830, 22056990). The activity of SAMHD1 is regulated by the concentration of dNTPs, which allosterically bind SAMHD1 to regulate tetramerization and catalytic activity (PMID: 28502830, 25760601). In addition, SAMHD1 may also have ribonuclease activity; however, this finding is controversial (PMID: 25038827, 26101257). SAMHD1 has been implicated in additional cellular functions including innate immunity and DNA end resection during DNA repair (PMID: 19525956, 28834754). SAMHD1 is also a restriction factor that renders myeloid and dendritic cells refractory to HIV infection by hydrolyzing intracellular dNTPs in non-cycling cells, decreasing the dNTP pool required for DNA synthesis (PMID: 21613998, 22926205). Germline mutations in SAMHD1 are found in patients with Aicardi-Goutières syndrome, a neurodevelopmental disorder that aberrantly activates the immune system and resembles congenital infection (PMID: 19525956). Somatic SAMHD1 mutations are found in patients with chronic lymphocytic leukemia (PMID: 24335234). SAMHD1 is predicted to function as a tumor suppressor as mutations in SAMHD1 result in reduced protein expression (PMID: 24335234). Expression of SAMHD1 can also result in resistance to nucleoside-based chemotherapies by hydrolyzing the active triphosphate metabolites, namely in acute myeloid leukemia (PMID: 28502830, 27991919). True +ENST00000300175 NM_001144757.1 6447 SCG5 True SCG5, a secreted chaperone protein, is infrequently altered by amplification and mutation in neuroendocrine tumors. Germline mutations in SCG5 are associated with hereditary mixed polyposis syndrome and predispose to colorectal cancers. SCG5 (also Secretogranin V or 7B2) is a secreted chaperone protein that is a member of the granin family (PMID: 2053134, 21862681, 22947085). SCG5 is predominantly expressed in neuroendocrine tissues and functions to reduce the aggregation of other secreted proteins (PMID: 21862681, 22947085). In addition, SCG5 activates the proprotein convertase (PC2) enzyme which initiates neuroendocrine peptide maturation by facilitating transport of protein precursors through the endoplasmic reticulum and secretory pathway (PMID: 11719503, 11439082, 10799554, 9881669). Additional studies have identified SCG5 as a β-cell associated antigen that is recognized by naïve CD8-positive T-cells (PMID: 30078552). Aberrant SCG5 activity has been implicated in neurodegenerative disorders and mediates amyloid-β and α-synuclein aggregation (PMID: 23172224). Germline duplications involving a region including SCG5 and GREM1 are found in patients with hereditary mixed polyposis syndrome and these alterations may be associated with colorectal cancer risk (PMID: 27984123, 22561515, 18084292). Various neuroendocrine tumors, including renal cell, pancreatic and small cell lung cancers, are found to have altered expression of SCG5 (PMID: 2548871, 29796168, 25023465). False +ENST00000264932 NM_004168.2 6389 SDHA False SDHA encodes a tumor suppressor involved in the electron transport chain. Germline mutations of SDHA are associated with paraganglioma and pheochromocytoma and predispose to gastrointestinal cancers. SDHA (Succinate dehydrogenase A) is one of the four components of the succinate dehydrogenase (SDH) complex and is a critical enzyme in the mitochondrial electron transport chain. SDHA localizes to the inner membrane of mitochondria and couples the oxidation of succinate to fumarate and transfers electrons directly to the ubiquinone pool (PMID: 16892081, 21771581). SDHA and other SDH complex family members function as tumor suppressors; loss of function mutations in these genes have been shown to stabilize hypoxia-inducible factors (HIF), thus leading to a hypoxic state that promotes tumorigenesis (PMID: 20484225, 11605159, 16103922). Mutations in components of the SDH complex lead to accumulation of succinate, which can competitively inhibit the action of alpha-ketoglutarate-dependent histone- and DNA-demethylases in a variety of cancers and lead to a hypermethylator phenotype (PMID: 23707781). Germline loss-of-function mutations in the SDH genes, including SDHA, cause hereditary paraganglioma and pheochromocytoma (PMID: 21771581). Mutations in SDH genes have also been linked to gastrointestinal tumors (PMID: 23730622). True +ENST00000301761 NM_017841.2 54949 SDHAF2 False SDHAF2 encodes a tumor suppressor involved in the electron transport chain. Germline mutations of SDHAF2 are associated with head and neck parangangliomas. SDHAF2 (Succinate dehydrogenase assembly factor 2) is critical to the appropriate assembly of the succinate dehydrogenase (SDH) protein complex, which is important in the mitochondrial electron transport chain. SDHAF2 physically resides in the inner membrane of mitochondria (PMID: 19628817) and ensures appropriate incorporation of flavin adenine dinucleotide (FAD) into the SDH complex (PMID:19628817). Mutations in SDHAF2 have been associated with hereditary head and neck paragangliomas and pheochromocytomas (PMID: 20071235, 21224366). Paragangliomas associated with SDHAF2 mutations typically have a young age of onset and do not co-occur with mutations in SDH components (e.g. SDHA). Notably, it was identified that children who inherited a maternal mutant SDHAF2 allele were not affected by the disease, suggesting that parent-of-origin for the mutant allele is important in the development of the disease (PMID: 21771581). True +ENST00000375499 NM_003000.2 6390 SDHB False SDHB encodes an enzyme involved in the electron transport chain. Germline mutations of SDHB are associated with pheochromocytomas and paragangliomas and gastrointestinal, renal cell and pituitary cancers. SDHB (Succinate dehydrogenase B) is one of the four components of the succinate dehydrogenase (SDH) complex and is a critical enzyme in the mitochondrial electron transport chain. SDHB localizes to the inner membrane of mitochondria and couples the oxidation of succinate to fumarate and transfers electrons directly to the ubiquinone pool (PMID: 16892081, 21771581). SDHB and other SDH complex family members function as tumor suppressors; loss of function mutations in these genes have been shown to stabilize hypoxia-inducible factors (HIF), thus leading to a hypoxic state that promotes tumorigenesis (PMID: 18978332). SDH mutations have been involved in the pathogenesis of pheochromocytomas, paragangliomas, gastrointestinal stromal tumors (GISTs), renal-cell carcinomas and pituitary adenomas (PMID: 25394176). Mutations in components of the SDH complex lead to accumulation of succinate, which can competitively inhibit the action of alpha-ketoglutarate-dependent histone- and DNA-demethylases in a variety of cancers and lead to a hypermethylator phenotype (PMID: 23707781, 23743927). Germline loss of function mutations in the SDH genes, including SDHB, cause hereditary paraganglioma and pheochromocytoma (PMID: 21771581). True +ENST00000367975 NM_003001.3 6391 SDHC False SDHC encodes an enzyme involved in the electron transport chain. Germline mutations of SDHC are associated with pheochromocytomas and paragangliomas and gastrointestinal, renal cell and pituitary cancers. SDHC (Succinate dehydrogenase C) is one of the four components of the succinate dehydrogenase (SDH) complex and is a critical enzyme in the mitochondrial electron transport chain. While SDHA and SDHB form the catalytic domain of the SDH complex, SDHC and SDHD anchor the complex to the inner mitochondrial membrane (PMID: 10657297). SDHC and other SDH complex family members function as tumor suppressors; loss of function mutations in these genes have been shown to stabilize hypoxia-inducible factors (HIF), thus leading to a hypoxic state that promotes tumorigenesis (PMID: 18978332, 17102089). SDH mutations have been involved in the pathogenesis of pheochromocytomas, paragangliomas, gastrointestinal stromal tumors (GISTs), renal-cell carcinomas and pituitary adenomas (PMID: 25394176). Mutations in components of the SDH complex lead to accumulation of succinate, which can competitively inhibit the action of alpha-ketoglutarate-dependent histone- and DNA-demethylases in a variety of cancers and lead to a hypermethylator phenotype (PMID: 23707781, 23743927 ). Germline loss of function mutations in the SDH genes can cause hereditary paraganglioma and pheochromocytoma (PMID: 21771581). True +ENST00000375549 NM_003002.3 6392 SDHD False SDHD encodes an enzyme involved in the electron transport chain. Germline mutations of SDHD are associated with pheochromocytomas and paragangliomas and gastrointestinal, renal cell and pituitary cancers. SDHD (Succinate dehydrogenase D) is one of the four components of the succinate dehydrogenase (SDH) complex and is a critical enzyme in the mitochondrial electron transport chain. While SDHA and SDHB form the catalytic domain of the SDH complex, SDHC and SDHD anchor the complex to the inner mitochondrial membrane (PMID: 10657297). SDHD and other SDH complex family members function as tumor suppressors; loss of function mutations in these genes have been shown to stabilize hypoxia-inducible factors (HIF), thus leading to a hypoxic state that promotes tumorigenesis (PMID: 18978332, 17102089). SDH mutations have been involved in the pathogenesis of pheochromocytomas, paragangliomas, gastrointestinal stromal tumors (GISTs), renal-cell carcinomas and pituitary adenomas (PMID: 25394176). Mutations in components of the SDH complex lead to accumulation of succinate, which can competitively inhibit the action of alpha-ketoglutarate-dependent histone- and DNA-demethylases in a variety of cancers and lead to a hypermethylator phenotype (PMID: 23707781, 23743927 ). Germline loss of function mutations in the SDH genes can cause hereditary paraganglioma and pheochromocytoma (PMID: 21771581). True +ENST00000283752 NM_006919.2 6317 SERPINB3 True SERPINB3, a serine protease inhibitor, is altered by mutation in solid tumors. Somatic mutations of SERPINB3 may be predictive of improved response to immunotherapy. SERPINB3 is a cysteine/serine protease inhibitor that is a member of the SERPIN protein family (PMID: 27637160). SERPIN proteins predominantly function by disrupting the active sites of proteases and forming irreversibly covalent SERPIN-protease complexes (PMID: 27637160). Specifically, SERPINB3 mainly targets papain-like cysteine proteases such as Cathepsin L, S, and K and papain (PMID: 27637160). SERPINB3, and the tandemly duplicated paralog SERPINB4, have a domain that shares sequence homology with ovalbumin, a classic model antigen (PMID: 26375851). Increased expression of SERPINB3 is found in respiratory inflammatory diseases including asthma, chronic obstructive pulmonary disease (COPD), and tuberculosis, implicating SERPINB3 in stress responses and autoimmunity (PMID: 19332150, 23325331, 25111616). In addition, SERPINB3 has been associated with the regulation of apoptosis due to altered surface antigen presentation (PMID: 19332150). SERPINB3 expression is associated with poor prognosis in several cancer types; however, functional experiments have identified both growth-promoting and inhibitory roles of SERPINB3 (PMID: 29491058, 27637160, 25544768). Somatic mutations in SERPINB3 are found in patients with cutaneous melanoma, and these alterations are associated with improved survival following immune checkpoint blockade therapies (PMID: 26091043, 27668655). Improved responses to immunotherapy may be due to the ability of mutated SERPINB3 to serve as an epitope, leading to immune recognition (PMID: 27668655). True +ENST00000341074 NM_002974.3 6318 SERPINB4 False SERPINB4, a serine protease inhibitor, is altered by mutation in solid tumors. SERPINB4 is a cysteine/serine protease inhibitor that is a member of the SERPIN protein family (PMID: 27637160). SERPIN proteins predominantly function by disrupting the active sites of proteases and forming irreversibly covalent SERPIN-protease complexes (PMID: 27637160). Specifically, SERPINB4 mainly targets chymotrypsin-like serine proteases such as chymase and cathepsin G (PMID: 27637160). SERPINB4, and the tandemly duplicated paralog SERPINB3, have a domain that shares sequence homology with ovalbumin, a classic model antigen (PMID: 26375851). SERPINB4 is not as well-studied as SERPINB3, however, the family members are predicted to have similar activities (PMID: 27637160). SERPINB3 has been implicated in stress responses, autoimmunity, and apoptosis due to altered surface antigen presentation (PMID: 19332150, 23325331, 25111616, 19332150). SERPINB4 expression is associated with poor prognosis in several cancer types; however, functional experiments have not yet delineated if SERPINB4 functions as a tumor suppressor or oncogene (PMID: 17291250, 27637160, 30376194). Somatic mutations in SERPINB4 are found in patients with cutaneous melanoma, and these alterations are associated with improved survival following immune checkpoint blockade therapies (PMID: 26091043, 27668655). Improved responses to immunotherapy may be due to the ability of mutated SERPINB4 to serve as an epitope, leading to enhanced immune recognition (PMID: 27668655). False +ENST00000436639 NM_014454.2 27244 SESN1 False SESN1, a regulator of mTORC1, is mutated at low frequencies in various cancers. The SESN1 gene encodes a member of the sestrin family. Sestrin proteins are negative regulators of mTORC1 (PMID: 27273098, 27174209). Sestrins are leucine sensors that, in absence of this amino acid, interact with GATOR2 protein, a partner of the Rag GTPase protein GATOR1. This interaction prevents mTORC1 translocation to the lysosomal surface (PMID: 25263562, 26449471, 26586190, 25819761). The presence of leucine disrupts sestrin-GATOR interaction and allows mTORC1 signaling. Sestrin-mediated mTORC1 inhibition is partly mediated by activation of AMP-activated protein kinase (AMPK) (PMID: 25457612, 27273098). Sestrins are stress-regulated proteins and also play a role in protection from oxidative stress (PMID: 23274085, 15105503). Genetic alterations of SESN1 are rare events in cancer (cBioPortal, MSKCC, Dec. 2016). True +ENST00000253063 NM_031459.4 83667 SESN2 False SESN2, a regulator of mTORC1, is mutated at low frequencies in various cancer. The SESN2 gene encodes a member of the sestrin family. Sestrin proteins are negative regulators of mTORC1 (PMID: 27273098, 27174209). Sestrins are leucine sensors that, in the absence of this amino acid, interact with GATOR2 protein, a partner of the Rag GTPase protein GATOR1. This interaction prevents mTORC1 translocation to the lysosomal surface (PMID: 25263562, 26449471, 26586190, 25819761). The presence of leucine disrupts the sestrin-GATOR interaction and allows mTORC1 signaling. Sestrin-mediated mTORC1 inhibition is partly mediated by activation of AMP-activated protein kinase (AMPK) (PMID: 25457612, 27273098). Sestrins are stress-regulated proteins and also play a role in protection from oxidative stress (PMID: 23274085, 15105503). SESN2 protein structure and mechanisms are better characterized than other sestrin family members. Genetic alterations of SESN2 are rare events in cancer (cBioPortal, MSKCC, Dec. 2016). True +ENST00000536441 NM_144665.3 143686 SESN3 False SESN3, a regulator of mTORC1, is mutated at low frequencies in various cancers. The SESN3 gene encodes a member of the sestrin family. Sestrin proteins are negative regulators of mTORC1 (PMID: 27273098, 27174209). Sestrins are leucine sensors that, in absence of this amino acid, interact with GATOR2, a partner of the Rag GTPase protein GATOR1. This interaction prevents mTORC1 translocation to the lysosomal surface (PMID: 25263562, 26449471, 26586190, 25819761). The presence of leucine disrupts the sestrin-GATOR interaction and allows mTORC1 signaling. Sestrin-mediated mTORC1 inhibition is partly mediated by activation of AMP-activated protein kinase (AMPK) (PMID: 25457612, 27273098). Sestrins are stress-regulated proteins and also play a role in protection from oxidative stress (PMID: 23274085, 15105503). Genetic alterations of SESN3 are rare events in cancer (cBioPortal, MSKCC, Dec. 2016). True +ENST00000372692 NM_001122821 6418 SET True SET, a multifunctional protein and inhibitor of histone acetyltransferase, is infrequently altered by translocation in leukemia. SET, also known as template activating factor-Iβ (TAF-Iβ), is a multi-functioning protein that acts as a template activating factor, histone chaperone and phosphatase 2A inhibitor (PMID: 34021475). SET is involved in DNA replication through processes such as transcription, nucleosome assembly and chromatin remodeling (PMID: 34021475). As a subunit of the inhibitor of histone acetyltransferase (INHAT) complex, SET inhibits the activity of histone acetyltransferase and exerts chaperone activity by binding to core histones, specifically histone 3 and histone 4 (PMID: 34021475,17360516). Inhibiting the acetylation of nucleosomes is an important event in chromatin remodeling and transcriptional regulation (PMID: 11163245). The SET complex, composed of SET and granzyme A-activated endonuclease NH23-H1, also regulates apoptosis following the attack of cytolytic T cells and NK cells (PMID: 1618237). In response to superoxide generated by granzyme A, the SET complex translocates from the endoplasmic reticulum to the nucleus and regulates apoptosis through the inhibition of phosphatase 2A (PP2A), a major mammalian protein serine-threonine phosphatase, which is a tumor suppressor that inhibits cell proliferation via the dephosphorylation of Bcl-2 (PMID: 34021475, 862667). Impaired regulation of PP2A by SET loss may lead to acute myeloid leukemia (PMID: 8626647), and translocations involving the SET gene are found in various forms of acute myeloid leukemia (PMID: 34021475, 8626647). False +ENST00000282030 NM_015559.2 26040 SETBP1 True SETBP1, an epigenetic remodeling protein, is frequently altered by mutation in a range of hematopoietic malignancies. SETBP1 is a DNA binding protein that functions as an epigenetic remodeler (PMID: 28881700). Binding of SETBP1 to proteins with SET domains, typically present in histone methyltransferases, allows for the methylation of substrates, including histone tails (PMID: 25306901). SETBP1 activates gene expression in part by mediating the recruitment of the HCF1/KMT2A/PHF8 epigenetic complex to regions of chromatin (PMID: 29875417). In addition, SETBP1 binds the protein SET, an inhibitor of the phosphatase PP2A, and overexpression of SETBP1 results in reduced PP2A expression and leukemic proliferation (PMID: 19965692). In preclinical studies, SETBP1 has been shown to mediate self-renewal in leukemia cells and to regulate the expression of the HOXA gene cluster (PMID: 22566606, 25306901). Expression of SETBP1 is also associated with organ development and neuronal activation (PMID: 29875417). Germline mutations in SETBP1 have been identified in patients with Schinzel-Giedion syndrome, a congenital disorder that presents with neurological symptoms and increased risk of malignancy (PMID: 28346496, 20436468). Somatic SETBP1 mutations are found in patients with hematopoietic malignancies, including myeloproliferative neoplasms and atypical chronic myeloid leukemia (PMID: 23832012, 23222956). Alterations in SETBP1 occur in a hotspot region that is within a degron motif that facilitates substrate recognition by the SCF-β-TrCP E3 ubiquitin ligase. These mutations disrupt SETBP1 degradation by the E3 ligase complex, suggesting that SETBP1 functions as an oncogene (PMID: 29875417, 28346496). False +ENST00000262519 NM_014712.2 9739 SETD1A True SETD1A, a histone methyltransferase that binds actively transcribed genes, is infrequently altered across a diverse range of cancers. SETD1A (also KMT2F, hSET1, SET1A, SET1) is a histone methyltransferase that is a member of the MLL family of trithorax-related chromatin remodeling enzymes (PMID: 18838538, 25550471). SETD1A modifies histone tails by trimethylating histone H3 at lysine 4, resulting in an epigenetic signal that is associated with actively transcribed genes or genes poised for transcription (PMID: 18838538, 24126056). Histone proteins, essential components of the nucleosome, consist of DNA wrapped around eight histone protein molecules (two sets of each H2A, H2B, H3, and H4 histones), and histone tail modifications provide signals for the activation or repression of gene expression (PMID: 11498575). The formation of an epigenetic complex including CFP1, RBBP5, ASH2, WDR5, and WDR82 is required for effective SETD1A enzymatic modification of histone tails (PMID: 17998332). SETD1A shares substantial homology with SETD1B, however, these two methyltransferases have non-redundant functions in the regulation of gene expression (PMID: 17355966). In addition, the SETD1A complex binds to RNA polymerase II and influences the initiation of transcription (PMID: 17998332 ). SETD1A also interacts with several additional chromatin-modifying enzymes that influence gene expression and chromatin state (PMID: 18765639, 20622854, 23353889). The activity of SETD1A is required for many stages of development including embryonic and neural stem cell survival, maternal oocyte gene expression and hematopoietic lineage specification (PMID: 24550110, 28619824, 27141965, 23754954, 25550471). In addition, SETD1A has been implicated in the maintenance of stalled replication fork and the regulation of DNA repair pathways with implications for genome stability (PMID: 29937342, 29348130). Loss-of-function mutations in SETD1A are found in patients with schizophrenia and developmental disorders (PMID: 26974950, 24853937). SETD1A is overexpressed in several cancer types and has been shown to promote cell proliferation and survival in functional studies (PMID: 19426701, 24247718, 25373480, 29474905). False +ENST00000604567 XM_005253858.3 23067 SETD1B False SETD1B, a histone methyltransferase protein, is recurrently mutated in a variety of human cancers. SETD1B (also SETB1, KMT2G) is a histone methyltransferase that is a member of the MLL family of chromatin remodeling enzymes (PMID: 17355966, 28160335). SETD1B modifies histone tails by trimethylating histone H3 at lysine 4, resulting in an epigenetic signal that is associated with actively transcribed genes or genes poised for transcription (PMID: 17355966). Histone proteins, essential components of the nucleosome, consist of DNA wrapped around eight histone protein molecules (two sets of each H2A, H2B, H3, and H4 histones), and histone tail modifications provide signals for the activation or repression of gene expression (PMID: 11498575). The formation of an epigenetic complex including CFP1, RBBP5, ASH2, WDR5, and WDR82 is required for effective SETDB1 enzymatic modification of histone tails (PMID: 17355966). The activity of SETD1B is also required for many stages of development including embryonic and neural stem cell survival and maternal oocyte gene expression (PMID: 24550110, 28619824). Microdeletions and mutations in SETD1B have been associated with disorders that result in intellectual disability and craniofacial abnormalities (PMID: 27106595, 29322246). Somatic fusion proteins and mutations have been identified in several tumor types including hematopoietic malignancies, oesophageal squamous cell carcinoma, and endometrial cancers, among others (PMID: 24925220, 24670651, 24382738, 27997699, 29967129). These SETD1B mutations predominantly occur as nonsense and/or frameshift mutations, suggesting that SETD1B may function as a tumor suppressor. False +ENST00000409792 NM_014159.6 29072 SETD2 False SETD2, an H3K36 trimethylase, is altered in a variety of cancer types. SETD2 encodes a chromatin modulating enzyme that functions by site specific trimethylation of histone H3K36. It was originally identified as a contributing enzyme in the pathogenesis of Huntington Disease and thus was initially named Huntington Interacting Protein B (HYPB) (PMID: 9700202). Histone methylation is a highly controlled biological process that regulates gene expression by altering the ability of RNA polymerase II to interact with DNA and thus initiate transcription (PMID:16118227, 25123655). Additionally, the SETD2-regulated H3K36 histone mark has been shown to play a role in regulating DNA mismatch repair. This suggests that inactivation of this protein can lead to enhanced genetic instability, enrichment of nonsense and frameshift mutations and ultimately oncogenic transformation of cells (PMID: 23622243, 25123655, 25728682, 24931610). Importantly, SETD2-mutant renal tumors failed to activate the p53 tumor suppressor, thus providing an alternative pathway for the inactivation of p53 that leads to defects in DNA damage repair (PMID: 24843002). True +ENST00000331768 NM_032233.2 84193 SETD3 False SETD3, a histone methyltransferase, is infrequently altered by fusion or mutation in a variety of human cancers. SETD3 is a histone methyltransferase that is a member of the SET domain family of chromatin remodeling enzymes (PMID: 21832073). SETD3 modifies histone tails by methylating histone H3 at lysine 4 and lysine 36, resulting in an epigenetic signal that is associated with actively transcribed genes or genes poised for transcription (PMID: 21832073). Histone proteins, essential components of the nucleosome, consist of DNA wrapped around eight histone protein molecules (two sets of each H2A, H2B, H3 and H4 histones), and histone tail modifications provide signals for the activation or repression of gene expression (PMID: 11498575). SETD3 is ubiquitously expressed and also binds and methylates non-histone substrates including PCNA, a protein involved in DNA replication (PMID: 26030842) and FOXM1, a protein involved in hypoxia (PMID: 27845446), among others. The activity of SETD3 is important in mediating muscle differentiation by activating the expression of muscle-associated genes (PMID: 21832073). Expression of SETD3 has been associated with oncogenesis and metastasis in several tumor types (PMID: 28442573, 29099276). Rare SETD3 mutations and fusion proteins have been identified in human cancers including B-cell lymphomas (PMID: 23065515). False +ENST00000332131 NM_017438.4 54093 SETD4 False SETD4, a histone methyltransferase, is infrequently altered by mutation in a variety of human cancers. SETD4 is a histone methyltransferase that is a member of the SET domain family of chromatin remodeling enzymes (PMID: 24738023). SETD4 modifies histone tails by tri-methylating histone H4 at lysine 20 as evidenced in model organisms, however, the specific methyltransferase activity of SETD4 has not yet been determined in mammalian studies (PMID: 28031330). Histone proteins, essential components of the nucleosome, consist of DNA wrapped around eight histone protein molecules (two sets of each H2A, H2B, H3, and H4 histones), and histone tail modifications provide signals for the activation or repression of gene expression (PMID: 11498575). SETD4 has been shown to be overexpressed in breast cancer cells that are estrogen receptor negative (PMID: 24738023). Knockdown of SETD4 expression in breast cancer cells results in reduced proliferation and cell cycle progression (PMID: 24738023). Infrequent SETD4 mutations have been identified in human cancers; however, additional functional experiments are necessary to determine the impact of these alterations (cbioportal, September 2018). False +ENST00000402198 NM_001080517.2 55209 SETD5 False SETD5, a histone methyltransferase, is infrequently altered by mutation in a variety of human cancers. SETD5 is a histone methyltransferase that is a member of the SET domain family of chromatin remodeling enzymes (PMID: 24680889). SETD5 is predicted to methylate histone tails to regulate gene expression, however, the specific methyltransferase activity of SETD5 has not yet been determined in mammalian studies. Histone proteins, essential components of the nucleosome, consist of DNA wrapped around eight histone protein molecules (two sets of each H2A, H2B, H3, and H4 histones), and histone tail modifications provide signals for the activation or repression of gene expression (PMID: 11498575). SETD5 interacts with the PAF1 co-transcriptional complex and the NCor-associated histone deacetylase complexes. Loss of SETD5 expression results in increased histone acetylation at transcriptional start sites, suggesting a role in histone deacetylation (PMID: 27864380). SETD5 deletion in murine models results in developmental defects including cardiac defects, aberrant neural tube development, and altered vascular structure (PMID: 27864380). Germline mutations in SETD5 have been associated with human disorders that result in intellectual disability and craniofacial abnormalities (PMID: 23613140, 24680889, 24768552, 28120103). Rare somatic mutations in SETD5 have also been identified in several human cancer types, including prostate cancer, (PMID: 24768552). False +ENST00000219315 NM_001160305.1 79918 SETD6 False SETD6, a histone methyltransferase, is infrequently altered by mutation in a variety of human cancers. SETD6 is a histone methyltransferase that is a member of the SET domain family of chromatin remodeling enzymes (PMID: 23324626). SETD6 modifies histone tails by monomethylating histone H2AZ, a histone variant, at lysine 7 (PMID: 23324626). Histone proteins, essential components of the nucleosome, consist of DNA wrapped around eight histone protein molecules (two sets of each H2A, H2B, H3, and H4 histones), and histone tail modifications provide signals for the activation or repression of gene expression (PMID: 11498575). The H2AZK7me1 mark is found at chromatin locations also marked by H3K27me3, a repressive mark, suggesting that this mark reduces gene expression in embryonic stem cells (PMID: 23324626). SETD6 can also methylate non-histone proteins including PAK4 and RELA (PMID: 26841865, 21131967), leading to altered WNT and NF-KB signaling, respectively. SETD6 monomethylates RELA, a component of the NF-KB signaling pathway, resulting in a methylated protein that binds chromatin at RELA target genes (PMID: 21131967). The methylated RELA protein reduces chromatin accessibility at NF-KB target genes, leading to a restrained NF-KB inflammatory response (PMID: 21131967, 21515635). In addition, SETD6 has been implicated in oxidative response pathways and maintenance of embryonic stem cells (PMID: 26780326, 23324626). SETD6 is overexpressed in some tumor types, including breast cancer; however, SETD6 is infrequently altered across human cancers (PMID: 24751716, 28122346). False +ENST00000274031 NM_001306199.1 80854 SETD7 False SETD7, a histone methyltransferase, is infrequently mutated in a variety of human cancers. SETD7 (also SET7, SET9, SET7/9) is a histone methyltransferase that is a member of the SET domain family of chromatin remodeling enzymes (PMID: 11779497). SETD7 modifies histone tails by methylating histone H3 at lysine 4, resulting in an epigenetic signal that is associated with actively transcribed genes or genes poised for transcription (PMID: 11779497, 11850410, 12540855). Histone proteins, essential components of the nucleosome, consist of DNA wrapped around eight histone protein molecules (two sets of each H2A, H2B, H3, and H4 histones), and histone tail modifications provide signals for the activation or repression of gene expression (PMID: 11498575). In addition to methylation of histone substrates, SETD7 can also methylate non-histone substrates in order to regulate their stability or functional activity. SETD7 methylates P53 in a mechanism that restricts P53 to the nucleus leading to transcriptional stabilization and activation (PMID: 17646389, 18280244, 21855806). SETD7 also stabilizes the estrogen receptor and NF-KB for recruitment to transcriptional targets (PMID: 18471979). In addition, SETD7 methylates DNMT1 (a DNA methyltransferase), E2F1 (a cell cycle factor involved in regulating DNA damage-induced cell death), and YAP (a transcription factor involved in WNT regulation), among others (PMID: 19282482, 19684477, 21151116, 20603083, 27046831). Somatic mutations in SETD7 are rare in human cancers; however, SETD7 has been implicated as both a tumor suppressor and oncogene in different cellular contexts (PMID: 26848522, 26779630, 26701885, 26116705, 27183310). False +ENST00000271640 NM_001145415.1 9869 SETDB1 True SETDB1, a histone methyltransferase, is altered by amplification, mutation, and fusion in melanoma, lung cancer, and mesothelioma. SETDB1 (also ESET, KMT1E) is a histone methyltransferase that is a member of the SET domain family of chromatin remodeling enzymes. SETDB1 modifies histone tails by methylating histone H3 at lysine 9, resulting in an epigenetic signal that is associated with repressed gene expression and genes poised for activation (PMID: 11959841). Histone proteins, essential components of the nucleosome, consist of DNA wrapped around eight histone protein molecules (two sets of each H2A, H2B, H3, and H4 histones), and histone tail modifications provide signals for the activation or repression of gene expression (PMID: 11498575). SETDB1-dependent H3K9me3 methylation results in the recruitment of HP1-alpha, leading chromatin remodeling to a more heterochromatic state (PMID: 11959841). In addition, SETDB1 binds protein complexes implicated in transcriptional repression including KRAB-KAP1 and MDB1-CAF1 (PMID: 11959841, 15327775). SETDB1 also interacts with several proteins involved in sister chromatid cohesion, DNA repair, and homologous recombination (PMID: 18501190, 26206670) and mediates gene repression in embryonic and hematopoietic stem cells (PMID: 19884255, 21624812, 27301860). SETDB1 can also regulate the activity of other epigenetic complexes involved in the repression of gene expression, including Polycomb Repressive Complex 2 (PRC2) (PMID: 26160163). SETDB1 can methylate non-histone substrates including p53, which leads to recognition and degradation of P53 by MDM2 (PMID: 26471002). SETDB1 has been identified within a melanoma susceptibility locus and SETDB1 expression promotes melanoma formation (PMID: 26471002, 21430779). In addition, SETDB1 is recurrently amplified in melanoma and lung cancer (PMID: 21430779, 23770855). Somatic mutations, fusion events, and splice alterations are found in mesothelioma, leading to protein inactivation, suggesting that SETDB1 can function as either a tumor suppressor or oncogene in distinct cellular contexts (PMID: 26928227, 26824986). True +ENST00000354234 NM_031915.2 83852 SETDB2 False SETDB2, a histone methyltransferase, is altered by deletion in breast cancers. SETDB2 (also CLLD8, KMT1F) is a histone methyltransferase that is a member of the SET domain family of chromatin remodeling enzymes (PMID: 20404330). SETDB2 modifies histone tails by methylating histone H3 at lysine 9, resulting in an epigenetic signal that is associated with repressed gene expression and genes poised for activation (PMID: 20404330). Histone proteins, essential components of the nucleosome, consist of DNA wrapped around eight histone protein molecules (two sets of each H2A, H2B, H3, and H4 histones), and histone tail modifications provide signals for the activation or repression of gene expression (PMID: 11498575). SETDB2 functions to recruit HP1-alpha to centromeres and maintains heterochromatin states in repetitive elements and centromere-associated repeats, implicating SETDB2 in chromosome condensation (PMID: 20404330). SETDB2 is also important in the regulation of acute immune responses, is activated during viral infection, and may mediate bacterial infection susceptibility (PMID: 27572307, 25419628). Homozygous deletions in SETDB2 have been identified in breast cancer (PMID: 25537518); however, somatic alterations in SETDB2 are relatively rare in human cancers. True +ENST00000335508 NM_012433.2 23451 SF3B1 True 4 SF3B1, a component of the spliceosome complex, is frequently mutated in hematologic malignancies. SF3B1 (splicing factor 3b subunit 1) is a component of the spliceosome complex that regulates the removal of introns from messenger RNA (PMID: 28958291). SF3B1 binds to nucleosomes to identify exon and intron junctions of coding genes (PMID: 25892229). Importantly, SF3B1 preferentially regulates alternative splicing and 3’ splice site selection (PMID: 28445500). In addition, SF3B1 plays a role in the maintenance of genomic integrity due to contributions to sister chromatid cohesion and chromosome segregation (PMID: 25257310). Somatic mutations in SF3B1 are recurrent in uveal melanoma (PMID: 26842708) and myelodysplastic syndromes (MDS) (PMID: 21909114, 21995386), especially those with refractory anemia with ring sideroblasts (RARS) and refractory cytopenia with multilineage dysplasia and ring sideroblasts (RCMD-RS) (PMID: 21995386, 21998214). Mutations in SF3B1 lead to altered gene expression and aberrant alternative splicing (PMID: 25428262) and tend to be missense mutations rather than nonsense or frameshift mutations, suggesting either gain-of-function or dominant negative activity (PMID: 22150006, 21909114). The SF3B spliceosome complex can be inhibited by naturally occurring compounds, including spliceostatin A (PMID: 17643111), and SF3B1-mutant cells are preferentially sensitive to spliceosome inhibitors (PMID: 29457796). False +ENST00000322535 NM_006842 10992 SF3B2 True SF3B2, a subunit of the splicing factor 3b protein complex, is infrequently altered in cancer. SF3B2 encodes for subunit 2 of the splicing factor 3b protein (SF3B) complex, which functions in pre-mRNA splicing (PMID: 27720643). The SF3B complex assembles with 12S RNA to form the U2 small nuclear ribonucleoprotein complex (U2 snRNP) to bind pre-mRNA upstream of the intron branch site (PMID: 12234937). Haploinsufficiency of SF3B2 has been associated with sporadic and familial craniofacial microsomia (PMID: 34344887). Knockout of SF3B2 in cancer cell lines and models suppresses tumor growth and cellular migration and invasion, suggesting that SF3B2 functions predominantly as an oncogene (PMID: 35715826, 34611311). Amplification of SF3B2 has been identified in various types of cancer, including prostate cancer, bladder cancer and acute myeloid leukemia (PMID: 31431456). SF3B2 is suggested to confer resistance to AR-targeting therapy in prostate cancer by promoting AR-V7 expression through RNA splicing (PMID: 31431456). False +ENST00000220772 NM_003012.4 6422 SFRP1 False SFRP1, a negative regulator of WNT signaling, is infrequently altered by mutation and deletion in various cancer types. SFRP1 is an extracellular signaling ligand that is a member of the secreted frizzled-related protein family (PMID: 24316024, 23258168). SFRP1 functions as a negative regulator of the WNT signaling pathway by binding to WNT or Frizzled (Fz) receptors and precluding WNT-mediated activation of downstream signaling (PMID: 24316024, 23258168). WNT signaling is a critical developmental pathway with roles in determining cell fate, tissue identity and polarity (PMID: 28218291). SFRP1-mediated antagonism of WNT results in the activation of the β-catenin destruction complex (containing APC, GSK3β, and AXIN) which targets β-catenin for degradation (PMID: 23258168). In the absence of WNT signaling, TCF and LEF transcription factors form a repressive complex, leading to inhibition of β-catenin target genes (PMID: 24316024, 23258168). In addition, SFRP1 activity has been linked to the regulation of stress-related senescence, proliferation and metastasis (PMID: 22927647, 11593386, 24316024). Somatic mutations in SFRP1 are not well studied in human cancers; however, epigenetic silencing of SFRP1 transcription has been implicated in several cancer types, including breast cancer (PMID: 28218291, 11992124, 16449975, 11593386). SFRP1 loss of heterozygosity has also been identified in some cancer types, including colorectal cancer, suggesting that SFRP1 functions predominantly as a tumor suppressor (PMID: 10086345, 22927647). True +ENST00000274063 NM_003013.2 6423 SFRP2 True SFRP2, a negative regulator of WNT signaling, is overexpressed in various cancer types. SFRP2 is an extracellular signaling ligand that is a member of the secreted frizzled-related protein family (PMID: 24316024, 23258168). SFRP2 functions as a negative regulator of the WNT signaling pathway by binding to WNT or Frizzled (Fz) receptors and precluding WNT-mediated activation of downstream signaling (PMID: 24316024, 23258168). WNT signaling is a critical developmental pathway with roles in determining cell fate, tissue identity and polarity (PMID: 28218291). SFRP2-mediated antagonism of WNT results in the activation of the β-catenin destruction complex (containing APC, GSK3β and AXIN) which targets β-catenin for degradation (PMID: 23258168). In the absence of WNT signaling, TCF and LEF transcription factors form a repressive complex, leading to inhibition of β-catenin target genes (PMID: 24316024, 23258168). In addition to roles in antagonizing WNT, SFRP2 associates with integrin complexes and mediates cell adhesion (PMID: 14709558). SFRP2 is secreted by stromal cells in the tumor microenvironment, such as by aging fibroblasts, and promotes epithelial-to-mesenchymal transition in breast cancer (PMID: 14999144, 14709558, 16791480, 27042933). Somatic mutations in SFRP2 are not well studied in human cancers; however, epigenetic silencing of SFRP2 transcription has been implicated in several cancer types, including prostate and colorectal cancer (PMID: 22175903, 25197341, 27659069, 31516566, 26291085). SFRP2 is more commonly overexpressed in other cancers and associated with poor prognosis, suggesting that SFRP2 may function as either a tumor suppressor or oncogene (PMID: 14999144, 14709558, 28218291, 30385632). True +ENST00000237305 NM_005627.3 6446 SGK1 True SGK1, a serine/threonine kinase in the PI3K signaling pathways, is altered by mutation in hematologic malignancies. SGK1 is a serine/threonine kinase that is a member of the AGC family of protein kinases (PMID: 28236975). SGK1 (serum and glucocorticoid-inducible kinase) is activated by growth factors and is a signaling effector in the phosphoinositide 3 (PI 3)-kinase signaling pathway (PI3K) (PMID: 8455596, 10357815). In the PI3K signaling pathway, SGK1 is phosphorylated and activated by the kinases PDK1 and mTORC2 (PMID: 10357815). SGK1 regulates the expression of a variety of downstream targets including NDRG1, GSK3β, FOXO3, NEDD4L, and PIKFYVE, among others (PMID: 11154281, 10191262). AKT and SGK1 signaling have some overlapping upstream and downstream effectors and SGK1 can partially compensate for AKT activity (PMID: 29055016). In addition, SGK1 increases the activity of a variety of ion channels, ion carriers and the Na+/K+ ATPases; therefore, salt levels and other environmental stimuli are predicted to activate SGK1 activity (PMID: 23467085). SGK1 signaling has been implicated in a variety of other cellular functions including cellular proliferation, apoptosis, membrane protein turnover, regulation of cell volume, transcription and macrophage recruitment (PMID: 22556335, 28236975, 9114008). Somatic gain-of-function mutations in SGK1 are found in patients with nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) and T-cell/histiocyte-rich large B-cell lymphoma (PMID: 26658840, 30213827). In addition, overexpression of SGK1 is found in patients with breast cancer (PMID: 16246546). SGK1 signaling mediates resistance to PI3Kα and AKT inhibition due to compensatory regulation of mTORC1 signaling (PMID: 27451907, 23581296). False +ENST00000341259 NM_005475.2 10019 SH2B3 False SH2B3 is an adaptor protein that regulates growth factor and cytokine signaling. Mutations are found in hematopoietic disorders including leukemias and myeloid disease. SH2B3 (also LNK) is a plasma membrane-associated adaptor protein that negatively regulates signal transduction initiated by growth factor and cytokine receptor kinases (PMID:11805142, 18753636). SH2B3 is most highly expressed in hematopoietic cells and negatively regulates the activity of several hematopoietic kinases including c-Kit, MPL (thrombopoietin receptor), JAK2 (Janus Kinase 2), PDGFR (Platelet Derived Growth Factor Receptor, and EPOR (erythropoietin receptor). Deletion of SH2B3 in murine models results in abnormal hematopoiesis characterized by expansion of the hematopoietic progenitor population (PMID: 11805142). SH2B3-regulated signaling has been implicated in B-cell development, T-cell activation, and hematopoietic stem cell proliferation and differentiation (PMID:11114373, 10799879, 11805142). Germline mutations in SH2B3 are associated with autoimmune diseases such as diabetes, celiac disease and hypertension (PMID:19430479, 18311140, 19073967) as well as predisposition to leukemia (PMID:23908464). Somatic SH2B3 alterations are found in Down syndrome-related myeloid disorders, acute lymphoblastic leukemias and myeloproliferative neoplasms (PMID:24056718, 22897847, 20404132, 22237106) and these mutations are predicted to result in loss-of-function. True +ENST00000371139 NM_002351.4 4068 SH2D1A False SH2D1A encodes a SH2 domain protein that acts to modulate signaling in lymphocytes through the SLAM receptor. Mutations are associated with X-linked immune dysfunction and lymphoproliferative diseases. SH2D1A (also SAP) is an adaptor protein that binds to the lymphocyte cell surface protein Signaling Lymphocytic Activation Molecule (SLAM) (PMID: 9774102). SLAM receptors are expressed on hematopoietic cells and regulate lymphocyte activity (PMID: 18031694). SH2D1A competes with the recruitment of signaling molecules such as SHP-2 phosphatase and also functions as a scaffold to recruit Fyn kinase (PMID: 12458214). Recruitment of SH2D1A is important for the regulation and development of B-cells, NK cells, and T-cells including humoral immunity, cytokine production, and cytotoxicity (PMID: 15711562, 20153220, 15774582, 12529646). SH2D1A plays a role in the regulation of apoptosis and mediates lymphocyte proliferation via the apoptotic pathway (PMID: 19738428). Germline mutations and deletions in SH2D1A are associated with X-linked immune dysfunction, susceptibility to EBV infection, and lymphoproliferative disease (PMID: 9771704). Patients with X-linked lymphoproliferative disease are predisposed to the development of hemophagocytosis, lymphomas, and cytopenias (PMID: 11049992, 20926771, 23589280). Somatic variants in SH2D1A are infrequent in human cancers. True +ENST00000369452 NM_007373.3 8036 SHOC2 True SHOC2, a positive regulator of Ras-MAPK activity, is rarely altered in human cancers, but germline mutations are found in patients with Noonan-like syndromes. The SHOC2 gene encodes a positive regulator of the Ras-MAPK pathway. SHOC2 forms a complex with the catalytic subunit of protein phosphatase 1 (PP1c) and enhances growth factor- and Ras-mediated MAPK pathway activation, whereas it has no effect on Raf- and MEK-induced mechanisms (PMID: 10783161, 16630891). Mechanistically, under M-ras activation, SHOC2 facilitates PP1c-mediated dephosphorylation of the Raf-1 Ser-259 inhibitory site (PMID: 16630891). SHOC2 overexpression induces proliferation and tumorigenic growth in EGF-mediated and Ras-mutant cancer cells (PMID: 25514808, 24211266). Genetic alterations of SHOC2 are rarely seen in tumors. Germline mutations at specific SHOC2 sites are causal variants of neuro-cardio-facial-cutaneous disorders such as Noonan-like syndrome and other RASopathies (PMID: 19684605, 23918763, 25137548). False +ENST00000325599 NM_018130.2 55164 SHQ1 False SHQ1 is a nucleocytoplasmic shuttle protein with function in rRNA processing pathways. Loss of SHQ1 is frequently observed in prostate cancer. SHQ1 (H/ACA ribonucleoprotein assembly factor) is located on chromosome 3p13. SHQ1 is suggested to function in rRNA processing and has been shown to be involved in the formation of a protein-RNA complex (snoRNP [small nucleolar ribonucleoprotein]) known as the H/ACA box (PMID: 19383767, 12228251). The H/ACA box is involved in processing of rRNA, modifications of species of RNAs, and stabilization of telomeres (PMID: 20227365, 19383767). SHQ1 are shown to bind NAP57, which is an essential member of H/ACA, prior to the binding of another accessory protein, NAF1, and is thought to assist in the shuttling of the complex to nucleoli (PMID: 20227365, 19383767). SHQ1 contains a protein-protein interaction domain known as the CS domain (named after CHORD-containing proteins and SGT1) which appears to be essential for H/ACA complex formation (PMID: 19426738, 19019820). The genetic locus of SHQ1 is frequently deleted in prostate cancers and one somatic mutation has been observed (PMID: 20579941). True +ENST00000308377 NM_001104587.1 91607 SLFN11 False SLFN11, an interferon-regulated DNA damage protein, is epigenetically silenced in a variety of cancer types resulting in resistance to genotoxic therapies. SLFN11 is an interferon-stimulated gene that is a member of the Schlafen family of proteins (PMID: 23570387). SLFN11 binds and negatively regulates RPA (Replication Protein Complex A), a complex that associates with single-stranded DNA at stalled replication forks and recruits repair proteins to resolve the forks (PMID: 26658330). SLFN11 mediates the destabilization of the RPA-single-stranded-DNA complex and inhibits DNA repair by altering checkpoint maintenance and homologous recombination (PMID: 26658330). In addition, SLFN11 inhibits the translation of the DNA damage kinases ATR and ATM via specific cleavage of transfer RNAs (PMID: 30374083). SLFN11 couples IFN-γ to the DNA repair pathway and loss of SLFN11 dampens T-cell responses (PMID: 30753225). Expression of SLFN11 predicts for sensitivity to PARP inhibitors, topoisomerase inhibitors, alkylating agents, and DNA synthesis inhibitors in cancer cell line datasets and in clinical studies (PMID: 22460905, 22927417, 29906251, 27708213). In small cell lung cancer, SLFN11 expression is repressed in models of chemoresistance due to chromatin-mediated silencing (PMID: 26658330). Expression of SLFN11 predicts for improved survival in a variety of cancer types including small cell lung cancer, ovarian cancer, and Ewing sarcoma, among others (PMID: 25779942, 22927417, 26525741, 26625211, 27440269, 27923837). Rare somatic mutations in SLFN11 are found in patients with Ewing sarcomas (PMID: 26179511). In addition, SLFN11-deficient cells are sensitive to ATR inhibition due to dependency on that pathway for DNA repair (PMID: 27708213, 29395061). True +ENST00000504154 NM_004787 9353 SLIT2 False SLIT2, a secreted glycoprotein, is infrequently altered in cancer. SLIT2, a member of the Slit family, encodes for a secreted glycoprotein that primarily functions in regulating cellular migration through binding to ROBO1 and ROBO2 receptors to activate the SLIT/ROBO signaling pathway (PMID: 32807784, 35550611, 34181595). SLIT2 is proteolytically processed into C-terminal fragments (SLIT2-C) and N-terminal fragments (SLIT2-N), which both function in promoting chemotaxis through regulation of chemoattractants and increasing cell migration speed (PMID: 10102266, 30510066). The oncogenic function of SLIT2 is likely tissue-specific. Knockdown of SLIT2 in various cancer cell lines and models induces cellular migration and invasion, suggesting that SLIT2 functions predominantly as a tumor suppressor gene in these tissue-specific contexts (PMID: 30648543, 18611862, 34093772, 25490006). Downregulation of SLIT2 has been identified in various types of cancer, including gastric cancer, lung cancer and breast cancer (PMID: 24297051, 20068157, 34400395). Hypermethylation of the SLIT2 promoter region has also been identified in chronic myeloid leukemia and non-small cell lung cancer (PMID: 36411451, 35053460). Conversely, upregulation of SLIT2, along with ROBO1 upregulation, has been observed in osteosarcoma, colorectal cancer, and mucoepidermoid carcinoma (PMID: 21283129, 29523788, 22366001). Overexpression of SLIT2 has been identified to promote tumorigenesis by inducing tumor cell migration and invasion in these tissue-specific contexts (PMID: 24840330, 17268810). False +ENST00000519560 NM_003062 6586 SLIT3 False SLIT3, a secreted glycoprotein, is frequently altered in various cancer types. SLIT3 is a secreted glycoprotein involved in endothelial cell migration guidance and cell-environmental interaction via its interaction with transmembrane proteins called roundabout receptors (ROBOs) (PMID: 21743955, 23720784). There are three slit guidance ligand (SLIT) proteins in humans, all of which function during embryonic development to direct the growth of axons via repulsive guidance cues (PMID: 19741192, 11804571). In addition to its function in central nervous system growth, SLIT3 also plays a role in regulating non-neuron-related processes including kidney and diaphragm formation, angiogenesis, leukocyte migration and prevention of osteoporosis (PMID: 19741192, 21078908, 34423586). The SLIT/ROBO pathway regulates apoptosis, cell migration and invasion; dysregulation of SLIT/ROBO signaling plays a part in tumor progression (PMID: 25245168, 18829537). Expression of SLIT3 inhibits migration of malignant melanoma cells in mice and suppresses tumor growth in breast cancer cells suggesting SLIT3 functions as a tumor suppressor gene (PMID: 21743955, 18829537, 31258778). SLIT3 is frequently downregulated by hypermethylation of its promoter region in various cancer types including glioma and breast cancer, and less frequently by allelic loss in colorectal and lung cancers (PMID: 15534609, 18829537). SLIT3 methylation is also found in breast, lung, colorectal, glioma and gastric cancer cell lines (PMID: 15534609, 27082735). The SLIT3 locus also encodes miR-218-2, an intronic mRNA that is downregulated in multiple types of malignant cancers (PMID: 23720784). True +ENST00000294008 NM_032444.2 84464 SLX4 False SLX4, a protein involved in DNA damage repair, is mutated in the germline of the FANCP subtype of Fanconi anemia patients. The SLX4 protein is involved in various processes related to DNA damage repair. SLX4 localizes at double-strand breaks (DSB) on DNA where it forms a multi-protein complex by recruiting proteins involved in DNA repair and genome stability, such as ERCC1/ERCC4 and SLX1 endonucleases, MSH2/MSH3 mismatch repair complex, and telomeric TRF2, among others (PMID: 19596235, 19596236, 19595721, 19595722). SLX4 is essential for several types of DNA repair including DNA interstrand crosslinks (ICLs), Holliday junction (HJ) resolution and telomere homeostasis (PMID: 24938228). The SLX4 protein is mutated at low frequencies in various tumors, and germline mutations in the gene are the cause of a subtype of Fanconi anemia (FANCP) (PMID: 21240275, 21240277). SLX4 was studied as a putative genetic factor in familial non-BRCA1/2 breast cancer patients, but several studies failed to demonstrate its contribution (PMID: 22911665, 22401137, 21805310, 23211700). True +ENST00000262160 NM_001003652.3 4087 SMAD2 False SMAD2 encodes a tumor suppressor and transcription factor that is a downstream effector in the TGF-ß signal transduction pathway. SMAD2 is infrequently mutated in a diverse range of cancers. SMAD2 is a transcription factor that functions as an effector in the transforming growth factor beta (TGFß) signal pathway. TGFß signaling controls multiple biological processes including cellular proliferation, differentiation and tissue homeostasis (PMID: 22992590, 11057902). SMAD signaling molecules are activated by membrane receptor serine kinases following binding of TGFß superfamily of cytokines (e.g. TGFß1, TGFß2, TGFß3, activin and nodal) (PMID: 25935112, 9759503). Following dimerization and activation of TGFß receptors, two phosphorylated receptor-regulated SMAD proteins, including SMAD2, form a trimeric complex with a co-SMAD, such as SMAD4, to allow for binding to DNA (PMID: 9759503). The SMAD trimeric complex can translocate to the nucleus and regulate TGFß-mediated gene transcription in a cell-type dependent manner specified, in part, by the availability of transcriptional co-activators and chromatin accessibility (PMID: 22992590, 9759503). The contextual nature of TGFß-dependent transcription allows the TGFß pathway to suppress tumorigenesis in premalignant states and promote invasiveness and metastasis during cancer progression (PMID: 22992590, 18662538, 20495575). Loss of SMAD2 expression occurs at a low frequency in colorectal, gastric and ovarian cancer and correlates with poor prognosis (PMID: 25935112, 23139211, 9679244, 8752209, 12967141, 22539990, 12894231). Notably, both elevated and decreased levels of phosphorylated SMAD2 are associated with poor prognosis in several cancer types (PMID: 21110833, 22539990, 16788944, 25373709). Although infrequent, SMAD2 mutations are found in colorectal cancer and less frequently in various other cancer types, such as lung and hepatocellular cancer (PMID: 23139211, 22895193, 22810696, 8752209, 8971158, 10490821, 16959974). True +ENST00000327367 NM_005902.3 4088 SMAD3 False SMAD3 encodes a tumor suppressor and transcription factor that is a downstream effector in the TGF-ß signal transduction pathway. SMAD3 is infrequently mutated in a diverse range of cancers. SMAD3 is a transcription factor that functions as a critical effector in the transforming growth factor beta (TGFß) signal pathway. TGFß signaling controls multiple biological processes including cellular proliferation, differentiation and tissue homeostasis (PMID: 22992590, 11057902). SMAD signaling molecules are activated by membrane receptor serine kinases following binding of TGFß superfamily of cytokines (e.g. TGFß1, TGFß2, TGFß3, activin and nodal) (PMID: 25935112, 9759503). Following dimerization and activation of TGFß receptors, two phosphorylated receptor-regulated SMAD proteins, including SMAD3, form a trimeric complex with a co-SMAD, such as SMAD4, to allow for binding to DNA (PMID: 9759503). The SMAD trimeric complex can translocate to the nucleus and regulate TGFß-mediated gene transcription in a cell-type dependent manner specified, in part, by the availability of transcriptional co-activators and chromatin accessibility (PMID: 22992590, 9759503). The contextual nature of TGFß-dependent transcription allows the TGFß pathway to suppress tumorigenesis in premalignant states and promote invasiveness and metastasis during cancer progression (PMID: 22992590, 18662538, 20495575). Germline SMAD3 mutations are found in hereditary syndromes in the Loeys-Dietz phenotypic series of diseases (PMID: 22167769, 21217753, 21778426). Although infrequent, somatic SMAD3 loss-of-function mutations and deletions have been identified in colorectal cancer, in accordance with studies in transgenic mice (PMID: 22810696, 23139211, 9753318, 16959974). SMAD3 alterations have also been observed in various other tumor types (PMID: 16959974, 14647420, 21771027, 15295048, 12161532). True +ENST00000342988 NM_005359.5 4089 SMAD4 False SMAD4 encodes a tumor suppressor and transcription factor that is a downstream effector in the TGF-ß signal transduction pathway. SMAD4 is frequently mutated in pancreatic and colorectal cancer and infrequently mutated in various other cancers. SMAD4 is a transcription factor that functions as a critical effector in the transforming growth factor beta (TGFß) signal pathway. TGFß signaling controls multiple biological processes including cellular proliferation, differentiation and tissue homeostasis (PMID: 22992590, 11057902). The SMAD receptor-regulated signaling molecules (such as SMAD2 and SMAD3) are activated by membrane receptor serine kinases following binding of TGFß superfamily of cytokines (e.g. TGFß1, TGFß2, TGFß3, activin and nodal) (PMID: 25935112, 9759503). Following dimerization and activation of TGFß receptors, two phosphorylated receptor-regulated SMAD proteins form a trimeric complex with SMAD4 to allow for binding to DNA (PMID: 9759503). The SMAD trimeric complex can translocate to the nucleus and regulate TGFß-mediated gene transcription in a cell-type dependent manner specified, in part, by the availability of transcriptional co-activators and chromatin accessibility (PMID: 22992590, 9759503). The contextual nature of TGFß-dependent transcription allows the TGFß pathway to suppress tumorigenesis in premalignant states and promote invasiveness and metastasis during cancer progression (PMID: 22992590, 18662538, 20495575). Germline mutations in SMAD4 have been associated with juvenile polyposis syndrome (JPS) (PMID: 9545410, 8553070, 8673134, 18662538). Loss of SMAD4 expression or somatic mutations in SMAD4 are found in pancreatic cancer and are associated with tumor grade (PMID: 8553070, 8673134, 9766641, 9135016, 10327057, 19273710, 12821112). Somatic alterations in SMAD4 are observed at lower frequencies in multiple tumor types, including colon and lung adenocarcinoma (PMID: 23139211, 19841540, 16959974, 22810696, 15867212, 25589618, 25890228). True +ENST00000371122 NM_003069 6594 SMARCA1 True SMARCA1, an ATPase involved in chromatin remodeling, is infrequently altered in cancer. SMARCA1, a member of the switch/sucrose non-fermentable (SWI/SF) family, encodes for an ATPase that functions primarily in the chromatin remodeling complex (PMID: 28801535, 15310751). SMARCA1 is a catalytic subunit of the imitation SWI (ISWI) chromatin remodeling complex, which facilitates access to DNA for processes such as DNA replication, transcription and repair (PMID: 28801535). An isoform of SMARCA1 has been identified in humans to be catalytically inactive and function as a negative regulator to chromatin remodeling through forming inactive complexes (PMID: 15310751). Loss-of-function germline mutations of SMARCA1 are associated with the multisystem disorder Schimke immuno-osseous dysplasia (PMID: 20013129). The oncogenic function of SMARCA1 is likely dependent on tissue-specific contexts. Knockdown of SMARCA1 in myoepithelial cell lines induces DNA damage, growth inhibition and cancer cell death, suggesting that SMARCA1 functions predominantly as an oncogene in this context (PMID: 19996304). SMARCA1 upregulation has been identified in colon adenocarcinoma, cervical squamous cell carcinoma and endocervical adenocarcinoma (PMID: 36126083). In contrast, knockdown of SMARCA1 in gastric cancer and melanoma cell lines induces cellular growth, migration, invasion and downregulation of genes related to cellular homeostasis, suggesting that SMARCA1 functions predominantly as a tumor suppressor gene in this context (PMID: 25462860, 22508985). SMARCA1 has been identified to be silenced through DNA methylation in gastric cancer (PMID: 25462860). True +ENST00000349721 NM_001289396.1 6595 SMARCA2 False SMARCA2, a tumor suppressor involved in chromatin remodeling, is infrequently altered by mutation in various cancer types. Germline mutations of SMARCA2 are associated with Nicolaides-Barraitser syndrome. SMARCA2 (also BRM) is an ATP-dependent helicase that is a catalytic subunit of the SWI/SNF chromatin remodeling complex (PMID: 28391084, 21654818, 26601204). The SWI/SNF complex plays a role in altering chromatin structure, a process that is necessary for various cellular functions, including gene regulation, DNA repair, differentiation, and lineage specification (PMID: 28391084, 21654818, 26601204). SMARCA2, or the ATP helicase SMARCA4, form a multicomponent complex by partnering with 15 core and adaptor proteins to mediate interactions with DNA and chromatin (PMID: 28391084, 26601204). Germline heterozygous mutations in SMARCA2 are found in patients with Nicolaides-Baraitser syndrome (NCBRS), a disorder characterized by intellectual disabilities and altered development (PMID: 22366787, 31375262). NCBRS-associated SMARCA2 mutations result in enhancer reprogramming, leading to a redistribution of SMARCA4 on chromatin (PMID: 31375262). Somatic mutations in SMARCA2 in human cancers are more uncommon than SMARCA4 alterations; however, SMARCA2 has been found to be silenced by epigenetic mechanisms in several cancer types (PMID: 29391527, 28391084, 17546055). Because SMARCA2 can replace SMARCA4 in SMARCA4-deficient tumors, SMARCA2 inhibition may be efficacious in cancer types with SMARCA4 mutations (PMID: 24421395, 24520176). Furthermore, inhibitors targeting Polycomb Repressive Complex 2 (PRC2) have been found to have activity in cancers with low SMARCA2 expression (PMID: 28391084). True +ENST00000358026 NM_001128849.1 6597 SMARCA4 False 3A SMARCA4, a tumor suppressor involved in chromatin remodeling, is recurrently altered in small cell carcinoma of the ovaries, hypercalcemic type (SCCOHT). SMARCA4 is an ATP-dependent helicase that is a catalytic subunit of the SWI/SNF chromatin remodeling complex (PMID: 21654818). This complex plays a role in altering chromatin structure, a process that is necessary for various cellular functions, including transcription, DNA synthesis and DNA repair (reviewed in PMID: 25387058). Secondary to ARID1A, SMARCA4 is the most frequently mutated gene among the SWI/SNF subunits and is significantly altered in malignant rhabdoid tumors, lymphoma, medulloblastoma, lung and ovarian cancer (PMID: 23644491, 25060813, 23143597). Mutations in the SMARCA4 gene result in loss of function, suggesting its tumor suppressor properties. Germline SMARCA4 mutations predispose to pediatric atypical teratoid/rhabdoid tumors (AT/RT) (PMID: 20137775, 25060813) and small cell carcinoma of the ovaries, hypercalcemic type (SCCOHT) (PMID: 24658002, 24658004). Almost all SCCOHT cases have mutations in the SMARCA4 gene. In the majority of cases this is the only mutation present, and thus thought to be a driver mutation for this disease (PMID: 24658002, 24658004, 24658001). True +ENST00000263121 NM_003073.3 6598 SMARCB1 False 1 SMARCB1, a protein involved in chromatin remodeling, is inactivated by mutation or deletion in various cancer types including soft tissue sarcomas and CNS cancers. SMARCB1 (INI1, BAF47, SNF5) is present in all known variants of the SWI/SNF chromatin remodeling complex, and is thus considered a core subunit (PMID: 10078207). SWI/SNF complexes are ATP dependent nucleosome remodelers which are required for efficient accessibility of genes to the transcriptional machinery (PMID: 14964309). SWI/SNF complexes are important for normal human development and are required for the transition of transcriptional programs during cellular differentiation(PMID: 23568486). In cancer, SMARCB1 acts as a strong tumor suppressor. It is mutated in rhabdoid tumours, familial schwannomatosis, small-cell hepatoblastomas, extraskeletal myxoid chondrosarcomas, undifferentiated sarcomas, epitheliod sarcomas, meningiomas and poorly differentiated chordomas (PMID: 9671307, 21057957, 17357086, 18985717, 18580682, 18997735, 15899790, 20930055). Heterozygous SMARCB1 mutations are found in patients with rhabdoid predisposition syndrome, which is characterized by the inheritance of a defective SMARCB1 allele followed by the loss of the remaining allele in the tumours (PMID: 10521299). Mouse models of SMARCB1 mutations recapitulate the tumor suppressor functions observed in humans (PMID: 11095756, 12450796, 16301525). The exact mechanism by which SMARCB1 loss leads to malignant transformation is not yet well understood, however, expression analyses have shown that one consequence of SMARCB1 loss is the activation of gene expression programmes that are associated with proliferation and dedifferentiation (PMID: 21076395). Recently, it was found that SMARCB1 mutant cells depend on the PRC2 component EZH2 which has lead to clinical trials of EZH2 inhibitors in patients with SMARCB1 mutant cancers (PMID: 21654818, 20951942, 26552009, 23620515). True +ENST00000394963 NM_003076.4 6602 SMARCD1 False SMARCD1 (also known as BAF60A), is a member of the SWI/SNF family, and acts in recruiting transcription factors and nuclear receptors to the SWI/SNF chromatin remodeling complex. The SMARCD1 gene has been found mutated in breast cancer and the SMARCD1 protein is derepressed in gastric and prostate cancer. The SMARCD1 gene encodes the protein SMARCD1, (SWI/SNF related, Matrix associated, Actin dependent Regulator of Chromatin, subfamily D, member 1) also known as BAF60A (BRG1-Associated Factor 60A). The SMARCD1 protein is a member of the SWI/SNF (SWItch/Sucrose NonFermentable) complex, an ATP-dependent chromatin remodeling complex that alters the location or conformation of nucleosomes by using the energy of ATP hydrolysis and thus can regulate transcription of certain genes. To this end, SMARCD1 interacts with a wide repertoire of transcription factors including Oct3/4, Sox2, Sox10, c-Fos/c-Jun, peroxisome proliferator-activated receptor α, vitamin D receptor, glucocorticoid receptor, retinoid-related orphan receptor α, androgen receptor and recruits them to the SWI/SNF complex (PMID: 11053448, 12917342, 14698202, 18680712, 19762545, 20508149, 21725993, 22334693). SMARCD1 is required for Tbx1-driven expression of Wnt5a, a non-canonical Wnt ligand that promotes cell migration and invasion in gastric cancer (PMID: 22438823, 17079465). Moreover, SMARCD1 interacts directly and indirectly with key regulators of pluripotency in embryonic stem cells, which in some cases maintains pluripotency (PMID:19279220) and in other cases restricts it (PMID: 25818293). A series of recent studies showed that SMARCD1 is a direct target of tumor-suppressive miRNA (micro RNAs), namely miR-99 in prostate cancer (PMID: 21212412), miR-490-3p in gastric and ovarian cancer (PMID: 25503559, 25819031) and miR-100 in breast cancer stem-like cells (PMID: 25217527). On the other hand, tumor-suppressive properties of SMARCD1 have been reported; interaction between SMARCD1 and p53 is required for p53-mediated cell-cycle arrest and apoptosis (PMID: 18303029) and SMARCD1 is frequently inactivated by truncating mutations in breast cancer (PMID: 22722201). It becomes therefore obvious that the function of SMARCD1 in carcinogenesis is complex and context-dependent. False +ENST00000348513 NM_003079.4 6605 SMARCE1 True SMARCE1, an adaptor protein involved in chromatin remodeling, is infrequently altered by mutation and amplification in various cancer types. Germline mutations of SMARCE1 are associated with spinal meningiomas and Coffin-Siris syndrome. SMARCE1 (also BAF57) is a core subunit of the SWI/SNF chromatin remodeling complex (PMID: 28391084, 21654818, 26601204). The SWI/SNF complex plays an important role in altering chromatin structure, a process that is necessary for various cellular functions, including gene regulation, DNA repair, differentiation, and lineage specification (PMID: 28391084, 21654818, 26601204). The SMARCE1 subunit has the ability to bind cruciform structures in DNA which might lead to SWI/SNF targeting to sites with distinct chromatin architecture (PMID: 26601204, 27149204). In addition, SMARCE1 is predicted to have a role in mediating chromatin relaxation and disassembly of the SWI/SNF complex (PMID: 27149204). SMARCE1 also has roles in lymphocyte development and in both androgen and estrogen-mediated transcription (PMID: 12110891, 16769725, 18559499, 23493350). Familial alterations in SMARCE1 are found in patients with Coffin-Siris syndrome, a developmental disorder (PMID: 25168959, 31273213). Germline loss-of-function mutations in SMARCE1 are also found in almost all patients in non-NF2 driven spinal meningiomas (PMID: 23377182, 26601204). In human cancer, somatic mutations in SMARCE1 are rare (PMID: 26601204). However, amplification of SMARCE1 is found in some cancer types, including in breast cancer, and is implicated in metastatic progression (PMID: 26601204, 27149204). True +ENST00000322213 NM_006306.3 8243 SMC1A False SMC1A, an ATPase that functions as a subunit of the cohesin complex, is recurrently mutated in Cornelia de Lange syndromes, hematologic malignancies, and solid tumors. SMC1A (also SMC1L1) is an ATPase that is a member of the SMC family of proteins. SMC1A functions as a subunit of the cohesin complex that aligns and stabilizes sister chromatids during metaphase (PMID: 24854081). Cohesion between sister chromatids is initiated during DNA replication and must be maintained throughout mitosis or meiosis to ensure proper chromosome-spindle attachments (PMID: 26903600). The cohesin ring that encircles sister chromatids is comprised of two large structural proteins, SMC1A and SMC3, and this ring opens and closes through the binding of alpha-kleisin subunits to the RAD21 and STAG adapter proteins (PMID: 24854081, 22885700). The cohesin complex also functions to maintain chromatin looping structures or 3D arrangements of DNA that allow for regulatory control of gene expression (PMID: 19468298). SMC1A localizes to chromatin sites bound by the insulator protein CTCF, which inhibits tissue-specific enhancer-promoter interactions (PMID: 19468298, 23704192). Germline mutations in SMC1A have been identified in patients with cohesinopathies, including Cornelia de Lange syndrome, leading to a spectrum of developmental defects (PMID: 17221863, 17273969, 18996922). Somatic mutations and deletions in SMC1A have been identified in acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), bladder cancers, and additional hematopoietic malignancies, among others (PMID: 23955599, 24121791, 24335498, 25080505, 24056718, 18299561, 20514443). Mutations in SMC1A are predicted to be loss-of-function and impact the association of SMC proteins with chromatin (PMID: 18996922). Alterations in SMC1A are also predicted to be initiating events in acute myeloid leukemia (PMID: 22932223). True +ENST00000361804 NM_005445.3 9126 SMC3 False SMC3, an ATPase that functions as a subunit of the cohesin complex, is recurrently mutated in Cornelia de Lange syndromes, hematologic malignancies, and solid tumors. SMC3 is an ATPase that is a member of the SMC family of proteins. SMC3 functions as a subunit of the cohesin complex that aligns and stabilizes sister chromatids during metaphase (PMID: 24854081). Cohesion between sister chromatids is initiated during DNA replication and must be maintained throughout mitosis or meiosis to ensure proper chromosome-spindle attachments (PMID: 26903600). The cohesin ring that encircles sister chromatids is comprised of two large structural proteins, SMC1A and SMC3, and this ring opens and closes through the binding of alpha-kleisin subunits to the RAD21 and STAG adapter proteins (PMID: 24854081, 22885700). The cohesin complex also functions to maintain chromatin looping structures or 3D arrangements of DNA that allow for regulatory control of gene expression (PMID: 19468298). SMC3 localizes to chromatin sites bound by the insulator protein CTCF, which inhibits tissue-specific enhancer-promoter interactions (PMID: 19468298, 28467304). Loss of SMC3 in murine models results in aberrant hematopoietic stem cell function and altered expression of genes important in lineage commitment (PMID: 26438361). Germline mutations in SMC3 have been identified in patients with cohesinopathies, including Cornelia de Lange syndrome, leading to a spectrum of developmental defects (PMID: 17221863, 17273969, 18996922, 25655089). Somatic mutations and deletions in SMC3 have been identified in acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), bladder cancers, and additional hematopoietic malignancies, among others (PMID: 23955599, 24335498, 24056718, 18299561, 28152414, 27470916, 27207471). Mutations in SMC3 are predicted to be loss-of-function and impact the association of SMC proteins with chromatin (PMID: 26438361, 25006131). True +ENST00000446231 NM_015092.4 23049 SMG1 False SMG1, a serine/threonine kinase involved in nonsense-mediated decay, is infrequently altered across a diverse range of cancers. SMG1 is a serine/threonine kinase that is a member of the Phosphatidylinositol 3-kinase-related kinase family (PIKK) (PMID: 11544179). SMG1 is an essential protein that regulates nonsense-mediated mRNA decay (NMD), a process that removes incorrect mRNAs that contain premature translation termination codons, and hence encode for aberrant proteins (PMID: 11544179). SMG1 phosphorylates UPF1, an ATPase and RNA helicase involved in NMD, and binds additional proteins involved in mRNA surveillance (PMID: 11544179, 12554878, 18160036). UPF1 and SMG1 form a complex with translation release factors and function as a translation termination complex (PMID: 19417104). SMG1 activity is required for various cellular functions including cell cycle progression, mRNA export, translation, DNA repair, genome stability, apoptosis, and telomere maintenance (PMID: 16199763, 16488880, 16861888, 18326048, 18332866). In addition, NMD or disruption of SMG1 mRNA surveillance activity can lead to alternative splicing to circumvent premature translation termination codons (PMID: 17693403, 20566848). Loss or overexpression of SMG1 results in accumulation or degradation of mRNAs with premature termination codons as demonstrated in functional experiments (PMID: 11544179). NMD can exacerbate developmental disorders that result in mRNAs with premature translation termination codons, such as Ullrich’s disease, and inhibition of SMG1 can restore some normal cellular function (PMID: 16807116). SMG1 is infrequently mutated in human cancers, however, heterozygous loss of SMG1 in murine models results in tumor formation (PMID: 23277562) suggesting that SMG1 functions as a tumor suppressor. Expression of SMG1 is found in several tumor types including acute myeloid leukemia (AML) and head and neck squamous cell carcinomas (PMID: 22247495, 25257528). In kinase screens, SMG1 was identified as a possible target in multiple myeloma (PMID: 19996089). True +ENST00000249373 NM_005631.4 6608 SMO True SMO, a G-protein coupled receptor, is mutated in various cancers including basal cell carcinoma and medulloblastoma. Smoothened (SMO) is a conserved signal transducer of the hedgehog signaling pathway, playing important roles in normal embryonic and neuronal development as well as tumorigenesis (PMID: 23719536, 21614026, 26912893). SMO is a seven-transmembrane domain protein bearing some structural and functional similarity to G-protein coupled receptors (PMID: 23636324). SMO activity is normally inhibited by patched (PTCH1), an upstream component of the Hedgehog pathway, via poorly understood mechanisms (PMID: 23719536). Binding of extracellular Hedgehog ligands to PTCH1 leads to consecutive activation of SMO, which in turn induces modifications of the downstream GLI transcription factors leading to their activation. Activating mutations in SMO lead to constitutive activation of GLI-mediated transcription of important oncogenic genes. Such mutations have been implicated in sporadic basal cell carcinoma (PMID: 9422511, 26950094) and medulloblastoma (PMID: 21614026) and have been identified in many other tumor types. Recent efforts have been made to specifically target SMO (PMID: 26781311, 26931153, 26919418, 26843616, 26527777). A distinct set of mutations in the ligand binding pocket of SMO, however, has been described to confer resistance to SMO inhibitors such as vismodegib and related cyclopamine drugs (PMID: 25759014, 26960983). False +ENST00000388985 NM_001167740.1 64754 SMYD3 True SMYD3, a histone methyltransferase and transcriptional activator, is amplified in a subset of breast and other cancers. The SMYD3 gene encodes a histone lysine methyltransferase. SMYD3 specifically di- and trimethylates lysine-4 of histone 4 (H3K4me2/3), as well as the lysine-5 residue of the same histone. SMYD3-induced methylation generates transcription activating marks that induce gene expression. SMYD3 itself is part of the RNA polymerase complex, present on genes being actively transcribed (PMID: 15235609, 22419068). SMYD3 activity induces cell proliferation, migration and carcinogenesis in various in vitro and in vivo cancer systems via transcriptional activation of different target genes (PMID: 15235609, 25980436, 24174655, 22194464). SMYD3 is altered by amplification in a subset of breast cancers and other tumors (cBioPortal, MSKCC, Dec. 2016). False +ENST00000332029 NM_003745.1 8651 SOCS1 False SOCS1, a negative regulator of cytokine signaling, is altered in various hematologic malignancies, most frequently in diffuse large B-cell lymphoma. SOCS1 is an adaptor protein that suppresses cytokine signaling and functions in negative feedback inhibition of the JAK-STAT signaling pathway (PMID:9202125). SOCS1 binds the phosphotyrosines on receptor and non-receptor kinases to mediate inhibition of cytokine signaling (PMID:10064597). In addition, SOCS1 can target proteins for degradation via the SOCS box domain (PMID: 9202125). Regulation of cytokine signaling by SOCS1 is important for effective immune regulation and lymphocyte development (PMID:10490100, 14499118, 12433373, 16415872, 24086733). Somatic loss-of-function SOCS1 mutations have been found in Hodgkin’s lymphoma and primary mediastinal lymphomas (PMID:17652621, 23296022,19734449). SOCS1 mutations present as truncating mutations and lead to activated JAK-STAT kinase signaling (PMID:16532038), suggesting that SOCS1 functions as a tumor suppressor. Silencing of SOCS1 transcription has also been identified in myeloid diseases, leukemias, ovarian cancer and breast cancer (PMID: 25123164, 15327527, 15361843). True +ENST00000330871 NM_003955.4 9021 SOCS3 False SOCS3, a negative regulator of cytokine signaling, is infrequently mutated in various cancer types. SOCS3 is an adaptor protein that suppresses cytokine signaling and functions in negative feedback inhibition of the JAK-STAT signaling pathway (PMID: 17525754). SOCS3 binds phosphotyrosines on receptor and non-receptor kinases to mediate inhibition of cytokine signaling (PMID:10064597, 24600449). Namely, SOCS3 negatively regulates the activity of the JAK non-receptor tyrosine kinase family, leading to reduced translocation of activated STAT3 transcription factor complexes to the nucleus (PMID: 22342841, 24600449, 22566904). In addition, SOCS3 can target proteins for degradation via interactions with E3 ubiquitin ligase complexes (PMID: 29712772, 25939384). Regulation of cytokine signaling by SOCS3 is an important mediator of various cellular functions including immune homeostasis, inflammation, proliferation, and survival (PMID: 24069550, 24600449, 22566904). Somatic mutations in SOCS3 are relatively rare in human cancer; however, epigenetic silencing of SOCS3 transcription has been identified in several hematopoietic malignancies and solid tumors including mantle cell lymphomas, myeloproliferative neoplasms and prostate cancer, among others (PMID: 23432547, 26216197, 18440067, 20717995). Deletion of SOCS3 in myeloid suppressor populations in the tumor microenvironment also promotes tumor progression in solid tumors, due to dampening of anti-tumor immune responses (PMID: 26967393, 25649351, 29626115). True +ENST00000402219 NM_005633.3 6654 SOS1 True SOS1, a RAS activator, is altered at low frequencies in various cancers. SOS1 is a guanine exchange factor (GEF) that positively regulates the activation of the RAS proteins in the MAP-kinase (MAPK) pathway. SOS1 is recruited to the plasma membrane, binds the adaptor molecule GRB2 and facilitates the activated, GTP-bound state of RAS, which in turn initiates the MAPK pathway signaling cascade (PMID: 8493579). The activity of SOS1 is required to mediate cell proliferation, cell cycle progression, oxidative stress, cell migration, and invasion (PMID: 27157612). SOS1 also activates the G protein RAC by promoting the exchange of GDP for GTP (PMID: 9438849, 22042618). Germline mutations in SOS1 have been identified in certain forms of Noonan syndrome, a hereditary disorder of congenital heart disease (PMID: 17143285, 17143282). However, somatic alterations in SOS1 are rare events in human cancers (PMID: 18064648; cBioPortal, MSKCC, Jan. 2018). False +ENST00000360880 NM_006941 6663 SOX10 True SOX10, a transcription factor involved in embryonic development and cell fate, is altered by amplification in melanoma. SOX10 encodes a member of the SRY-related HMG-box (SOX) family of transcription factors that functions as a regulator of organogenesis and histogenesis during embryonic development (PMID: 28751573, 33082503). During embryogenesis, SOX10 is localized to neural crest cells and regulated by WNT signaling (PMID: 12812785). SOX10 is a transcriptional target of the WNT pathway, but also functions as a regulator of WNT pathway target genes (PMID: 25301735). Due to its role during embryogenesis, deleterious mutations of SOX10 have been implicated in various developmental disorders (PMID: 9462749, 11454798, 23643381). Knockdown of SOX10 in melanoma cell lines and models suppresses cellular proliferation, tumor growth and cell cycle progression, suggesting that SOX10 functions predominantly as an oncogene (PMID: 34557039, 22772081, 23913827). SOX10 amplification has been identified in various cancers, including melanoma, bladder cancer and nasopharyngeal carcinoma (PMID: 27051302, 28258492, 23197006). False +ENST00000297316 NM_022454.3 64321 SOX17 False SOX17 encodes a transcription factor involved in embryonic development and cell fate. Methylation and downregulation of SOX17 are found in colon, liver, lung and breast cancers. SOX17 encodes a member of the SRY-related HMG-box (SOX) family of transcription factors and acts as an important antagonist of the canonical Wnt/beta-catenin signaling pathway by promoting the degradation of β-catenin/TCF via a GSK3β-independent mechanism. The Wnt signaling pathway is involved in many biological processes including embryonic development to stem cell maintenance. For example, conditional ablation of SOX17 in mouse uterine tissue resulted in inhibition of endometrial adenogenesis and a loss of reproductive capacity (PMID:27102016). Interestingly, conditional deletion of SOX17 from mouse hematopoietic stem cells (HSCs) led to the loss of fetal and neonatal but not adult HSCs, proving its importance in the maintenance of fetal and neonatal HSCs but not adult HSCs (PMID:17655922). True +ENST00000325404 NM_003106.3 6657 SOX2 True SOX2 encodes a transcription factor involved in embryonic development and cell fate. Amplifications of SOX2 are found in glioblastomas, small cell lung cancers and squamous cell carcinomas. SOX2 encodes a transcriptional factor essential to embryonic stem cell development and the determination of cell fate. It functions as an activator or suppressor of gene transcription through a highly specific DNA binding (high-mobility group) domain (PMID: 20016762). Together with Oct-4 and Nanog, Sox2 positive regulates transcription of pluripotency factors involved in the Leukemia inhibitory factor signaling pathway (PMID:19571885). SOX2 has recently been implicated in cancer development, by promoting oncogenic signaling and maintaining cancer stem cells. It has been shown to promote cellular proliferation in breast (PMID: 22561374), prostate (PMID: 24659665), pancreatic (PMID: 23917223) and cervical cancers (PMID: 21415100); and to evade apoptotic signaling in prostate (PMID: 24325912), gastric cancer (PMID: 21415100) and non small cell lung cancer (PMID: 24233838). SOX2 has also been associated with an increased in the metastatic potential of these cancers (PMID: 22069467, 22184093, 22912670, 23895273). SOX2 amplification is observed in several cancer types including glioblastoma, small-cell lung cancer and many forms of squamous cell carcinoma (PMID: 20126410, 21518820, 22069467, 20372069, 19801978, 21334718, 22941189, 19787784). Its heterozygous mutations have been associated with developmental disorders, such as aanophthalmia-esophagel-genital (AEG) syndrome (PMID: 16543359) and syndromic microphthalmia, a structural eye malformation (PMID: 23463581). False +ENST00000245479 NM_000346.3 6662 SOX9 True SOX9 encodes a putative tumor suppressor and transcription factor involved in organ and skeletal development. This gene is frequently mutated in colorectal cancer. The SOX9 (Sex-determining Region Y box 9) gene encodes a transcription factor involved in organ and skeletal development. It is expressed widely throughout the body and regulates multiple developmental processes, such as embryonal cell-fate determination, chondrogenesis and testis formation; however, SOX9 also functions in developed tissues (PMID: 25685828). SOX9 is a transcriptional target of the WNT pathway, but also functions as a regulator of WNT pathway target genes (PMID: 17698607). Additionally, SOX9 can facilitate β-catenin degradation by promoting its phosphorylation (PMID: 19047045). Due to its role in development, deleterious mutations of SOX9 can cause developmental disorders; mutations of SOX9 are also implicated in various other disorders (PMID: 25685828). SOX9 mutations are frequent in colorectal cancer and dysregulation of SOX9 is implicated in cancer development in multiple tissue types (PMID: 22810696, 24302456, 22246670, 15084848, 20049725). True +ENST00000392045 NM_007237.4 11262 SP140 False SP140, a protein that associates with nuclear bodies, is altered by mutation in hematologic malignancies. SP140 is a nuclear protein that is a member of the SP100 family of proteins (PMID: 8695863). SP140 is predominantly expressed in lymphoid cells and associates with nuclear bodies, which are suborganelles that carry out specific nuclear functions (PMID: 28577509). These functions include the processing of pre-ribosomal RNA, oxidative stress response, gene expression regulation, cellular proliferation and innate immunity, among others (PMID: 21068152). SP140 shares homology with SP100, a protein known to associate with PML in nuclear bodies to mediate various cellular processes (PMID: 8910577, 10913195). In acute promyelocytic leukemia, SP140 co-localizes with PML in nuclear bodies and this association increases after treatment with retinoic acid (PMID: 8910577). SP140 can also function as an epigenetic reader protein, which is important in mediating the repression of immune response related genes (PMID: 24267382, 28783698). Loss of SP140 in macrophages results in altered expression of transcriptional programs and compromises the immune response to microbe infection (PMID: 28783698). SP140 is predicted to function as a tumor suppressor in chronic lymphocytic leukemia (CLL) and several variants in SP140 have been associated with increased risk for CLL (PMID: 18758461, 22235315). In addition, SP140 is hypomethylated in acute myeloid leukemia and chronic myeloid leukemia, leading to decreased gene expression (PMID: 22395470, 26568194). Somatic mutations in SP140 are also found in patients with multiple myeloma (PMID: 25743686). True +ENST00000375759 NM_015001.2 23013 SPEN False SPEN encodes a tumor suppressor that regulates transcription of ERα-target genes and has been associated with tumor growth inhibition. Somatic mutations and loss of heterozygosity of SPEN have been found in breast cancer. The SPEN gene encodes the protein, SMRT/HDAC1-associated repressor protein (SHARP), mainly involved in transcriptional repression, embryogenesis and development through regulation of the Notch, TCF/LEF, and EGFR signaling pathways. SHARP is a large 402 kDA protein composed of four N-terminal RNA-binding domains and a conserved C-terminal Spen Paralog and Ortholog C-terminal (SPOC) domain. Through these domains, SHARP directly interacts with SMRT, HDAC1, and HDAC2. SPEN also acts as an estrogen-inducible cofactor by binding the steroid receptor RNA coactivator SRA which enhances ERα activity and ultimately modulates the transcription of ERα target genes. (PMID: 11331609, 26297734) Recent studies studying ERα-expressing breast cancer cell lines have identified mutations and LOH in SPEN that lead to underexpression that may be a predictive biomarker of tamoxifen response. ERα-positive breast cell lines expressing higher levels of SPEN correlated with better outcome in patients who received adjuvant tamoxifen therapy. (PMID: 26297734). True +ENST00000347630 NM_001007228.1 8405 SPOP False SPOP encodes an adaptor protein involved in targeting proteins for degradation. SPOP mutations are predominantly found in prostate and endometrial cancers; however, the full functional consequence of these mutations remains under investigation. SPOP (Speckle-type POZ protein) is an adaptor protein in the CUL3 ubiquitin ligase complex that recognizes substrates for ubiquitination and subsequent degradation via the proteasome (PMID: 19818708). The repertoire of SPOP substrates is not well characterized; however, notable proteins include SRC3, DAXX, H2AFY, AR, BMI1, DEK, ESR1 and TRIM24 (PMID: 25278611, 15897469, 25274033, 21577200, 25766326). The CUL3-SPOP complex negatively regulates the transcriptional repressor DAXX, hence impacting the expression of endothelial pathway genes that are regulated by DAXX (PMID: 28216678). Somatic mutations in SPOP are reported in approximately 5% of endometrial cancers (PMID: 23104009) and 10% of prostate cancers (PMID: 21307934, 22610119). SPOP-mediated degradation has also been implicated in the regulation of PD-L1, a key regulatory immune ligand (PMID: 29160310). SPOP mutations in both endometrial and prostate cancer cluster in conserved residues of the MATH domain important for substrate recognition, suggesting that the mutations either alter substrate recognition or act as a dominant negative to prevent substrate degradation (PMID: 21307934, 22610119). There is emerging evidence that SPOP may be a more general tumor suppressor in glioblastoma, gastric and colorectal cancers, as SPOP expression is decreased through tumor progression (PMID: 25351530, 23216165). True +ENST00000299084 NM_152594.2 161742 SPRED1 False SPRED1, a negative regulator of the MAP-kinase pathway, is mutated at low frequencies in various cancers. The SPRED1 gene encodes a member of the Sprouty family of proteins. SPRED1 is a negative regulator of the MAP-kinase (MAPK) pathway (PMID: 15683364, 21364986). The mechanism by which SPRED1 inhibits MAPK signaling involves NF1 (neurofibromatosis type 1), which, upon interaction with SPRED1, localizes to the plasma membrane and facilitates RAS inactivation (PMID: 22751498, 26635368). Overexpression of SPRED1 in a hepatocellular carcinoma model leads to a decrease in cell motility and an increase in the expression of metalloproteinases, which are involved in invasion and metastasis (PMID: 16652141). SPRED1 is rarely mutated in cancers (cBioPortal, MSKCC, Dec. 2016). However, germline loss-of-function mutations in SPRED1 are the cause of Legius syndrome, a familial disorder with neurofibromatosis-like features (PMID: 24334617, 17704776, 19366998) and SPRED1 has been shown to act as a tumor suppressor in mucosal melanoma (PMID: 30385465). True +ENST00000295050 NM_032018.6 83932 SPRTN False SPRTN, a metalloprotease that functions as a DNA repair protein, is recurrently altered by mutation in early-onset hepatocellular carcinoma. SPRTN (also C1orf124, Spartan, or DVC1) is a metalloprotease that functions as a DNA repair adaptor protein (PMID: 25496645, 27852435). SPRTN recruits the protein segregase p97 to stalled replication forks, allowing for p97 to remove the translesional synthesis polymerase (Pol η) and for DNA replication to bypass lesions (PMID: 23042605). The activity of SPRTN is required to block excessive translesional DNA synthesis and reduce mutations caused by DNA damage (PMID: 23042607, 23042605). SPRTN associates with monoubiquitinated PCNA, the processivity factor that promotes translesional synthesis, to remove p97 from blocked replication forks (PMID: 23042605, 27084448). SPRTN also has the ability to resolve DNA-protein crosslinks, which contributes to the role of SPRTN in the DNA damage response (PMID: 27852435, 27871365). Loss of SPRTN expression results in increased mutagenesis after UV light stimulation, cellular senescence, hypersensitivity to replication stress-inducing agents and age-related phenotypes in mice (PMID: 23042605, 25501849, 27871366, 28199696). Germline mutations in SPRTN are found in patients with Ruijs-Aalfs syndrome, which presents with early-onset hepatocellular carcinoma, premature aging and genomic instability (PMID: 25261934). Patient samples with SPRTN mutations have reduced cell cycle checkpoint control when treated with genotoxic agents (PMID: 25261934). True +ENST00000389805 NM_003900 8878 SQSTM1 True SQSTM1, an autophagy adaptor protein, is infrequently altered by translocation in cancer. SQSTM1 (or p62) is a stress-inducible adaptor protein that regulates the activation of various signaling pathways such as the Nrf2, mTORC1, NF-kB and autophagy signaling pathways via feedback loops (PMID: 22264792, 20452972, 21617040, 24462201, 21258367, 24011591). Multiple kinases, including mTORC1 and MEKK3, phosphorylate SQSTM1 and allow it to bind to ubiquitin-associated proteins (PMID: 24011591). Phosphorylated SQSTM1 then sequesters or degrades via selective autophagy proteins that negatively regulate important signaling pathways, thus activating these pathways (PMID: 25609235). Examples of this are the binding of KEAP1, the negative regulator of Nrf2, or the binding of the ubiquitin-editing enzyme A20, the negative regulator of NF-kB (PMID: 28842501, PMID: 25609235). SQSTM1, therefore, serves as a regulator for diverse cellular processes such as inflammatory response, antioxidant response, anabolism and catabolism (PMID: 21981924, 10747026, 20173742, 24462201). Accumulation of SQSTM1 promotes tumorigenesis through the overactivation of these cellular processes (PMID: 27345495, 24332042, 27246794). SQSTM1 translocations have been identified in a variety of tumor types including papillary thyroid cancer, ALK-positive large B-cell lymphoma, adult T-cell acute lymphoblastic leukemia and lung adenocarcinoma (PMID: 28351223, 21134980, 20851865, 33768710). False +ENST00000358208 NM_198291.2 6714 SRC True SRC encodes a tyrosine kinase involved in cell cycle control, cytokinesis, cell survival/proliferation and migration/motility. Amplification of SRC is found in colorectal, breast, brain and pancreas cancers, among others. SRC encodes the c-SRC proto-oncogene, a non-receptor tyrosine protein kinase implicated in cell cycle control, cytokinesis, cell survival/ proliferation and migration/motility (PMID: 25662515). Furthermore, c-SRC has been strongly correlated with a variety of human malignancies including colorectal and breast cancer among others (PMID:19581523). The c-SRC protein consists of a N-terminal myristolation sequence, important for membrane localization and subsequent functionality, followed by an unique SH4 domain, a SH3 domain, a SH2 domain, a linker to the protein-tyrosine kinase domain and a C-terminal regulatory domain (PMID: 8672527). c-SRC is closely related to nine additional non-receptor tyrosine kinases that share homology with c-SRC, the SRC Family Kinases (SFK), which exert similar functions and are also implicated in human cancers (PMID: 25207369, 24948875, 24574860, 24522479, 24388104, 24361441). False +ENST00000342756 NM_006947 6731 SRP72 True SRP72, a subunit of the signal recognition particle complex, is infrequently altered in cancer. Germline SRP72 mutations are associated with familial aplasia and myelodysplasia. SRP72 encodes for a subunit of the signal recognition particle (SRP) ribonucleoprotein complex, which functions in translocation of the secretory and membrane proteins to the endoplasmic reticulum (PMID: 34020957). The SRP complex interacts with the signal sequence in nascent proteins to mediate transportation to the endoplasmic reticulum (PMID: 34020957). SRP72 contains an RNA-binding domain to interact with the signal recognition particle RNA, also known as the 7SL RNA, and mediate protein trafficking (PMID: 21073748, 15588816). SRP72 germline mutations have been implicated in familial aplasia and myelodysplasia (PMID: 22541560, 26492932). Overexpression and hypomethylation of SRP72 was frequently identified in thyroid cancer, suggesting that SRP72 may function as an oncogene in this context (PMID: 26718127). SRP72 expression is suggested to confer radioresistance as knockdown of SRP72 in preclinical studies demonstrate increased radiosensitivity (PMID: 28494188). False +ENST00000359995 NM_003016.4 6427 SRSF2 False 4 SRSF2, an RNA splicing factor, is frequently mutated in hematological malignancies. SRSF2 (serine/arginine-rich splicing factor 2) is an RNA splicing factor that mediates constitutive or alternative splicing of pre-mRNA (PMID: 25965569). As a member of the spliceosome, SRSF2 interacts with splicing factors and mediates mRNA splicing by binding to pre-mRNA via an RNA recognition motif (PMID: 22262462). Loss of SRSF2 expression in cell lines and murine hematopoietic models results in abnormal differentiation, cell cycle, apoptosis and mis-splicing of target mRNAs (PMID: 25965569). SRSF2 has also been implicated in the nuclear transport of mRNAs to and from the nucleus (PMID: 22262462). Somatic mutations in SRSF2 have been found in myelodysplastic syndrome, acute myeloid leukemia and myeloid disorders (PMID: 21909114, 25550361, 25231745, 26464169, 23660863). Alterations in SRSF2 are predominantly heterozygous missense mutations that impact the RNA recognition domain (PMID: 26261309). SRSF2 mutations result in aberrant pre-mRNA splicing at differential splicing enhancer sequences leading to exon misrecognition (PMID: 26124281, 25965569). In hematopoietic cells, key regulatory genes such as EZH2 are mis-spliced in cells with SRSF2 mutations, leading to degradation of EZH2 (PMID: 25965569). Inhibitors of the spliceosome are in preclinical and clinical testing and may be a therapeutic strategy in spliceosome-mutant disease (PMID: 26575690). False +ENST00000415083 NM_001007559.2 6760 SS18 True SS18, a transcription factor, is frequently altered by chromosomal rearrangement in synovial sarcoma. SS18 encodes a transcription factor that is a member of a SWI/SNF complex, which is a global transcription co-activator. Co-purification studies have confirmed that SS18 is specifically part of the BAF-type SWI/SNF complexes (PMID: 22442726, 11734557). SWI/SNF complexes remodel chromatin in an ATP-dependent manner to re-position and/or facilitate the binding of transcriptional activator proteins to nucleosomes (PMID: 11734557). The proteins of SWI/SNF complexes are known to be mutated and/or altered in multiple types of cancer due to the potential oncogenic effects of chromatin remodeling and transcriptional activation. False +ENST00000383202 NM_005862.2 10274 STAG1 False STAG1, a subunit of the cohesin complex, is altered by mutation in acute myeloid leukemia. STAG1 (also SA-1) is a subunit of cohesin, a multi-protein complex that mediates sister chromatid separation during cell division. Cohesin is a ring-shaped structure that regulates sister chromatid cohesion at the centromere from DNA replication to prometaphase during both meiosis and mitosis (PMID: 12034751, 19822671, 21444719). STAG1, or the homolog STAG2, in collaboration with SMC1A, SMC3, and RAD21, make up the cohesin ring-structure that surrounds chromatin (PMID: 24856830). During metaphase, cohesin subunits are released from chromosomes leading to the dissolution of cohesion between sister chromatids (PMID: 19056890). STAG1 also binds CTCF, a protein that mediates chromatin looping and has been implicated as a regulator of insulator regions (PMID: 18550811, 27219007). The cohesin complex is also important for other cellular functions including mediating epigenetic state and transcription in post-mitotic cells and regulation of the DNA damage response (PMID: 19056890). Germline mutations in STAG1 are found in cohesinopathies, developmental syndromes associated with loss of cohesin activity (PMID: 28119487). Loss of STAG1 in mice results in transcriptional changes consistent with Cornelia de Lange syndrome and other cohesinopathies (PMID: 22415368). Somatic mutations in STAG1 have been identified in acute myeloid leukemia (PMID: 24335498) and these mutations are predicted to be loss-of-function (PMID: 28430577). STAG1 overexpression has also been identified in several human cancers (PMID: 11568975). STAG1 and STAG2 have a synthetic lethal relationship, suggesting that targeting both components could be therapeutically valuable (PMID: 28691904). True +ENST00000218089 NM_001042749.1 10735 STAG2 False STAG2, a component of the cohesin complex, is recurrently altered by mutation in various cancer types,. STAG2 is a component of the cohesin complex that is required for cohesion of the sister chromatids at the centromere after DNA replication in both meiosis and mitosis (PMID: 12034751, 19822671, 21444719). Microduplication of the Xq25 chromosome, containing the locus of STAG2, is seen in some types of cohesinopathies that are characterized by abnormal behavior, intellectual disability, distinctive facial appearance and disorders in speech (PMID: 23637084, 25677961, 25450604, 26443594). Inactivating mutations in STAG2 lead to aneuploidy and chromosomal instability in cancer (PMID: 21852505). Nonsense mutations and deletions of STAG2 are found together in melanoma, Ewing sarcoma, glioblastoma, head and neck carcinoma, bladder carcinoma and myeloid neoplasms, whereas deletions alone are observed in gastric, colorectal and prostate cancers (PMID: 24856830, 21852505, 26122845, 25010205, 24270882, 24121792, 25186949, 22668012, 25223734, 23955599, 25501392, 24121789, 20687102, 24056718, 24335498, 24121791, 25867412). Somatic mutations of STAG2 are observed in myeloid malignancies, such as myelodysplastic syndrome and acute myeloid leukemia, and are associated with worse overall survival and better response to some therapeutic treatments (PMID: 25501392, 25006131, 24335498). STAG2 mutations are prevalent in leukemia patients with IDH2 mutations and are found in more than 95% of patients with secondary leukemia (PMID: 25836588, 25550361). Nonsynonymous mutations are found in glioblastoma, uterine carcinoma and breast carcinoma (PMID: 26352260). Of importance, glioblastomas harboring STAG2 mutations are more sensitive to PARP inhibition (PMID: 24356817). True +ENST00000361099 NM_007315.3 6772 STAT1 False STAT1, a transcription factor, is altered by mutation in immunodeficiency disorders. STAT1 is a transcription factor that is activated by cytokine and growth factor stimulation of receptor kinases (PMID: 26631912). Activated non-receptor JAK tyrosine kinases phosphorylate STAT1 in response to receptor kinase stimulation, leading to dimerization and nuclear translocation of STAT complexes (PMID: 22520844). STAT1 functions as a homodimer known as the IFN-gamma activator complex, or heterodimerizes with STAT2 molecules (PMID: 28184222). The latter can complex with interferon-regulated genes such as IRF9 to regulate context-specific transcriptional programs known as the interferon-stimulated gene factor 3 or ISGF3 (PMID: 28184222). JAK-STAT signaling is initiated by various cytokines, including interleukin and interferon molecules, which stimulate STAT-mediated transcription in the nucleus (PMID: 29921905). STAT1 signaling is critical for regulation of innate and adaptive immunity, including protection from pathogen infections (PMID: 26631912, 29921905). In addition, STAT1 regulates the expression of the immune recognition molecule MHC-I, which promotes clearance of tumor cells by NK and cytotoxic T cells (PMID: 30796216, 19811323). Loss of STAT1 in murine models results in depleted responses to interferon signaling, leading to aberrant T-cell function (PMID: 30796216). STAT1 also regulates various other cellular functions including differentiation, proliferation and cell death (PMID: 26631912). Germline, heterozygous, gain-of-function mutations in STAT1 result in chronic mucocutaneous candidiasis, a malignancy that results in persistent infections (PMID: 22651901, 21714643, 21727188). Somatic mutations in STAT1 are not well-studied in human cancers; however, loss of STAT1 in mammary tumor models promotes tumor progression, suggesting STAT1 may function as a tumor suppressor (PMID: 26631912, 21076615, 21311224). Additional studies have indicated that STAT1 may also have context-specific growth promoting roles (PMID: 24726362, 26631912). False +ENST00000314128 NM_005419.3 6773 STAT2 False STAT2, a transcription factor, is altered by mutation in immunodeficiency disorders. STAT2 is a transcription factor that is activated by cytokine and growth factor stimulation of receptor kinases (PMID: 27053489). Activated non-receptor JAK tyrosine kinases phosphorylate STAT2 in response to receptor kinase stimulation, leading to dimerization and nuclear translocation of STAT complexes (PMID: 26631912). STAT2 functions as a homodimer or heterodimerizes with STAT1 molecules (PMID: 28184222, 27053489). The latter can complex with interferon-regulated genes such as IRF9 to regulate context-specific transcriptional programs known as the interferon-stimulated gene factor 3, or ISGF3 (PMID: 28184222, 8621447, 31266943). JAK-STAT2 signaling is initiated by various cytokines, including interferon type I (IFN-I) molecules, which stimulate STAT-mediated transcription in the nucleus (PMID: 29921905, 30671054, 28165510). STAT2 signaling is critical for the regulation of anti-viral, immune, apoptotic, and proliferative responses initiated by IFN-I stimulation (PMID: 31605750, 30337919). Loss of STAT2 in murine models leads to deficiencies in various immune cell populations, leading to an ineffective host response to viral infection (PMID: 30134157, 27233962). Germline mutations in STAT2 are found in patients with susceptibility to viral infections due to deficiencies in IFN-I immunity (PMID: 23391734, 28087227, 23391734). STAT2 alterations have also been linked to neurodegeneration following viral infection due to mitochondrial fission defects (PMID: 26122121). Somatic mutations in STAT2 are not well-studied in human cancers; however, STAT2 activity has a critical role in regulating interferon signaling in various contexts in cancer cells (PMID: 30940163, 31605750, 29581268). False +ENST00000264657 NM_139276.2 6774 STAT3 True STAT3, a transcription factor, is altered by mutation or amplification in various solid and hematologic malignancies. STAT3 (Signal transducer and activator of transcription 3) is a transcription factor that is activated by cytokine and growth factor stimulation of receptor kinases (PMID: 26464811). Non-receptor JAK tyrosine kinases subsequently phosphorylate STAT3, leading to dimerization and nuclear translocation of STAT complexes (PMID: 25527793). STAT3 is involved in regulating development of the skin, central nervous system and mammary tissue (PMID:11994402, 10342556). Activated STAT3 is found in various cancer types, most notably in breast cancer, and is implicated in pathways important for survival, immune dysregulation, tumor microenvironment modulation and invasion (PMID: 25342631, 11420660, 21310826, 16463269). Germline mutations in STAT3 are associated with autoimmunity and lymphoproliferation (PMID: 25359994). STAT3 germline mutations have also been identified in hyper-IgE syndrome characterized by elevated IgE levels, connective tissue abnormalities and immunodeficiency (PMID: 17881745). Somatic activating STAT3 mutations are found in large granular lymphocytic leukemia and more rarely in myelodysplastic syndrome, aplastic anemia and lymphomas (PMID: 22591296, 23926297, 25586472). STAT3 mutations have also been found in inflammatory hepatocellular adenomas and copy number alterations are present in breast cancer samples (PMID: 21690253, 25470049). False +ENST00000358470 NM_001243835 6775 STAT4 True STAT4, a transcription factor, is altered by mutation in autoimmune disorders. STAT4 is a transcription factor that is a member of the signal transducer and activator of transcription (STAT) protein family (PMID: 8007943). Activated non-receptor JAK tyrosine kinases phosphorylate STAT4 in response to receptor kinase stimulation, leading to dimerization and nuclear translocation of STAT complexes (PMID: 25527793). STAT4 functions predominantly as a mediator of the innate and adaptive immune response (PMID: 15356157, 34138758). STAT4-dependent signaling to modulate Tfh cell secretion of IL-21 and IFN-y is activated by type I interferon signaling (PMID: 33512094). Mutations of STAT4 have been implicated in various autoimmune diseases (PMID: 27178308, 23755762). Knockdown of STAT4 in cancer cell lines and models suppresses tumor growth, cellular proliferation, migration and invasion, suggesting that STAT4 functions predominantly as an oncogene (PMID: 33636177, 25864744, 28114283). Amplification of STAT4 has been identified in various cancers, including ovarian cancer and lung cancer (PMID: 28114283, 30987235). Conversely, up-regulation of STAT4 in patients with hepatocellular carcinoma and cell lines demonstrate better prognosis and inhibits cellular proliferation, suggesting that there may be tissue-specific tumor suppressive roles for STAT4 (PMID: 24965572, 25852285). False +ENST00000345506 NM_003152.3 6776 STAT5A True STAT5A encodes a transcription factor involved in the JAK signaling cascade. Mutations of STAT5A are found in prostate and breast cancers and leukemias, among others. STAT5A (Signal transducer and activator of transcription 5A) is a transcription factor that is activated by cytokine and growth factor stimulation of receptor kinases (PMID:15313458, 9630227). Activated non-receptor JAK tyrosine kinases subsequently phosphorylate STAT5A, leading to the dimerization and nuclear translocation of STAT complexes (PMID:25527793). STAT5A regulates the development and differentiation of tissues and cell types including the mammary gland, hepatocytes, erythrocytes, platelets, B-cells and T-cells (PMID:15711548, 23773921, 8961260, 8906870, 18347089, 16418296). In cancer, STAT5A signaling is important for tumor progression, therapy resistance and transformation in various cancers including prostate cancer, breast cancer, myeloproliferative neoplasms and leukemias (PMID:22234689, 23660011, 18508994). STAT5A copy number alterations have been identified in breast cancer samples (PMID: 25470049), however, somatic mutations in STAT5A are infrequent in human cancers. In leukemias and myeloproliferative neoplasms, STAT5A signaling is hyperactivated through mutations in the JAK proteins or the FLT3 receptor (PMID:17356133, 17379095, 22234689). False +ENST00000293328 NM_012448.3 6777 STAT5B True STAT5B, a transcription factor, is altered in various solid and hematologic malignancies. STAT5B (Signal transducer and activator of transcription 5B) is a transcription factor that is activated by cytokine and growth factor stimulation of receptor kinases (PMID:15313458, 9630227). Activated non-receptor JAK tyrosine kinases subsequently phosphorylate STAT5B, leading to the dimerization and nuclear translocation of STAT complexes (PMID: 25527793). STAT5B regulates the development and differentiation of tissues and cell types including the mammary gland, hepatocytes, erythrocytes, platelets, B-cells and T-cells (PMID:15711548, 23773921, 8961260, 8906870, 18347089, 16418296). In cancer, STAT5B signaling is important for tumor progression, therapy resistance, and transformation in various cancers including prostate cancer, breast cancer, myeloproliferative neoplasms and leukemias (PMID:22234689, 23660011, 18508994). Somatic activating STAT5B mutations have been identified in large granular lymphocytic leukemia and subtypes of lymphomas (PMID:23596048, 25586472, 24972766). STAT5B is also found in rare translocations with RARA in cases of acute promyelocytic leukemia (PMID:22749039). False +ENST00000300134 NM_001178078.1 6778 STAT6 True STAT6, a transcription factor involved with immune regulation, is recurrently altered by mutation and amplification in lymphomas and solid tumors. STAT6 fusions are found in all patients with solitary fibrous tumor and meningeal haemangiopericytoma. STAT6 is a transcription factor that is a member of the signal transducer and activator of transcription (STAT) protein family (PMID: 8085155). STAT6 is activated by cytokine and growth factor stimulation of receptor kinases (PMID: 11345192). Activated non-receptor JAK tyrosine kinases subsequently phosphorylate STAT6, leading to the dimerization and nuclear translocation of STAT complexes (PMID: 8085155, 25527793). In the nucleus, STAT6 binds DNA and regulates the expression of a range of transcriptional targets involved in T-cell mediated inflammatory signaling (PMID: 8816495, 20620946). STAT6 activity mediates the development of T-helper type 2 (Th2) cells and IL-4 stimulated T cell responses (PMID: 8624821, 8085155). In addition, STAT6 is involved in a variety of other cellular functions including immunoglobulin class switching in B cells, lymphocyte homeostasis, apoptosis, chromatin state changes and transcriptional regulation (PMID: 8602264, 12023955, 21442426). STAT6 fusions are found in all patients with solitary fibrous tumor (SFT), a metastasizing mesenchymal cancer, and meningeal haemangiopericytoma, a soft tissue sarcoma in the meninges (PMID: 23313952, 29703757, 28295484, 25482924, 23575898). Somatic activating mutations in STAT6 are found in hematopoietic malignancies including diffuse large B cell lymphoma, follicular lymphoma, and mediastinal B cell lymphomas (PMID: 25428220, 26647218, 19423726). Amplification and overexpression of STAT6 have also been identified in a range of cancers (PMID: 24457460, 15044251), suggesting that STAT6 predominantly functions as an oncogene. False +ENST00000326873 NM_000455.4 6794 STK11 False 4 STK11, a tumor suppressor and intracellular kinase, is frequently mutated in lung cancer. STK11 encodes serine/threonine kinase 11, also known as liver kinase B1 (LKB1), that functions as a tumor suppressor. STK11 activates the AMPK (adenine monophosphate-activated protein kinase) pathway via formation of a biologically active heterotrimer with the pseudokinase, STRAD, and the adaptor protein, MO25. Activated AMPK phosphorylates TSC2 and Raptor, which leads mTORC1 hyperactivation (PMID: 14651849, 18439900). STK11-AMPK signaling regulates cell metabolism and energy homeostasis, as well as cellular stress responses to DNA damage and nutrient scarcity (PMID: 21396365). In response to the metabolic stress and hypoxic conditions that often exist within tumors, STK11-AMPK signaling is activated, resulting in inhibition of anabolism, induction of cell cycle arrest and ultimately, suppression of tumor growth (PMID: 25244018). Loss of STK11 has been shown to lead to disorganized cell polarity and tumor growth in nutrient poor conditions. Activation of STK11 by ATM under conditions of DNA damage leads to downstream inhibition of the mTOR pathway (PMID: 20160076). Mutations in STK11 have been found in lung, breast, cervical, testicular, and liver cancers, as well as malignant melanoma, and pancreatic and biliary carcinoma (PMID: 25244018). In addition, the hereditary disease Peutz-Jeghers syndrome, in which STK11 mutations were initially discovered, is characterized by an increased risk of developing both benign and malignant gastrointestinal tumors, other cancer types and mucocutaneous pigmentation (PMID: 20581245). True +ENST00000375331 NM_004197.1 8859 STK19 True STK19, a nuclear protein, is mutated in a subset of skin cancers. STK19 encodes for a nuclear DNA-binding protein that was originally misidentified as a serine/threonine kinase (PMID: 9812991). STK19 is located on chromosome 6, close to the major histocompatibility complex, a region frequently associated with several traits in case-control studies (PMID: 21323541, 23263863, 19851445, 23535732, 19423540). Despite being named as a serine/threonine kinase, STK19 has no intrinsic kinase activity and previous research of STK19’s kinase activity is suggested to be due to an STK19-associated kinase (PMID: 32531245, 32531246). STK19 is tightly chromatin-associated, however its functions as a nuclear protein are currently unknown (PMID: 32531245). STK19 is suggested to bind with an unknown kinase, leading to the phosphorylation and activation of NRAS to drive melanomagenesis, which may be sensitive to STK19 small molecule inhibition (PMID: 30712867, 32531246). STK19 mutations have been identified in a subset of skin cancers (PMID: 22817889, 25600636, 25303977). False +ENST00000373129 NM_032017.1 83931 STK40 False STK40 encodes a serine/threonine kinase involved in regulation of NF-κB- and p53-mediated transcription. Altered expression of STK40 is found in ovarian and esophageal cancers, among others. STK40 (Serine/Threonine Kinase 40) is a pseudokinase that functions predominantly as an adaptor signaling molecule (PMID: 26663584,13679039). Structural studies demonstrate that while STK40 has a serine/threonine kinase domain, the protein cannot bind ATP (PMID: 28089446). Overexpression of STK40 inhibits NF-κB activation and p53-mediated transcription, suggesting that STK40 functions as a negative regulator of NF-κB and p53 (PMID:26663584,13679039). STK40 also has been shown to bind the E3 ligase COP1, implicating the adaptor in regulation of protein stability (PMID: 28089446). Loss of STK40 expression in several cell line and murine models suggests a role for STK40 in cell differentiation including in hematopoietic cells and skeletal muscle (PMID: 28358362, 27899448). Somatic mutations in STK40 are infrequent in human cancer, however, STK40 expression has been found to be upregulated in several cancer cell line models (PMID: 26286729). False +ENST00000369902 NM_016169.3 51684 SUFU False SUFU encodes the protein suppressor of fused, which is a negative regulator of hedgehog signaling. Truncating mutations in SUFU are strongly associated with pediatric medulloblastoma. SUFU encodes the protein suppressor of fused which is part of the hedgehog signaling pathway, one of the key regulators of embryonic development (PMID: 23686138). SUFU can sequester GLI transcription factors in the cytoplasm repressing their activity (PMID: 19055941, 10564661, 10559945). SUFU can repress Wnt signaling by exporting beta-catenin from the nucleus (PMID: 11477086) it also can serve as a point of interaction between the hedgehog and p63 pathways which may be an important part of the regulation of keratinocyte differentiation (PMID: 23686138). SUFU is a tumor-suppressor in which truncating germline or somatic mutations, often accompanied by loss of the wildtype allele, are strongly associated with pediatric medulloblastoma (PMID: 12068298, 24651015). Germline mutations in SUFU can cause Gorlin syndrome (PMID: 25403219). No drugs specifically target SUFU although there are drugs that target the hedgehog signaling pathway (PMID: 23291299). True +ENST00000322652 NM_015355.2 23512 SUZ12 False SUZ12, a component of the polycomb group of transcriptional repressors, is altered in hematologic diseases and sarcomas. The SUZ12 (Suppressor of Zeste 12) is a component of the Polycomb Repressive Complex 2 (PRC2), which is responsible for transcriptional repression by catalyzing di- and tri-methylation of Histone H3 lysine 27 (H3K27) (PMID: 16630818). SUZ12 is necessary for both the histone methyltransferase activity and silencing function of PRC2 (PMID: 15225548), which are important in regulating development and expression of cell identity genes, including the HOX cluster of genes (PMID: 16625203). SUZ12 is commonly mutated in malignant peripheral nerve sheath tumors, T-cell acute lymphoblastic leukemia, and myeloid neoplasms (PMID: 25240281, 22237151, 22237106, 23486531). Translocations involving SUZ12 have been identified in endometrial stromal tumors (PMID: 11371647). Mutations in SUZ12 can cooperate with Ras pathway signaling in cellular transformation and may sensitize tumor cells to bromodomain inhibitors (PMID: 25119042). True +ENST00000375746 NM_003177.5 6850 SYK True SYK encodes a tyrosine kinase involved in signal transduction. Upregulation of SYK is found in lymphomas, leukemias and select epithelial tumors. SYK is a cytoplasmic tyrosine kinase that is recruited to the cell membrane through binding of its SH2 domain to membrane receptors and is subsequently activated via phosphorylation (PMID:7538118). SYK is predominantly expressed in hematopoietic cells and activation of SYK-mediated signaling pathways is necessary for B-cell and lymphatic system development (PMID:10963601,17699797, 23609194). In B- and T-cell signal transduction, SYK binds ITAM adaptor molecules that complex with the B-cell receptor (BCR) and T-cell receptor (TCR) mediating critical immune regulatory pathways (PMID:7477353,12522250). SYK activity is required to activate various other signaling pathways that mediate cellular adhesion, osteoclast maturation, platelet activation and vascular development (PMID: 20467426). Somatic mutations in SYK are rare in human cancers; however, activated SYK signaling has been identified in leukemias and lymphomas (PMID: 24525236,19800574, 26575169, 23764004). In addition, activation of SYK signaling has been described as a mechanism of ovarian cancer chemoresistance (PMID:26096845). Case reports have reported translocations in SYK in myelodysplastic syndromes (MDS) and lymphomas (PMID:11159536,16341044). The SYK tyrosine kinase inhibitor fostamatinib is currently being evaluated in clinical trials for efficacy in hematopoietic malignancies (PMID: 26575169, 23764004). False +ENST00000562955 NM_015284 23334 SZT2 False SZT2, a multifunctional protein, is infrequently altered in cancer. SZT2 encodes the seizure threshold 2 homolog protein, which is expressed in the brain, predominantly in the parietal frontal cortex and dorsal root ganglia, and in other tissues at lower levels (PMID: 34685691). Expression of SZT2 in the brain suggests that it may play a role during early brain development through neuronal migration, axon guidance, and synapse formation (PMID: 30970654, 19624305). While its biological function is not fully understood, the SZT2 protein is highly conserved and has been implicated in the regulation of endoplasmic reticulum homeostasis and protein quality control. Other potential functions of SZT2 include involvement in calcium homeostasis, mitochondrial function and the cellular stress response pathway (PMID: 30970654). Mutations in the SZT2 gene cause severe epileptic and neurological encephalopathy (PMID: 34685691, 36250465, 28199315, 30970654). SZT2 is a component of the KICSTOR complex which is required for the localization of the GATOR1 complex on the lysosome surface. Both the KICSTOR and GATOR1 complexes act as negative regulators of mTORC1 activity (PMID: 33685991, 30970654). In hematopoietic stem cells, loss of SZT2 causes an elevation of mTORC1 activity and reactive oxygen species production and impairs the repopulating capacity of the cells (PMID: 36250465). Mutations in the SZT2 gene have been identified in patients with PIK3CA-mutated ER+ breast cancer and head and neck squamous cell carcinoma (PMID: 33685991, 30970654). False +ENST00000423759 NM_001286074.1 6872 TAF1 True TAF1, a transcription factor, is infrequently altered in cancer. TAF1 encodes for a subunit of the transcription factor polymerase II (TFIID) basal transcription factor complex, which functions in the initiation of RNA polymerase II-dependent transcription (PMID: 33795473). The TFIID multi-subunit complex is composed of the TATA binding protein and multiple TATA binding protein associated factors (TAFs) (PMID: 8340360). TAF1 is the largest subunit of the TFIID complex and functions as the core scaffold and forms the promoter DNA binding subcomplex of TFIID through interaction with TAF7 and TAF2 (PMID: 33795473). TAF1 mediates cell cycle progression through transcriptional activity regulation (PMID: 25412659, 15053879). Overexpression of TAF1 in various cancer cell lines and models induces epithelial-to-mesenchymal transition, cellular proliferation, migration and invasion, suggesting that TAF1 functions predominantly as an oncogene (PMID: 20181722, 30854104, 36368153, 31664040). Amplification and mutations of TAF1 have been identified in various cancers, including prostate cancer, non-small cell lung cancer and gastric cancer (PMID: 20181722, 36368153, 27571988). False +ENST00000294339 NM_001287347.2 6886 TAL1 True TAL1, a transcription factor, is recurrently altered by chromosomal rearrangement in T-lymphoblastic leukemias. TAL1 (also SCL) is a transcription factor that is a member of the class II basic helix-loop-helix family (bLHL) (PMID: 28179281). TAL1 is expressed in many hematopoietic cell types including hematopoietic stem cells, multipotent progenitors, megakaryocytes, and erythroid cells; however, TAL1 is silenced in lymphoid lineages (PMID: 7678994, 28179281). Like other bLHL transcription factors, TAL1 functions as a heterodimer with class I bHLH transcription factors and binds E-box motifs to regulate gene expression (PMID: 9214632). TAL1 regulates the activity of numerous genes via interaction with other hematopoietic transcription factors including LMO2, GATA1, LDB1, RUNX1, ETS family proteins, among others (PMID: 20887958). Binding of TAL1 across the genome is distinct depending on hematopoietic cell type, suggesting that TAL1 transcriptional regulation is context dependent (PMID: 21179004). In addition, TAL1 likely has additional roles in the activation of transcription factor partners beyond the role in DNA binding (PMID: 10498694). Loss of TAL1 in mice results in the absence of blood formation during early hematopoietic development and the depletion of differentiated hematopoietic cells in adults, demonstrating that TAL1 is critical in early hematopoietic lineage specification (PMID: 7830794, 8689686). TAL1 overexpression is common in patients in T-acute lymphoblastic leukemia (T-ALL), and recurrent translocations that result in TAL1 activation are also found in T-ALL, suggesting that TAL1 functions predominantly as an oncogene (PMID: 19562638, 21057528). False +ENST00000354258 NM_000593.5 6890 TAP1 False TAP1, a transport protein, is altered by amplification in various cancers. The TAP1 gene encodes a membrane-associated protein that belongs to the family of ATP-binding cassette (ABC) transporters. TAP1 is involved in the transport of antigens from the cytoplasm to the endoplasmic reticulum, as well as their association with MHC class I molecules (PMID: 14679198, 12594855, 17947644, 22638925). TAP1 overexpression has been associated with prostate cancer progression and breast cancer metastasis (PMID: 22065046, 25403418). Mechanistically, the role of TAP1 in cancer is unclear, but it likely has a role in cell proliferation (PMID: 25398693). TAP1 is altered by amplification in various cancers (cBioPortal, MSKCC, Dec. 2016). False +ENST00000374899 NM_018833.2 6891 TAP2 False TAP2, a transport protein, is altered by amplification in various cancers. The TAP2 gene encodes a membrane-associated protein that belongs to the family of ATP-binding cassette (ABC) transporters. TAP2 is involved in the transport of antigens from the cytoplasm to the endoplasmic reticulum, as well as their association with MHC class I molecules (PMID: 14679198, 12594855, 17947644, 22638925). TAP2 expression is deregulated in several cancers, and it correlates with differential antigen processing and immune system response (PMID: 18385764, 26799285, 14558951, 23302073). TAP2 is altered by amplification in various cancers (cBioPortal, MSKCC, Jan. 2017). False +ENST00000430069 NM_024665.4 79718 TBL1XR1 True TBL1XR1, a transcriptional repressor that binds the NCoR/SMRT protein complex, is recurrently altered by mutation and fusion in hematologic malignancies. TBL1XR1 (also TBLR1) is a transcriptional regulatory protein that is a member of the WD40 repeat-containing protein family (PMID: 26069883). TBL1XR1 functions as a transcriptional co-repressor by binding the NCoR (nuclear receptor corepressor)/SMRT (silencing mediator of retinoic acid and thyroid hormone receptors) complex and mediates histone deacetylation at target genes (PMID: PMID: 26069883). TBL1XR1, in collaboration with TBL1X, stabilizes the NCoR/SMRT complex on chromatin via interactions with histone H2B and H4 (PMID: 28687524, 18202150). In addition, TBL1XR1 mediates the ubiquitination and subsequent degradation of the NCoR/SMRT complexes after ligand binding to nuclear receptors (PMID: 26069883, 14980219). Ligand binding initiates activation of several hormone receptors, including the androgen receptor and retinoic acid receptor (PMID: 26069883, 16893456). TBL1XR1 also functions as a transcriptional regulator of NF-κB and WNT signaling genes (PMID: 26069883). Familial mutations in TBL1XR1 are found in patients with intellectual disability disorders including Pierpont syndrome, Rett’s syndrome and autism (PMID: 30365874, 28687524, 26769062, 28687524, 29038029, 28152507, 23160955). Somatic loss-of-function mutations in TBL1XR1 are found in patients with diverse forms of lymphoma including MALT lymphomas (PMID: 29674500), primary central nervous syndrome lymphomas (PMID: 25991819), marginal zone lymphomas (PMID: 28152507, 27248180) and relapsed/refractory diffuse large B-cell lymphomas (PMID: 26608593), among others. TBL1XR1 mutations have been found to increase binding to the NCoR/SMRT complex, enhance degradation of NCoR, and dysregulate NF-κB and WNT signaling (PMID: 28588275, 28348241, 28152507). In addition, TBL1XR1 is a recurrent fusion partner in acute promyelocytic leukemia, acute myeloid leukemia, and other hematologic malignancies (PMID: 29921692, 29437595, 28509585, 24782508, 22496164). Overexpression of TBL1XR1 may be associated with increased invasion and metastasis in solid tumors, including breast, gastric and colorectal cancers (PMID: 29091326, 28127799, 27694893, 24874481). False +ENST00000257566 NM_016569.3 6926 TBX3 False TBX3, a transcription factor, is altered in various cancers including breast cancer. TBX3 is a transcription factor that binds DNA using a T-box domain and mediates transcriptional repression (PMID:25294936). Transcriptional regulation by TBX3 is important for embryonic patterning, stem cell specification, maintenance of pluripotency and organ system development including the cardiac conduction system, mammary gland and liver (PMID: 24319661, 15158141,12668638, 18356246, 19571885, 20139965). Loss of TBX3 expression corresponds to an increased invasive phenotype in breast cancer models (PMID: 27553211). TBX3 is expressed in various cancer types and has been implicated in cell survival, interactions with the TP53 pathway and tumor invasiveness (PMID:17283120,16222716,18245468,18829543, 24316392). Germline mutations in TBX3 have been identified in Ulnar-mammary syndrome leading to defects of the limbs, apocrine gland, teeth and genital systems (PMID: 9207801). Somatic alterations in TBX3 have been found in breast cancer and predominantly result in frameshift mutations, suggesting loss-of-function (PMID:22722201, 26451490, 26249178). True +ENST00000344749 NM_001136139.2 6929 TCF3 False TCF3, a transcription factor involved in lymphopoiesis, is altered by mutation or deletion in various cancer types. TCF3 is a member of the E protein family of helix-loop-helix transcription factors (Transcription factor 3, E2A immunoglobulin enhancer-binding factors E12/E47), which activate transcription by binding to regulatory E-box sequences on target genes. TCF3 expression is essential for lymphopoiesis, and B and T lymphocyte development. It has been shown to play a role in repressing Wnt signaling, specifically beta-catenin expression, during neuronal differentiation and proliferation of neural precursor cells (PMID 24832538, 21730189). Together with p53, TCF3 enforces p21 expression and cell-cycle arrest in response to genotoxic stress (PMID: 23684607). Its deletions or diminished protein activity have been associated with several lymphoid malignancies, including pre-B-cell acute lymphoblastic leukuemia, childhood leukemia and acute leukemia (PMID: 12700034). The TCF3 locus is a common target of chromosome rearrangements in diverse leukemias, leading to E2A chimeric proteins (PMID: 17311319, 17593026, 11588043, 11243406). True +ENST00000543371 NM_001146274.1 6934 TCF7L2 False TCF7L2, a tumor suppressor and transcription factor, is altered by mutation or deletion in various cancer types, most frequently in colorectal cancer. TCF7L2 (also known as TCF4) is a transcription factor that positively regulates the WNT/beta-catenin pathway (PMID: 22934027, 23260145). WNT-ligand induced pathway activation results in destabilization of the beta-catenin destruction complex, leading to stabilization of beta-catenin. TCF7L2 forms a bipartite transcription factor complex in the nucleus with beta-catenin to activate WNT-dependent target genes (PMID: 22934027). Loss of TCF7L2 activity in murine models results in reduced hepatic glucose production and dysregulation of metabolic gene expression programs (PMID: 23260145). TCF7L2 has also been found to regulate gene expression programs in a variety of cell types that impact cellular proliferation and metabolism (PMID: 26955760, 29301589, 29190896, 18289012). A single nucleotide polymorphism (SNP) within TCF7L2 has been identified as the most significant genetic marker associated with risk of Type 2 diabetes (PMID: 22872755) and gestational diabetes (PMID: 23690305). Germline mutations in TCF7L2 have been associated with predisposition to colorectal cancer (PMID: 18398040, 18478343) and genome-wide sequencing studies have identified TCF7L2 frameshift mutations in colorectal cancer (PMID: 8621708). TCF7L2 is hypothesized to function as a tumor suppressor by repressing cell growth-promoting genes in several contexts (PMID: 18621708). True +ENST00000402399 NM_001098725.1 8115 TCL1A True TCL1A, a co-activator of the AKT signaling pathway, is frequently altered by chromosomal rearrangement in hematologic malignancies. TCL1A is a signaling molecule that is a member of the T-Cell Leukemia/Lymphoma 1 (TCL1) protein family (PMID: 16056259, 30151355). TCL1A is predominantly expressed during development and in immature lymphocytes (PMID: 12181493, 15479728). TCL1A functions as an intracellular protein that stabilizes AKT heterodimers at the cytoplasmic membrane, augments effector signaling and mediates AKT nuclear localization (PMID: 10716693, 10983986). The concentration of TCL1A proteins is important to regulate signaling pathways that control proliferation, survival, and immune regulation (PMID: 10716693, 10983986, 9285687). TCL1A also interacts with a variety of proteins including NF-κB, Hsp70, ATM, TP63, and DNMT3A, among others, implicating TCL1A in the regulation of additional cellular activities (PMID: 19668332, 23160471, 22065599, 29048125, 22308499). In murine models, increased expression of TCL1A results in the transformation of B and T cells, leading to the development of T-cell leukemias (PMID: 9520462, 12011454, 12672960). Overexpression of TCL1A in T- and B-cell malignancies are common, suggesting that TCL1A predominantly functions as an oncogene (PMID: 9407948, 16056259). Rearrangements involving TCL1A are recurrent in T-acute lymphoblastic leukemias (T-ALL), typically due to aberrant VDJ recombination of T-cell receptor genes and leading to TCL1A activation (PMID: 3258192). False +ENST00000340722 NM_004918.3 9623 TCL1B True TCL1B, a co-activator of the AKT signaling pathway, is commonly altered by chromosomal rearrangement in hematologic malignancies. TCL1B is a signaling molecule that is a member of the T-Cell Leukemia/Lymphoma 1 (TCL1) protein family (PMID: 16056259, 10344735, 10077617). TCL1B is predominantly expressed during development and immature lymphocytes (PMID: 10077617, 10588720). Like the more well-studied family member TCL1A, TCL1B functions as an intracellular protein that stabilizes AKT heterodimers at the cytoplasmic membrane, augments effector signaling and mediates AKT nuclear localization (PMID: 10716693, 10983986). The concentration of TCL1B proteins is important to regulate signaling pathways that control proliferation, survival, and immune regulation (PMID: 10716693, 10983986, 9285687, 11839817). Further biochemical experiments are required to more clearly delineate the function of TCL1B. Over-expression of TCL1A in T- and B-cell malignancies is common, suggesting that TCL1A predominantly functions as an oncogene (PMID: 11839817). Rearrangements involving TCL1B are recurrent in T-acute lymphoblastic leukemias (T-ALL), typically due to aberrant VDJ recombination of T-cell receptor genes and leading to TCL1A activation (PMID: 24042734, 3258192). False +ENST00000380036 NM_000459.3 7010 TEK False TEK, a receptor tyrosine kinase involved in angiogenesis, is rarely mutated in cancers. The TEK gene encodes a receptor tyrosine kinase (RTK) protein also known as angiopoietin-1 receptor. Signaling via the TEK receptor has roles in angiogenesis, cell migration and proliferation (PMID: 12816861, 9204896, 14665640, 18425120, 19223473). The role of TEK in cancer depends on the predominant ligand binding the receptor, with angiopoietin-1 having an agonist effect and promoting angiogenesis and angiopoietin-2 having an antagonistic role (PMID: 20651738). TEK mutations are rare events in human cancers (cBioPortal, MSKCC, Dec. 2016). False +ENST00000369448 NM_017709.3 54855 TENT5C False TENT5C, a non-canonical poly(A) polymerase, is most frequently altered by mutation and deletion in multiple myelomas. TENT5C is a protein that belongs to the group XXV nucleotidyltransferase superfamily and functions as a non-canonical poly(A) polymerase (PMID: 27060136). TENT5C expression has been shown to regulate cell cycle progression, cell differentiation, and regulation of RAS/MAPK signaling (PMID: 28341836). Loss-of-function TENT5C mutations and deletions have been identified in multiple myeloma, suggesting that TENT5C is a tumor suppressor (PMID: 21430775, 26282654, 20616218, 24434212). Mutations or deletions in TENT5C are associated with reduced overall survival in patients with multiple myleoma (PMID: 21994415). Rearrangements between MYC and TENT5C have also been found in patients with multiple myeloma (PMID: 24632883). True +ENST00000310581 NM_198253.2 7015 TERT True TERT is an enzyme that functions to maintain telomere length and genomic stability. The TERT promoter is frequently mutated in various cancer types. The TERT gene encodes the catalytic subunit of telomerase, an enzyme that maintains telomere length and genomic integrity. TERT expression is low or absent in somatic cells; however, telomerase activity is upregulated in a vast majority of tumors and likely contributes to cancer cell immortality (PMID: 24657534, 9282118). Sequencing of the TERT promoter identified activating mutations in a number of cancer types including melanoma, hepatocellular carcinoma, urothelial carcinoma, medulloblastoma and glioma (PMID: 23348506, 23530248). Tumors with highly recurrent TERT promoter mutations tend to originate from tissues with lower rates of self-renewal (PMID: 23530248). TERT promoter mutations, C228T and C250T, account for the majority of the somatic TERT promoter alterations and occur 124 and 146 base pairs upstream of the ATG start codon of TERT, respectively. Both promoter mutations create binding motifs for erythroblast transformation-specific (ETS)/ T-cell factor (TCF) transcription factors and enhance telomerase activity (PMID: 23348503, 23348506, 26194807). In addition to promoter mutations, TERT, located on chromosome 5p, is amplified across many cancer types (PMID: 20164920). False +ENST00000373644 NM_030625.2 80312 TET1 False TET1 encodes a tumor suppressor and DNA demethylase involved in the epigenetic regulation of gene expression. TET1 is infrequently mutated in solid tumors. TET1 is an iron- and alpha-ketoglutarate-dependent enzyme that is involved in converting 5-methylcytosine to 5-hydroxymethylcytosine (5hmC) (PMID: 19372391). This conversion of the DNA base to 5hmC is the initial step in active DNA methylation, which is important in gene regulation, cellular reprogramming, and mammalian development (PMID: 20639862). TET enzyme activity is inhibited by 2-hydroxyglutarate (2-HG), an inhibitory metabolite produced by specific mutations in IDH1 and IDH2 whose production results in a highly specific DNA methylation profile and is often found in certain glioblastomas and leukemias (PMID: 21383741). TET1 was first identified as a translocation partner of the MLL gene and a key oncogenic driver in acute myeloid leukemias (PMID: 23818607). Reduced TET1 expression has also been observed in various human cancers. In breast cancer, reduced TET1 levels were shown to associate with increased tumor growth and metastasis (PMID: 23716660), and in colon cancer cell lines, reduced TET1 expression was associated with an aberrant CpG methylation profile and WNT pathway activation (PMID: 27977763, 25362856). Reduced TET1 expression has also been associated with KRAS-induced cellular transformation (PMID: 25466250). True +ENST00000380013 NM_001127208.2 54790 TET2 False TET2, a tumor suppressor and DNA demethylase, is frequently mutated in hematologic malignancies. TET2 belongs to a family of alpha-ketoglutarate and iron-dependent enzymes involved in converting 5-methylcytosine to 5-hydroxymethylcytosine (PMID: 19372391). This modification is implicated in active DNA demethylation, a process that is important for cellular reprogramming and gene regulation (PMID: 20639862). TET2 has been shown to function as a tumor suppressor with mutations leading to loss-of-function, particularly those affecting the C-terminal catalytic domain (PMID: 21057493). In animal models, TET2 loss cooperates with other mutations such as JAK2 and FLT3-ITD mutations to promote cancer progression and can induce genomic hypermethylation and increase stem cell self-renewal (PMID:21723200, 25281607, 25873173, 25886910). TET2 mutations are most often found in hematologic malignancies (PMID: 24220273). Isolated mutations in TET2 have also been found in individuals with clonal hematopoiesis but with no apparent hematologic disease (PMID: 23001125). However, these patients are at a higher risk of developing hematologic cancer with aging (PMID: 25426837, 25426838). TET family enzyme activity is also inhibited by specific mutations in IDH1 and IDH2 that produce an inhibitory co-factor, 2-hydroxyglutarate (PMID: 21130701). Mutations in WT1 may also affect TET2 function as an associated co-factor (PMID: 25482556, 25601757). True +ENST00000409262 NM_144993 200424 TET3 False TET3, an epigenetic enzyme that catalyzes cytosine oxidation, is altered by mutation in hematopoietic malignancies. TET3 is an enzyme that belongs to a family of alpha-ketoglutarate and iron-dependent enzymes involved in converting 5-methylcytosine (5-mc) to 5-hydroxymethylcytosine (5-hmc) (PMID: 19372391). The 5-hmc modification is implicated in active DNA demethylation, a process that is important for cellular reprogramming and gene regulation (PMID: 20639862). The TET enzymes, including TET1 and TET2, are also involved in the oxidation of 5-mc to other cytosine derivatives (PMID: 21778364). TET3 also bind O-GlcNAc transferase (OGT) and REST to promote the binding of methyltransferases to chromatin (PMID: 23353889, 24304661, 25843715). In addition, TET3 physically associates with WT1 to mediate DNA methylation in leukemic cells (PMID: 25482556 ). TET-mediated hydroxymethylation has been implicated in a variety of cellular process including the regulation of somatic cell reprogramming (PMID: 24529596), hematopoietic differentiation (PMID: 24619230, 26257178), DNA damage response (PMID: 28325772), and telomere elongation (PMID: 25223896). Altered TET family member expression and 5-hmc levels have been correlated with tumor progression and prognosis in a variety of cancer types (PMID: 23671639, 26207381, 27848178). Somatic loss-of-function mutations in TET3 have been found in myelodysplastic syndromes, acute myeloid leukemia and colon cancer, among others (PMID: 19388938, 19420352, 22895193, 28452984, 29531217). TET3-mutant cancers may be sensitive to DNA methylation inhibitors, such as 5-azacytidine (PMID: 28193779). True +ENST00000315869 NM_006521.5 7030 TFE3 True TFE3, a transcription factor involved in nutrient sensing and lysosomal biogenesis, is recurrently altered by fusion in renal cell carcinomas and alveolar soft part sarcomas. TFE3 is a transcription factor that is a member of the MTF/TFE family of proteins (PMID: 24448649). TFE3 functions as a critical transcriptional regulator of lysosomal homeostasis, energy metabolism, nutrient sensing and cellular stress (PMID: 22297304, 24448649, 26813791, 24448649). When nutrients are abundant, TFE3 is retained in the cytoplasm by mTORC1 phosphorylation and binding to the scaffolding protein 14-3-3 (PMID: 24448649). Activity and localization of TFE3 are also mediated by Rag GTPases, under control of the amino acid sensor Ragulator (PMID: 24448649, 22980980). In response to nutrient deprivation, TFE3 regulates the number of lysosomes in the cell (PMID: 24448649). TFE3 translocates to the nucleus upon starvation and upregulates a variety of genes involved in autophagy and lysosomal biogenesis (PMID: 24448649, 22576015). In addition, TFE3 mediates a variety of immune-related activities including autophagy, proinflammatory cytokine expression and antibody production, among others (PMID: 26813791, 26813791, 30917316). Expression of TFE3 is implicated in hematopoietic and osteoclast differentiation (PMID: 17046750, 23599343). Overexpression of TFE3 is found in patients with pancreatic cancer, resulting in increased lysosomal function to maintain intracellular amino acid pools (PMID: 26168401). Oncogenic fusion proteins that place TFE3 downstream of a strong promoter are found in an aggressive subtype of renal cell carcinoma and alveolar soft part sarcomas, a rare soft tissue tumor (PMID: 22705279, 8872474, 30849994). False +ENST00000374994 NM_004612.2 7046 TGFBR1 False TGFBR1 encodes a receptor kinase that signals to downstream effectors in the TGFß signaling pathway. TGFBR1 is infrequently mutated in cancer; however, germline mutations in this gene are associated with Marfans syndrome and Loeys-Dietz syndrome. TGFBR1 is a serine/threonine protein kinase that belongs to the transforming growth-factor β (TGF β) family (PMID: 22992590). TGFß signaling controls multiple biological processes including cellular proliferation, differentiation and tissue homeostasis (PMID: 22992590, 11057902). TGFBR1 is a type I receptor that heterodimerizes with other TGFß receptor family members to initiate ligand binding (PMID: 22992590). Following ligand activation, TGFBR1 phosphorylates its dimerization partner and induces phosphorylation of downstream effectors such as the SMAD proteins, which control gene regulation (PMID: 22992590, 18662538). Germline mutations in TGFBR1 have been identified in the autosomal Loeys-Dietz syndrome type 1 and Marfan syndromes (PMID: 16928994,16791849, 16596670, 18781618). Other hereditary variants have been found to be associated with non-small cell lung cancer (PMID: 21225232, 19690145). Somatic mutations in TGFBR1 are infrequent in human cancer; however, loss-of-function mutations and deletions have been identified in colorectal cancer and several other cancer types (PMID: 22992590, 11057902). Targeting of the TGFß pathway is being explored as a therapeutic approach in multiple cancers (PMID: 11057902, 18662538) and small molecule inhibitors targeting the kinase activity of TGFBR1 have entered into clinical trials (PMID: 11057902, 18662538). True +ENST00000295754 NM_003242.5 7048 TGFBR2 False TGFBR2 encodes a receptor kinase that signals to downstream effectors in the TGFß signaling pathway. TGFBR2 is infrequently mutated in cancer; however, germline mutations in this gene are associated with Marfan syndrome and Loeys-Dietz syndrome. TGFBR2 is a serine/threonine protein kinase that belongs to the transforming growth-factor β (TGFβ) family (PMID: 22992590). TGFß signaling controls multiple biological processes including cellular proliferation, differentiation and tissue homeostasis (PMID: 22992590, 11057902). TGFBR2 is a type II receptor that heterodimerizes with other TGFß receptor family members to initiate downstream signaling (PMID: 22992590). Following TGFß-family ligand activation, TGFBR2 phosphorylates its dimerization partner and induces phosphorylation of downstream effectors such as the SMAD proteins, which control gene regulation (PMID: 22992590, 18662538). Germline mutations in TGFBR2 have been identified in the autosomal Loeys-Dietz syndrome type 2 and Marfan syndromes (PMID: 15731757, 15235604, 8317497). TGFBR2 mutations associated with Loeys-Dietz syndrome were shown in cell lines to inactive the receptor function (PMID: 15235604). Somatic mutations in TGFBR2 are infrequent in human cancer; however, loss-of-function mutations have been identified in gastrointestinal and pancreatic cancers (PMID: 22992590, 11057902). Targeting of the TGFß pathway is being explored as a therapeutic approach in multiple cancers (PMID: 11057902, 18662538) and small molecule inhibitors targeting the kinase activity of TGFß receptors have entered clinical trials (PMID: 11057902, 18662538). True +ENST00000179259 NM_020375 57103 TIGAR True TIGAR, a TP53-regulated phosphatase, is infrequently altered in cancer. TIGAR, also known as C12orf5, encodes for a phosphatase that primarily functions in the inhibition of glycolysis by reducing fructose 2,6-bisphosphate through its conserved catalytic domain (PMID: 19015259). Through translocation to various organelles under different stress stimuli, TIGAR has been identified to regulate other cellular processes including cell cycle arrest, DNA damage repair regulation, apoptosis and production of reactive oxygen species (PMID: 25928429, 24872551, 25085248, 23185017). Overexpression of TIGAR in various cancer cells and xenograft models induces increased cellular proliferation, cellular invasion, tumor progression and suppression of apoptosis and autophagy, suggesting that TIGAR functions predominantly as an oncogene (PMID: 31799200, 31983610, 19713938, 26212201). Amplification of TIGAR has been identified in various types of cancer, including colon cancer, breast cancer and glioblastoma (PMID: 23726973, 21820150, 22887998). False +ENST00000376499 NM_001303103.1 7088 TLE1 False TLE1, a transcriptional repressor, is altered by overexpression and deletion in various cancer types. TLE1 is a transcriptional co-repressor that is a member of the Groucho (Gro)/Transducin-like enhancer (TLE) of split family proteins (PMID: 1303260, 27852056). The TLE family of transcriptional regulators cannot bind DNA but function as adaptor proteins that modulate the activity of transcription factors, such as RUNX, NKX and HES family transcription factors (PMID: 27852056, 10825294). TLE1 functions as a homotetramer that recruits both epigenetic and transcriptional effector proteins to allow for remodeling of chromatin and repression of gene expression (PMID: 27852056, 29069783). TLE1 binds cofactors that mediate the activity of several signaling pathways including NOTCH, WNT and NF-KB (PMID: 27852056, 30563890). Expression of TLE1 has been implicated in a variety of cellular activities including cell fate specification, inflammation, hematopoiesis and apoptosis, among others (PMID: 27852056, 29069783, 30045946). TLE1 can function as either a tumor suppressor or oncogene in different cancer types, suggesting that TLE1 has context-specific roles in cancer progression (PMID: 27852056). Overexpression of TLE1 is found in patients with synovial sarcoma, lung cancer or invasive breast cancer, while the TLE1 gene is located in the 9q region that is commonly deleted in acute myeloid leukemia (PMID: 30563890, 27568668, 17255769, 27655370, 18258796). Specifically, in synovial sarcomas, TLE1 interacts with the SS18-SSX fusion to promote WNT-mediated gene expression programs (PMID: 26905812). False +ENST00000262953 NM_003260.4 7089 TLE2 False TLE2, a transcriptional repressor, is altered by overexpression in various cancer types. TLE2 is a transcriptional co-repressor that is a member of the Groucho (Gro)/Transducin-like enhancer (TLE) of split family proteins (PMID: 1303260, 27852056). The TLE family of transcriptional regulators cannot bind DNA but function as adaptor proteins that modulate the activity of transcription factors, such as RUNX, NKX and HES family transcription factors (PMID: 27852056, 10825294, 11283267). TLE2 functions as a homotetramer that recruits both epigenetic and transcriptional effector proteins to DNA to allow for remodeling of chromatin and repression of gene expression (PMID: 27852056, 29069783). While TLE1 is the most well-studied TLE family member, TLE2 has been shown to bind cofactors that mediate the activity of several signaling pathways including NOTCH and WNT (PMID: 27852056, 9874198, 8808280). Expression of TLE2 has been implicated in a variety of cellular activities including cell fate specification, neuronal development and inflammation, among others (PMID: 9572356, 18778483, 20356955, 9887105). Overexpression of TLE2 is found in patients with early grade astrocytomas and pituitary adenomas (PMID: 16896313, 16288009). False +ENST00000558939 NM_005078.3 7090 TLE3 False TLE3, a transcriptional repressor, is altered by mutation in various cancer types. TLE3 is a transcriptional co-repressor that is a member of the Groucho (Gro)/Transducin-like enhancer (TLE) of split family proteins (PMID: 27852056, 8989517). The TLE family of transcriptional regulators cannot bind DNA but function as adaptor proteins that modulate the activity of transcription factors, such as RUNX, NKX, and WNT family transcription factors (PMID: 27852056). TLE3 functions as a homotetramer or heterooligomer that recruits both epigenetic and transcriptional effector proteins to DNA to allow for remodeling of chromatin and repression of gene expression (PMID: 28689657, 25223786). TLE3 binds cofactors that mediate the activity of several signaling pathways including NOTCH and WNT (PMID: 30894540, 30894540). Expression of TLE3 has been implicated in a variety of cellular activities including cell fate specification, adipocyte development, osteoblast differentiation, proliferation and metastasis, among others (PMID: 28607151, 27298623, 26172616, 25779673, 21459326). TLE3 predominantly functions as a tumor suppressor by repressing gene targets involved in metastasis; however, TLE3 has also been found to promote proliferation in some cancer types, suggesting context-specific roles in cancer progression (PMID: 30719233, 29374067, 27669982). In prostate cancer, specific FOXA1 mutations disrupt an interaction with TLE3, resulting in loss of TLE3-mediated repression of WNT signaling and metastasis (PMID: 31243372). False +ENST00000376552 NM_007005.4 7091 TLE4 False TLE4, a transcriptional repressor, is altered by mutation and deletion in various cancer types. TLE4 is a transcriptional co-repressor that is a member of the Groucho (Gro)/Transductin-like enhancer (TLE) of split family proteins (PMID: 27852056). The TLE family of transcriptional regulators cannot bind DNA but function as adaptor proteins that modulate the activity of transcription factors, such as RUNX, NKX, and WNT family transcription factors (PMID: 27852056, 27486062, 10825294). TLE4 functions as a homotetramer or heterooligomer that recruits both epigenetic and transcriptional effector proteins to DNA to allow for remodeling of chromatin and repression of gene expression (PMID: 22169276). TLE4 binds cofactors that mediate the activity of several signaling pathways including NOTCH and WNT (PMID: 27486062, 15499562). Expression of TLE4 has been implicated in a variety of cellular activities including cell fate specification, immune regulation, neuronal development, metastasis and inflammation, among others (PMID: 30045946, 29395907, 27486062, 25153823). TLE4 can function as either a tumor suppressor or oncogene in different cancer types, suggesting that TLE4 has context-specific roles in cancer progression. The TLE4 gene is located in the 9q region that is commonly deleted in acute myeloid leukemia, while loss of TLE4 expression has found to be growth promoting in other cancer types such as colorectal cancer (PMID: 26701208, 18258796). False +ENST00000370196 NM_005521.3 3195 TLX1 True TLX1, a transcription factor, is recurrently altered by chromosomal rearrangement in T-cell acute lymphoblastic leukemia. TLX1 (also HOX11) is a transcription factor that is a member of the NK-like subfamily of homeobox genes (PMID: 19835636). TLX1 functions predominantly as a transcriptional repressor at T-cell lineage-specific enhancers and antagonizes NOTCH1 (PMID: 26108691). In collaboration with the transcription factor STAT5, TLX1 binds enhancer regions of genes that drive leukemic gene expression programs including BCL2 and MYC (PMID: 19835636). TLX1 is not expressed in the hematopoietic system; however, TLX1 activation is observed in several hematopoietic malignancies (PMID: 21326611). Transcriptional activity of TLX1 has been associated with several cellular functions including transformation, mitotic checkpoint control, and genome stability (PMID: 20972433, 9009195, 7905617). TLX1 downregulates the mitotic checkpoint gene CHEK2, leading to aneuploidy in TLX1-positive human and murine leukemic tumors (PMID: 20972433). Expression of TLX1 in several distinct murine models results in the development of T-ALL, with T cells typically arresting at the cortical stage of development (PMID: 20972433, 21326611). Recurrent TLX1 fusions are found in patients with T-acute lymphocytic leukemia (T-ALL) (PMID: 1676542). These rearrangements place TLX1 under the control of T-cell strong enhancers, suggesting that TLX1 functions predominantly as an oncogene (PMID: 27451956). False +ENST00000296921 NM_021025.2 30012 TLX3 True TLX3, a transcription factor involved in neuronal differentiation, is recurrently altered by chromosomal rearrangement in T-cell acute lymphoblastic leukemia. TLX3 (also HOX11L2) is a transcription factor that is a member of the NK-like subfamily of homeobox genes (PMID: 19835636). Expression of TLX3 is highest in the central nervous system, where it mediates glutamatergic neuronal differentiation (PMID: 11581159, 15064766, 27452274). TLX3 also functions as a transcriptional repressor at T-cell lineage-specific enhancers, similar to the closely related family member TLX1 (PMID: 30107177, 22516263, 22366949). TLX3 is not expressed in the hematopoietic system; however, TLX3 activation is found in leukemias (PMID: 12086890, 12454747). Expression of TLX3 in hematopoietic assays demonstrates restricted T cell differentiation at the cortical stage, likely due to transcriptional interactions with ETS1 and reduced T-cell receptor activity (PMID: 22516263). TLX3 mediates the expression of genes involved in T-cell differentiation and interacts with chromatin modifiers to regulate transcription (PMID: 29296717, 26258652). Transcriptional activity of TLX3 has been associated with several cellular functions including transformation, proliferation, and invasion (PMID: 16804919, 29296717). Recurrent TLX3 fusions are found in patients with T-cell acute lymphocytic leukemia (T-ALL) (PMID: 27451956, 28671688). These rearrangements lead to TLX3 activation by positioning TLX3 under the control of T-cell mediated regulatory units, suggesting that TLX3 functions predominantly as an oncogene (PMID: 27451956). False +ENST00000258439 NM_001193304.2 55654 TMEM127 False TMEM127 is a transmembrane protein and tumor suppressor identified in pheochromocytoma and paraganglial tumors, in which hereditary variants are found. TMEM127 (transmembrane protein 127) encodes a tumor suppressor protein with three predicted transmembrane domains. In vitro experiments confirm the localization of TMEM127 at the plasma membrane and indicate a tumor-suppressor role through reduction of mTORC1 activity, demonstrated by phosphorylation of the mTOR effector, S6K, upon TMEM127 depletion (PMID: 20923864, 20154675, 21156949). The latter has also been shown in a tissue sample from a patient with pheochromocytoma (PMID: 20923864). Cell line studies suggest that the failure of mutated TMEM127 to inhibit mTORC1 is due to loss of association with the mTOR inhibitor RAB5. Truncating germline variants in TMEM127, often in concert with loss of heterozygosity at its genomic locus, confer increased risk for pheochromocytoma and paraganglial tumors (PMID: 20923864, 20154675, 21156949, 22541004, 21613359). TMEM127 mutations have also been observed in renal cancer. True +ENST00000398585 NM_001135099.1 7113 TMPRSS2 False TMPRSS2, a transmembrane serine protease, is recurrently altered by chromosomal rearrangements in prostate cancer. TMPRSS2 is a transmembrane serine protease that functions to cleave substrates in epithelial cells. Although its role in normal epithelial cells is not well understood, TMPRSS2 is highly expressed in the prostate epithelium and is an androgen responsive gene (PMID:11245484). TMPRSS2 can cleave components of the tumor microenvironment, such as pro-HGF (hepatocyte growth factor) to promote invasion and metastasis (PMID: 25122198). TMPRSS2 is recurrently fused to ETS-family transcription factors in about 50% of primary prostate cancers, including the TMPRSS2-ERG and TMPRSS2-ETV1 fusions, resulting in overexpression of these ETS family members (PMID: 16254181). TMPRSS2 gene fusions in prostate cancer often occur in the setting of PTEN loss and subsequent PI3-kinase pathway activation (PMID:19396168,19396167). In these cancers, ETS transcription factors modify the chromatin landscape of prostate cancer cells, allowing for increased androgen receptor (AR) binding and priming prostate cancer initiation in response to PTEN loss (PMID: 23817021, 28783165). False +ENST00000237289 NM_006290.3 7128 TNFAIP3 False TNFAIP3 encodes an enzyme involved in regulation of the NF-κB pathway. Mutations of TNFAIP3 are found in lymphomas and leukemias. TNFAIP3 encodes TNF alpha induced protein 3 that is induced by Tumor necrosis factor (TNF) alpha and regulates the NF-κB pathway (PMID: 11009421). TNFAIP3 has ubiquitin ligase and de-ubiquitination activities that suppress the NF-κB pathway (PMID: 15258597). Its activity is important in regulating B-cell survival and apoptosis, inflammatory response, and dendritic cell function in regulating T-cells (PMID: 20705491, 18311150, 25043000). Polymorphisms in TNFAIP3 are associated with many autoimmune diseases such as systemic lupus erythematosus, Sjögren's syndrome, multiple sclerosis, and rheumatoid arthritis (PMID:19165919, 25684197, 24097067,17982455). Germline loss of function mutations are associated with autoimmune disease (PMID: 26642243). Mutations are found in B-cell lymphomas, T-cell large granular lymphocytic (LGL) leukemia, and peripheral T-cell lymphomas (PMID: 19412163, 21115979, 21625233, 26199174). TNFAIP3 mutation has been associated with transformation of lymphomas to more aggressive disease and varying prognosis depending on subtype (PMID: 24362818, 23327292, 21266526). True +ENST00000355716 NM_003820.2 8764 TNFRSF14 False TNFRSF14, a cell surface receptor in the tumor necrosis factor family, is recurrently altered by mutation and deletion in hematologic malignancies. TNFRSF14 (also HVEM) is a cell surface receptor in the tumor necrosis factor family (PMID: 8898196). It is expressed on several types of cells, including T cells, B cells, NK cells, dendritic cells, and myeloid cells, as well as non-lymphoid organs including lung, liver and kidney (PMID: 9162061). TNFRSF14 is a tumor suppressor and immunogenicity regulation factor and is capable of sending both stimulatory and inhibitory signals to T cells depending on the particular ligand it binds (PMID: 23023713, 20884631). Mutations in TNFRSF14 has been demonstrated in the pathogenesis of both diffuse large B-cell lymphoma (PMID: 22343534 ) and follicular lymphoma (FL) (PMID: 20884631, 24435047, 24162788, 21941365). These mutations are associated with high-risk clinical features, and patients with a mutation in TNFRSF14 responded poorly to rituximab (PMID: 20884631). Recurrent copy number loss of the region containing TNFRSF14 was observed in 42% of the cases with classical Hodgkin lymphoma (CHL) (PMID:26650888). Finally, TNFRSF14 expression is deregulated in colorectal cancer (PMID: 25750286), hepatocellular carcinoma (PMID: 25468715) and esophageal squamous cell carcinoma (PMID:24249528). True +ENST00000053243 NM_001192 608 TNFRSF17 True TNFRSF17, a transmembrane glycoprotein primarily expressed on the surface of B lymphocytes, is altered by amplification in multiple myeloma. TNFRSF17, a member of the TNF-receptor superfamily, encodes for a transmembrane glycoprotein TNF receptor expressed primarily on mature B lymphocytes and functions in B-cell activating factor (BAFF) recognition (PMID: 8165126, 1396583). TNFRSF17 mediates the development of the B lymphocytes and their autoimmune response through interaction with ligands BAFF and APRIL (PMID: 16116167). Overexpression of TNFRSF17 in various cancer cell lines and models induces tumor growth and angiogenesis, suggesting that TNFRSF17 functions predominantly as an oncogene (PMID: 27127303, 21642598, 30131941). TNFRSF17 amplification has been identified in multiple myeloma (PMID: 22804669, 27127303, 26960399). False +ENST00000338784 NM_003808 8741 TNFSF13 True TNFSF13, a tumor necrosis factor receptor ligand, is infrequently altered in cancer. TNFSF13, a member of the tumor necrosis factor (TNF) ligand family, encodes the proliferation-inducing ligand for the TNF receptors TNFRSF13B and TNFRSF17 (PMID: 33036273, 30131941). Through binding these receptors, TNFSF13 functions in B cell and T cell activation, survival and proliferation to regulate humoral immunity response (PMID: 19828625, 10973284, 14707116). TNFSF13 has been identified to have three transcript variants encoding distinct isoforms as a result of alternative splicing (PMID: 10706119). Overexpression of TNFSF13 in mouse models and cancer cell lines induces increased tumor growth, migration and proliferation, suggesting that TNFSF13 functions primarily as an oncogene (PMID: 24436270, 17190854, 19573525, 16793914, 30819903). Amplification of TNFSF13 can also be accompanied by the amplification of driver oncogenes, such as EGFR and PDK4, and the deletion and mutation of tumor suppressor genes, such as CDKN2A and PTEN (PMID: 34712225). TNFSF13 overexpression and mutation has been identified in various cancers, including breast cancer and multiple myeloma (PMID: 18366696, 30135465, 25750171). False +ENST00000409379 NM_013432 4796 TONSL False TONSL, a DNA repair protein, is altered by amplification in breast cancer. TONSL encodes the Tonsoku-like DNA repair protein, which is a multi-domain scaffold protein that plays a critical role in resistance to replication stress and maintaining genome integrity. TONSL interacts with various DNA replication and repair factors including anti-silencing function 1 (ASF1), minichromosome maintenance complex component helicases (MCM helicases), H3 and H4 histones and methanesulfonate sensitivity protein 22-like protein (MMS22L) (PMID: 32959051, 30773278). TONSL, in a heterodimer complex with MMS22L, is involved in repairing spontaneous DNA lesions through homologous recombination (PMID: 30773278). The MMS22L-TONSL complex functions in the DNA damage response upon replication fork collapse and to mediate recovery from replicative stress (PMID: 36622344, 37057595). The MMS22L-TONSL complex is recruited by replication protein A (RPA1, RPA2, and RPA3) to sites of stalled replication forks during normal S-phase replication and promotes homologous recombination by facilitating the assembly of RAD51 (PMID 30773278, 30773277, 32959051). TONSL is thought to negatively regulate NF-kappa-B by binding to NF-kappa-B complexes and trapping them in the cytoplasm, preventing them from interacting with DNA ((PMID: 30723051, 31158361). NF-kappa-B complexes can then enter the nucleus upon phosphorylation and ubiquitination of TONSL (PMID: 30723051). Overexpression of TONSL in human gastric cancer cell lines reduces cellular proliferation and colony formation and negatively regulates migration and invasion compared to control cells (PMID: 31158361). Breast primary cells overexpressing TONSL have demonstrated upregulated DNA repair via homologous recombination (PMID: 37057595). Amplification of the TONSL gene is found in breast, liver, lung, esophageal, and cervical cancer (PMID: 37057595, 30723051, 31158361) and mutations in TONSL have been identified in individuals with Sponastrime dysplasia (PMID 32959051, 30773278). False +ENST00000361337 NM_003286.2 7150 TOP1 True TOP1, a DNA topoisomerase, is infrequently altered in cancer. TOP1 (DNA topoisomerase 1) is a DNA topoisomerase that catalyzes the decatenation of DNA entanglements that occur during transcription (PMID: 12042765). This transesterification reaction results in the breaking of a DNA strand and subsequent rejoining (PMID: 25693836). Amplification of TOP1 in yeast and cancer cell lines induces genomic instability and susceptibility to DNA damage, suggesting that TOP1 functions primarily an oncogene (PMID: 11353773, 28961461, 36170822). TOP1 overexpression has been identified in various cancers, including breast cancer, ovarian cancer and liver cancer (PMID: 33144457, 26207989, 30132517). TOP1 amplification may be sensitive to treatment with TOP1 inhibitors, such as evodiamine and nitidine chloride (PMID: 26207989, 30132517). Acquired mutations in TOP1 have been identified to confer resistance to TOP1 inhibition (PMID: 21619602, 23836376, 11844605, 16546964, 21978643). False +ENST00000423485 NM_001067 7153 TOP2A True TOP2A, a DNA topoisomerase, is altered in various cancers. TOP2A is one of two isoforms of DNA topoisomerase II that plays a key role in resolving topological DNA entanglements during transcription by creating temporary double stranded breaks in the DNA phosphodiester backbone (PMID: 31216997, 36678591). In normal cells, TOP2A assists chromosome condensation and chromatid separation during interphase and mitosis and expression levels of TOP2A peak during the G2/M phase of the cell cycle (PMID: 31216997). Cancer cells take advantage of TOP2A function to alleviate DNA replication and transcription stress created by the rapid pace of malignant cell growth (PMID: 36678591). Suppression of TOP2A lengthens the duration of mitosis and causes severe defects in chromosome separation, rendering cells unable to complete the cell cycle (PMID: 35778520, 22067657, 25328138). Overexpression of TOP2A is seen in many cancer types including carcinomas, sarcomas, diffuse large B-cell lymphoma, and lower-grade glioma, and is usually associated with aggressive disease and a less favorable prognosis (PMID: 35778520, 23533247). Multiple studies have demonstrated that knockdown of TOP2A reduces oncogenesis suggesting that TOP2A functions as an oncogene (PMID: 29761838, 2976183). Anthracycline agents that target TOP2A, including aclarubicin, have demonstrated efficacy in adrenocortical carcinoma cell lines (PMID: 23533247, 30519354). While topoisomerase II inhibitors such as doxorubicin, etoposide, and teniposide are widely used in clinical practice, optimizing selective topoisomerase II agents is an ongoing area of research (PMID: 37094479). TOP2A is also the target of a preclinical vaccine that both reduces tumor incidence and decreases tumor growth of triple-negative breast cancer in mice (PMID: 37880313). False +ENST00000269305 NM_000546.5 7157 TP53 False 3A TP53, a tumor suppressor in the DNA damage pathway, is the most frequently mutated gene in cancer. TP53 encodes the p53 tumor suppressor protein, a transcription factor that responds to cellular stresses, including DNA damage and oncogenic activation, by inducing downstream anti-tumor responses such as DNA repair and apoptosis (PMID: 11099028). p53 levels are kept low in healthy cells due to negative regulation by MDM2/4, Cop1 and Trim24 and constant degradation by the ubiquitin-proteasome system (PMID: 36859359, 36207426). When DNA is damaged, a network of pathways is activated to detect and repair lesions in a cell- and context-specific manner (PMID: 36207426). p53 is rapidly phosphorylated by upstream regulators such as ATM, ATR, and CHL1/2, which results in the accumulation of stable p53 (PMID: 36207426). p53 then binds to specific DNA sequences to direct the expression of a wide variety of genes, including those involved in apoptosis, cell cycle arrest, DNA repair, senescence, stem cell differentiation, autophagy, cellular metabolism, and others (PMID: 27141080, 36859359, 36207426). Oncogenic mutations of TP53 often result in the dysregulation of p53 function, usually due to structural changes in the DNA binding domain (PMID: 36859359). Loss of p53 function can have various outcomes including tumorigenesis, invasion and metastasis, drug resistance, metabolic reprogramming, immune evasion and overall genomic instability (PMID: 36859359). TP53 is the most commonly mutated gene in human cancers, and germline mutations occur in the cancer predisposition syndrome Li-Fraumeni (PMID: 22713868, 21765642). Clinical and preclinical research into drugs that target TP53 is ongoing, notably with MDM2 inhibitors that aim to restore p53 function and are being tested in combination with other cancer therapies (PMID: 36859359, 37818252). True +ENST00000382044 NM_001141980.1 7158 TP53BP1 False TP53BP1, a tumor suppressor and DNA repair protein, is altered by mutation or deletion in various cancer types, most frequently in skin cancers. The TP53BP1 gene encodes a protein originally identified as a partner of tumor suppressor gene TP53. TP53BP1 plays a role in DNA damage recognition and DNA repair (PMID: 12364621, 21144835, 17190600, 18804090). Tumor suppressor roles for TP53BP1 have been described in several cancers, mostly related to functions of TP53, BRCA1 and ATM, although some contradictory results exist (PMID: 15970701, 17546051, 15279780, 12447382, 22266878, 20453858, 24681733). TP53BP1 is predominantly mutated in skin cancers such as cutaneous squamous cell carcinomas and melanomas (cBioPortal, MSKCC, Dec. 2016). True +ENST00000264731 NM_003722.4 8626 TP63 True TP63, a transcription factor, is recurrently altered by chromosomal rearrangement in hematologic malignancies. TP63 is a member of the TP53 family of transcription factors. The TP63 protein exists as two different isoforms due to usage of alternative promoters, producing variants with (TAp63) and without (ΔNp63) the N-terminal transactivation domain (TAD) (PMID: 23344544). TP63 transactivates downstream target genes in collaboration with TP53 and TP73, however, the TAp63 and ΔNp63 isoforms have opposing cellular functions (PMID: 24488880). TAp63 has been implicated as a tumor suppressor and plays a role in the regulation of apoptosis, cell cycle arrest, response to DNA damage, suppression of metastasis, and transactivation of TP53 family target genes (PMID: 16601753, 21760596). ΔNp63 antagonizes TP53/TAp63/TP73 transactivation of target genes by competing for TAp63 binding sites and blocking transactivation, leading to cellular proliferation (PMID: 23344544). ΔNp63 has been shown to inhibit oxidative-stress induced death and inhibits apoptosis (PMID: 29212036). TP63 is most highly expressed in epithelial cells and neurons and loss of TP63 in mouse models result in depletion of epithelial patterning (PMID: 10227293, 10227294). Expression of TP63 has also been identified as a stem cell marker in several contexts (PMID: 23344544). Germline alterations in TP63 have been associated with several disorders including ectodermal dysplasia and cleft lip/ palate syndrome (EEC) and limb mammary syndrome (LMS), among others; however, these patients do not have increased cancer risk (PMID: 17224651). Somatic mutations in TP63 are relatively infrequent in human malignancies. However, TP63 has been associated with overexpression and amplification in squamous tumors (PMID: 15754296). Translocations of TP63 have also been found in hematopoietic malignancies (PMID: 24893616, 22496164). True + 6955 TRA True TRA, the α-chain of the T-cell receptor, is recurrently altered by chromosomal rearrangement in T-cell acute lymphoblastic leukemia. TRA is the T-cell receptor A locus which encodes the α-chain of the T-cell receptor (TCR) (PMID: 29261409, 25484883). TCRs are protein complexes found on the surface of T cells that engage antigens associated with major histocompatibility complex (MHC) molecules on antigen presenting cells (PMID: 16087711). T cells are important in coordinating effector and memory immune responses in response to antigen display (PMID: 24292902). MHC class I molecules are recognized by TCRs on CD8+ T cells and MHC class II molecules are recognized by TCRs on CD4+ T cells (PMID: 6504140, 25484883). Most TCRs are composed of α and β heterodimers (encoded by TRA and TRB), with a fraction of TCRs composed of γ and δ subunits (PMID: 29261409, 20164930). TRA proteins share substantial homology to immunoglobulin proteins and exhibit sequence diversity following recombination and thymic selection (PMID: 24830344). Engagement of antigen-presenting MHC class proteins with TRA/TRB heterodimers results in conformational changes and activation of downstream pathways leading to activation of TCR-mediated signaling (PMID: 29261409). TRA rearrangements are recurrently found in patients with T-acute lymphoblastic leukemias, typically leading to activation of the fusion partner (PMID: 29279377, 28671688). Chimeric antigen receptor T cell (CAR-T) therapy is FDA-approved for patients with non-Hodgkin lymphoma and diffuse large B-cell lymphoma, in which cancer cells from patients are engineered to express TCRs that are recognized by the immune system (PMID: 29914976, 29539277, 29113977). False +ENST00000247668 NM_021138.3 7186 TRAF2 False TRAF2 is a protein that mediates signaling from members of the TNF receptor family and regulates downstream NFkB pathway activation. Mutations are found in meyloma, lymphomas, and more rarely in epithelial cancers. TRAF2 is an adaptor molecule that interacts with and transduces signals from the Tumor necrosis factor (TNF) receptor (PMID:8565075, 8985011, 8898208). Following TNF engagement, TRAF2 mediates the assembly of signaling scaffolds to activate the NF-κB pathway, JNK (Jun amino-terminal kinases), and anti-apoptotic pathways (PMID:8565075, 8985011, 8898208). TRAF2 also has ubiquitin ligase activity that can regulate protein stability (PMID: 23142077, 20577214). Signaling cascades mediated by TRAF2 have been implicated in lymphocyte proliferation and survival, immune response, and hematopoietic stem cell activation (PMID: 9390693, 9390694, 11435475). In cell line and murine cancer models, TRAF2 expression is involved in NF-κB activation leading to tumor cell survival and resistance to targeted therapy (PMID: 25843712,19336568, 22589389). Somatic mutations in TRAF2 have been identified multiple myeloma, lymphomas, and nasopharyngeal carcinomas (PMID:17692805, 24362935,19412164, 23868181). TRAF2 mutations are predicted to be loss-of-function and dysregulate NF-κB signaling (PMID: 24362935,19412164, 23868181). Amplification of TRAF2 has also been identified in epithelial cancers (PMID: 24362534). False +ENST00000392745 NM_003300.3 7187 TRAF3 False TRAF3, a signaling molecule and E3 ligase, is recurrently mutated and deleted in B cell lymphoma and multiple myeloma. TRAF3 is an E3 ligase and signaling molecule that is a member of the tumor necrosis factor (TNFR)-associated factor (TRAF) family (PMID: 21660053). TRAF3 functions downstream of Interleukin-1 (IL-1) or Toll-like receptor (TLR) pathways, which are important in the regulation of innate immunity and inflammation (PMID: 21660053). TRAF3 can function as an E3 ligase in TLR pathways, promoting K63-linked polyubiquitination in order to maintain protein-protein interactions (PMID: 21660053, 25847972). Alternatively, TRAF3 can function as a negative regulator of cytokine activity by binding MAPK effectors; degradation of TRAF3 releases MAPK-regulatory proteins, such as MAP3K1, leading to MAPK pathway activation (PMID: 30140268). In addition, TRAF3 can bind TRAF2 and cIAPs to negatively regulate the NF-κB pathway, and TRAF3 degradation results in the release of NF-κB effector molecules, such as NIK (PMID: 21660053, 15383523). TRAF3 also positively regulates the expression of IRF3 and IRF7, proteins that activate the transcription of type I interferon cytokines (PMID: 16306937). Loss of TRAF3 results in the overproduction of inflammatory cytokines (PMID: 16306937) and reduced B cell homeostasis (PMID: 17723217). TRAF3 can also bind CD40, a costimulatory protein on T cells that is required for T cell activation, and the TRAF3/CD40 interaction mediates class switching (PMID: 8934568, 12354380). Alterations of TRAF3 have been associated with immune deficiencies in response to primary infection (PMID: 20832341). Loss-of-function mutations in TRAF3 are found in multiple myeloma (PMID: 17692804, 17692805), resulting in activation of NF-κB signaling. Deletions of TRAF3 have also been identified in B cell lymphomas (PMID: 19693093, 22033491, 22469134, 25468570). True +ENST00000261464 NM_001033910.2 7188 TRAF5 False TRAF5, a signaling adaptor molecule, is infrequently altered by mutation in lymphomas. TRAF5 is a signaling molecule that is a member of tumor necrosis factor (TNFR)-associated factor (TRAF) family (PMID: 8663299). TRAF5 functions downstream of TNFR and Toll-like receptor (TLR) pathways, which are important in the regulation of innate immunity and inflammation (PMID: 12842894). TRAF5 functions as an adaptor molecule in signaling complexes that negatively regulate TLR signaling, in part by activating downstream signaling cascades and mediating cytokine signaling (PMID: 10623461). TRAF5 predominantly acts as an adaptor molecule that binds a complex including TRAF2, leading to activation of downstream NF-κB, JNK and MAPK signaling pathways (PMID: 8790348, 8999898). In addition, TRAF5 can also bind CD40, a costimulatory protein on T cells that is required for T cell activation (PMID: 8790348). An interaction between TRAF2 and TRAF5 is also associated with inhibition of JAK kinase dimerization, leading to inhibition of JAK-STAT signaling (PMID: 29668931). TRAF5 has also been implicated in the regulation of inflammation, as loss of TRAF5 leads to a marked reduction in immune cell infiltration in several tissue types (PMID: 29596835). Mutations in TRAF5 are relatively rare in human cancers; however, loss-of-function alterations have been identified in diffuse large B cell lymphoma (PMID: 19412164). True +ENST00000326181 NM_032271.2 84231 TRAF7 False TRAF7, an E3 ubiquitin ligase, is frequently altered in meningiomas. TRAF7 is an E3 ligase and signaling molecule that is a member of the tumor necrosis factor receptor-associated factor (TRAF) family (PMID: 27808423). TRAF7 activity is important for the regulation of the MAPK and NF-kB signal transduction pathways (PMID: 27808423). TRAF7 binds and potentiates the activity of MEKK3, a protein implicated in the activation of downstream MAPK and NF-kB signaling (PMID: 15001576). Additional functional studies have demonstrated that TRAF7 can mediate the stability of several NF-kB pathway members including NEMO and p65 (PMID: 21518757). TRAF7 has also been identified as an agonist for the JNK-AP1 pathway (PMID: 14743216). In addition, TRAF7 targets ubiquitination of c-FLIP, an antiapoptotic molecule, as well as p53, implicating TRAF7 in apoptosis and cellular proliferation (PMID:14743216, 23128672). Recurrent somatic mutations in TRAF7 have been identified meningiomas, including in 93% of secretory meningiomas (PMID: 23348505, 23404370), and predominantly occur as loss-of-function mutations. TRAF7 mutations commonly co-occur with KLF4 and AKT1 mutations and are mutually exclusive with NF2 alterations (PMID: 23404370). TRAF7 is also mutated in Merkel cell carcinomas and mesotheliomas (PMID: 27808423, 26655088). False + 6957 TRB True TRB, the β-chain of the T-cell receptor, is recurrently altered by chromosomal rearrangement in patients with T-cell acute lymphoblastic leukemia. TRB is the T-cell receptor B locus which encodes the β-chain of the T-cell receptor (TCR) (PMID: 29261409, 25484883). TCRs are protein complexes found on the surface of T cells that engage antigens associated with major histocompatibility complex (MHC) molecules on antigen presenting cells (PMID: 16087711). T cells are important in coordinating effector and memory immune responses in response to antigen display (PMID: 24292902). MHC class I molecules are recognized by TCRs on CD8+ T cells and MHC class II molecules are recognized by TCRs on CD4+ T cells (PMID: 6504140, 25484883). Most TCRs are composed of α and β heterodimers (encoded by TRA and TRB), with a fraction of TCRs composed of γ and δ subunits (PMID: 29261409, 20164930). TRB proteins share substantial homology to immunoglobulin proteins and exhibit sequence diversity following recombination and thymic selection (PMID: 24830344). Engagement of antigen-presenting MHC class proteins with TRA/TRB heterodimers results in conformational changes and activation of downstream pathways leading to activation of TCR-mediated signaling (PMID: 29261409). TRB rearrangements are recurrently found in patients with T-acute lymphoblastic leukemias, typically leading to activation of the fusion partner (PMID: 23033986, 19841179, 15470492). Chimeric antigen receptor T cell (CAR-T) therapy in FDA-approved for patients with non-Hodgkin lymphoma and diffuse large B-cell lymphoma, in which cancer cells from patients are engineered to express TCRs that are recognized by the immune system (PMID: 29914976, 29539277, 29113977). False + 6964 TRD True TRD, the δ-chain of the T-cell receptor, is recurrently altered by chromosomal rearrangement in B- and T-cell acute lymphoblastic leukemia. TRD is the T-cell receptor D locus which encodes the δ-chain of the T-cell receptor (TCR) (PMID: 29261409, 25484883). TCRs are protein complexes found on the surface of T cells that engage antigens typically associated with major histocompatibility complex (MHC) molecules on antigen presenting cells (PMID: 16087711). T cells are important in coordinating effector and memory immune responses in response to antigen display (PMID: 24292902). Most TCRs are composed of α and β heterodimers, but a small fraction of TCRs are composed of γ and δ subunits (encoded by TRG and TRD, termed γδ T-cells). (PMID: 29261409, 20164930). γδ T-cells are unconventional in that that recognize non-peptide stress antigens in the absence of MHC molecules (PMID: 20539306). γδ T-cell responses are commonly initiated following stress, leading to cytokine production, inflammatory responses, and pathogen clearance via direct or indirect cytotoxic activity (PMID: 28713381, 20539306). TRD proteins undergo programming during thymic maturation, restricting the expression of specific TCRs (PMID: 20539306). Engagement of antigens with TRD/TRG heterodimers results in conformational changes and activation of downstream pathways leading to activation of TCR-mediated signaling (PMID: 29261409). TRD rearrangements are recurrently found in patients with B- and T-acute lymphoblastic leukemias, typically leading to activation of the fusion partner (PMID: 16572206, 16386788, 16531254). Chimeric antigen receptor T cell (CAR-T) therapy is FDA-approved for patients with non-Hodgkin lymphoma and diffuse large B-cell lymphoma, in which cancer cells from patients are engineered to express TCRs that are recognized by the immune system (PMID: 29914976, 29539277, 29113977). False + 6965 TRG True TRG, the γ-chain of the T-cell receptor, is recurrently altered by chromosomal rearrangement in B- and T-cell acute lymphoblastic leukemia. TRG is the T-cell receptor G locus which encodes the γ-chain of the T-cell receptor (TCR) (PMID: 29261409, 25484883). TCRs are protein complexes found on the surface of T cells that engage antigens typically associated with major histocompatibility complex (MHC) molecules on antigen presenting cells (PMID: 16087711). T cells are important in coordinating effector and memory immune responses in response to antigen display (PMID: 24292902). Most TCRs are composed of α and β heterodimers, but a small fraction of TCRs are composed of γ and δ subunits (encoded by TRG and TRD, termed γδ T-cells) (PMID: 29261409, 20164930). γδ T-cells are unconventional in that they recognize non-peptide stress antigens in the absence of MHC molecules (PMID: 20539306). γδ T-cell responses are commonly initiated following stress, leading to cytokine production, inflammatory responses, and pathogen clearance via direct or indirect cytotoxic activity (PMID: 28713381, 20539306). TRG proteins undergo programming during thymic maturation, restricting the expression of specific TCRs (PMID: 20539306). Engagement of antigens with TRD/TRG heterodimers results in conformational changes and activation of downstream pathways leading to activation of TCR-mediated signaling (PMID: 29261409). TRG rearrangements are recurrently found in patients with B-cell and T-cell acute lymphoblastic leukemias, typically leading to activation of the fusion partner (PMID: 11972513, 15470492, 18245528). Chimeric antigen receptor T cell (CAR-T) therapy is FDA-approved for patients with non-Hodgkin lymphoma and diffuse large B-cell lymphoma (PMID: 29914976, 29539277, 29113977). False +ENST00000217233 NM_001301188 57761 TRIB3 True TRIB3, a pseudokinase, is infrequently altered in cancer. TRIB3 encodes for a pseudokinase that functions primarily in the regulation of the integrated stress response in the endoplasmic reticulum (PMID: 15775988, 15781252). TRIB3 inhibits the transcriptional activity of DDIT3 and ATF4, nuclear proteins that function in programmed cell death and regeneration, and upregulates the PI3K/AKT/mTOR signaling pathway through binding at both the C-terminal and N-terminal regions of TRIB3 (PMID: 15775988, 33717256, 33896816). TRIB3 has also been identified to stabilize and inhibit the ubiquitination of TWIST1, an epithelial-mesenchymal transition-inducing transcription factor (PMID: 31235507). Overexpression of TRIB3 in various cancer cell lines and mouse models induces upregulation of phosphorylated ERK1/2, JAG1 and SMAD3, and increases cellular proliferation, migration and invasion, suggesting that TRIB3 functions predominantly as an oncogene (PMID: 23319603, 23632994, 30745845). TRIB3 amplification has been identified in various types of cancer, including breast cancer, renal cell carcinoma and gastric cancer (PMID: 31844113, 30745845, 27573078). False +ENST00000377199 NM_006510 5987 TRIM27 True TRIM27, an E3 ubiquitin ligase, is frequently altered by amplification in cancer. TRIM27, also known as RFP, encodes an E3 ubiquitin ligase that is part of the zinc finger protein superfamily, and contains a tripartite motif that consists of a RING finger, B-box zinc finger and coiled-coil domain (PMID: 9247190). TRIM27 induces the ubiquitination of proteins such as PTEN, RIP1 and JAK1 to regulate signaling pathways, which includes promoting the PI3K/AKT and NF-kB signaling pathways (PMID: 30143645, 27612028, 26607717, 31719796, 34284744). Overexpression of TRIM27 in cancer cell lines results in tumor invasion, metastasis and cell proliferation, suggesting that TRIM27 predominantly functions as an oncogene (PMID: 29767249, 31719796). TRIM27 amplification has been identified in various cancer types, including colorectal cancer and ovarian cancer (PMID: 23342271, 29767249). Fusion of TRIM27 with the receptor tyrosine kinase RET has also been identified in various cancer types, including salivary intraductal carcinoma and papillary thyroid cancer (PMID: 31162284, 32326537). False +ENST00000166345 NM_004237.3 9319 TRIP13 True TRIP13, an ATP hydrolase involved in meiosis and spindle checkpoint assembly, is recurrently altered by mutation in Wilms tumor and overexpression in a variety of cancer types. TRIP13 (also PCH2) is an ATP hydrolase that is a member of the AAA+ ATPase family (PMID: 24367111, 26832417). TRIP13 is localized to the nucleolus and mediates strand invasion and crossover events that occur during homologous chromosome segregation in meiosis (PMID: 17696610, 20711356). TRIP13 is required for the appropriate distribution of meiotic proteins along chromosomes that mediate a variety of functions including crossover formation, double-strand break (DSB) repair, mitotic checkpoint regulation, synaptonemal complex formation and higher order chromatin regulation (PMID: 19851446, 19851446, 22072981, 25092294, 23382701, 25012665, 26324890). Importantly, TRIP13 regulates the switch of the checkpoint protein MAD2 from an active to inactive conformation (PMID: 25918846, 29208896, 29973720). Loss of TRIP13 results in spermatocyte death and recombination defects in murine models (PMID: 17696610, 20711356, 25768017,10319812, 25768017). In addition, increased expression of TRIP13 in cell lines results in transformation, enhanced error-prone nonhomologous end joining and chemoresistance (PMID: 25078033). Biallelic loss-of-function mutations are found in patients with Wilms tumors (PMID: 28553959). Patient samples with TRIP13 mutations have impaired spindle assembly checkpoint function and chromosomal missegregation (PMID: 28553959). Overexpression of TRIP13 is also found in several tumor types including colorectal, head and neck squamous cancer (PMID: 28105232, 25078033, 28968952, 28424416, 28157697, 29567476). TRIP13 is also included in an amplified region in non-small cell lung cancer, suggesting that TRIP13 may function both as a tumor suppressor and oncogene (PMID: 18328944). True +ENST00000298552 NM_000368.4 7248 TSC1 False 1 TSC1, a tumor suppressor in the mTOR signaling pathway, is inactivated by mutation or deletion in a diverse range of cancers. Germline and somatic TSC1 mutation are a feature of the disease Tuberous sclerosis complex (TSC). TSC1 (also hamartin) is a key negative regulator of the pro-oncogenic mTOR signaling pathway (PMID: 23485365, 20301399, 10205261). The mTOR signaling pathway has a central role in promoting cellular growth and regulating protein synthesis. TSC1 acts as a scaffold to form a heteromeric complex with TBC1D7 and TSC2; the resulting TSC complex functions as a GTPase activating protein (GAP) and inhibits RHEB (PMID: 22795129, 24529379, 24714658), which is a GTPase that functions as a small molecular switch, activating mTORC1 when bound to GTP (PMID: 24863881). Both TSC1 and TSC2 are also phosphorylated by several kinases (e.g., AKT, RSK1, ERK, AMPK, and GSK3) thus providing regulatory inhibition of the mTOR pathway via several different signaling pathways (PMID: 16959574). Germline mutations in TSC1 are associated with tuberous sclerosis, a disorder that results in benign and occasionally malignant tumor growths (PMID: 23485365, 9242607). Somatic TSC1 mutations have been identified in several cancers, including hepatocellular carcinoma, and predominantly present as truncating loss-of-function mutations (PMID: 25526364). TSC1 loss-of-function mutations result in constitutive activation of the mTORC1 complex resulting in sensitivity to mTOR-inhibiting agents (i.e., rapamycin analogs) (PMID: 22923433). True +ENST00000219476 NM_000548.3 7249 TSC2 False 1 TSC2, a tumor suppressor in the mTOR signaling pathway, is inactivated by mutation or deletion in a diverse range of cancers. Germline and somatic TSC2 mutations are a feature of the disease Tuberous sclerosis complex (TSC). TSC2 (also tumerin) is a key negative regulator of the pro-oncogenic mTOR signaling pathway (PMID: 23485365, 20301399, 10205261). The mTOR signaling pathway has a central role in promoting cellular growth and regulating protein synthesis. TSC2 acts as a scaffold to form a heteromeric complex with TBC1D7 and TSC1; the resulting TSC complex functions as a GTPase activating protein (GAP) and inhibits RHEB (PMID: 22795129, 24529379, 24714658), which is a GTPase that functions as a small molecular switch, activating mTORC1 when bound to GTP (PMID: 24863881). Both TSC1 and TSC2 are also phosphorylated by several kinases (e.g., AKT, RSK1, ERK, AMPK, and GSK3) thus providing regulatory inhibition of the mTOR pathway via several different signaling pathways (PMID: 16959574). Both TSC1 and TSC2 are also phosphorylated by several kinases (e.g., AKT, RSK1, ERK, AMPK, and GSK3) thus providing regulatory inhibition of the mTOR pathway via several different signaling pathways (PMID: 16959574). Germline mutations in TSC2 are associated with tuberous sclerosis, a disorder that results in benign and occasionally malignant tumor growths (PMID: 23485365, 9242607). Somatic TSC2 mutations have been identified in several cancers, including liver and endometrial cancers, and predominantly present as truncating loss-of-function mutations (cBioPortal, MSKCC, February 2018). TSC2 loss-of-function mutations result in constitutive activation of the mTORC1 complex resulting in sensitivity to mTOR-inhibiting agents (i.e., rapamycin analogs) (PMID: 22923433). True +ENST00000298171 NM_000369.2 7253 TSHR True TSHR (thyroid stimulating hormone receptor) is mutated in various cancers, including skin cancer. TSHR (thyroid stimulating hormone receptor) is a transmembrane protein that binds thyrotropin and thyrostimulin (PMID: 2556796). TSHR is expressed in the thyroid gland and regulates the growth of thyroid cells and the release of thyroid hormone (PMID:24931193). It belongs to the family of G-protein coupled receptors (PMID: 18719020). Activation of the receptor results higher cAMP levels, increased Protein Kinase A activity and phosphorylation of nuclear transcription factors such as cAMP regulatory element-binding protein (CREB) (PMID:11158328). TSHR may also activate other pathways including the RAS-MAPK, Protein Kinase C, and NFkB pathways (PMID: 11039907, 15062572, 18719020). Germline activating mutations result in hyperthyroidism while loss-of-function mutations lead to hypothyroidism (PMID: 7920658, 23154162, 20926595). Activating mutations are found in thyroid carcinomas (PMID:7478621,26260781). TSHR pathway activation has been found to cooperate with BRAF mutations in thyroid tumor initiation (PMID:21220306). False +ENST00000264818 NM_003331.4 7297 TYK2 True TYK2, a non-receptor kinase, is infrequently altered by mutation and rearrangement in hematopoietic malignancies. TYK2 is a non-receptor tyrosine kinase that is a member of the JAK kinase family (PMID: 17721432, 18682296). TYK2 requires a cognate cytokine receptor to initiate extracellular cytokine signaling cascades, including interferon signaling (PMID: 24654603). Activation of TYK2 leads to the recruitment and phosphorylation of downstream effectors, such as STAT3/5 and MAPK, enabling the translocation of these signaling molecules to the nucleus to activate transcription (PMID: 29162862, 28295194). TYK2 is an important mediator of inflammation and loss of TYK2 in murine models results in reduced cytokine responses (PMID: 11070173). Mutations in TYK2 have been identified in patients with hyper-IgE syndrome (HIES), a malignancy in which patients have increased mycobacterial and viral infections due to impaired cytokine signaling (PMID: 26304966). Fusion proteins containing TYK2 have been identified in patients with hematopoietic malignancies (PMID: 25207766). Germline mutations in TYK2 have been found in acute myeloid leukemia patients; however, somatic TYK2 mutations are relatively rare (PMID: 18270328). While somatic mutations in TYK2 are uncommon, activation of the TYK2/STAT pathway has been found to be oncogenic in many tumor types, including in T-cell acute lymphoblastic leukemia (T-ALL) and breast cancer (PMID: 23471820, 21864028). TYK2 can also mediate drug resistance to the JAK2 inhibitor ruxolitinib via the formation of drug-resistant TYK2/JAK2 heterodimers (PMID: 22820254). False +ENST00000291552 NM_006758.2 7307 U2AF1 True 4 U2AF1, a splicing factor, is recurrently mutated in hematologic malignancies. U2AF1 (U2 small nuclear RNA auxiliary factor 1) is the splicing factor subunit protein, U2AF35, which together with its binding partner, U2AF65, regulates the removal of introns from pre-mRNAs to produce mature mRNAs that will be translated during protein synthesis (PMID:1388271). The U2AF1 protein is essential for constitutive and enhancer-dependent splicing since it recruits the whole U2AF complex to the 3' end of the pre-mRNA intron that will be spliced (PMID: 8647433, 10617206, 10617208). Mutations in the U2AF1 gene have been found recurrently similarly in hematological malignancies such as myelodysplastic syndromes (MDS) (PMID:22389253) and Acute Myeloid Leukemia (AML) (PMID: 22158538) or Chronic Myelomonocytic leukemia (CMML) (PMID: 22323480). Interestingly it has been proposed that mutations in RNA splicing genes are drivers of the transition from MDS to different sort of myeloid leukemias (PMID:24030381). Therefore, the U2AF1 protein has been proposed as a potential therapeutic target (PMID: 21909114, 22158538, 22323480, 25965570, 25326705). Importantly, it has been shown that mutations in the U2AF1 gene happen early in leukemia development as it has been shown in secondary acute myeloid leukemia (s-AML) and can persist during disease progression (PMID:25550361). False +ENST00000308924 NM_007279.2 11338 U2AF2 False U2AF2, an mRNA splicing protein, is altered by mutation in hematopoietic cancers. U2AF2 (also U2AF65) is an RNA binding protein that functions as the large component of the U2 auxiliary factor (U2AF) protein complex (PMID: 1285125, 21753750, 25901584). The U2AF complex is necessary for the binding of U2 small nuclear RNA molecules to the pre-mRNA branch site, which is required for formation of the pre-spliceosome complex and 3’ splice site selection (PMID: 7685763, 9528748). U2AF2 specifically coordinates the annealing of complementary sequences, RNA binding and regulation of RNA helicases to mediate the formation of duplex RNA (PMID: 7685763). U2AF regulates the splicing of many genes at enhancer-dependent introns including WT1 (PMID: 9784496) and FAS (PMID: 16109372), among others (PMID: 11421359). In addition, U2AF2 has a role in the nuclear export of mRNA (PMID: 11724776) and immune regulation (PMID: 29275860). Altered U2AF2 function has been linked to diseases associated with neurodegeneration due to the presence of CAG repeats in mRNA (PMID: 21725067). U2AF2 mediates alternative splicing of CD44 in melanoma, resulting in CD44 alternative isoforms that mediate tumor progression and metastasis (PMID: 27041584). Somatic U2AF2 mutations are found in myeloproliferative neoplasms (MPN), myelodysplastic syndromes (MDS), and acute myeloid leukemia (AML) (PMID: 22389253). U2AF2 alterations reduce the affinity of U2AF2 for the splice acceptor site resulting in mis-spliced mRNA transcripts (PMID: 25311244, 28850223). False +ENST00000335972 NM_003334.3 7317 UBA1 True UBA1, a ubiquitin-like enzyme, is altered by mutation in hematological malignancies. UBA1 encodes for a ubiquitin-like enzyme which functions primarily in the ubiquitin-proteasome system as a catalyst (PMID: 1447181, 24816100). UBA1 catalyzes the first step of three in the E1-E2-E3 enzymatic cascade and adenylates ubiquitin at the C-terminal glycine (PMID: 1447181, 18662542). UBA1 is a required component in ubiquitylation-dependent signaling for DNA repair and recruits TP53BP1 and BRCA1 in response to DNA damage (PMID: 22456334). Mutations in UBA1 are associated with X-linked infantile spinal muscular atrophy and the prototypical hematoinflammatory disease VEXAS syndrome (PMID: 35996994, 35793467). VEXAS syndrome is characterized by vacuoles in myeloid and erythroid precursor cells and predisposes to myelodysplastic syndrome and plasma cell dyscrasias (PMID: 38398362, 37084382). Knockdown of UBA1 in liver cancer, leukemia and myeloma cell lines reduces cellular proliferation, migration and invasion, suggesting that UBA1 functions predominantly as an oncogene (PMID: 20075161, 33344241). UBA1 mutations have been identified in hematological malignancies (PMID: 36823397, 38687605). UBA1 inhibitors have demonstrated sensitivity in preclinical studies and are currently in clinical development (PMID: 19360080, 29884901, 36959858, 30344936, 38091008). False +ENST00000371558 NM_003336 7319 UBE2A True UBE2A, an E2 ubiquitin-conjugating enzyme, is infrequently altered in cancer. UBE2A, a member of the E2 ubiquitin-conjugating enzyme family, functions in the ubiquitin-proteasome pathway of protein degradation (PMID: 26476408). UBE2A accepts ubiquitin from the E1 complex UBE1 via a trans-thioesterification reaction to catalyze association with E3 ligases and ubiquitination of target proteins (PMID: 20061386, 19325620). DNA polymerase cofactor PCNA is a target for UBE2A ubiquitination, activating the protein’s translesion DNA repair following DNA damage (PMID: 36162503, 30531907). UBE2A amplification in cancer cell lines induces chromosomal instability and transformation, suggesting that UBE2A functions primarily as an oncogene (PMID: 11929833). UBE2A overexpression and point mutations have been identified in various cancer types, including ovarian cancer, breast cancer and melanoma (PMID: 26679603, 12640129, 24891954). False +ENST00000520539 NM_015902.5 51366 UBR5 True UBR5, an E3 ubiquitin ligase, is recurrently altered by mutation in mantle cell lymphomas. UBR5 (also EDD, HYD) is an E3 ubiquitin ligase that is a member of the HECT ligase family (PMID: 10030672). E3 ligase proteins define substrate specificity for proteins targeted to the proteasome for degradation. UBR5 appears to target proteins for degradation via the N-end rule for substrates, identifying proteins for degradation based on N-terminal amino acids (PMID: 16055722, 17462990). UBR5 is responsible for the degradation of a variety of substrates including PAIP2, a poly-A tail regulatory binding protein, and TOPBP1, a DNA damage protein (PMID: 16601676, 11714696). UBR5 has also been implicated in the regulation of WNT activity by directly ubiquitinating β-catenin (PMID: 28689657). UBR5 has a number of additional substrates that are involved in translational elongation, telomerase activity, gluconeogenesis, epigenetic regulation and histone degradation after DNA damage (PMID: 21127351, 21726808, 23362280, 27647897, 27647897). In addition, UBR5 is an important regulator of the cell cycle DNA damage checkpoint and loss of UBR5 results in the accumulation of polyploid cells, suggesting a role in genome stability (PMID: 17074762, 18073532, 21383020, 25833949). Overexpression of UBR5 has been identified in patients with breast and ovarian cancer and is associated with poorer patient outcome (PMID: 28330927, 12902990, 18349819). Increased UBR5 expression is linked to metastasis and cisplatin resistance in ovarian and breast cancer cells (PMID: 28330927, 24379240). However, somatic mutations in UBR5 are found in patients with mantle cell lymphomas and are predicted to be loss-of-function (PMID: 23407552). False +ENST00000302904 7343 UBTF True UBTF, an rRNA transcription factor, is recurrently altered in acute myeloid leukemia and other hematologic malignancies. UBTF, upstream binding transcription factor, encodes for a high mobility group (HMG)-box DNA binding protein that is essential in the transcription of ribosomal RNA (rRNA) genes by RNA polymerase I (PMID: 26317157, 34663332, 36448876, 28692053). UBTF mediates the binding of pre-initiation factor SL1-TIF1B (Selectivity Factor 1/Transcription Initiation Factor IB) and the assembly of the pre-initiation complex at the rRNA gene promoter (PMID: 26317157, 34663332). UBTF also plays a role in chromatin remodeling and pre-RNA processing through the formation of a nucleosome-like structure that replaces histone chromatin throughout the transcribed region of rRNA genes, allowing for the regulation of RNA polymerase I transcription (PMID: 26317157, 34663332). In addition, UBTF is indirectly involved in cell growth and proliferation, as ribosome biogenesis is driven by the synthesis of rRNA by RNA polymerase I (PMID: 26317157, 21151873). UBTF promotes cellular proliferation in colorectal cancer and osteosarcoma by facilitating ribosomal DNA transcription (PMID: 28692053, 21151873). Loss of UBTF in fibroblasts and lymphoma cells has been shown to suppress cellular proliferation and DNA replication, resulting in cell cycle arrest (PMID: 26317157, 30701204). Overexpression of UBTF in melanoma cells promotes cell growth, while knockdown of UBTF suppresses cell growth and promotes apoptosis, supporting its role as an oncogene (PMID: 34663332). UBTF-ITD (internal tandem duplications) in exon 13 of the UBTF gene have been described as a recurrent alteration and poor prognostic factor in pediatric patients with acute myeloid leukemia (AML) (PMID: 36448876, 37085611, 35176137, 37236968). False +ENST00000284440 NM_004181 7345 UCHL1 True UCHL1, a deubiquitinating enzyme, is infrequently altered in cancer. UCHL1 encodes for ubiquitin C-terminal hydrolase L1, a deubiquitinating enzyme that has dual effects on the regulation of protein degradation. This protein can stabilize other proteins by removing ubiquitin or add ubiquitin to proteins to mark them for degradation (PMID: 38244540). UCHL1 can enhance or inhibit multiple ubiquitin-dependent biological processes in normal cells (PMID: 37032833, 38244540). UCHL1 expression is highest in the nervous system. In the brain, UCHL1 maintains normal neuronal activity by removing abnormal proteins via interactions with components of the autophagy machinery and the ubiquitin-proteasome system (PMID: 36218038). In cancer cells, overexpression of UCHL1 activates the MAPK/ERK and AKT signaling pathways enhancing tumor invasion, metastasis and drug resistance, suggesting its role as a potential oncogene (PMID: 26293643, 18820707). UCHL1 overexpression in mice results in spontaneous development of lymphomas and lung tumors (PMID: 20574456, 31497243). Additionally, knockdown of UCHL1 in breast cancer cells, lung adenocarcinoma cells, and high-grade glioma cells demonstrates decreased cell proliferation and invasiveness, further supporting its role as an oncogene (PMID: 23664488, 28472177, 31497243). UCHL1 overexpression has been found in many cancers including brain, lung, breast, colorectal, kidney, pancreas, prostate and bladder cancers, non-small cell lung cancer, lymphomas, and neuroendocrine carcinomas (PMID: 36218038, 37815895, 28472177, 38244540). However, UCHL1 promoter hypermethylation has been reported in multiple cancer types, including esophageal, gastric, renal, prostate, head and neck squamous cell carcinoma, hepatocellular, ovarian, and colorectal cancers, which may indicate a dual role in tumor suppression (PMID: 20395212, 26293643, 20574456). False +ENST00000262803 NM_002911.3 5976 UPF1 False UPF1, involved in mRNA surveillance, is rarely mutated in cancers. UPF1 is an RNA helicase involved in mRNA surveillance. UPF1 is essential for nonsense-mediated mRNA decay, which is a pathway that degrades aberrant mRNA transcripts (PMID: 11163187, 16086026, 21145460, 21419344). Following recruitment of UPF1 to target mRNA substrates, UPF1 scans the mRNA transcript, remodels the messenger ribonucleoprotein complex, and regulates the degradation of target transcripts (PMID: 21145460). Disruption of UPF1 function results in decreased nonsense-mediated mRNA decay and contributes to epithelial-mesenchymal transition (PMID: 28663146). Somatic mutations in the UPF1 gene have been identified in pancreatic adenosquamous carcinoma (PMID: 24859531) and decreased levels of UPF1 in lung adenocarcinoma has been associated with tumor progression (PMID: 28663146). UPF1 function is associated with prostate cancer metastasis (PMID: 23881279) and with SMAD7-mediated tumorigenesis in hepatocellular carcinoma (PMID: 26759305). False +ENST00000339950 NM_003368.4 7398 USP1 True USP1, a protein deubiquitinase, is overexpressed in various cancers. USP1 is a protein deubiquitinase that regulates DNA repair, most notably in the Fanconi anemia pathway (PMID: 18082604, 16531995). In conjunction with its cofactor UAF1, USP1 deubiquitinates the FANCD2-FANCI homodimer, which disrupts the recruitment of DNA repair proteins to sites of interstrand crosslinking (PMID: 18082604, 15694335). Similarly, USP1 deubiquitinates PCNA, which prevents the recruitment of translesion synthesis polymerases to sites of DNA damage and halts DNA repair (PMID: 16531995). In osteosarcoma cells, USP1 is implicated in maintaining stemness and reducing differentiation by deubiquitinating and stabilizing ID1, ID2 and ID3, which are normally expressed during the development of undifferentiated and proliferating cells (PMID: 22387046, 21925315). Inhibition of USP1 in mouse models increases the sensitivity of B-cell lymphoma and ovarian cancer cells to chemotherapy and enhances the sensitivity of colorectal cancer and renal cell carcinoma cells to chemotherapy in vitro (PMID: 36352191, 31086816, 31921663, 36153316). There are preclinical and early clinical studies examining the efficacy of USP1 inhibition in various malignancies (Abstract: Yap et al. Abstract# 3005, ASCO 2024. https://ascopubs.org/doi/10.1200/JCO.2024.42.16_suppl.3005) (PMID: 36228090, 30531833). False +ENST00000250066 NM_004505 9098 USP6 True USP6, a deubiquitinase, is altered by chromosomal translocation in various neoplasms. USP6, a member of the ubiquitin-specific peptidases and deubiquitinases families, encodes for deubiquitinase that functions in regulating various cellular functions such as intracellular trafficking, inflammatory signaling, cell transformation and protein turnover (PMID: 12604796, 29061731, 27162353). USP6 is a hominoid-specific gene predominantly expressed in the testes (PMID: 12604796). Overexpression of USP6 in various cancer cell lines and models induces tumorigenesis, epithelial-to-mesenchymal transition and increased pathway activation, suggesting that USP6 functions predominantly as an oncogene (PMID: 15026324, 20418905, 27162353, 22081069, 35926707). USP6 chromosomal rearrangements have been identified in various neoplasms, collectively known as USP6-associated neoplasms (PMID: 36727055, 36404122, 32583473, 33558945). False +ENST00000307179 NM_001128610.2 9101 USP8 True USP8, a ubiquitin hydrolase involved in protein stabilization, is altered by mutation in Cushing's disease and by overexpression in various cancer types. USP8 (also UBPY) is a ubiquitin isopeptidase that is a member of the UBP hydrolase family (PMID: 9628861). Ubiquitin hydrolases deubiquitinate target proteins, protecting them from degradation via the proteasome or lysosome (PMID: 16120644). USP8 mediates the stabilization of numerous proteins, including growth factor receptors such as EGFR (PMID: 16120644, 25675982, 30221684, 29933386, 29626091). Because USP8 is important in the regulation of a variety of proteins, USP8 activity mediates various cellular processes including cellular proliferation, apoptosis, DNA repair, and ciliogenesis, among others (PMID: 29472535, 27321185, 26683461). USP8 phosphorylation recruits the adaptor molecule 14-3-3, leading to inactivation of USP8 catalytic activity (PMID: 17720156, 20736164, 29473952). Stabilization of USP8 results in the inability of target substrates to be appropriately targeted for degradation (PMID: 25675982). Recurrent gain-of-function mutations in USP8 are found in patients with Cushing's disease, a disorder that results in the overproduction of cortisol and development of associated tumors that localize to the pituitary gland (PMID: 25675982, 28505279, 28982703, 30315484). USP8 mutations that are associated with Cushing's disease commonly occur in the 14-3-3 binding region, resulting in uncontrolled activation of USP8 (PMID: 25675982). Altered USP8 expression results in the increased expression of proopiomelanocortin (POMC), the precursor of adrenocorticotropic hormone (ACTH), which is overproduced in Cushing’s disease (PMID: 25675982). Overexpression of USP8 has been identified in several cancer types (PMID: 29880877, 23748694). False +ENST00000602142 NM_005428.3 7409 VAV1 True VAV1, a guanine nucleotide exchange factor involved in hematopoiesis, is recurrently altered by mutation and rearrangement in hematologic malignancies and solid tumors. VAV1 is a guanine nucleotide exchange factor (GEF) that is a member of the VAV family of proteins (PMID: 26353933). GEFs are proteins that regulate the activity of monomeric GTPases by coordinating the binding of GTP and the release of GDP (PMID: 26353933). VAV1 is expressed predominantly in the hematopoietic system and has selective substrate specificity for the GTPase Rac (PMID: 11781818). The activity of VAV1 is regulated by tyrosine phosphorylation (PMID: 11781818) via several tyrosine kinases dependent on cellular context including TCR (T cell receptor), BCR (B cell receptor), and chemokine receptors (PMID: 1531699, 1375396, 10092764, 15872091). VAV1 signaling is required for appropriate lineage commitment and differentiation in a variety of hematopoietic cell types (PMID: 26353933). VAV1 has been implicated in a variety of cellular functions including T cell function, actin cytoskeleton reorganization, MAPK signaling and transcriptional regulation (PMID: 15886116, 10669724). In a hematopoietic screen, VAV1 was determined to have activity as a proto-oncogene (PMID: 2477241), but can also have tumor suppressive activity in functional studies (PMID: 23342133, 30297765, 26353933). Somatic mutations in VAV1 are found in T-cell leukemias/lymphomas and lung adenocarcinomas, among others (PMID: 26437031, 27369867, 28062691, 27158780, 25426554) and are predicted to be gain-of-function. Fusion proteins containing VAV1 have also been identified in peripheral T-cell lymphomas and other hematopoietic malignancies (PMID: 28062691, 28832024). Overexpression of VAV1 is found across a range of solid tumors, suggesting VAV1 predominantly functions as an oncogene in this context (PMID: 19533802, 23342133, 15652748). False +ENST00000371850 NM_001134398.1 7410 VAV2 True VAV2, a guanine nucleotide exchange factor involved in hematopoiesis, is infrequently altered in a range of cancer types. VAV2 is a guanine nucleotide exchange factor (GEF) that is a member of the VAV family of proteins (PMID: 26353933). GEFs are proteins that regulate the activity of monomeric GTPases by coordinating the binding of GTP and the release of GDP (PMID: 26353933). VAV2 is ubiquitously expressed across many cell types and has selective substrate specificity for the GTPase RAC (PMID: 17996485). The activity of VAV2 is regulated by phosphorylation (PMID: 11781818) via several tyrosine kinases dependent on cellular context including BCR (B cell receptor) and chemokine receptors (PMID: 11376343, 14623913). VAV2 signaling is required for appropriate lineage commitment and differentiation in a variety of hematopoietic cell types, with some redundant and non-redundant roles with family members VAV1 and VAV3 (PMID: 14623913, 15941910). In transformation assays, VAV2 was implicated as an oncogene and mediates cell proliferation and foci formation (PMID: 8710375). Overexpression of VAV2 is implicated in a variety of cancer types including breast cancer and head and neck squamous cell carcinomas (HNSCC) (PMID: 26910843, 17234718, 23033540). Somatic mutations in VAV2 are rare; however, VAV2 coordinates cellular proliferation and invasion in various cancer models via an EGFR/RAC1 signaling pathway (PMID: 20940296). False +ENST00000523873 NM_001171623.1 7422 VEGFA True VEGFA encodes a homodimeric glycoprotein that can be an essential component of tumor initiation and the primary stimulus for angiogenesis. VEGFA is commonly over-expressed in many solid tumors. VEGFA (also VEGF) is a growth factor that is a member of the family of vascular endothelial growth factors (VEGFs) and platelet-derived growth factors (PDGFs). VEGFA binds the receptor tyrosine kinases VEGFR1 and VEGFR2 to mediate downstream signaling, with almost all of the known cellular responses mediated by VEGFR2 (PMID: 16951216). Other types of receptors contribute to VEGFA signaling, including platelet-derived growth factor receptors (PMID: 17470632) and neuropilins (PMID: 22948112, 23116416). Expression of VEGFA is critical for mediating angiogenesis and vascular permeability, stimulating the migration and proliferation of vascular endothelial cells (PMID: 24263190). Autocrine VEGF signaling contributes to angiogenesis and cell proliferation (PMID: 22693250) and has been shown to promote the function of cancer stem cells (PMID: 22012397, 20141840). Paracrine VEGFA signaling also impacts the function of nearby immune cells (PMID: 23045606) and fibroblasts (PMID: 22738912, 21057529). Overexpression of VEGFA has been associated with the familial disorder Crow-Fulcase syndrome that is characterized by reduced vasopermeability (PMID: 9771661). VEGFA predominantly functions as an oncogene in human cancers and is commonly overexpressed in many solid tumor types, likely mediating enhanced tumor angiogenesis (PMID: 24263190). The VEGFA inhibitors bevacizumab (PMID: 17212999) and aflibercept (PMID: 22446028) are FDA-approved for the treatment of metastatic colorectal cancer and glioblastoma. False +ENST00000256474 NM_000551.3 7428 VHL False VHL is a tumor suppressor involved in protein degradation. Germline mutations of VHL are associated with Von Hippel-Lindau syndrome and predispose to renal cell carcinoma. VHL is an E3 ligase that functions predominantly as a tumor suppressor gene (PMID: 10102622, 9671762). The VHL protein forms a ternary complex with transcription elongation factors B and C, which is critical for the stabilization and activity of VHL (PMID: 25533676). VHL mutations that disrupt this complex lead to an unstable VHL protein that is aberrantly degraded (PMID: 7660130, 7660122). Under normal oxygen conditions, VHL plays a crucial role in the regulation of the hypoxia-inducible transcription factors (HIFs); VHL binds HIF proteins and targets them for ubiquitination and degradation via the proteasome (PMID: 10878807). HIFs are responsible for the transcription of numerous genes in response to hypoxic conditions, including pro-angiogenic factors such as vascular endothelial growth factor (VEGF) (PMID: 25533676). Loss of VHL leads to activation of HIF downstream target genes and can promote tumorigenesis in normoxic conditions (PMID: 21386872). VHL loss can cause hereditary and sporadic forms of von Hippel-Lindau disease, which is associated with hemangioblastomas, renal cysts, renal cell carcinoma, pheochromocytomas, paragangliomas, pancreatic cysts, neuroendocrine tumors and endolymphatic sac tumors (PMID: 25533676, 35579632, 35709961). Somatic functional inactivation of VHL has been reported through biallelic loss of the VHL gene in cases of 3p deletion (PMID: 2885753), heterozygous VHL mutations (PMID: 7915601, 21715564) or promoter methylation (PMID: 7937876) in human cancers. Inhibitors that target VEGF receptors and HIF proteins may have therapeutic efficacy in tumors with VHL loss (PMID: 25533676). True +ENST00000369458 NM_024626.3 79679 VTCN1 False VTCN1 encodes B7-H4, a T-cell regulator of the immunoglobulin superfamily. B7-H4 is highly expressed in various human tumors. VTCN1 encodes the V-set domain containing T cell activation inhibitor 1, also known as B7-H4 and plays critical roles in regulating T cell-mediated immune response through inhibiting T cell proliferation, cytokine secretion, and the development of cytotoxicity (PMID: 19641607, 12818166, 14568939). B7-H4 is highly expressed in various human tumors, including breast (PMID: 15756008, 15878339), ovarian (PMID: 19955922), lung (PMID: 16782226, 23874109), pancreatic (PMID: 25170273), gastric (PMID: 20872810, 21748517) and urothelial cell carcinoma (PMID: 25400757, 25364421). Soluble B7-H4 (sB7-H4) has been detected in blood samples from various cancer patients, including ovarian (PMID: 16452214, 17490732), gastric (PMID: 24947047), lung (PMID: 25636447), renal cell carcinoma (PMID: 18676826), bladder urothelial carcinoma (PMID: 25364421), hepatocellular carcinoma (PMID:25963168) and high levels of sB7-H4 were a significant prognostic indicator. Moreover, the VTCN1 genetic variants rs10754339, rs10801935, and rs3738414 indicate they could be connected with the risk of breast cancer (PMID: 25385143). False +ENST00000286574 NM_007191.4 11197 WIF1 False WIF1, a negative regulator of WNT signaling, is altered by mutation and rearrangement in various cancer types. WIF1 is an extracellular lipid-binding protein that functions as a WNT antagonist (PMID: 10201374, 24316024, 23258168). WIF1 functions as a negative regulator of the WNT signaling pathway by binding to WNT or Frizzled (Fz) receptors and precluding WNT-mediated activation of downstream signaling (PMID: 24316024, 23258168). WNT signaling is a critical developmental pathway with roles in determining cell fate, tissue identity and polarity (PMID: 28218291). WIF1-mediated antagonism of WNT results in the activation of the β-catenin destruction complex (containing APC, GSK3β and AXIN), which targets β-catenin for degradation (PMID: 23258168). In the absence of WNT signaling, TCF and LEF transcription factors form a repressive complex, leading to inhibition of β-catenin target genes (PMID: 24316024, 23258168). In addition to roles in antagonizing WNT, WIF1 has roles in mesodermal specification, cellular senescence, tissue homeostasis and proliferation (PMID: 24853424, 10201374, 30574494). Germline mutations in WIF1 have been found in families with a predisposition to cancer, as well as in patients with Nail-Patella syndrome (PMID: 25716654, 28383544). Somatic mutations in WIF1 are not well studied in human cancers; however, rare alterations are found in patients with diffuse large B-cell lymphomas (PMID: 23292937). Epigenetic silencing of WIF1 transcription and WIF1 overexpression have both been implicated in distinct cancer types, suggesting that WIF1 may function as a tumor suppressor or oncogene in different cellular contexts (PMID: 20596629, 26291085, 25432628, 15579438). Fusion proteins involving WIF1 are also found in adenomyoepitheliomas, a rare breast cancer, and in salivary gland tumors (PMID: 30675516, 17171686, 18828159). True +ENST00000298139 NM_000553 7486 WRN False WRN, a DNA helicase, is altered by mutation in various cancer types. WRN, a member of the RecQ helicase family, encodes for an ATP-dependent DNA helicase that functions in supporting genome stability through DNA repair, replication, transcription and telomere maintenance (PMID: 16264192, 17284601, 9774636, 36583333). WRN unwinds DNA strands to target abnormalities. Additionally, WRN functions as a 3’ to 5’ exonuclease for double-stranded DNA and plays a role in DNA end processing (PMID: 9771700, 10954593, 16622405). Germline mutations of WRN are associated with the autosomal recessive disorder Werner syndrome, which is characterized by a predisposition to cancer and accelerated aging (PMID: 20443122). Loss of WRN function in various microsatellite instability-high cancer cell lines and models induces accumulation of DNA damage and increased tumor mutational burden, suggesting that WRN functions predominantly as a tumor suppressor gene (PMID: 37662356, 32455893). Loss of function WRN mutations have been identified in various cancers, including colorectal cancer and soft-tissue sarcomas (PMID: 32455893, 8722214). True +ENST00000332351 NM_024426.4 7490 WT1 True WT1, a transcription factor, is overexpressed in various cancer types including leukemias. WT1 (Wilms tumor 1 gene) is a transcription factor expressed in a tissue-specific manner throughout development (PMID: 20013787, 17524167, 17361230, 12835718). WT1 has been implicated in the protein stabilization of TP53 and regulates the expression of several target genes include MYC and BCL2, which are important for cellular growth and metabolism (PMID: 7585606, 8389468). In hematopoietic cells, WT1 interacts with the epigenetic proteins TET2 and TET3 that regulate hydroxymethylation of DNA, an epigenetic modification of DNA that may also serve as a methylation state intermediate (PMID: 25482556). Loss of WT1 expression results in depletion of global 5-hydroxymethylation levels (PMID: 25482556), implicating WT1 in the regulation of DNA methylation. WT1 was initially discovered as a tumor suppressor in Wilms’ tumor (PMID: 2163761, 9090524); however, WT1 loss only contributes to the pathogenesis of a fraction of Wilms' tumors (PMID: 16110318). Somatic WT1 mutations have been identified in patients with acute myeloid leukemia (AML) and are predicted to be loss-of-function, leading to decreased DNA binding activity (PMID: 25482556). Importantly, TET and IDH family mutations are mutually exclusive with WT1 mutations in AML patients, suggesting that WT1 functions as a regulator of DNA methylation (PMID: 25482556). Patients with WT1 mutations may be increasingly sensitive to hypomethylating agents, such as azacytidine, due to the role of WT1 in the regulation of methylation (PMID: 27252512). WT1 is overexpressed in a large percentage of patients with myeloid and lymphoid leukemias (PMID: 27252512, 16461320, 15084694). Vaccines that target overexpression of WT1 are currently in clinical development (PMID: 23486779, 26389576). True +ENST00000265428 NM_007013.3 11059 WWP1 True WWP1, an E3 ubiquitin ligase, is infrequently altered by amplification in prostate and breast cancers. WWP1 (WW domain-containing E3 ubiquitin protein ligase 1) is an E3 ubiquitin ligase that regulates diverse processes in the cell, including protein trafficking and signaling (PMID: 22051607). WWP1 is responsible for mediating the polyubiquitination of PTEN. When polyubiquitinated, PTEN is prevented from dimerizing, localizing to the membrane and functioning as a tumor suppressor (PMID: 31097636). Thus, WWP1 is responsible for PTEN inactivation. WWP1 is also involved in TGF-beta signaling by regulating the degradation of Smad2 (PMID: 15221015). WWP1 knockout in cell lines leads to decreased colony formation and increased apoptosis compared to wildtype, while xenograft tumors carrying WWP1 mutations exhibit increased growth rate compared to wildtype (PMID: 31097636, 32459922). WWP1 is amplified and/or overexpressed in breast, prostate and gastric cancers, among others (PMID: 17330240, 17016436, 25293520). Germline WWP1 variants are enriched in patients with Cowden syndrome and patients with PTEN-related cancers including colorectal adenocarcinoma and thyroid cancer (PMID: 32459922). False +ENST00000360632 NM_001168280.1 25937 WWTR1 True WWTR1, a transcriptional coactivator, is altered by amplification in various cancers. The WWTR1 gene encodes the WWTR1/TAZ protein, a transcriptional coactivator involved in the Hippo signaling pathway (PMID: 26045258, 25266986). TAZ, which shares homology and function with the Yes-associated protein (YAP), is able to translocate to the nucleus and interact with TEAD1-4 to activate a transcriptional program that promotes cell proliferation and epithelial to mesenchymal transition (EMT) (PMID: 11118213, 18227151, 19324877). The Hippo signaling pathway negatively regulates TAZ function via LATS1/2 phosphorylation, which prevents TAZ nuclear translocation (PMID: 18227151). WWTR1/TAZ is considered a novel oncogene in breast and lung cancer (PMID: 18413727, 21258416). WWTR1 is amplified in several tumors, such as lung, ovarian and head and neck cancer (cBioPortal, MSKCC, Nov 2016). Cancers with defective Hippo signaling pathway and subsequent TAZ activation are good candidates for novel small-molecule Hippo modulator drugs (PMID: 27262779, 24336504). False +ENST00000216037 NM_005080.3 7494 XBP1 True XBP1, a transcription factor involved in the unfolded protein response, is infrequently altered in a range of human cancers. XBP1 is a transcription factor that is an important regulator of the unfolded protein response (UPR) (PMID: 28741511). XBP1 undergoes unconventional splicing after the accumulation of unfolded or misfolded proteins in the endoplasmic reticulum (ER) resulting in the activation of UPR (PMID: 28741511). The function of the UPR is to stop protein translation, degrade abnormal proteins, and increase chaperone production in response to ER stress; otherwise, the cell is targeted for apoptosis (PMID: 21061914). The transmembrane protein IRE1α coordinates the splicing of XBP1 upon ER stress, resulting in a newly spliced transcript that contains a transactivation domain, which is critical for mediating UPR transcriptional activity in the nucleus (PMID: 28741511, 19609461). XBP1 has been implicated in a variety of cellular functions including adaptive immunity, innate immunity, glycolysis, gluconeogenesis, DNA repair, lipid metabolism, cellular differentiation, and DNA replication, among others (PMID: 17612490, 21061914, 12612580). Variants in XBP1 have been linked to inflammatory bowel syndrome and Crohn’s disease (PMID: 18775308). Overexpression of XBP1 expression has been found in leukemias and breast cancers (PMID: 16491124, 19470730, 20028872). Increased XBP1 activity is important for the growth of tumor cells in hypoxic conditions (PMID: 15342372) and can mediate drug resistance (PMID: 17660348). Somatic mutations in XBP1 are found in patients with follicular lymphoma (PMID: 27959929), however, these alterations have not been functionally characterized. False +ENST00000355640 NM_001167.3 331 XIAP True XIAP encodes a protein that is involved in inhibiting cell death (apoptosis). Germline mutations and overexpression of XIAP are associated with X-linked lymphoproliferative syndrome and resistance to various cancer treatments. XIAP encodes for the gene X-linked inhibitor of apoptosis, an anti-apoptotic protein belonging to the family of baculovirus IAP domain repeat-containing proteins (PMID:25065885). The IAP domain mediates anti-apoptotic activity by binding and inhibiting caspases and is blocked by SMAC protein binding (PMID:9230442, 11242052). XIAP also contains a RING domain that mediates ubiquitination through E3 ligase activity (PMID:15803136, 18708583). It regulates Tumor necrosis factor (TNF) response, MAPK signaling, copper metabolism, and cellular differentiation (PMID: 24975362, 24497535, 20154138, 19011619, 23928917). In cancer, XIAP can mediate resistance to therapy (PMID:23727860, 22491673, 11280739, 12384799). Gerrmline mutations are associated with X-linked lymphoproliferative syndrome characterized by lymphohystiocytosis, hypogammaglobulinaemia, lymphomas, and immune disorders (PMID: 17080092, 23973892). Inhibitors of XIAP are in development for cancer therapy by inducing an apoptosis response (PMID: 15353805, 14749124). False +ENST00000375128 NM_000380 7507 XPA False XPA, a DNA damage repair factor involved in the nucleotide excision repair (NER) pathway, is infrequently altered in cancer. XPA encodes for a zinc finger protein that functions primarily in the nucleotide excision repair (NER) pathway as a scaffolding protein (PMID: 12897146, 25056193). XPA coordinates the assembly of other NER repair factors, such as RPA and the ERCC1-XPF endonuclease, around the site of DNA damage to prepare for lesion excision (PMID: 21148310, 7697716). Germline mutations of XPA are associated with the autosomal recessive disease xeroderma pigmentosum, resulting in a decreased ability to repair DNA damage caused by ultraviolet (UV) rays (PMID: 24135642, 8814338, 20574439). Loss of XPA in various cancer cell lines and models induces increased UV-induced mutations and disruption to DNA repair pathways, suggesting that XPA functions predominantly as a tumor suppressor gene (PMID: 11376684, 38664429, 32170071). Downregulation of XPA has been identified in bladder cancer (PMID: 28222669). True +ENST00000285021 NM_004628 7508 XPC False XPC, a DNA damage repair factor involved in the nucleotide excision repair (NER) pathway, is frequently altered by mutation or deletion in squamous cell carcinoma. Germline mutations of XPC are associated with xeroderma pigmentosum and predispose to skin cancers. XPC encodes for a DNA damage repair factor which functions as a DNA binding component of the XPC-RAD23B complex (PMID: 10873465, 20028083, 20798892). The XPC-RAD23B complex is a part of the nucleotide excision repair mechanism and recognizes DNA lesions to initiate DNA repair (PMID: 33035795, 31372632). Germline mutations of XPC are associated with the autosomal recessive disease xeroderma pigmentosum, resulting in a decreased ability to repair DNA damage caused by ultraviolet rays (PMID: 27413738). Knockdown of XPC in various cancer cell lines and models induces tumor formation, oxidative DNA damage and cellular proliferation and migration, suggesting that XPC functions predominantly as a tumor suppressor gene (PMID: 21763452, 9540983, 25871391). Downregulation of XPC has been identified in various types of cancers, including squamous cell carcinoma and melanoma (PMID: 20616346, 17575131). True +ENST00000401558 NM_003400.3 7514 XPO1 True XPO1, a nuclear export protein, is altered by mutation in some leukemias and lymphomas. The XPO1 (Exportin 1) encodes a protein that mediates nuclear export of proteins and RNA (PMID: 9323132, 10786834). XPO1 recognizes proteins containing a nuclear export signal (NES) and leads to their export from the nucleus to the cytoplasm. XPO1 has been reported to be involved in ribosome biogenesis by exporting the 60S ribosome subunit through binding to NMD3 (PMID: 26048327, 12724356). In the context of cancer, XPO1 has oncogenic properties. This has been mostly attributed to the fact that proteins exported by XPO1 include important tumor suppressors (eg. APC, TP53, SMARCB1 etc.)(PMID: 12070164, 11782423, 17891139, 20803015). High nuclear XPO1 expression is associated with adverse prognosis in various tumor entities (PMID: 18306389, 19082467, 20003838) and XPO1 mutations have been reported in some cases of chronic lymphatic leukemia (CLL) as well as diffuse large B-cell lymphoma (DLBCL) (PMID: 21642962, 26608593). XPO1 translocations have been reported in T-ALL (PMID: 25377562). Small molecule inhibitors of nuclear export (SINEs) have been developed and tested in preclinical studies in various tumor types and show promising therapeutic efficacy (PMID: 23034282, 23373539, 23970380, 25057921, 24431073, 23588715, 25366336). False +ENST00000262887 NM_006297 7515 XRCC1 False XRCC1, a scaffold protein, is infrequently altered in cancer. XRCC1, X-ray repair cross complementing 1, encodes a scaffold protein that is involved in maintaining genomic stability through the repair of both damaged nucleotide bases and single-stranded breaks in DNA (PMID: 16550161, 31324530). The protein participates in the base excision repair pathway through interactions with DNA ligase III, DNA polymerase beta, and poly (ADP-ribose) polymerase (PARP) (PMID: 31324530, 35055077, 36573562). XRCC1 has essential roles in microhomology-mediated end joining (MMEJ) repair of double-strand breaks and replication fork restart in the absence of BRCA2 (PMID: 31324530, 35055077). Mutations in the gene have been associated with neurological disorders and cancer predisposition as a result of unrepaired DNA damage (PMID: 35055077). The risk of various cancers, including breast and head and neck squamous cell carcinoma, have been associated with polymorphisms in this gene (PMID: 32562117, 36573562). True +ENST00000359321 NM_005431.1 7516 XRCC2 False XRCC2 encodes a protein involved in DNA double-strand break repair. Germline mutations of XRCC2 are associated with an increased risk developing of breast cancer. XRCC2 is a member of the RAD51 recombinase family that functions in homologous recombination (HR)-mediated repair of double-stranded DNA breaks (DSBs). RAD51 acts at an early step in the DSB pathway: the 5’ended DNA strands flanking the DSB break site are resected and the single-stranded overhangs are coated by RAD51 forming a nucleo-protein filament (PMID: 25833843). XRCC2 is a member of the BCDX2 complex that includes the RAD51 paralogs RAD51B, RAD51C, and RAD51D. The BCDX2 complex stabilizes the sites of damaged DNA and recruits RAD51 to initiate strand repair by homologous recombination (PMID: 9126486,10517641). Knockdown of XRCC2 activity in cell line and murine models results in a 100-fold decrease in DSB repair function through defective homologous recombination repair (PMID: 10517641, 14678973, 14645207, 24627042). There is conflicting data on whether germline variants of XRCC2 increase the risk of breast cancer (PMID: 22464251, 23054243,12023982,17141189) and XRCC2 is infrequently mutated in human cancers. True +ENST00000282441 NM_001130145.2 10413 YAP1 True YAP1 is a transcriptional co-activator and downstream effector of the Hippo pathway. High expression of YAP due to gene amplification or epigenetic activation is found in a diverse range of human cancers. YAP1 is a transcriptional co-activator and downstream effector of the Hippo pathway. The Hippo pathway is involved in several processes of cancer progression and physiologically has important regulatory functions in organ development and regeneration (PMID: 23467301, 24825474, 24336504). YAP1 largely mediates the downstream transcriptional effects of Hippo signaling (PMID: 20951342) by shuttling between the cytoplasm and the nucleus. In the nucleus, YAP1 induces expression of proliferative and anti-apoptotic genes via interactions with transcription factors, namely TEAD family members (PMID: 20951342). Hyperactivation of YAP1 leads to contact-inhibition, epithelial-mesenchymal transition, metastatic potential and stem cell defects (PMID: 17974916, 24336504, 25702974). Germline mutations in YAP1 have been identified in patients with coloboma, a familial disorder resulting in ocular defects (PMID: 24462371). Overexpression of YAP1 is widespread in human cancer; however, somatic mutations are rare (PMID: 25592648, 24336504). Reports of YAP1 gene amplification and epigenetic activation in cancer support the role of YAP1 as a classic oncogene (PMID: 25592648, 24336504). YAP1 fusions have also been identified in ependymomas (PMID: 29258295). Although YAP1 behaves as an oncogene in most cancers, data suggest that YAP1 can also act as a tumor suppressor in certain cellular contexts (PMID: 24976009, 22234184). Overexpression of YAP1 has been associated with resistance to MEK and BRAF inhibitors (PMID: 25665005). Verteporfin, a small molecule inhibitor that targets the YAP1-TEAD interaction, has demonstrated efficacy in preclinical models of YAP1 overexpression and is synthetic lethal with MEK and BRAF inhibition (PMID: 29299145). False +ENST00000314574 NM_005433.3 7525 YES1 True YES1 encodes a tyrosine kinase involved in regulation of cell growth and survival, apoptosis, cell-cell adhesion, cytoskeleton remodeling and differentiation. Overexpression of YES1 is found in colorectal, hepatocellular, breast and esophageal cancers and melanomas. YES1 is a non-receptor SRC protein tyrosine kinase that is activated by growth-factor binding to receptor tyrosine kinases, including PDGFR, EGFR and VEGFR (PMID: 8356071, 12496267, 16400523). Following activation, YES1 phosphorylates various substrates, including CDK4 and PAR3 to control cell cycle progression and regulate cell-cell adhesion (PMID: 18479465, 17053785). Additionally, YES1 stimulates chemokine-directed T-cell migration by phosphorylating collapsin response mediator protein 2 (CRMP2), promotes cell migration through activation of the PI3K/AKT signaling pathway and induces apoptosis in hepatocytes through its participation in the CD95L signaling pathway (PMID: 19276087, 21713032, 15917250). YES1 plays a central role in malignant mesothelioma cell growth (PMID: 22948717) and has been shown to act as an oncogene in several tumor models through increased expression and kinase activity (PMID: 7690925, 9816313, 17007035, 7690926). YES1 is amplified in basal-like breast cancer and esophageal squamous carcinoma (PMID: 21779430, 11756219) and has been implicated in resistance to trastuzumab and lapatinib in HER2-positive breast cancer (PMID: 28158234). In colorectal carcinoma, increased YES1 activation correlates with poor prognosis, as YES1 activity is elevated in adenomas with the highest risk (PMID: 7806032). However, somatic YES1 mutations are rare in human cancers. False +ENST00000262238 NM_003403.4 7528 YY1 True YY1, a transcription factor, is rarely altered by chromosomal alteration in mesothelioma. YY1 is a ubiquitously expressed zinc-finger transcription factor of the Polycomb Group family. The protein contains a DNA binding domain as well as two distinct domains involved in transcriptional activation and repression (PMID: 16314846) of multiple cellular pathways. YY1 has been shown to be a SMAD-interacting protein, involved in the regulation of TGFβ and BMP-induced cell differentiation (PMID:12808092) as well as DNA repair (PMID: 11394900). Additionally, YY1 has been suggested to play roles in the regulation of the cell cycle through interaction with cyclins and p53, apoptosis through interactions with NFkB and Fas, and inflammatory response through IFN-γ (PMID: 16314846). Mouse studies have confirmed the importance of YY1 activity in later stages of mouse embryogenesis (PMID: 10490658). False +ENST00000474710 NM_001164342.2 26137 ZBTB20 True ZBTB20, a transcription factor involved in immune regulation and pituitary function, is altered by overexpression in various cancer types. Germline mutations in ZBTB20 are found in patients with Primrose syndrome and other neurodevelopmental disorders. ZBTB20 is a transcription factor that is a member of the BTB/POZ family of DNA binding proteins. ZBTB20 is most highly expressed during hippocampus development and in mature endocrine cells (PMID: 26782407, 27079169). Deletion of ZBTB20 in mice results in decreased secretion of pituitary growth hormones, such as prolactin (PRL), and loss of mature lactotrope cells in the anterior pituitary (PMID: 26782407, 27079169). ZBTB20 directly binds the promoter of PRL and activates transcription (PMID: 27079169) and PRL overexpression has been implicated in ZBTB20-dependent models of autoimmune encephalomyelitis (PMID: 31570595). Expression of ZBTB20 is important in immune regulation in B cells, including in plasma cell differentiation and longevity (PMID: 29616049, 24711583, 23776228). The deletion of ZBTB20 in murine models can result in long-term antibody defects (PMID: 29616049). The activity of ZBTB20 has been implicated in other cellular functions including liver regeneration, lipogenesis, neuronal development and maintenance of circadian rhythms, among others (PMID: 29700307, 27657167, 27000654, 25564625, 28327662). Germline mutations in ZBTB20 are associated with Primrose syndrome, a congenital malformation syndrome associated with abnormal immunoglobulin levels, as well as other neurodevelopmental disorders (PMID: 31821719, 31321892, 29681083, 25017102). These loss-of-function alterations lead to alterations in dendritic spine morphology (PMID: 30281617). ZBTB20 has been implicated as a tumor suppressor in the context of PTEN loss (PMID: 28319090); however, overexpression of ZBTB20 is also associated with poor prognosis and metastatic progression in several cancer types including hepatocellular and lung cancers (PMID: 31556767, 26893361, 21702992, 25311537). True +ENST00000322357 NM_015898 51341 ZBTB7A True ZBTB7A, a zinc finger transcription factor, is infrequently altered in cancer. ZBTB7A, a member of the POK family of transcriptional repressors, encodes for a zinc finger transcription factor that functions in the repression of genes involved in cellular proliferation and differentiation (PMID: 17595526, 14701838, 11865059). ZBTB7A negatively regulates SMAD4 transcriptional activity in the TGF-β signaling pathway through recruitment of chromatin regulator HDAC1 to the SMAD4-DNA complex and by preventing further recruitment of transcriptional activators (PMID: 25514493). ZBTB7A can function as an AR transcriptional corepressor through the recruitment of NCOR1 and NCOR2 to suppress AR-mediated signaling and cellular proliferation (PMID: 20812024). The oncogenic function of ZBTB7A is likely tissue-specific. Overexpression of ZBTB7A in various types of cancer cell lines and models induces cellular proliferation and migration and epithelial-to-mesenchymal transition, suggesting that ZBTB7A functions predominantly as an oncogene in these tissue contexts (PMID: 17907153, 31385585, 21176152, 33167891). Amplification of ZBTB7A has been identified in various cancers, including non-small cell lung cancer, hepatocellular carcinoma and colorectal cancer (PMID: 17907153, 27982429, 33167891). In contrast, the knockdown of ZBTB7A in other types of cancer cell lines and models induces cellular proliferation and tumor metastasis, suggesting that ZBTB7A functions predominantly as a tumor suppressor gene in these tissue contexts (PMID: 36596853, 25184678, 29699474). Downregulation of ZBTB7A has been identified in various cancers, including melanoma, prostate cancer and glioblastoma (PMID: 25995384, 31444154, 36596853). True +ENST00000268489 NM_006885.3 463 ZFHX3 False ZFHX3, a tumor suppressor and transcription factor, is altered by mutation or deletion in various cancer types, most frequently in endometrial and skin cancers. ZFHX3 is a transcription factor expressed in the brain, liver, lung and the gastrointestinal tract. Normally, ZFHX3 suppresses transcription of alpha-fetoprotein by binding to an enhancer motif (PMID: 7507206, 11786962) and negatively regulates expression of the proto-oncogene MYB (PMID: 10318867). ZFHX3 is mutated in advanced gastric cancers (PMID: 17671116, 20599712) and prostate cancer (PMID: 15750593). Functional studies support a tumor suppressor role for this protein. Specifically, a ZFHX3 conditional knockout mouse develops hyperplasia and prostatic intraepithelial neoplasia (PMID: 24934715). Suppression of ZFHX3 in a prostate cell line increases proliferation, while exogenous expression of ZFHX3 decreases soft agar colony formation (PMID: 15750593). In breast cancer, ZFHX3 is not frequently mutated (PMID: 16932943, 18796146), however, it can inhibit estrogen receptor-mediated cell proliferation (PMID: 20720010). True +ENST00000336440 NM_001244698.1 677 ZFP36L1 False ZFP36L1, an RNA binding protein involved in mediating mRNA decay, is altered by mutation in various cancer types. ZFP36L1 is an RNA binding protein that is a member of the zinc-finger containing ZFP36 protein family (PMID: 29426877, 23428348). ZFP36L1 is a critical regulator of mRNA decay and binds to adenylate-uridylate-rich elements (ARE), which are located in the 3’ untranslated region (UTR) of mRNAs (PMID: 31551365, 25106868). ZFP36L1 binds the 3’ UTR of many cancer and cell-cycle related genes including HIF1A, CCND1, and E2F1 (PMID: 31551365, 29709483, 29426877). In addition, ZFP36L1 can bind to other proteins involved in mRNA degradation including mRNA decapping subunits, the exosome component RRP4, and deadenylases, among others (PMID: 15687258). Overexpression of ZFP36L1 in cancer cell lines results in reduced proliferation and cell cycle progression, suggesting that ZFP36L1 predominantly functions as a tumor suppressor (PMID: 31551365, 26542173). Deletion of ZFP36L1 in mice results in a severe defect in B-cell development, due to the role of ZFP36L1 in mediating cellular quiescence, which is required for the maintenance of genomic integrity during V(D)J recombination (PMID: 27102483, 28394372). ZFP36L1 has also been implicated in thymocyte development, and loss of ZFP36L1 results in T-acute lymphoblastic leukemias in mice (PMID: 20622884, 27566829). ZFP36L1 is also involved in the regulation of other cellular functions including differentiation, apoptosis, fate specification and hypoxia (PMID: 31551365, 30982771, 28206953, 26542173, 25014217, 26542173). Somatic mutations of ZFP36L1 have been identified in several cancer types, including breast and bladder cancer (PMID: 31551365). Epigenetic silencing of ZFP36L1 is another mechanism identified in cancer cells that results in ZFP36L1 downregulation (PMID: 31551365). True +ENST00000282388 NM_006887.4 678 ZFP36L2 False ZFP36L2, a zinc finger RNA-binding protein, is frequently altered by deletion in cancer. ZFP36L2, or TIS11D, encodes a zinc finger RNA-binding protein that negatively regulates protein synthesis through poly(A) tail deadenylation for cytoplasmic AU-rich element (ARE)-containing mRNA transcripts (PMID: 25106868). ZFP36L2 binds to the 3'-untranslated region of mRNA transcripts and recruits the CCR4-NOT-deadenylase complex to promote destabilization of the mRNA transcript (PMID: 25106868). Phosphorylation of the C-terminus of ZFP36L2 by p90 ribosomal S6 kinase results in the dissociation of the CCR4-NOT-deadenylase complex and stabilization of the mRNA transcript (PMID: 25106868). Overexpression of ZFP36L2 in cancer cell lines results in decreased cell viability and cell cycle arrest, suggesting that ZFP36L2 predominantly functions as a tumor suppressor (PMID: 21109922, 29426877). Loss of ZFP36L2 has been identified in various cancer types, including T-cell acute lymphoblastic leukemia, acute myeloid leukemia and colorectal cancer (PMID: 20622884, 21109922, 27463018). Epigenetic silencing of ZFP36L2 through hypermethylation in cancer cell lines results in ZFP36L2 downregulation (PMID: 28860350). ZFP36L2 overexpression is a prognostic marker in gastric cancer and low-grade glioma (PMID: 31048690, 35910229). True +ENST00000314425 NM_005096 9203 ZMYM3 False ZMYM3, a zinc finger protein, is infrequently altered in cancer. ZMYM3 encodes a zinc finger protein that functions primarily in transcriptional regulation and is a component of histone-deacetylase-containing multiprotein complexes (PMID: 22011512, 33173136). ZMYM3 regulates BRCA1 localization to chromatin in the DNA-damage response pathway (PMID: 28242625). Knockdown of ZMYM3 in cancer cell lines induces impaired homologous recombination repair and genomic instability, suggesting that ZMYM3 functions predominantly as a tumor suppressor gene (PMID: 28242625). Downregulation and loss function mutations of ZMYM3 have been identified in various types of cancer, including prostate cancer, chronic lymphocytic leukemia and medulloblastoma (PMID: 33115829, 22150006, 22722829). True +ENST00000302342 NM_006526 7764 ZNF217 True ZNF217, a transcription factor, is altered by amplification in various cancers. ZNF217 encodes for a Krüppel-like zinc finger transcription factor which functions as a DNA-binding transcriptional repressor through interaction with epigenetic regulators (PMID: 19242095, 16940172, 18625718). ZNF217 interacts with CTBP2, RCOR1 and various histone modifying enzymes to form a DNA-binding core transcriptional complex to regulate target genes (PMID: 18625718, 17259635). ZNF217 can attenuate pro-apoptotic signals from telomere dysfunction and DNA damage to promote cell survival (PMID: 16203743). Overexpression of ZNF217 in breast cancer and ovarian cancer cell lines and models induces cellular proliferation and tumor growth, suggesting that ZNF217 functions predominantly as an oncogene (PMID: 25031722, 21059223, 22593193, 22728437). Amplification of ZNF217 has been identified in breast cancer, ovarian cancer and prostate cancer (PMID: 22728437, 22139760, 27768596). False +ENST00000369577 NM_015021.1 23036 ZNF292 False ZNF292, a zinc finger transcription factor, is recurrently altered by mutation or downregulation in various cancers. ZNF292, a zinc finger protein, encodes a highly conserved, growth hormone-dependent transcription factor that is highly expressed in the developing brain and is critical for neurodevelopment (PMD: 27150435, 25559195, 31723249, 35125808). While the exact role of ZNF292 in neurodevelopment is still unknown, mutations have been linked to intellectual disability and autism spectrum disorder (PMID: 31723249). Mutations in ZNF292, including deletions and frameshift mutations, have been identified in gastric cancer, colorectal cancer, liver cancer and chronic lymphocytic leukemia (PMID: 27150435, 25559195, 33194728, 26200345). Loss of ZNF292 in various cancer cell lines and models results in increased cell proliferation, colony formation, and tumor growth, suggesting that ZNF292 functions predominantly as a tumor suppressor gene (PMID: 25559195, 35125808). Furthermore, loss of ZNF292 expression in esophageal squamous cell carcinoma (ESCC) and chronic lymphocytic leukemia (CLL) is associated with poor prognosis (PMID: 35125808, 33194728). True +ENST00000269394 NM_024702.2 79755 ZNF750 False ZNF750, a transcription factor, is altered by mutation and deletion in various cancer types. ZNF750 is a transcription factor that functions as a regulator of epidermal differentiation (PMID: 27819679, 22364861). ZNF750 modulates epithelial homeostasis by controlling the activation of key late-stage epidermal differentiation gene programs (PMID: 27819679, 30466065, 26545810, 22936986). Binding of ZNF750 to target genes is important for various cellular activities including differentiation, apoptosis, angiogenesis, metastasis and barrier function (PMID: 32341351, 30518868, 29113187, 26527742). ZNF750 cooperates with other transcriptional and chromatin regulators, such as FOXC2, KDM1A, and HDAC1, to activate gene expression (PMID: 32341351, 32313225, 25805135, 25228645). Through p63-mediated activation, ZNF750 coordinates the expression of KLF4 in skin cells to regulate cellular identity (PMID: 22364861). Germline alterations in ZNF750 have been detected in patients with psoriasis and psoriasiform dermatitis (PMID: 22185198). Decreased expression of ZNF750 is detected in various cancer types, including esophageal squamous cancers, suggesting that ZNF750 functions as a tumor suppressor (PMID: 27819679, 32341351, 32246873). Somatic mutations and deletions in ZNF750 are found in patients with cutaneous and squamous carcinomas of varied origins, including esophageal, cervix, head and neck, and lung, among others (PMID: 27819679, 31148199, 30563911, 29760388, 29216641, 28608921, 27749841, 25839328). True +ENST00000544604 NM_001206998.1 84133 ZNRF3 False ZNRF3, a transmembrane E3 ligase that negatively regulates WNT signaling, is altered by deletion or mutation in adrenocortical and colorectal carcinomas. ZNRF3 is a transmembrane E3 ubiquitin ligase that negatively regulates the WNT signaling pathway (PMID: 30692207, 24225776, 22575959). WNT signaling is activated following ligand engagement of WNT receptors and co-receptors, including Frizzled (FZD) and LRP5/6, resulting in increased downstream signaling (PMID: 30692207, 24225776, 22575959). ZNRF3 antagonizes WNT signaling by targeting FZD and LRP6 for degradation via ubiquitin-mediated endocytosis (PMID: 30692207, 22575959, 24349440). Other WNT signaling molecules, including the phosphoprotein Dishevelled (DSH), are required to mediate the activity of ZNRF3 at the membrane (PMID: 22575959, 22895187, 25891077). In addition, the RSpondin (RSPO) family of proteins, which function as agonists of the WNT pathway, promote membrane clearance of ZNRF3 and stability of FZD, leading to WNT pathway activation (PMID: 22575959, 22895187, 24165923, 29769720). WNT signaling is a critical regulator of tissue homeostasis, proliferation, and maintenance of the stem cell niche (PMID: 22895187, 27088858, 30692207) and loss of ZNRF3 expression results in expansion of the intestinal stem cell zone (PMID: 22895187). Downregulation of ZNRF3 is found in a variety of cancer types and overexpression leads to reduced cellular proliferation, suggesting that ZNRF3 functions as a tumor suppressor (PMID: 29088784). Somatic loss-of-function mutations and deletions are found in patients with adrenocortical carcinomas and serrated pathway colorectal cancers, among others (PMID: 24747642, 25490274, 29879932, 27661107, 24236197). True +ENST00000307771 NM_005089.3 8233 ZRSR2 False 4 ZRSR2, a splicing factor, is altered in various hematological malignancies. ZRSR2 encodes a splicing factor U2 small nuclear ribonucleoprotein auxiliary factor 35 kDa subunit-related protein 2. It is involved in the splicing of introns and is important for recognizing the 3' splice site and assembly of the spliceosome (PMID:21041408). Mutation in hematopoietic cells results in mis-splicing and retention of the U12 type intron in pre-messenger RNA (PMID:25586593). Mutations are found in myelodysplastic syndrome, secondary acute myeloid leukemia, and other myeloid dysorders (PMID: 22389253, 25550361, 25212276). Targeted inhibition of the spliceosome may be a therapeutic strategy in spliceosome mutant disease (PMID:26575690). False diff --git a/data/common_input/isoform_overrides_oncokb_grch38.txt b/data/common_input/isoform_overrides_oncokb_grch38.txt index 9f9d2f8..700d040 100644 --- a/data/common_input/isoform_overrides_oncokb_grch38.txt +++ b/data/common_input/isoform_overrides_oncokb_grch38.txt @@ -1,726 +1,905 @@ -enst_id ref_seq entrez_gene_id hugo_symbol oncogene highest_sensitive_level highest_resistance_level summary background tsg highest_resistanc_level -ENST00000318560 NM_005157.4 25 ABL1 True 1 R1 False R1 -ENST00000502732 NM_007314.3 27 ABL2 True False -ENST00000321945 NM_139076.2 84142 ABRAXAS1 False True -ENST00000573283 NM_001199954.1 71 ACTG1 False True -ENST00000263640 NM_001111067.2 90 ACVR1 True False -ENST00000396623 NM_144650 137872 ADHFE1 True False -ENST00000265343 NM_014423 27125 AFF4 True False -ENST00000373204 NM_012199.2 26523 AGO1 True False -ENST00000220592 NM_012154.3 27161 AGO2 False False -ENST00000262713 NM_032876.5 84962 AJUBA False True -ENST00000349310 NM_001014431.1 207 AKT1 True 3A False -ENST00000392038 NM_001626.4 208 AKT2 True False -ENST00000263826 NM_005465.4 10000 AKT3 True False -ENST00000295897 NM_000477.5 213 ALB False False -ENST00000261733 NM_000690 217 ALDH2 False True -ENST00000389048 NM_004304.4 238 ALK True 1 R2 False R2 -ENST00000647874 NM_001139.2 242 ALOX12B True True -ENST00000374869 NM_152424.3 139285 AMER1 False True -ENST00000301030 NM_013275.5 29123 ANKRD11 False True -ENST00000257430 NM_000038.5 324 APC False True -ENST00000257254 NM_005161.4 187 APLNR True True -ENST00000374690 NM_000044.3 367 AR True False -ENST00000377045 NM_001654.4 369 ARAF True 2 False -ENST00000404338 NM_004491.4 2909 ARHGAP35 True True -ENST00000426542 NM_001177693.1 64283 ARHGEF28 True False -ENST00000324856 NM_006015.4 8289 ARID1A False 4 True -ENST00000647938 NM_020732.3 57492 ARID1B False True -ENST00000334344 NM_152641.2 196528 ARID2 False True -ENST00000263620 NM_005224.2 1820 ARID3A False True -ENST00000346246 NM_001307939.1 10620 ARID3B True False -ENST00000378909 NM_001017363.1 138715 ARID3C False False -ENST00000355431 NM_002892.3 5926 ARID4A False True -ENST00000264183 NM_001206794.1 51742 ARID4B False True -ENST00000357485 NM_212481.1 10865 ARID5A False False -ENST00000279873 NM_032199.2 84159 ARID5B False True -ENST00000375687 NM_015338.5 171023 ASXL1 False True -ENST00000435504 NM_018263.4 55252 ASXL2 False True -ENST00000262053 NM_005171.4 466 ATF1 True False -ENST00000278616 NM_000051.3 472 ATM False 1 True -ENST00000295598 NM_000701 476 ATP1A1 True True -ENST00000369762 NM_001183.5 537 ATP6AP1 False False -ENST00000276390 NM_001693.3 526 ATP6V1B2 False True -ENST00000350721 NM_001184.3 545 ATR False True -ENST00000320211 NM_130384 84126 ATRIP False True -ENST00000373344 NM_000489.3 546 ATRX False True -ENST00000550104 NM_002973.3 6311 ATXN2 False True -ENST00000295900 NM_000333.3 6314 ATXN7 True False -ENST00000312783 NM_003600.2 6790 AURKA True False -ENST00000585124 NM_004217.3 9212 AURKB True False -ENST00000262320 NM_003502.3 8312 AXIN1 False True -ENST00000307078 NM_004655.3 8313 AXIN2 False True -ENST00000301178 NM_021913.4 558 AXL True False -ENST00000559916 NM_004048.2 567 B2M False True -ENST00000297574 79870 BAALC True False -ENST00000359435 NM_001033549.1 29086 BABAM1 False False -ENST00000257749 NM_001170794.1 60468 BACH2 False True -ENST00000460680 NM_004656.3 8314 BAP1 False True -ENST00000260947 NM_000465.2 580 BARD1 False 1 True -ENST00000449228 NM_001127240.2 27113 BBC3 False True -ENST00000648566 NM_003921.4 8915 BCL10 False True -ENST00000357195 NM_138576.3 64919 BCL11B False True -ENST00000333681 NM_000633.2 596 BCL2 True False -ENST00000307677 NM_138578.1 598 BCL2L1 False False -ENST00000393256 NM_138621.4 10018 BCL2L11 False True -ENST00000164227 NM_005178 602 BCL3 True False -ENST00000232014 NM_001706.4 604 BCL6 True False -ENST00000234739 NM_004326.3 607 BCL9 True False -ENST00000378444 NM_001123385.1 54880 BCOR False True -ENST00000218147 NM_021946.4 63035 BCORL1 False True -ENST00000305877 NM_004327.3 613 BCR True False -ENST00000263464 NM_182962.2 330 BIRC3 False False -ENST00000355112 NM_000057.2 641 BLM False True -ENST00000372037 NM_004329.2 657 BMPR1A False True -ENST00000646891 NM_004333.4 673 BRAF True 1 False -ENST00000357654 NM_007294.3 672 BRCA1 False 1 True -ENST00000380152 NM_000059.3 675 BRCA2 False 1 True -ENST00000303407 NM_007371 8019 BRD3 True False -ENST00000263377 NM_058243.2 23476 BRD4 True False -ENST00000259008 NM_032043.2 83990 BRIP1 False 1 True -ENST00000309383 NM_032430 84446 BRSK1 False True -ENST00000256015 NM_001731.2 694 BTG1 False True -ENST00000290551 NM_006763 7832 BTG2 False True -ENST00000308731 NM_000061.2 695 BTK True R1 False R1 -ENST00000316448 NM_004343.3 811 CALR True False -ENST00000396946 NM_032415.4 84433 CARD11 True False -ENST00000327064 NM_199141.1 10498 CARM1 False False -ENST00000358485 NM_001080125.1 841 CASP8 False True -ENST00000412916 NM_022845.2 865 CBFB False True -ENST00000264033 NM_005188.3 867 CBL False True -ENST00000276014 NM_033031.2 85417 CCNB3 True False -ENST00000227507 NM_053056.2 595 CCND1 True False -ENST00000261254 NM_001759.3 894 CCND2 True False -ENST00000372991 NM_001760.3 896 CCND3 True False -ENST00000262643 NM_001238.2 898 CCNE1 True 4 False -ENST00000576892 NM_152274.4 92002 CCNQ False True -ENST00000381577 NM_014143.3 29126 CD274 True False -ENST00000318443 NM_001024736.1 80381 CD276 True False -ENST00000324106 NM_006139.3 940 CD28 True False -ENST00000369489 NM_001779.2 965 CD58 False True -ENST00000221972 NM_001783.3 973 CD79A True False -ENST00000392795 NM_001039933.1 974 CD79B True False -ENST00000344548 NM_001791.3 998 CDC42 True False -ENST00000367435 NM_024529.4 79577 CDC73 False True -ENST00000261769 NM_004360.3 999 CDH1 False True -ENST00000447079 NM_016507.2 51755 CDK12 False 1 True -ENST00000257904 NM_000075.3 1019 CDK4 True 4 False -ENST00000265734 NM_001145306.1 1021 CDK6 True False -ENST00000381527 NM_001260.1 1024 CDK8 True False -ENST00000244741 NM_078467.2 1026 CDKN1A False True -ENST00000228872 NM_004064.3 1027 CDKN1B False True -ENST00000304494 NM_000077.4 1029 CDKN2A False 4 True -ENST00000276925 NM_004936.3 1030 CDKN2B False True -ENST00000262662 NM_078626.2 1031 CDKN2C False True -ENST00000498907 NM_004364.3 1050 CEBPA False True -ENST00000335756 NM_001809.3 1058 CENPA False False -ENST00000428830 NM_001274.5 1111 CHEK1 False 1 True -ENST00000404276 NM_007194.3 11200 CHEK2 False 1 True -ENST00000398235 NM_001039690 54921 CHTF8 False True -ENST00000575354 NM_015125.3 23152 CIC False True -ENST00000324288 NM_000246.3 4261 CIITA False True -ENST00000338099 NM_001099642.1 55783 CMTR2 False True -ENST00000367669 NM_022457.5 64326 COP1 True False -ENST00000231948 NM_016302.3 51185 CRBN False True -ENST00000432329 NM_134442.3 1385 CREB1 True False -ENST00000262367 NM_004380.2 1387 CREBBP False True -ENST00000354336 NM_005207.3 1399 CRKL True False -ENST00000381566 NM_022148.4 64109 CRLF2 True False -ENST00000438362 NM_001242891.1 7812 CSDE1 False False -ENST00000286301 NM_005211.3 1436 CSF1R False False -ENST00000361632 NM_000760.3 1441 CSF3R True False -ENST00000264010 NM_006565.3 10664 CTCF False True -ENST00000648405 NM_005214.4 1493 CTLA4 True False -ENST00000349496 NM_001904.3 1499 CTNNB1 True False -ENST00000361367 NM_014633.4 9646 CTR9 False True -ENST00000264414 NM_003590.4 8452 CUL3 False True -ENST00000292535 NM_181552.3 1523 CUX1 False True -ENST00000241393 NM_003467.2 7852 CXCR4 True False -ENST00000398568 NM_001042355.1 1540 CYLD False True -ENST00000396402 NM_000103.4 1588 CYP19A1 True False -ENST00000282018 NM_020377.2 57105 CYSLTR2 True False -ENST00000266000 NM_001141970.1 1616 DAXX False True -ENST00000233078 NM_018959.3 26528 DAZAP1 False False -ENST00000292782 NM_020640.2 54165 DCUN1D1 True False -ENST00000346473 NM_001195057.1 1649 DDIT3 False False -ENST00000367921 NM_006182.2 4921 DDR2 True False -ENST00000478993 NM_001356.4 1654 DDX3X False True -ENST00000505374 NM_024415.2 54514 DDX4 True False -ENST00000330503 NM_016222.4 51428 DDX41 False True -ENST00000652689 NM_003472.4 7913 DEK True False -ENST00000393063 NM_177438.2 23405 DICER1 False True -ENST00000377767 NM_014953.3 22894 DIS3 False True -ENST00000373970 NM_012242.2 22943 DKK1 False False -ENST00000285311 NM_014421.2 27123 DKK2 False False -ENST00000326932 NM_001018057.1 27122 DKK3 False False -ENST00000220812 NM_014420.2 27121 DKK4 False False -ENST00000254322 NM_006145.1 3337 DNAJB1 False False -ENST00000340748 NM_001379.2 1786 DNMT1 True False -ENST00000264709 NM_022552.4 1788 DNMT3A False True -ENST00000328111 NM_006892.3 1789 DNMT3B False True -ENST00000398665 NM_032482.2 84444 DOT1L True False -ENST00000344624 NM_013235.4 29102 DROSHA False False -ENST00000257600 NM_004416.2 1840 DTX1 False True -ENST00000344450 NM_020185.4 56940 DUSP22 False True -ENST00000240100 NM_001394.6 1846 DUSP4 False True -ENST00000346618 NM_001949.4 1871 E2F3 True False -ENST00000367682 NM_001077706.2 345930 ECT2L False True -ENST00000263360 NM_003797.3 8726 EED False True -ENST00000308874 NM_201446.2 51162 EGFL7 True False -ENST00000275493 NM_005228.3 1956 EGFR True 1 R2 False R2 -ENST00000239938 NM_001964.2 1958 EGR1 False True -ENST00000379607 NM_001412.3 1964 EIF1AX False False -ENST00000424014 NM_001414 1967 EIF2B1 False True -ENST00000323963 NM_001967.3 1974 EIF4A2 True False -ENST00000280892 NM_001130678.1 1977 EIF4E True False -ENST00000359651 NM_004433.4 1999 ELF3 True True -ENST00000284811 NM_005648.3 6921 ELOC False False -ENST00000263253 NM_001429.3 2033 EP300 False True -ENST00000389561 NM_015409.3 57634 EP400 False True -ENST00000263734 NM_001430.4 2034 EPAS1 False False -ENST00000263735 NM_002354.2 4072 EPCAM False True -ENST00000336596 NM_005233.5 2042 EPHA3 False True -ENST00000273854 NM_004439.5 2044 EPHA5 False False -ENST00000369303 NM_004440.3 2045 EPHA7 True True -ENST00000398015 NM_004441.4 2047 EPHB1 False True -ENST00000222139 NM_000121.3 2057 EPOR True False -ENST00000269571 NM_004448.2 2064 ERBB2 True 1 False -ENST00000267101 NM_001982.3 2065 ERBB3 True False -ENST00000342788 NM_005235.2 2066 ERBB4 True False -ENST00000391945 NM_000400.3 2068 ERCC2 False 3A True -ENST00000285398 NM_000122.1 2071 ERCC3 False True -ENST00000311895 NM_005236.2 2072 ERCC4 False True -ENST00000652225 NM_000123.4 2073 ERCC5 False True -ENST00000222329 NM_006494.2 2077 ERF False True -ENST00000288319 NM_182918.3 2078 ERG True False -ENST00000377482 NM_018948.3 54206 ERRFI1 False True -ENST00000305188 NM_001017420.2 157570 ESCO2 False True -ENST00000206249 NM_001122740.1 2099 ESR1 True 1 False -ENST00000272342 NM_019002.3 54465 ETAA1 False True -ENST00000671733 NM_018638.4 55500 ETNK1 False False -ENST00000405192 NM_001163147.1 2115 ETV1 True False -ENST00000319349 NM_001079675.2 2118 ETV4 True False -ENST00000306376 NM_004454.2 2119 ETV5 True False -ENST00000396373 NM_001987.4 2120 ETV6 False True -ENST00000397938 NM_005243.3 2130 EWSR1 True False -ENST00000378204 NM_000127 2131 EXT1 False True -ENST00000428826 NM_001991.3 2145 EZH1 True False -ENST00000320356 NM_004456.4 2146 EZH2 True 1 True -ENST00000342995 340602 EZHIP True False -ENST00000389301 NM_000135.2 2175 FANCA False True -ENST00000289081 NM_000136.2 2176 FANCC False True -ENST00000675286 NM_001018115.1 2177 FANCD2 False True -ENST00000233741 NM_018062.3 55120 FANCL False 1 True -ENST00000652046 NM_000043.6 355 FAS False True -ENST00000441802 NM_005245.3 2195 FAT1 False True -ENST00000403359 NM_001190274.1 80204 FBXO11 False True -ENST00000608872 NM_012164 26190 FBXW2 False False -ENST00000281708 NM_033632.3 55294 FBXW7 False True -ENST00000295727 NM_017521.2 54738 FEV False False -ENST00000294312 NM_005117.2 9965 FGF19 True False -ENST00000334134 NM_005247.2 2248 FGF3 True False -ENST00000168712 NM_002007.2 2249 FGF4 True False -ENST00000425967 NM_001174067.1 2260 FGFR1 True 1 False -ENST00000358487 NM_000141.4 2263 FGFR2 True 1 False -ENST00000440486 NM_000142.4 2261 FGFR3 True 1 False -ENST00000292408 NM_213647.1 2264 FGFR4 True False -ENST00000366560 NM_000143.3 2271 FH False True -ENST00000285071 NM_144997.5 201163 FLCN False True -ENST00000527786 NM_002017.4 2313 FLI1 True 4 False -ENST00000282397 NM_002019.4 2321 FLT1 True False -ENST00000241453 NM_004119.2 2322 FLT3 True 1 False -ENST00000261937 NM_182925.4 2324 FLT4 True False -ENST00000250448 NM_004496.3 3169 FOXA1 True True -ENST00000262426 NM_001451.2 2294 FOXF1 True True -ENST00000648323 NM_023067.3 668 FOXL2 True True -ENST00000379561 NM_002015.3 2308 FOXO1 False True -ENST00000318789 NM_001244814.1 27086 FOXP1 True True -ENST00000370768 NM_003902.3 8880 FUBP1 False True -ENST00000268171 NM_001289823.1 5045 FURIN True False -ENST00000254108 NM_004960 2521 FUS True False -ENST00000368678 NM_153047.3 2534 FYN True False -ENST00000395095 NM_001136198 51343 FZR1 True True -ENST00000262994 NM_002039.3 2549 GAB1 True False -ENST00000361507 NM_080491.2 9846 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6927 HNF1A False True -ENST00000290295 NM_006361.5 10481 HOXB13 True True -ENST00000451590 NM_005343.2 3265 HRAS True 3A False -ENST00000421577 NM_001098521 10553 HTATIP2 False True -ENST00000407780 NM_015259.4 23308 ICOSLG True False -ENST00000374561 NM_002167.4 3399 ID3 False True -ENST00000345146 NM_005896.2 3417 IDH1 True 1 False -ENST00000330062 NM_002168.2 3418 IDH2 True 1 False -ENST00000367739 NM_000416.2 3459 IFNGR1 False True -ENST00000307046 NM_001111285.1 3479 IGF1 True False -ENST00000650285 NM_000875.3 3480 IGF1R True False -ENST00000434045 NM_001127598.1 3481 IGF2 True False -ENST00000581977 NM_014002.3 9641 IKBKE True False -ENST00000331340 NM_006060.6 10320 IKZF1 False False -ENST00000346872 NM_012481.4 22806 IKZF3 True True -ENST00000423557 NM_000572.2 3586 IL10 False False -ENST00000296870 NM_000588.3 3562 IL3 True False -ENST00000336909 NM_002184.3 3572 IL6ST True False -ENST00000303115 NM_002185.3 3575 IL7R True False -ENST00000243786 NM_002191.3 3623 INHA False True -ENST00000242208 NM_002192.2 3624 INHBA True True -ENST00000074304 NM_001134224.1 3631 INPP4A False False -ENST00000262992 NM_001101669.1 8821 INPP4B False True -ENST00000298229 NM_001567.3 3636 INPPL1 False True -ENST00000302850 NM_000208.2 3643 INSR True False -ENST00000311234 NM_012141 26512 INTS6 False True -ENST00000245414 NM_002198.2 3659 IRF1 False True -ENST00000380956 NM_002460.3 3662 IRF4 True False -ENST00000268638 NM_002163.2 3394 IRF8 False True -ENST00000305123 NM_005544.2 3667 IRS1 True False -ENST00000375856 NM_003749.2 8660 IRS2 True False -ENST00000342505 NM_002227.2 3716 JAK1 True True -ENST00000381652 NM_004972.3 3717 JAK2 True 2 False -ENST00000458235 NM_000215.3 3718 JAK3 True False -ENST00000341776 NM_004973.3 3720 JARID2 True True -ENST00000371222 NM_002228.3 3725 JUN True False -ENST00000265713 NM_006766.4 7994 KAT6A False False -ENST00000395288 NM_016506.5 55709 KBTBD4 False False -ENST00000399788 NM_001042603.1 5927 KDM5A True False -ENST00000375401 NM_004187.3 8242 KDM5C False True -ENST00000377967 NM_021140.2 7403 KDM6A False 4 True -ENST00000263923 NM_002253.2 3791 KDR True False -ENST00000171111 NM_203500.1 9817 KEAP1 False True -ENST00000288135 NM_000222.2 3815 KIT True 1 R2 False R2 -ENST00000248071 NM_016270.2 10365 KLF2 False True -ENST00000261438 NM_016531.5 51274 KLF3 False True -ENST00000374672 NM_004235.4 9314 KLF4 True True -ENST00000377687 NM_001730.4 688 KLF5 True False -ENST00000534358 NM_001197104.1 4297 KMT2A False 3A True -ENST00000420124 NM_014727.3 9757 KMT2B False True -ENST00000262189 NM_170606.2 58508 KMT2C False True -ENST00000301067 NM_003482.3 8085 KMT2D False True -ENST00000402868 NM_020382.7 387893 KMT5A False False -ENST00000249776 NM_033286.3 90417 KNSTRN False False -ENST00000311936 NM_004985.3 3845 KRAS True 1 R1 False R1 -ENST00000339824 283455 KSR2 True False -ENST00000316157 NM_015155.2 23185 LARP4B False False -ENST00000253339 NM_004690.3 9113 LATS1 False True -ENST00000382592 NM_014572.2 26524 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-ENST00000344686 NM_003954.3 9020 MAP3K14 True False -ENST00000347699 NM_001242559 9448 MAP4K4 True False -ENST00000215832 NM_002745.4 5594 MAPK1 True False -ENST00000263025 NM_002746.2 5595 MAPK3 True False -ENST00000265960 NM_001006617.1 79109 MAPKAP1 False False -ENST00000358664 NM_002382.4 4149 MAX False True -ENST00000355673 NM_052897.3 114785 MBD6 False True -ENST00000369026 NM_021960.4 4170 MCL1 True False -ENST00000376406 NM_014641.2 9656 MDC1 False False -ENST00000258149 NM_002392.5 4193 MDM2 True 4 False -ENST00000367182 NM_002393.4 4194 MDM4 True False -ENST00000468789 NM_001105078.3 2122 MECOM True False -ENST00000374080 NM_005120.2 9968 MED12 True True -ENST00000424583 NM_001145785.1 100271849 MEF2B True False -ENST00000348159 NM_005920.3 4209 MEF2D True False -ENST00000312049 NM_130799.2 4221 MEN1 False True -ENST00000397752 NM_000245.2 4233 MET True 1 R2 False R2 -ENST00000219905 NM_001164273.1 23269 MGA False True -ENST00000549489 NM_004668.2 8972 MGAM True False 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True 3A False -ENST00000372115 NM_001048171.1 4595 MUTYH False True -ENST00000522677 NM_001080416 4603 MYBL1 True False -ENST00000621592 NM_002467.4 4609 MYC True False -ENST00000397332 NM_001033082.2 4610 MYCL True False -ENST00000281043 NM_005378.4 4613 MYCN True False -ENST00000396334 NM_002468.5 4615 MYD88 True False -ENST00000300036 NM_002474 4629 MYH11 False True -ENST00000250003 NM_002478.4 4654 MYOD1 False True -ENST00000341426 NM_001198993.1 65220 NADK True False -ENST00000265433 NM_002485.4 4683 NBN False True -ENST00000371998 NM_181659.2 8202 NCOA3 True False -ENST00000268712 NM_006311.3 9611 NCOR1 False True -ENST00000405201 NM_006312.6 9612 NCOR2 False False -ENST00000294785 NM_015331.2 23385 NCSTN True False -ENST00000357731 NM_173808.2 257194 NEGR1 False False -ENST00000356175 NM_000267.3 4763 NF1 False 1 True -ENST00000338641 NM_000268.3 4771 NF2 False True -ENST00000312156 NM_001136023.2 4778 NFE2 True False -ENST00000397062 NM_006164.4 4780 NFE2L2 True False 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NM_002730.3 5566 PRKACA True False -ENST00000358598 NM_212471.2 5573 PRKAR1A False False -ENST00000295797 NM_002740.5 5584 PRKCI True False -ENST00000331968 NM_002742.2 5587 PRKD1 False False -ENST00000366898 NM_004562.2 5071 PRKN False True -ENST00000304992 NM_006445 10594 PRPF8 False True -ENST00000311737 NM_002769.4 5644 PRSS1 False False -ENST00000373237 NM_002794 5690 PSMB2 True False -ENST00000331920 NM_000264.3 5727 PTCH1 False 3A True -ENST00000371953 NM_000314.4 5728 PTEN False 4 True -ENST00000626021 NM_003463.4 7803 PTP4A1 False False -ENST00000371621 NM_001278618.1 5770 PTPN1 True True -ENST00000351677 NM_002834.3 5781 PTPN11 True False -ENST00000309660 NM_002828.3 5771 PTPN2 False True -ENST00000356435 NM_002839.3 5789 PTPRD False True -ENST00000587303 NM_002850.3 5802 PTPRS False True -ENST00000373198 NM_133170.3 11122 PTPRT False True -ENST00000257075 NM_014676 9698 PUM1 False False -ENST00000229340 NM_006861.6 11021 RAB35 True False -ENST00000356142 NM_018890.3 5879 RAC1 True False -ENST00000249071 NM_002872.4 5880 RAC2 True False -ENST00000380774 NM_133339 5884 RAD17 False True -ENST00000297338 NM_006265.2 5885 RAD21 False True -ENST00000378823 NM_005732.3 10111 RAD50 False True -ENST00000267868 NM_002875.4 5888 RAD51 False True -ENST00000487270 NM_133509.3 5890 RAD51B False 1 True -ENST00000337432 NM_058216.2 5889 RAD51C False 1 True -ENST00000345365 NM_002878.3 5892 RAD51D False 1 True -ENST00000358495 NM_134424.2 5893 RAD52 False False -ENST00000371975 NM_001142548.1 8438 RAD54L False 1 False -ENST00000251849 NM_002880.3 5894 RAF1 True 2 False -ENST00000254066 NM_000964.3 5914 RARA False False -ENST00000274376 NM_002890.2 5921 RASA1 False True -ENST00000267163 NM_000321.2 5925 RB1 False True -ENST00000628161 NM_001204468.1 8241 RBM10 False True -ENST00000369784 NM_022768.4 64783 RBM15 True True -ENST00000421138 NM_002907.3 5965 RECQL False True -ENST00000617875 NM_004260.4 9401 RECQL4 False True -ENST00000295025 NM_002908.2 5966 REL True False -ENST00000428762 NM_005045.3 5649 RELN False False -ENST00000309042 NM_001193508.1 5978 REST False True -ENST00000355710 NM_020975.4 5979 RET True 1 False -ENST00000358835 NM_002912 5980 REV3L True False -ENST00000262187 NM_005614.3 6009 RHEB True False -ENST00000418115 NM_001664.2 387 RHOA True False -ENST00000357387 NM_152756.3 253260 RICTOR True False -ENST00000368323 NM_006912.5 6016 RIT1 True False -ENST00000221486 NM_006397 10535 RNASEH2A True False -ENST00000336617 NM_024570 79621 RNASEH2B False True -ENST00000407977 NM_017763.4 54894 RNF43 False True -ENST00000464233 NM_002941.3 6091 ROBO1 False True -ENST00000368508 NM_002944.2 6098 ROS1 True 1 False -ENST00000334205 NM_003942.2 8986 RPS6KA4 True False -ENST00000312629 NM_003952.2 6199 RPS6KB2 True False -ENST00000306801 NM_020761.2 57521 RPTOR True False -ENST00000373001 NM_022157.3 64121 RRAGC True False -ENST00000246792 NM_006270.3 6237 RRAS True False -ENST00000256196 NM_012250.5 22800 RRAS2 True False -ENST00000360203 NM_001283009.2 51750 RTEL1 False True -ENST00000300305 NM_001754.4 861 RUNX1 False True -ENST00000265814 NM_001198626.1 862 RUNX1T1 True False -ENST00000481739 NM_002957.4 6256 RXRA False False -ENST00000477973 NM_012234.5 23429 RYBP False True -ENST00000646673 NM_015474.3 25939 SAMHD1 False True -ENST00000300175 NM_001144757.1 6447 SCG5 True False -ENST00000264932 NM_004168.2 6389 SDHA False True -ENST00000301761 NM_017841.2 54949 SDHAF2 False True -ENST00000375499 NM_003000.2 6390 SDHB False True -ENST00000367975 NM_003001.3 6391 SDHC False True -ENST00000375549 NM_003002.3 6392 SDHD False True -ENST00000283752 NM_006919.2 6317 SERPINB3 True True -ENST00000341074 NM_002974.3 6318 SERPINB4 False False -ENST00000436639 NM_014454.2 27244 SESN1 False True -ENST00000253063 NM_031459.4 83667 SESN2 False True -ENST00000536441 NM_144665.3 143686 SESN3 False True -ENST00000372692 NM_001122821 6418 SET True False -ENST00000649279 NM_015559.2 26040 SETBP1 True False -ENST00000262519 NM_014712.2 9739 SETD1A True False -ENST00000604567 XM_005253858.3 23067 SETD1B False False -ENST00000409792 NM_014159.6 29072 SETD2 False True -ENST00000331768 NM_032233.2 84193 SETD3 False False -ENST00000332131 NM_017438.4 54093 SETD4 False False -ENST00000402198 NM_001080517.2 55209 SETD5 False False -ENST00000219315 NM_001160305.1 79918 SETD6 False False -ENST00000274031 NM_001306199.1 80854 SETD7 False False -ENST00000271640 NM_001145415.1 9869 SETDB1 True True -ENST00000317257 NM_031915.2 83852 SETDB2 False True -ENST00000335508 NM_012433.2 23451 SF3B1 True 4 False -ENST00000220772 NM_003012.4 6422 SFRP1 False True -ENST00000274063 NM_003013.2 6423 SFRP2 True True -ENST00000237305 NM_005627.3 6446 SGK1 True False -ENST00000341259 NM_005475.2 10019 SH2B3 False True -ENST00000371139 NM_002351.4 4068 SH2D1A False True -ENST00000369452 NM_007373.3 8036 SHOC2 True False -ENST00000325599 NM_018130.2 55164 SHQ1 False True -ENST00000308377 NM_001104587.1 91607 SLFN11 False True -ENST00000294008 NM_032444.2 84464 SLX4 False True -ENST00000262160 NM_001003652.3 4087 SMAD2 False True -ENST00000327367 NM_005902.3 4088 SMAD3 False True -ENST00000342988 NM_005359.5 4089 SMAD4 False True -ENST00000349721 NM_001289396.1 6595 SMARCA2 False True -ENST00000646693 NM_001128849.3 6597 SMARCA4 False True -ENST00000618915 NM_003073.3 6598 SMARCB1 False 1 True -ENST00000394963 NM_003076.4 6602 SMARCD1 False False -ENST00000348513 NM_003079.4 6605 SMARCE1 True True -ENST00000322213 NM_006306.3 8243 SMC1A False True -ENST00000361804 NM_005445.3 9126 SMC3 False True -ENST00000446231 NM_015092.4 23049 SMG1 False True -ENST00000249373 NM_005631.4 6608 SMO True False -ENST00000490107 NM_001167740.1 64754 SMYD3 True False -ENST00000332029 NM_003745.1 8651 SOCS1 False True -ENST00000330871 NM_003955.4 9021 SOCS3 False True -ENST00000402219 NM_005633.3 6654 SOS1 True False -ENST00000297316 NM_022454.3 64321 SOX17 False True -ENST00000325404 NM_003106.3 6657 SOX2 True False -ENST00000245479 NM_000346.3 6662 SOX9 True True -ENST00000392045 NM_007237.4 11262 SP140 False True -ENST00000375759 NM_015001.2 23013 SPEN False True -ENST00000347630 NM_001007228.1 8405 SPOP False True -ENST00000299084 NM_152594.2 161742 SPRED1 False True -ENST00000295050 NM_032018.6 83932 SPRTN False True -ENST00000389805 NM_003900 8878 SQSTM1 True False -ENST00000358208 NM_198291.2 6714 SRC True False -ENST00000359995 NM_003016.4 6427 SRSF2 False 4 False -ENST00000415083 NM_001007559.2 6760 SS18 True False -ENST00000383202 NM_005862.2 10274 STAG1 False True -ENST00000218089 NM_001042749.1 10735 STAG2 False True -ENST00000361099 NM_007315.3 6772 STAT1 False False -ENST00000314128 NM_005419.3 6773 STAT2 False False -ENST00000264657 NM_139276.2 6774 STAT3 True False -ENST00000345506 NM_003152.3 6776 STAT5A True False -ENST00000293328 NM_012448.3 6777 STAT5B True False -ENST00000300134 NM_001178078.1 6778 STAT6 True False -ENST00000326873 NM_000455.4 6794 STK11 False 4 True -ENST00000375331 NM_004197.1 8859 STK19 True False -ENST00000373129 NM_032017.1 83931 STK40 False False -ENST00000369902 NM_016169.3 51684 SUFU False True -ENST00000322652 NM_015355.2 23512 SUZ12 False True -ENST00000375746 NM_003177.5 6850 SYK True False -ENST00000294339 NM_001287347.2 6886 TAL1 True False -ENST00000354258 NM_000593.5 6890 TAP1 False False -ENST00000383119 NM_018833.2 6891 TAP2 False False -ENST00000430069 NM_024665.4 79718 TBL1XR1 False True -ENST00000257566 NM_016569.3 6926 TBX3 False True -ENST00000588136 NM_001136139.2 6929 TCF3 False True -ENST00000627217 NM_001146274.1 6934 TCF7L2 False True -ENST00000402399 NM_001098725.1 8115 TCL1A True False -ENST00000340722 NM_004918.3 9623 TCL1B True False -ENST00000380036 NM_000459.3 7010 TEK False False -ENST00000369448 NM_017709.3 54855 TENT5C False True -ENST00000310581 NM_198253.2 7015 TERT True False -ENST00000373644 NM_030625.2 80312 TET1 False True -ENST00000380013 NM_001127208.2 54790 TET2 False True -ENST00000409262 NM_144993 200424 TET3 False True -ENST00000315869 NM_006521.5 7030 TFE3 True False -ENST00000374994 NM_004612.2 7046 TGFBR1 False True -ENST00000295754 NM_003242.6 7048 TGFBR2 False True -ENST00000376499 NM_001303103.1 7088 TLE1 False False -ENST00000262953 NM_003260.4 7089 TLE2 False False -ENST00000558939 NM_005078.3 7090 TLE3 False False -ENST00000376552 NM_007005.4 7091 TLE4 False False -ENST00000370196 NM_005521.3 3195 TLX1 True False -ENST00000296921 NM_021025.2 30012 TLX3 True False -ENST00000258439 NM_001193304.2 55654 TMEM127 False True -ENST00000398585 NM_001135099.1 7113 TMPRSS2 False False -ENST00000237289 NM_006290.3 7128 TNFAIP3 False True -ENST00000355716 NM_003820.2 8764 TNFRSF14 False True -ENST00000361337 NM_003286.2 7150 TOP1 False True -ENST00000269305 NM_000546.5 7157 TP53 False 3A True -ENST00000382044 NM_001141980.1 7158 TP53BP1 False True -ENST00000264731 NM_003722.4 8626 TP63 True True - 6955 TRA True False -ENST00000247668 NM_021138.3 7186 TRAF2 False False -ENST00000392745 NM_003300.3 7187 TRAF3 False True -ENST00000261464 NM_001033910.2 7188 TRAF5 False True -ENST00000326181 NM_032271.2 84231 TRAF7 False False - 6957 TRB True False - 6964 TRD True False - 6965 TRG True False -ENST00000377199 NM_006510 5987 TRIM27 True False -ENST00000166345 NM_004237.3 9319 TRIP13 True True -ENST00000298552 NM_000368.4 7248 TSC1 False 1 True -ENST00000219476 NM_000548.3 7249 TSC2 False 1 True -ENST00000541158 NM_000369.2 7253 TSHR True False -ENST00000264818 NM_003331.4 7297 TYK2 True False -ENST00000291552 NM_006758.2 7307 U2AF1 True 4 False -ENST00000308924 NM_007279.2 11338 U2AF2 False False -ENST00000520539 NM_015902.5 51366 UBR5 True False -ENST00000262803 NM_002911.3 5976 UPF1 False False -ENST00000307179 NM_001128610.2 9101 USP8 True False -ENST00000602142 NM_005428.3 7409 VAV1 True False -ENST00000371850 NM_001134398.1 7410 VAV2 True False -ENST00000523873 NM_001171623.1 7422 VEGFA True False -ENST00000256474 NM_000551.3 7428 VHL False True -ENST00000369458 NM_024626.3 79679 VTCN1 False False -ENST00000286574 NM_007191.4 11197 WIF1 False True -ENST00000452863 NM_024426.4 7490 WT1 True True -ENST00000265428 NM_007013.3 11059 WWP1 True False -ENST00000360632 NM_001168280.1 25937 WWTR1 True False -ENST00000216037 NM_005080.3 7494 XBP1 True False -ENST00000355640 NM_001167.3 331 XIAP True False -ENST00000401558 NM_003400.3 7514 XPO1 True False -ENST00000359321 NM_005431.1 7516 XRCC2 False True -ENST00000282441 NM_001130145.2 10413 YAP1 True False -ENST00000314574 NM_005433.3 7525 YES1 True False -ENST00000262238 NM_003403.4 7528 YY1 True False -ENST00000474710 NM_001164342.2 26137 ZBTB20 True True -ENST00000268489 NM_006885.3 463 ZFHX3 False True -ENST00000336440 NM_001244698.1 677 ZFP36L1 False True -ENST00000282388 NM_006887.4 678 ZFP36L2 False True -ENST00000269394 NM_024702.2 79755 ZNF750 False True -ENST00000544604 NM_001206998.1 84133 ZNRF3 False True -ENST00000307771 NM_005089.3 8233 ZRSR2 False 4 False +enst_id ref_seq entrez_gene_id hugo_symbol oncogene highest_sensitive_level highest_resistance_level summary background highest_resistanc_level tsg +ENST00000622132 NM_001348946.2 5243 ABCB1 True ABCB1, an ATP-binding cassette transporter, is altered through amplification in various cancers. ABCB1, a member of the ATP-binding cassette (ABC) transporter family, encodes for a membrane-associated glycoprotein that functions as an efflux pump that transports endogenous molecules and xenobiotics across the blood-brain barrier (PMID: 990323, 2563168, 7910522). ABCB1, also called multi-drug resistance protein 1 (MRD1), has been identified to confer drug resistance when overexpressed in various cancers (PMID: 18056183, 1968964, 7946563, 11294418). As an efflux pump, ABCB1 can reduce the effectiveness of chemotherapies, such as doxorubicin, cisplatin and 5-fluorouracil, by reducing intracellular drug concentration (PMID: 32525624, 34031441, 28340578). ABCB1 overexpression has been identified in various cancers demonstrating chemotherapy resistance, including pancreatic cancer, breast cancer and ovarian cancer (PMID: 38163893, 38020048, 27415012). Preclinical studies demonstrate inhibition of ABCB1 can restore sensitivity to chemotherapeutic drugs in various cancer models (PMID: 36674503, 38367548). False +ENST00000318560 NM_005157.4 25 ABL1 True 1 R1 ABL1, a tyrosine kinase, is frequently altered by chromosomal translocations in leukemia. ABL1 (also ABL) is a non-receptor tyrosine kinase with ubiquitous cellular expression. ABL is located both in the cytoplasm and nucleus and can be activated by growth factor receptors, cellular kinases or DNA damage (PMID: 24421390, 1591775). In response to extrinsic ligand stimulation, ABL signaling regulates cellular proliferation, differentiation, apoptosis, and migration (PMID: 7651539, 7512450). ABL has additional cellular roles including regulation of actin polymerization, vascular development, transcription, and T cell maturation (PMID: 24421390). In chronic myelogenous leukemia (CML) and Philadelphia chromosome-positive acute lymphocytic leukemia (Ph+ ALL), translocations between the ABL and BCR genes result in the driver fusion protein BCR-ABL (PMID: 3460176, 2825022). The BCR-ABL fusion protein is a constitutively activated oncogenic tyrosine kinase that causes ligand-independent activation of signaling pathways in hematopoietic cells (PMID: 3460176, 2825022). The BCR-ABL fusion protein results in loss of auto-inhibition of ABL leading to activation of the kinase (PMID: 8246975). Alternative ABL1 translocations are also observed in myeloid disease (PMID: 9695962). Small molecule inhibitors of BCR-ABL, imatinib and dasatinib, have been developed and are FDA-approved for CML and Ph+ALL (PMID:11870241, 21931113). Mutations in the ABL kinase domain lead to resistance to these treatments and determine sensitivity to other second-generation inhibitors (PMID: 15256671). R1 False +ENST00000502732 NM_007314.3 27 ABL2 True ABL2, a tyrosine kinase, is altered by chromosomal rearrangement in acute lymphoblastic leukemia. ABL2 is a non-receptor tyrosine kinase that is a member of the ABL protein family (PMID: 26645050). ABL2 localizes to actin protrusions and mediates the formation and stabilization of actin filaments in coordination with cortactin (PMID: 30256707). β1 integrins signal via ABL2 pathways to control several cellular processes including neuronal stability, cell adhesion, cell migration, and invasion (PMID: 30256707, 25694433, 23365224). Phosphorylation of ABL2 by receptor tyrosine kinases and SRC family kinases results in ABL2 activation, autophosphorylation and subsequent activation of downstream signaling molecules, such as the transcription factor STAT3 (PMID: 21892207). ABL2 is localized in the cytoplasm and is overexpressed in a variety of solid tumors, resulting in enhanced cellular proliferation, invasion, and metabolic changes (PMID: 26645050). Recurrent ABL2 fusion proteins are found in patients with acute lymphoblastic leukemias and gangliogliomas (PMID: 29507076, 29880043, 25098428, 10706884). ABL2 fusions result in increased ABL2-mediated signaling, suggesting that ABL2 functions as an oncogene (PMID: 25207766). ABL-targeted small molecule kinase inhibitors may be efficacious in cancers with ABL2 positive rearrangements (PMID: 29464092, 19451690, 25207766). False +ENST00000321945 NM_139076.2 84142 ABRAXAS1 False ABRAXAS1, a tumor suppressor and DNA repair protein, is recurrently altered by mutation and deletion in various cancer types. The ABRAXAS1 is a DNA repair protein that mediates recruitment of BRCA1 to DNA double-strand breaks (DSBs) for DNA damage checkpoint regulation and DNA damage repair through direct binding to BRCA1. The ABRAXAS1-BRCA1 complex plays an important role in tumor suppression. ABRAXAS1 copy loss and somatic mutations have been observed in multiple human cancers, including endometrial, colon, lung, liver, kidney cancers, and in leukemia, with the highest mutation rate found in endometrial cancer (2.5%) (PMID: 25066119). A novel germ line mutation in Abraxas which abrogates BRCA1-dependent DNA repair function has been identified and shown to increases familial breast cancer susceptibility (PMID: 22357538). True +ENST00000272928 NM_020311 57007 ACKR3 True ACKR3, a chemokine receptor, is infrequently altered in cancer. ACKR3, also known as CXCR7, encodes for the atypical chemokine scavenger receptor specific for stromal-derived factors CXCL12 and CXCL11 (PMID: 16107333, 16940167). The ACKR3-CXCL12 signaling axis promotes cancer cell survival, migration, adhesion, angiogenesis and metastasis from ERK activation through MAPK signaling (PMID: 16940167, 20018651). As a scavenger receptor, ACKR3 is responsible for creating a CXCL12 gradient and influences cell migration and weakens CXCR4 activity through ACKR-CXCL12 internalization (PMID: 18267076). The oncogenic and tumor suppressive role of ACKR3 is likely tissue-type specific. Overexpression and silencing of ACKR3 in breast cancer and lung cancer cell lines and mouse models demonstrate tumorigenesis and cell survival (PMID: 17898181). In contrast, ACKR3 activation in neuroblastoma and colon cancer cell lines demonstrates suppression of tumor growth, cell growth and migration (PMID: 22916293, 24255072). Amplification of ACKR3 has been identified in various cancers, including breast cancer and hepatocellular carcinoma (PMID: 27572688, 26912435). Downregulation of ACKR3 has been identified in undifferentiated neuroblastoma (PMID: 22916293). Loss of ACKR3 in non-small cell lung cancer cell models has demonstrated attenuation of EGFR tyrosine kinase inhibitor resistance through inhibition of the MAPK-ERK signaling pathway (PMID: 31273063). True +ENST00000573283 NM_001199954.1 71 ACTG1 False ACTG1, a cytoskeletal protein, is infrequently altered across various cancer types. ACTG1 is a cytoskeletal protein that is a member of the actin family (PMID: 24098136, 19497859, 6420066). Actin proteins comprise cellular filaments and can be classified into three groups: alpha, beta and gamma actin, with ACTG1 functioning as cytoplasmic gamma-actin (PMID: 24098136). ACTG1 is highly expressed in the cytoskeleton of diverse cell types, as well as in the Z-discs and costamere structures of adult striated muscles (PMID: 6420066). ACTG1 monomers are important for a variety of cellular functions including cell motility, muscle contraction, cell signaling, cell junction establishment and maintenance of cell shape (PMID: 24098136). ACTG1, along with ACTB, is highly expressed in dividing cells and is critical for adequate muscle function (PMID: 6420066). Germline mutations in ACTG1 have been identified in patients with hearing loss and in Baraiser-Winter Syndrome, a developmental disorder characterized by short stature, ptosis and hearing loss (PMID: 13680526, 14684684, 22366783). Somatic ACTG1 mutations are relatively rare in human cancers; however, a SNP in ACTG1 is associated with extreme toxicity to vincristine, a therapy commonly used to treat childhood acute lymphoblastic leukemia (PMID: 25084203). Overexpression of ACTG1 has also been implicated in hepatocellular carcinoma with mechanisms related to altered glucose metabolism and cellular proliferation (PMID: 30881024, 30675230). True +ENST00000263640 NM_001111067.2 90 ACVR1 True ACVR1, a receptor protein, is mutated in various cancer types including diffuse intrinsic pontine glioma (DIPG). ACVR1 (activin receptor type 1), also known as ALK2, is a transmembrane protein with cytosolic serine/threonine kinase activity that participates in signaling of transforming growth factor β (TGF-B) superfamily members. It signals by binding to bone morphogenetic proteins (BMPs) and activins and forms a heteromeric complex with other receptors. This complex is composed of two type 1 receptors, which are essential for intracellular signaling, and two type 2 receptors, which are essential for ligand binding. Binding of the ligand to the type 2 receptor stabilizes the complex and results in phosphorylation of type 1 receptors, thus resulting in downstream signaling mediated by the SMAD family of proteins (PMID: 15621726). In normal tissues, signaling through ACVR1 regulates cell survival, differentiation and proliferation. Somatic gain-of-function mutations in ACVR1 are the basis of the autosomal dominant condition fibrodysplasia ossificans progressive (FOP), which results in heterotopic ossification in humans (PMID: 25337067), and similar mutations are present in diffuse intrinsic pontine glioma (DIPG) (PMID: 24769718). False +ENST00000257963 NM_004302 91 ACVR1B False ACVR1B, an activin receptor, is infrequently altered in cancer. ACVR1B encodes for a serine/threonine kinase activin A type IB receptor that functions as a transducer for activin-like ligands that are growth and differentiation factors (PMID: 30335480). ACVR1B mediates TGF-β pathway activation through phosphorylation of the SMAD proteins (PMID: 15689496, 30335480). Knockdown of ACVR1B in pancreatic cancer cell lines and models induces cellular growth, tumorigenesis and dysregulated TGF-β signaling, suggesting that ACVR1B functions predominantly as a tumor suppressor gene (PMID: 11248065, 24886203). Inactivating mutations of ACVR1B have been identified in pancreatic cancer and ER-negative breast cancer (PMID: 24886203, 26408346, 8519692). True +ENST00000241416 NM_001278579 92 ACVR2A True ACVR2A, an activin receptor, is infrequently altered in cancer. ACVR2A encodes for a serine/threonine kinase activin A type II receptor that functions as a transducer for activin-like ligands that are growth and differentiation factors (PMID: 35643319). ACVR2A regulates various biological processes through the mediation of TGF-β pathway activation and phosphorylation of SMAD proteins (PMID: 26497569, 32235336, 28569204). Mutations of ACVR2A are associated with an increased risk of the hypertension disorder preeclampsia (PMID: 29506428, 19126782). The oncogenic function of ACVR2A is likely tissue-specific. Knockdown of ACVR2A in colorectal cancer cell lines induces increased cellular migration, suggesting that ACVR2A functions predominantly as a tumor suppressor gene in this context (PMID: 30310521). However, ectopic expression of ACVR2A in gastric cancer cell lines induces increased cellular proliferation, migration and invasion, suggesting that ACVR2A functions predominantly as an oncogene in this context (PMID: 33420656, 32440149). Loss of ACVR2A expression and ACVR2A mutations are frequently identified in microsatellite instability-high cancers, including colorectal cancer and gastric cancer (PMID: 14988818, 32440149). True +ENST00000381312 NM_018702.4 105 ADARB2 True ADARB2, a double-stranded RNA adenosine deaminase, is infrequently altered in cancer. ADARB2, a member of the RNA-editing enzyme family, encodes for a double-stranded RNA adenosine deaminase that lacks RNA-editing activity (PMID: 10836796, 8943218). Despite lacking deaminase activity to initiate adenosine-to-inosine RNA-editing, ADARB2 has been suggested to regulate the activity of other ADAR-family RNA-editing enzymes through binding of double- and single-stranded RNA (PMID: 10836796, 35850307). ADARB2 is predominantly expressed in brain tissue and functions in regulating long-term memory formation and cognitive processes, however, the underlying molecular mechanism of such is unclear (PMID: 29719497). Overexpression of ADARB2 in glioblastoma cell lines and models inhibits RNA-editing of glutamate receptor GRIA2 and subsequently promotes cellular migration and invasion, suggesting that ADARB2 functions predominantly as an oncogene (PMID: 28167531). ADARB2 amplification has been identified in glioblastoma (PMID: 35922651). Preclinical studies suggest that ADARB2 overexpression in glioblastoma confers resistance to temozolomide (PMID: 35922651). False +ENST00000412232 NM_032777 25960 ADGRA2 True ADGRA2, an adhesion G protein-coupled receptor, is infrequently altered in cancer. ADGRA2, an orphan member of the adhesion G protein-coupled receptor family, encodes for an endothelial transmembrane receptor that functions primarily in regulating angiogenesis (PMID: 21071672, 25373781). ADGRA2 is a WNT7-specific coactivator that drives WNT signaling, and thus angiogenesis, through interaction with the GPI-anchored glycoprotein RECK in the central nervous system (PMID: 30026314, 21071672). Interaction between ADGRA2 and RECK is essential for neural crest development and regulation of the blood-brain barrier (PMID: 27979884, 28803732, 28858624). Mutations in ADGRA2 have been associated with hemorrhagic transformation and increased parenchymal hematoma risk (PMID: 32991049). Overexpression of ADGRA2 in various cancer cell lines and models induces cellular adhesion and increased cellular proliferation, suggesting that ADGRA2 functions predominantly as an oncogene (PMID: 28600358, 29402834). ADGRA2 alterations have been identified in colon cancer and leiomyosarcoma (PMID: 29844865, 31300531). False +ENST00000394143 NM_153834.4 139378 ADGRG4 False ADGRG4, a class B adhesion G protein-coupled receptor, is infrequently altered in cancer. ADGRG4, a member of the subfamily G of the class B adhesion G protein-coupled receptors, encodes for an orphaned G protein-coupled receptor (PMID: 37863265). ADGRG4 is theorized to have functional relevance as an in vivo sensor for mechanical forces in enterochromaffin and Paneth cells of the small intestine (PMID: 37863265). Although there is a lack of functional evidence demonstrating the biological and oncogenic function of ADGRG4, it has been identified as frequently mutated and amplified in various cancers, suggesting a possible role as an oncogene. Amplification of ADGRG4 has been identified in patients with uterine corpus endometrial cancer and breast cancer, and is correlated with poor overall survival (PMID: 35413679, 38834774). False +ENST00000396623 NM_144650 137872 ADHFE1 True ADHFE1, a hydroxyacid-oxoacid transhydrogenase, is infrequently altered in cancer. ADHFE1 encodes the hydroxyacid-oxoacid transhydrogenase enzyme which functions in the oxidation of gamma-hydroxybutyrate to succinic semialdehyde in mammalian tissue (PMID: 16616524). This oxidation reaction is coupled to the reduction of 2-ketoglutarate to D-2-hydroxyglutarate (PMID: 30250890). The promotion of reductive carboxylation by ADHFE1 supports increased acetyl-CoA synthesis and lipogenesis (PMID: 22106302). As ADHFE1 regulates multiple cellular functions, such as DNA replication and cell cycle control, depending on the tissue, its role in cancer has varied depending on cancer type (PMID: 34179501). MYC-induced overexpression of ADHFE1 in breast cancer cell lines promotes tumorigenesis through the accumulation of D-2-hydroxyglutarate and mitochondrial ROS, suggesting that ADHFE1 functions primarily as an oncogene in breast cancer (PMID: 29202474, 30250890). However, silencing of ADHFE1 in colorectal cancer patient-derived xenograft mice models and colorectal cancer cell lines increases tumor growth and cell proliferation (PMID: 31632063). Hypermethylation of ADHFE1 has been identified in various different types of cancer, including breast cancer, colon cancer and gastric cancer (PMID: 34179501). False +ENST00000683244 NM_001386888.1 4301 AFDN False AFDN, a scaffold protein, is infrequently altered in cancer. AFDN encodes for a multi-domain scaffold protein that functions primarily in cell-cell adhesion processes through interaction with adhesion molecules at adherens junctions (PMID: 10477764, 30463011). AFDN maintains the structural integrity of epithelial cells through interaction with nectin and the actin cytoskeleton (PMID: 11024295). Knockdown of AFDN in various cancer cell lines and models induces cellular migration, invasion and tumor growth, suggesting that AFDN functions predominantly as a tumor suppressor gene (PMID: 21478912, 25879875, 39047222, 35931706). AFDN loss has been identified in breast cancer and is associated with poor patient outcomes (PMID: 21478912). AFDN has been identified as a recurrent fusion partner with the gene KMT2A in acute myeloid leukemias with the t(6;11)(q27;q23) translocation (PMID: 34894139, 34864370). True +ENST00000265343 NM_014423 27125 AFF4 True AFF4, a scaffolding protein involved in transcriptional regulation, is infrequently altered in cancer. "AFF4 (AF4/FMR2 family member 4 ) is a scaffolding protein that helps assemble and is a core component of the transcription super elongation complex (SEC) (PMID: 31147444, PMID: 22895430). The SEC functions to remove RNA polymerase II from proximal-promoter pausing, thus regulating the rapid induction of gene transcription. AFF4 has also been shown to play a role in the transcriptional activation of HIV-1 viral genes (PMID: 28134250, PMID: 26007649). AFF4 has many direct transcriptional targets such as MYC and JUN, and has been linked to transcriptional upregulation of TMEM100, ZNF711, and FAM13C, among others (PMID: 25730767). Germline gain-of-function mutations in the highly conserved fourteen amino acid ALF (AF4/LAF4/FMR2) homology domain of AFF4 underlie the germline syndrome CHOPS (C-cognitive impairment and coarse facies; H-heart defects; O-obesity; P-pulmonary involvement; S-short stature and skeletal dysplasia)(PMID: 25730767, PMID: 31058441). AF4-domain-mutation of the AFF4 gene specifically in Purkinje cells in the brain was identified as the cause of neurodegeneration in a ""robotic mouse"" model that developed early-onset de novo ataxia and cataracts (PMID: 12629167). In cancer, alterations of the SEC can allow unregulated transcriptional elongation and lead to tumorigenesis. AFF4-KMT2A (MLL) fusions have been identified in pediatric acute leukemia, whereby the AF4 domain of AFF4 interacts with selectivity factor 1 (SL1) on chromatin to load TATA-binding protein (TBP) onto the promoter to initiate RNA polymerase II-dependent and constitutive transcription (PMID: 28701730, PMID: 27865805, PMID: 26593443). Overexpression of AFF4 has been observed in human head and neck squamous cell cancer (HNSCC) (PMID: 29741610) and melanoma (PMID: 33417923). In preclinical models, AFF4 overexpression enhanced proliferation, migration and invasion of HNSCC and melanoma cells through SOX-2 and c-Jun, which could be reversed with AFF4 depletion via siRNA. In bladder cancer cell line models, METTL3, an important RNA N6-adenosine methyltransferase, was found to be overexpressed resulting in m6A modification of AFF4, leading to enhanced promoter binding and transcription of MYC (PMID: 30659266)." False +ENST00000312916 NM_018046.5 55109 AGGF1 True AGGF1, an angiogenic factor, is infrequently altered in cancer. AGGF1 encodes for an angiogenic factor that functions in regulating angiogenesis and vascular development (PMID: 27522498). AGGF1 interacts with the angiogenic factor TNFSF12 and activates the AKT signaling pathway to promote angiogenesis (PMID: 14961121, 27522498). Germline mutations of AGGF1 have been implicated in the congenital condition Klippel-Trenaunay syndrome (PMID: 27522498, 23197652). Overexpression of AGGF1 in various cancer cell lines and models induces increased tumor angiogenesis and vascular invasion, suggesting that AGGF1 functions predominantly as an oncogene (PMID: 25796501, 34354374, 31881864). AGGF1 amplification has been identified in various cancers, including hepatocellular carcinoma and colorectal cancer (PMID: 29340079, 31881864). False +ENST00000373204 NM_012199.2 26523 AGO1 True AGO1, an enzyme involved in RNA-mediated gene silencing, is overexpressed in various cancer types. AGO1 (also Argonaute-1) is an RNA silencing protein that is a member of the Argonaute family (PMID: 15105377, 23746446). AGO1 regulates RNA-mediated gene silencing, or RNA interference (RNAi) (PMID: 15105377, 23746446). Argonaute proteins are an essential component of the RNA-induced silencing complex (RISC), which is guided to mRNA targets by mircoRNAs (miRNAs) and small interfering RNAs (siRNAs) (PMID: 19239886, 23654304, 17928262). Upon single-stranded RNA-mediated complementarity-based recognition of mRNAs, AGO1 inhibits translation of the mRNA target (PMID: 22231398). In addition, AGO1 has diverse roles in the regulation of small RNA processing including translation repression, regulation of miRNA maturation and heterochromatin formation (PMID: 22961379, 22231398). AGO1 is altered by overexpression in various cancers, such as in colorectal and hepatocellular cancer (PMID: 29487329, 20146808). Somatic mutations in AGO1 have been identified, however, have not been functionally characterized. Loss of AGO1 in hepatocellular cancer cell lines resulted in decreased proliferation and invasion, suggesting that AGO1 functions as an oncogene (PMID: 29487329, 24086155). False +ENST00000220592 NM_012154.3 27161 AGO2 False AGO2, an enzyme involved in the RNA-mediated gene silencing, is overexpressed in various cancer types. AGO2 is an essential protein that regulates RNA-mediated gene silencing, or RNA interference (RNAi). AGO2 is the catalytic component of the RNA-induced silencing complex (RISC) and has endonuclease activity (PMID: 15105377, 23746446). Upon single-stranded RNA-mediated, complementarity-based recognition of mRNAs, AGO2 either cleaves or inhibits translation of its targets (PMID: 19239886, 23654304). In addition, AGO2 has diverse roles in the regulation of small RNA processing including translation repression, regulation of miRNA maturation and heterochromatin formation (PMID: 26284139). Oncogenic proteins, such as mutant KRAS, can also complex with AGO2 to mediate gene silencing (PMID: 26854235). AGO2 is altered by amplification and overexpression in various cancers, such as ovarian, breast and prostate (PMID: 20146808, 24427355). In contrast, AGO2 protein levels are depleted in some melanoma tumor samples (PMID: 24169347). Differential AGO2 expression levels have been linked to dysregulated RNA processing (PMID: 23201202). False +ENST00000279146 NM_003977.4 9049 AIP True AIP, an aryl hydrocarbon receptor-interacting protein, is infrequently altered in cancer. AIP, a member of the FKBP family, encodes for an aryl hydrocarbon receptor-interacting protein (PMID: 9111057). AIP interacts with various proteins, such as phosphodiesterases and G-proteins, to regulate the cAMP-dependent protein kinase pathway (PMID: 29726992). The cAMP-dependent protein kinase pathway is involved in the regulation of pituitary cell proliferation and hormone secretion and is frequently dysregulated in pituitary tumors (PMID: 24373949). Germline mutations of AIP have been identified in familial isolated pituitary adenoma and sporadic macroadenomas (PMID: 23371967). The oncogenic function of AIP is likely tissue-specific. Overexpression of AIP in colon epithelial cells and diffuse large B-cell lymphoma samples induces increased cellular migration, invasion and increased cellular survival, suggesting that AIP functions predominantly as an oncogene in these contexts (PMID: 35347323, 31042473). In contrast, loss of AIP function in pituitary tissue induces cellular proliferation and tumor growth, suggesting that AIP functions predominantly as a tumor suppressor gene in this context (PMID: 18381572). AIP has been shown to interact with the RET signaling pathway in somatotropic cells, and AIP mutations have been found to disrupt the RET-mediated apoptotic pathway, thereby promoting tumor growth (PMID: 34588620). True +ENST00000262713 NM_032876.5 84962 AJUBA False AJUBA, a scaffolding protein included in many protein complexes, is altered by mutation in various cancer types including head and neck, orpharyngeal, and esophageal cancer. AJUBA is a scaffolding protein that is a member of the Zynzin/Ajuba LIM-domain containing protein family (PMID: 31740385, 15520811). AJUBA is a promiscuous protein that can shuttle between the nucleus and cytoplasm to mediate protein-protein interactions (PMID: 15520811, 17909014). Binding of AJUBA modulates the activity of many protein complexes involved in regulating diverse cellular processes including cellular adhesion, tension sensing, cellular motility, mitosis and microRNA processing, among others (PMID: 31740385, 12417594, 13678582, 20616046, 17621269). In addition, AJUBA is an important mediator of many signaling pathways including WNT, MAPK and Hippo pathways (PMID: 31740385, 24336325). For example, AJUBA interacts with LATS2, an important kinase in the Hippo pathway, to mediate downstream signaling (PMID: 24336325). In addition, AJUBA functions as a transcriptional co-repressor that interacts with SLUG domain proteins (involved in the epithelial to mesenchymal transition), nuclear hormone receptors and SP1 (PMID: 17909014, 20133701). Reduced activity of AJUBA in cancer-derived cell lines results in enhanced proliferation, anchorage-independent growth and increased growth in murine xenografts (PMID: 30006462, 24336325), suggesting that AJUBA predominantly functions as a tumor suppressor. However, AJUBA expression has also been found to be an indicator of poor prognosis and cancer progression in several tumor types (PMID: 27172796, 29299158, 30597111, 28422308). Somatic mutations in AJUBA are found in various cancer types including head and neck, orpharyngeal, esophageal squamous cancer, among others (PMID: 25631445, 30046007, 29127303, 25839328, 25303977). AJUBA alterations are predicted to be loss-of-function and patients with these alterations may be sensitive to mitotic inhibitors (PMID: 25631445, 28126323). True +ENST00000349310 NM_001014431.1 207 AKT1 True 1 AKT1, an intracellular kinase, is altered predominantly by mutation in various cancer types including breast and endometrial cancers. AKT1 is a serine/threonine protein kinase that is a critical downstream effector in the PI3K (phosphoinositide 3-kinase) signaling pathway. Following activation of PI3K, cytosolic inactive AKT1 is recruited to the membrane and engages PIP3 (PtdIns3,4,5-P3), leading to phosphorylation and activation of AKT1 (PMID: 28431241). AKT1 can activate a number of downstream substrates, including GSK3, FOXO and mTORC1, which are critical for cellular survival, proliferation, and metabolism (PMID: 9843996, 7611497). Negative regulation of AKT1 occurs when PI3K signaling is terminated by PTEN phosphatase activity (PMID: 28431241). AKT1 is frequently activated in cancers, typically through activation of the PI3K pathway or by inactivation of PTEN (PMID: 28431241). Activating mutations in AKT1 (PMID: 17611497, 23134728, 20440266) and infrequent AKT1 gene amplification (PMID: 18767981) have been identified in human cancers, which allow for phosphoinositide-independent AKT1 activation. The ATP-competitive AKT1 inhibitor AZD5363 has demonstrated activity in patients with AKT1-mutant cancers (PMID: 28489509). Negative feedback mechanisms can mediate AKT-inhibitor resistance in human cancers with dysregulated AKT signaling (PMID: 29535262, 29339542). False +ENST00000392038 NM_001626.4 208 AKT2 True AKT2, an intracellular kinase, is altered by mutation or amplification in various cancer types. The AKT2 protein is a serine/threonine protein kinase that is a critical downstream effector in the PI3K signaling pathway. AKT2, along with closely related AKT1 and AKT3, are members of the AGC kinase family. Effects of AKT activation include cell cycle progression and increased migration, differentiation and glucose homeostasis (PMID: 12094235). AKT2 activation occurs when its pleckstrin homology domain (PHD) dislodges from the kinase domain (KD), localizes to the cell membrane, and several of its key residues become phosphorylated (PMID: 9374542). AKT2 is an oncogene that is activated in numerous cancers, mostly through amplification of the 19q13.1-q13.2 chromosomal region (PMID: 1409633, 9496907) or overexpression (PMID: 11756242), which promote invasion and metastasis (PMID: 12517798). Germline autosomal dominant mutations in AKT2 are associated with familial diabetes mellitus in humans (PMID: 15166380). There are numerous drugs that target the PI3K/AKT pathway, including inhibitors of AKT itself, and inhibitors of PI3K and mTOR (PMID: 19629070). False +ENST00000263826 NM_005465.4 10000 AKT3 True AKT3, an intracellular kinase, is altered by mutation or amplification in various cancer types. The AKT3 protein is a serine/threonine protein kinase that is a downstream effector in the PI3K signaling pathway. AKT3, along with closely related AKT1 and AKT2, are members of the AGC kinase family. Effects of AKT activation include cell cycle progression and increased migration, differentiation and glucose homeostasis (PMID: 12094235). AKT3 activation occurs when its pleckstrin homology domain (PHD) dislodges from the kinase domain (KD), localizes to the cell membrane, and several of its key residues become phosphorylated (PMID: 1209423)5). AKT3 is an oncogene and is amplified in many cancers, including glioblastoma (PMID: 19597332, 25737557). There are numerous drugs that target the PI3K/AKT pathway, including inhibitors of AKT itself, as well as inhibitors of PI3K and mTOR (PMID: 19629070). False +ENST00000295897 NM_000477.5 213 ALB False ALB, an abundant protein in blood plasma, is infrequently altered in various cancer types. ALB (also serum albumin) is the most abundant protein in blood plasma and composes half of human serum (PMID: 30097614, 25161624). ALB is produced in the liver as the precursor prealbumin before transport to relevant sites for processing (PMID: 2503514). The main function of ALB is to serve as a carrier for proteins that aren’t soluble, including hormones, fatty acids, metals, toxins and bilirubin, among others (PMID: 26055641). In addition, ALB associates with drugs, which can either positively or negatively impact their activity (PMID: 26055641, 25161624, 31704999). Paciltaxel, a breast cancer therapy, is an example of a drug that can be pre-loaded onto albumin prior to injection in an effort to improve drug efficacy (PMID: 25161624). Receptor-mediated endocytosis of ALB is a mechanism of nutrient scavenging in rapidly proliferating cancer cells (PMID: 30097614, 26055641). ALB is then bound by the internal scavenging receptors gp30 and gp18, which break ALB into amino acids and fatty acids (PMID: 8463286). The Fc receptor is an important regulator of endocytic recycling of ALB; downregulation of this receptor is found in cancer (PMID: 27384673). Patients with various malignancies, including cancer, may experience hypoalbuminemia (low albumin) and hyperalbuminemia (high albumin) (PMID: 27612919). Serum albumin levels can be utilized as prognostic markers in several cancer types, with hypoalbuminemia predominantly a predictor of poor outcome (PMID: 28838406, 29183294,31531785). Variants in albumin have been identified; however, the exact function of these alterations is unclear (PMID: 23558059). False +ENST00000258494 NM_001034173 160428 ALDH1L2 True ALDH1L2, a mitochondrial aldehyde dehydrogenase, is infrequently altered in cancer. ALDH1L2 encodes for a folate-dependent mitochondrial aldehyde dehydrogenase that functions in lipid metabolism and various CoA-dependent pathways, such as B-oxidation and the Krebs cycle (PMID: 21238436, 33168096). ALDH1L2 is the mitochondrial homolog of the cytosolic aldehyde dehydrogenase, ALDH1L1 (PMID: 20498374). ALDH1L2 is a key enzyme in the production of reduced NADPH for the mitochondria, allowing for the reduction of oxidized glutathione, and facilitates the regeneration of tetrahydrofolate (PMID: 27211901, 24805240, 33168096, 30500537). Knockdown of ALDH1L2 in various cancer cells inhibits metastasis and cell growth, suggesting that ALDH1L2 functions predominantly as an oncogene (PMID: 26466563, 35565854). Amplification of ALDH1L2 has been identified in various types of cancer, including glioblastoma and colorectal cancer (PMID: 35565854, 20498374). False +ENST00000261733 NM_000690 217 ALDH2 False ALDH2, an acetaldehyde dehydrogenase, is infrequently altered in cancer. ALDH2, a member of the acetaldehyde dehydrogenase family, functions in the oxidation-reduction reaction of ethanol and aldehydic products (PMID: 22339434). The removal of endogenous aldehydes generated by ROS-mediated peroxidation is a significant function of ALDH2 as high levels of aldehydic products, such as malondialdehyde, have been associated with poor patient prognosis (PMID: 31597313, 31652642, 31168172). ALDH2 deficiency in various tumor cell and mouse models leads to acetaldehyde-induced DNA interstrand crosslinks, DNA double-strand breaks and tandem mutations, suggesting that ALDH2 functions predominantly as a tumor suppressor gene (PMID: 32066963, 21734703, 28114741, 29323295). Loss of ALDH2 function has been identified in various cancers, including lung adenocarcinoma, hepatocellular carcinoma and esophageal cancer (PMID: 31071657, 28027570, 16822169). The ALDH2 variant, ALDH2*2, is one of the most commonly identified polymorphisms associated with ALDH2 deficiency and leads to higher susceptibility to cancer risk with alcohol consumption (PMID: 17431955, 35048370). True +ENST00000389048 NM_004304.4 238 ALK True 1 R2 ALK, a receptor tyrosine kinase, is recurrently altered by chromosomal rearrangements in various cancer types including anaplastic large cell lymphoma, non-small cell lung cancer and inflammatory myofibroblastic tumors. ALK is a receptor tyrosine kinase that is a member of the insulin receptor family (PMID: 24060861). Ligand binding to ALK results in activation of downstream signaling including the JAK-STAT, RAS-MAPK, PI3K-mTOR and JUN pathways (PMID: 24060861, 24715763). ALK signaling plays an important role in nervous system development (PMID: 9053841) as well as regulation of cell growth, differentiation, and transformation (PMID: 19737948). ALK translocations are common in cancer and predominantly result in the constitutive activation of ALK kinase activity. The nucleophosmin (NPM1)-ALK fusion protein is found in 60% of anaplastic large cell lymphomas (ALCLs) (PMID: 9736036) while the EML4-ALK fusion protein is found in 3-5% of non-small cell lung cancer (NSCLC) (PMID: 25079552). Additional ALK translocations have been found in a variety of tumor types including inflammatory myofibroblastic tumor (IMT), neuroblastoma and rhabdomyosarcoma (PMID: 24060861). ALK is found overexpressed or somatically mutated in multiple cancers, and secondary mutations in ALK are common after treatment with tyrosine kinase inhibitor therapy (PMID: 24060861). The ALK kinase inhibitors crizotinib, ceritinib, alectinib, and brigatinib have been FDA-approved for the treatment of ALK-rearranged non-small cell lung cancer (PMID: 27413075, 25754348, 25170012). R2 False +ENST00000647874 NM_001139.2 242 ALOX12B True ALOX12B, an enzyme involved in lipid metabolism, is altered by mutation, deletion and amplification in various cancer types. ALOX12B (also 12R-LOX) is a lipoxygenase that is a member of the LOX protein family (PMID: 24021977). 12R-LOX, the enzyme encoded by the gene ALOX12B, mediates fatty acid metabolism by catalyzing the addition of an oxygen molecule to arachidonic acid, generating the molecule 12R-HPETE (PMID: 24021977). 12R-LOX is active primarily in the skin and other epithelial tissues (PMID: 9618483, 10100631, 10446122) and plays an important role in the establishment of the epidermal barrier function (PMID: 17403930, 21558561). Another LOX family member, eLOX3, is required for the downstream synthesis of hepoxilins after 12R-HPETE generation; these play key roles in epithelial permeability and signaling (PMID: 15629692, 24021977, 19558494). ALOX12B also mediates immunosuppressive activity by decreasing antigen presentation on T cells (PMID: 22503541). Inactivating mutations in ALOX12B have been observed in autosomal recessive congenital ichthyosis, a clinically and genetically heterogeneous disease characterized by dried, scaling skin (PMID: 11773004, 16116617, 15629692, 19131948, 17139268). Somatic missense, nonsense mutations and deletions of ALOX12B are found in a wide range of cancers, including melanoma and other skin cancers; however, these alterations have yet to be functionally validated (cBioPortal, MSKCC, April 2020). Amplification of ALOX12B in breast and ovarian cancer has been associated with reduced cytolytic activity by the immune system (PMID: 25594174). In addition, ALOX12B is activated in cancer cells treated with therapies that induce arachidonic acid via a p53-dependent mechanism (PMID: 30258081). True +ENST00000374869 NM_152424.3 139285 AMER1 False AMER1, a tumor suppressor involved in WNT signaling, is inactivated by mutation or deletion in various cancer types, most frequently in colorectal cancer. AMER1 (APC membrane recruitment 1) is an APC-binding protein that regulates the cellular localization of the APC tumor suppressor, thereby regulating APC-dependent cellular morphogenesis, cell migration and cell-cell adhesion (PMID: 17925383, 20843316, 27462415). AMER1 also functions as a negative regulator of WNT/β-catenin signaling (PMID: 21248786, 17510365, 20843316). In this capacity, AMER1 acts as a scaffold protein by assembling β-catenin and members of the destruction complex at the plasma membrane, which is necessary for β-catenin degradation (PMID: 17510365, 21498506). The AMER1 gene is mutated in approximately 5-10% of Wilms tumors, a pediatric kidney cancer (PMID: 17204608, 21248786, 19137020, 18311776, 26274016). Missense and truncating AMER1 mutations are found in approximately 7-10% of colorectal cancers and correlate with reduced WNT signaling (PMID: 26071483). This data is consistent with AMER1 functioning as a tumor suppressor, as loss of AMER1 results in activation of WNT/ β-catenin signaling (PMID: 17510365, 17510365). True +ENST00000301030 NM_013275.5 29123 ANKRD11 False ANKRD11, a tumor suppressor and chromatin regulator, is inactivated by mutation or deletion in various cancer types. ANKRD11 is an ankyrin repeat domain protein that binds and suppresses the function of the p160 coactivator family (PMID: 15184363), thereby inhibiting ligand-dependent transcriptional activation. ANKRD11 is also a coactivator of the p53 tumor suppressor (PMID: 18840648), thereby influencing many pathways relevant to cancer, including transcriptional initiation, cell cycle regulation, ion transport and Notch signaling. Studies in murine and human neural precursors demonstrate that ANKRD11 can function as a chromatin regulator that binds histone deacetylases and alters gene expression (PMID: 25556659). Heterozygous mutations in ANKRD11 have been reported to cause KBG syndrome, a rare disorder characterized by intellectual disability, behavioral problems, and macrodontia (PMID: 21782149). ANKRD11 is hypermethylated in breast cancer leading to decreased transcriptional activity, suggesting that ANKRD11 functions as a putative tumor suppressor gene (PMID: 22538187). True +ENST00000376087 NM_001256053 22852 ANKRD26 True ANKRD26, an ankyrin repeat protein, is altered by mutation in various cancers. Germline ANKRD26 mutations are implicated in ANKRD26-related thrombocytopenia and predispose to hematological malignancies. ANKRD26 encodes for an ankyrin repeat domain protein that functions primarily in regulation of megakaryopoiesis (PMID: 24430186). ANKRD6 is negatively regulated by RUNX1 and FLI1 through protein-protein interaction with the 5’ untranslated region (UTR) of ANKRD6 (PMID: 24430186). Mutations in the 5’ UTR region are implicated in the genetic non-syndromic autosomal dominant thrombocytopenic disorder ANKRD26-related thrombocytopenia, also known as thrombocytopenia-2, and induces persistent activation of the MAPK/ERK pathway and impairs proplatelet formation (PMID: 26478096, 24430186). ANKRD26-related thrombocytopenia is associated with predisposition to hematological malignancies (PMID: 37065357, 28976612). Overexpression of ANKRD26 in patient-derived megakaryocytes induces increased MAPK/ERK pathway signaling and thrombopoietin/myeloproliferative leukemia virus oncogene (TPO/MPL) signaling, suggesting that ANKRD26 functions predominantly as an oncogene (PMID: 24430186). Germline mutations of ANKRD26 have been identified in hematological malignancies (PMID: 36626254). False +ENST00000257430 NM_000038.5 324 APC False APC, a tumor suppressor involved in WNT signaling, is recurrently altered in colorectal cancer. APC is a negative regulator of the pro-oncogenic WNT/ β-catenin signaling pathway (PMID: 8259518, 8259519). The main tumor suppressive role of APC is to modulate intracellular levels of β-catenin (PMID: 11978510). APC is an essential member of the destruction complex, which targets cytosolic β-catenin for ubiquitination and degradation (PMID: 10984057). When the activity of APC is lost, there is an aberrant increase in WNT-pathway activation, often leading to hyperplasia and eventually tumor progression (PMID: 8259511). A threshold of APC expression is required to suppress tumor formation, and this level is finely balanced (PMID: 11743581). Germline mutations in the APC gene cause familial adenomatous polyposis (FAP) (PMID: 1651174, 1651562), also known as Turcot Syndrome, Gardner Syndrome, or Flat Adenoma Syndrome (FAS) (PMID: 8593545), which is associated with a very high risk of polyposis and colorectal cancer (PMID: 1528264, 31171120). In addition, heritable mutations in APC may be responsible for the development of attenuated FAP (PMID: 34666312) or gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS) (PMID: 21813476). APC mutations have been observed in 50-80% of sporadic colorectal cancers (PMID: 17143297). Somatic mutations in APC function as tumor-initiating events and are also observed in a number of other human cancers including breast, stomach, and prostate (PMID: 27302369, 29316426). The majority of APC mutations are loss-of-function and occur in a region important for β-catenin binding (PMID: 10784639, 1338904). Inhibitors of the WNT pathway are currently in clinical development (PMID: 24981364). True +ENST00000257254 NM_005161.4 187 APLNR True APLNR, a G-protein coupled receptor, is altered by mutation in various cancer types and may promote resistance to immunotherapy. APLNR (also AGTRL1) is a transmembrane receptor that is a member of the G-protein coupled receptor (GPCR) protein family (PMID: 28783722). GPCR proteins can bind ligands, which initiate a conformational change allowing the receptor to function as a guanine nucleotide exchange factor (GEF) and exchange GDP for GTP on an associated G protein (PMID: 28091541). APLNR binds the hormones APELA and APLN to activate downstream signaling pathways, including the MAPK and PI3K signaling cascades (PMID: 17412318). APLNR has diverse cellular functions including the regulation of cardiac function, blood vessel formation, proliferation, hypoxia and apoptosis, among others (PMID: 27083318, 17412318, 15530405, 29807055, 27825851, 30718358). In addition, APLNR interacts with the non-receptor tyrosine kinase JAK1 to initiate IFNγ-mediated downstream signaling and to mediate antigen presentation to the immune system (PMID: 28783722). Loss-of-function mutations in APLNR have been identified in patients with melanoma and lung cancer who exhibit resistance to T-cell based immunotherapies, such as ipilimumab, pembrolizumab and nivolumab (PMID: 28783722). However, APLNR is also found to be overexpressed in some cancer types and ALPNR-mediated signaling promotes angiogenesis, suggesting that APLNR may have context-specific roles in cancer progression (PMID: 27083318, 30783205, 30718358, 31267692). True +ENST00000374690 NM_000044.3 367 AR True AR (androgen receptor), a transcription factor, is most frequently altered in advanced or castration-resistant prostate cancer. AR (androgen receptor) is a nuclear receptor that is activated following binding of androgenic hormones (PMID: 1865110, 8809738). The AR protein acts as a steroid-hormone activated transcription factor that regulates gene transcription. In the absence of androgen, AR is predominantly maintained in an inactive conformation in the cytoplasm (PMID: 9175625, 12269826). Upon androgen binding, AR undergoes an activating conformational change that allows for its translocation into the nucleus, homodimerization and binding to DNA at sites with androgen response elements (ARE) motifs (PMID: 9175625, 12000757, 11376111, 8360187). In concert with accessory coactivators and corepressors, AR serves to activate or repress the transcription of AR-mediated target genes (PMID: 11931767, 17679089). Germline loss-of-function mutations in AR cause genetic XY males and rodents to develop as external phenotypic females, also lacking internal sexual secondary organs (PMID: 4402348, 2341409, 2041777, 3186717, 2594783). AR signaling is important in prostate cancers, particularly in tumors that become resistant to androgen deprivation therapies, termed castration-resistant prostate cancers (CRPC). AR is frequently altered in CRPCs resulting in continued activation despite a castrate level of androgen (PMID: 26566796). Mutations in AR can lead to clinical resistance to antiandrogen therapy in CRPC (PMID: 23580326). False +ENST00000377045 NM_001654.4 369 ARAF True 2 ARAF, an intracellular kinase, is infrequently altered by mutation or amplification in various cancer types. ARAF is a serine/threonine protein kinase and signaling component in the mitogen-activated protein (MAP)-kinase signaling pathway. ARAF is a member of the RAF kinase family, which also includes BRAF and CRAF (PMID: 17555829). ARAF is ubiquitously expressed, with the highest physiological levels found in the urogenital organs (PMID: 10768864). Upon activation by RAS proteins, ARAF forms dimers with BRAF and CRAF, resulting in phosphorylation and activation of the downstream signaling effectors MEK and subsequently ERK. Activation of the RAS signaling cascade ultimately leads to increased cell growth and proliferation (PMID: 21779496). ARAF activating mutations are found at low frequencies in cholangiocarcinomas, lung, uterine and histiocytic carcinomas (PMID: 25608663, 26566875). The most common oncogenic ARAF mutation impairs a phosphorylation site that negatively regulates RAS binding and ARAF activation, leading to hyperactivity of the MAP-kinase signaling pathway (PMID: 24569458). ARAF-mutant cancers may be sensitive to RAF and MAPK family inhibitors, such as sorafenib (PMID: 24569458). False +ENST00000274498 NM_015071 23092 ARHGAP26 True ARHGAP26, a GTPase activating protein that regulates RhoA, is altered by chromosomal rearrangement in gastric cancer. ARHGAP26 encodes for a GTPase activating protein which functions in hydrolysis of GTPases (PMID: 9858476). ARHGAP26 negatively regulates Rho GTPases through conversion to the inactive GDP-bound form (PMID: 9858476, 31004081, 25079317). Rho GTPases modulate actin-mediated cellular functions including cellular adhesion, migration and cell division (PMID: 31013840, 12606561).The oncogenic effect of ARHGAP26 is likely tissue specific. Fusion of ARHGAP26 with CLDN18 has been recurrently identified in gastric cancer and identified to promote tumorigenesis in preclinical studies (PMID: 29961079, 25079317, 32983960). Overexpression of circular RNA ARHGAP26 in gastric cancer cell lines and models induces cellular proliferation, invasion and migration (PMID: 30719998, 28544609). Conversely, downregulation of ARHGAP26 in ovarian and glioblastoma cancer cell lines and models suppresses cellular proliferation, invasion and migration, suggesting that ARHGAP26 functions predominantly as a tumor suppressor gene in this context (PMID: 31004081, 17611651). Inactivation and methylation of ARHGAP26 has been identified in acute myeloid leukemia and promyelocytic leukemia (PMID: 16404424, 10908648, 17611651). True +ENST00000404338 NM_004491.4 2909 ARHGAP35 True ARHGAP35, a GTPase activating protein that regulates RhoA, is altered by mutation and deletion across a variety of solid tumor types. ARHGAP35 (also GRLF1) is a GTPase activating protein (GAP) that negatively regulates the activity of Rho-family small GTPases (guanosine triphosphatases) (PMID: 31013840). Rho GTPases modulate actin-mediated cellular functions including cellular adhesion, migration and cell division (PMID: 31013840, 12606561). ARHGAP35 encodes the protein p190A which, along with the paralog p190B, function as the main GAP proteins that regulate Rho cellular activity (PMID: 8537347). GAP proteins, such as p190A, enhance nucleotide hydrolysis and inhibit GTPase signaling activity (PMID: 27628050). p190A interacts with a variety of effector molecules, including RHOA, RHOC and RAC1, among others, to regulate cell adhesion and migration (PMID: 28287334, 27646271). In addition, p190A associates with TFII-I and eIF3A to mediate gene expression and translation, respectively (PMID: 28007963, 15629714). p190A is also implicated in several other cellular processes including entosis, dendritic spine formation and endothelial permeability (PMID: 18045538, 18267090, 17562701). Somatic mutations in ARHGAP35 have been identified in a variety of tumor types in pan-cancer studies, most predominantly in uterine carcinomas (PMID: 24132290, 24390350). ARHGAP35 mutations have also been associated with Hürthle cell carcinoma, colorectal cancer and renal angiomyolipoma (PMID: 30107175, 28176259, 27494029). These alterations commonly occur as nonsense or frameshift mutations throughout the ARHGAP35 gene (PMID: 31013840, 27646271). However, disruption of p190A in functional assays has both growth inhibitory and proliferative effects, suggesting that p190A may function as a tumor suppressor or oncogene depending on the context (PMID: 31013840, 27646271). True +ENST00000397843 NM_015313 23365 ARHGEF12 True ARHGEF12, a Rho guanine nucleotide exchange factor, is infrequently altered in cancer. ARHGEF12, or leukemia-associated RhoGEF, encodes a protein of the diffuse B-cell lymphoma (Dbl) family of guanine nucleotide exchange factors that activates small GTPase Rho (PMID: 23255595). ARHGEF12 has been implicated in regulating various cellular pathways including cell morphology and polarization, invasion, the final steps of cytokinesis and integrin force regulation (PMID: 23885121, 33419897, 21572419). ARHGEF12 is implicated in an oncogenic positive feedback loop with RhoA-effector DIAPH1 and RhoA in the LPA-stimulated Rho/ROCK signaling pathway, promoting bleb-associated cancer cell invasion and tumor cell morphology (PMID: 17575049). Loss of ARHGEF12 has been identified in breast cancer and colorectal cancer (PMID: 19734946). Rare chromosomal rearrangements of ARHGEF12 have been identified in acute myeloid leukemia and acute lymphoblastic leukemia, and have been suggested to lead to loss of ARHGEF12 function to promote tumorigenesis (PMID: 33419897, 34237703, 19734946). True +ENST00000426542 NM_001177693.1 64283 ARHGEF28 True ARHGEF28, an intracellular kinase that regulates cell growth and metabolism, is infrequently altered in cancer. ARHGEF28 (also Rgnef and p190RhoGEF) is a Rho guanine exchange factor (GEF) that catalyzes the exchange of GDP for GTP (PMID: 24467206, 24006257). ARHGEF28 activates small RhoA GTPases by catalyzing the dissociation of GDP and facilitating a conformational change leading to GTP binding. ARHGEF28 activity is required for focal adhesion establishment, regulation of cell motility, contractility, and initiation of cell signaling (PMID: 24467206). ARHGEF28 binds and functions as either a GEF or a scaffolding protein to initiate FAK activation and cell contractility (PMID: 24467206, 24006257). Functional studies have demonstrated that the RhoA-FAK pathway is important for cancer cell proliferation and migration in breast and lung cancer models (PMID: 19147981, 23358651, 21224360). Both familial and sporadic mutations in ARHGEF28 have been identified in the neurological disease amyotrophic lateral sclerosis (ALS) (PMID: 23286752); however, somatic mutations in ARHGEF28 are infrequent in human cancers. False +ENST00000324856 NM_006015.4 8289 ARID1A False 4 ARID1A, a tumor suppressor involved in transcriptional regulation, is inactivated by mutation in various cancer types including endometrial and bladder cancers. ARID1A, also known as BAF250A, is a member of the SWI/SNF chromatin-remodeling complex, and plays a role in altering chromatin structure for various cellular functions, including transcription, DNA synthesis and DNA repair (PMID: 25387058, 23208470). ARID1A binds to AT-rich regions of DNA and helps recruit other members of the SWI/SWF complex, such as SMARCA and BAF complexes. Together, these complexes are involved in ATP-dependent chromatin remodeling via nucleosome displacement and thus allow for gene expression activation (PMID: 12672490, 10078207, 11073988). In a mouse model of colon cancer, ARID1A loss specifically altered enhancer-mediated gene regulation (PMID: 27941798). Germline mutations in ARID1A result in Coffin-Siris syndrome, which is characterized by developmental delay and coarse facial features (PMID: 11170086). Additionally, ARID1A has been identified as a tumor suppressor in multiple cancer types, including gynecologic cancers, ovarian clear cell carcinomas and endometrial cancers (PMID: 21900401, 21590771, 20826764). True +ENST00000647938 NM_020732.3 57492 ARID1B False ARID1B, a tumor suppressor involved in transcriptional regulation, is inactivated by mutation or deletion in various cancer types. ARID1B (AT-rich interactive domain-containing protein 1B), also known as BAF250B, is a member of the SWI/SNF chromatin-remodeling complex, and plays a role in altering chromatin structure for various cellular functions, including transcription, DNA synthesis and DNA repair (PMID: 15170388, 25387058). ARID1B binds to AT-rich regions of DNA and helps recruit other members of the SWI/SWF complex, such as SMARCA and BAF complexes. Together, these complexes are involved in ATP-dependent chromatin remodeling via nucleosome displacement and thus allow for gene expression activation (PMID: 12672490, 10078207, 11073988). ARID1B can substitute for ARID1A in BAF complexes despite ARID1A being more commonly present (PMID: 15170388). Like ARID1A, germline mutations in ARID1B result in Coffin-Siris syndrome, which is characterized by developmental delay and coarse facial features (PMID: 22426309). Inactivating ARID1B mutations have been identified in breast cancer (PMID: 22722201), gynecologic carcinosarcoma (PMID: 25233892), pancreatic cancer (PMID: 22233809) and neuroblastoma (PMID: 23202128). True +ENST00000334344 NM_152641.2 196528 ARID2 False ARID2, a tumor suppressor involved in transcriptional regulation, is inactivated by mutation or deletion in various cancer types. ARID2, also known as BAF200, is a subunit in the PBAF complex, a subtype of the SWI/SNF complex, which facilitates nuclear receptor-mediated, ligand-dependent transcriptional activation by modulating chromatin structure to make DNA more accessible (PMID: 19234488, 11780067). ARID2 contains a conserved AT-rich DNA interaction domain and is thought to confer specificity to the PBAF complex (PMID:15985610). Most ARID2 mutations found in tumors are inactivating, suggesting ARID2 is a tumor suppressor gene. ARID2 mutations are most commonly found in hepatocellular carcinoma (HCC), where they often lead to an inactive, truncated protein (PMID: 21822264). ARID2 mutations are also found in melanoma and non-small cell lung cancer (NSCLC) (PMID: 23047306, 22817889), and are associated with loss of heterozygosity (LOH). True +ENST00000263620 NM_005224.2 1820 ARID3A False ARID3A, a transcription factor important in B cell differentiation, is infrequently mutated in a diverse range of cancers. ARID3A (also Bright) is a member of the ARID family of DNA binding proteins. ARID3A functions as a transcription factor that regulates the transcription of genes relevant in B-cell biology, including the immunoglobulin heavy chain in lymphocytes (PMID: 24678314). Expression of ARID3A is tightly controlled during B cell differentiation with the highest expression occurring in hematopoietic stem cells, pre-B cells, transitional B cells, activated B cells, memory B cells and plasma cells (PMID: 15203319, 26685208, 21199920). ARID3A associates with BTK (Bruton's tyrosine kinase) and E2F1 to mediate DNA binding and regulation of transcription (PMID: 9780002, 15203319). Overexpression of ARID3A in murine studies results in autoimmunity highlighting the importance of ARID3A in B cell regulation (PMID: 15203319, 21963220). In addition to the role of ARID3A in B cells, ARID3A can also cooperate with TP53 to activate the expression of p21, a protein involved in cell cycle arrest, in a range of cell types (PMID: 22172947). Additional roles for ARID3A gene regulation have been identified, including in colorectal cancer studies (PMID: 26121572, 24366420). However, somatic mutations in ARID3A are relatively rare in human cancers. True +ENST00000346246 NM_001307939.1 10620 ARID3B True ARID3B, a DNA binding protein highly expressed in squamous epithelium, is infrequently mutated in a diverse range of cancers. ARID3B (also BDP) is a member of the ARID family of DNA binding proteins. ARID3B functions as a transcription factor that is most highly expressed in squamous epithelium (PMID: 24704276). ARID3B can homodimerize or heterodimerize with other ARID3 family members and interact with additional transcription factors including the Rb-associated proteins RBP1 and RBP2 to regulate gene expression in a variety of cellular contexts (PMID: 10446990). Expression of ARID3B is required for B cell differentiation (PMID: 27537840) and has been implicated in the regulation of oncogenic genes in the context of ovarian cancer (PMID: 26121572), oral squamous cancer (PMID: 25858147), and neuroblastomas (PMID: 16951138). ARID3B activity is also important in regulating cancer stemness (PMID: 25858157), the maintenance of mesenchymal stem cells (PMID: 16530748) and the organization of the chromatin state (PMID: 26776511). Somatic mutations in ARID3B are relatively rare in human cancers; however, ARID3B is overexpressed in ovarian cancer and neuroblastoma (PMID: 24704276). Consistent with these data overexpression of ARID3B in ovarian cancers has been shown to be transforming in preclinical studies (PMID: 25327563). False +ENST00000378909 NM_001017363.1 138715 ARID3C False ARID3C, a DNA binding protein expressed in lymphocytes, is infrequently mutated in a diverse range of cancers. ARID3C (also Brightlike) is a member of the ARID family of DNA binding proteins (PMID: 24704276). ARID3C functions as a transcription factor and shares substantial sequence homology with homologs ARID3A and ARID3B. The highest expression of ARID3C has been identified in B lineage lymphocytes and activated follicular B cells (PMID: 21955986). While the function of ARID3C has not been extensively characterized, ARID3C can bind ARID3A at known ARID3A chromatin binding sites (PMID: 21955986). Importantly, ARID3A and ARID3C co-regulate immunoglobulin heavy chain transcription in B lymphocytes (PMID: 21955986). Somatic mutations in ARID3C are rare in human cancers and further functional studies are required to delineate the role of ARID3C in cancer (PMID: 24704276). False +ENST00000355431 NM_002892.3 5926 ARID4A False ARID4A, a DNA binding protein involved in E2F transcription, is infrequently mutated in a diverse range of cancers. ARID4A (also RBBP1, RBP1) is a member of the ARID family of DNA binding proteins (PMID: 18728284). ARID4A, and the homologous gene ARID4B, function as transcription factors that regulate gene expression and chromatin state (PMID: 17043311). Both ARID4A and ARID4B bind retinoblastoma protein (Rb) and function as repressors of E2F-mediated transcription by acting as adaptors to recruit the mSin3A histone deacetylase (HDAC) histone-modifying complex to E2F target genes (PMID: 1857421, 11283269). The ARID4A-RB complex is involved in many cellular functions including cellular differentiation, cellular proliferation, apoptosis and DNA damage. ARID4A also interacts with breast cancer metastasis suppressor 1 (BRMS1), a protein that mediates anti-metastasis gene expression programs (PMID: 18211900, 14581478). Deletion of ARID4A in murine models results in a hematopoietic disorder, suggesting that ARID4A functions as a tumor suppressor in some cellular contexts (PMID: 18728284). Somatic ARID4A mutations are relatively rare in human cancers; however, alterations have been identified in several cancer types including colorectal cancer (PMID: 24382590). True +ENST00000264183 NM_001206794.1 51742 ARID4B False ARID4B, a DNA binding protein that mediates E2F binding, is infrequently mutated in a diverse range of cancers. ARID4B (also RBB1L1) is a member of the ARID family of DNA binding proteins (PMID: 18728284). ARID4B, and the homologous gene ARID4A, function as transcription factors that regulate gene expression and chromatin state (PMID: 17043311). Both ARID4A and ARID4B bind retinoblastoma protein (Rb) and function as repressors of E2F-mediated transcription by acting as adaptors to recruit the mSin3A histone deacetylase (HDAC) histone-modifying complex to E2F target genes (PMID: 1857421, 11283269). The ARID4B-RB complex is involved in many cellular functions including cellular differentiation, cellular proliferation, apoptosis and DNA damage. ARID4B also interacts with breast cancer metastasis suppressor 1 (BRMS1), a protein that mediates anti-metastasis gene expression programs (PMID: 22693453). Somatic ARID4B mutations are relatively rare in human cancers; however, mutations have been identified in several cancer types including relapsed childhood acute lymphoblastic leukemia (PMID: 26189108). Decreased expression of ARID4B has been identified in several cancer types including prostate cancer (PMID: 29797600), suggesting that ARID4B functions predominantly as a tumor suppressor. True +ENST00000357485 NM_212481.1 10865 ARID5A False ARID5A, an RNA binding protein, is infrequently mutated in a diverse range of cancers. ARID5A (also MRF1) is an RNA binding protein that is a member of the ARID transcription factor family (PMID: 29787158). ARID5A binds the 3’UTR of IL-6 mRNA (PMID: 23676272) and regulates IL-6 mRNA stability in response to cytokine stimulation (PMID: 23676272). ARID5A expression is increased in macrophages and T-cells in response to LPS, IL-1β, and IL-6 treatment (PMID: 23676272). IL-6 induces the expression of ARID5A in T-cells leading to differentiation into inflammatory T-cells (such as Th17 cells) via a STAT3 dependent mechanism (PMID: 24782182, 27022145). Loss of ARID5A in murine hematopoietic and lung tissues results in a reduction of STAT3 and IL-6 expression and a blunting of the immune response, suggesting that ARID5A plays a critical role in inflammation, T-cell differentiation and autoimmunity (PMID: 27022145, 28379390). IL-6 stability is also important for the regulation of key cell signaling pathways including the NF-κB and MAPK pathways (PMID: 28168301). In addition, ARID5A has been implicated in RNA binding to other T-cell-related mRNAs, including T-bet, and DNA binding in collaboration with Sox9 in chondrocytes (PMID: 21346191). Somatic ARID5A mutations are rare in human cancers; however, several mutations have been identified in a diverse range of cancers. False +ENST00000279873 NM_032199.2 84159 ARID5B False ARID5B, a tumor suppressor involved in transcriptional regulation, is altered at low frequencies in various cancer types. ARID5B (AT-rich interactive domain 5b) is part of the ARID family of transcription factors, which bind to AT-rich DNA and play a role in diverse biological functions including embryonic development, lymphocyte development, cell-type-specific gene expression and cell growth regulation (PMID:15640446). ARID5B is a binding partner of the demethylase PHF2 (PMID: 21532585); the ARID5B-PHF2 complex binds to the promoters of SOX9 target genes to transcriptionally activate chondrogenesis (PMID: 24276541). ARID5B polymorphisms confer increased risk of pediatric acute lymphoblastic leukemia (ALL) as determined by genome-wide association studies (PMID: 19684604, 19684603). It was further determined that these patients show significant association with the clinical phenotype of intracellular accumulation of methotrexate polyglutamates, which is consistent with greater sensitivity to methotrexate-based chemotherapies (PMID: 19710713). However, it is unknown how these alleles confer a greater risk of childhood ALL development. True +ENST00000375687 NM_015338.5 171023 ASXL1 False ASXL1, a tumor suppressor and epigenetic regulator, is inactivated by mutation in various cancer types, most frequently in myeloid malignancies. ASXL1 is a member of the Polycomb group of proteins, and is a chromatin binder that is involved in transcription regulation. ASXL1 is a member of the ASXL gene family that includes ASXL1, ASXL2 and ASXL3, which all have a C-terminal plant homology domain (PHD domain) that is predicted to recognize histone H3 tails via methylated lysines (PMID: 23147254). ASXL1 interacts directly with the Polycomb Repressive Complex 2 (PRC2) and has a role in the recruitment of PRC2 to chromatin and subsequent H3K27me3 histone modifications (PMID: 22897849). Mutations in ASXL1 result in the inability of Polycomb target genes to be effectively repressed leading to dysregulated gene expression, such as at the HOXA gene cluster (PMID: 22897849). ASXL1 also independently interacts with the chromatin protein BAP1 (PMID: 22878500). The BAP1-ASXL1 complex can regulate the H2AK119 ubiquitin mark placed by the Polycomb Repressive Complex 1 (PRC1) (PMID: 20436459). Germline heterozygous mutations in ASXL1 have been found in patients with Bohring-Opitz syndrome, a developmental disorder that results in distinctive craniofacial abnormalities (PMID: 21706002). Recurrent somatic ASXL1 loss-of-function mutations are very common in hematopoietic malignancies including myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CMML), myelofibrosis (MF), and acute myeloid leukemia (AML) (PMID: 23147254, 30651633). Furthermore, ASXL1 mutations frequently co-occur with N/K-Ras mutations in CMML to promote leukemogenesis (PMID: 21455215). True +ENST00000435504 NM_018263.4 55252 ASXL2 False ASXL2, a tumor suppressor and epigenetic regulator, is inactivated by mutation in various cancer types including acute myeloid leukemia. ASXL2, a member of the Polycomb group of proteins, is a chromatin binder that is involved in transcription regulation. ASXL2 belongs to the ASXL gene family that includes ASXL1, ASXL2 and ASXL3, all which have a C-terminal plant homology domain (PHD domain) that is predicted to recognize histone H3 tails via methylated lysines (PMID: 23147254). ASXL2 shares several conserved domains with ASXL1, a protein that regulates gene expression by interaction with the chromatin Polycomb Repressive Complex 2 (PRC2), and mutations in these genes are mutually exclusive in acute myeloid leukemia (AML), suggesting they may have similar functions and may contribute to transformation in the same way (PMID: 23147254, 19270745, 12888926). ASXL2 interacts with the chromatin-modifying enzyme BAP1 (PMID: 22878500), has been found to regulate nuclear receptors such as the retinoic acid receptor, LXRα and PPARγ (PMID: 25065743, 24321552, 21047783) and was identified as a protein that regulates bone density such that deletion of ASXL2 leads to deficient osteoclast formation in mice (PMID: 21490954, 26051940). True +ENST00000262053 NM_005171.4 466 ATF1 True ATF1, a transcription factor, is rarely altered by chromosomal rearrangements in a variety of cancer types. ATF1 is a leucine zipper transcription factor that binds to cAMP-inducible promoters. The protein is activated via phosphorylation by several kinases, such PKA, and dimerizes and binds to cAMP-responsive elements within promoters across the genome (PMID:8663317, 1655749). Direct interaction and activation of ATF1 by BRCA1 suggest involvement in response to cellular DNA damage (PMID: 10945975). Additionally, EGF-induced expression of specific transcription factors requires ERK/MAPK activation of ATF1 (PMID:12414794) in human cells. False +ENST00000236959 NM_004044 471 ATIC True ATIC, a bifunctional enzyme in the de novo purine synthesis pathway, is infrequently altered in cancer. ATIC encodes for a bifunctional enzyme which functions in both 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) formyltransferase and inosine monophosphate (IMP) cyclohydrolase activity for de novo purine biosynthesis (PMID: 36063996, 29063699). ATIC is the rate-limiting enzyme of the de novo purine synthesis pathway and produces the intermediate formyl-AICAR (FAICAR) and IMP in the final two steps of the pathway (PMID: 9598063). Overexpression of ATIC in various cancer cell lines and models induces cellular proliferation, invasion and metastasis, suggesting that ATIC functions predominantly as an oncogene (PMID: 35251351, 34803509, 29246230). ATIC amplification and rearrangements have been identified in various cancers, including multiple myeloma and lung adenocarcinoma (PMID: 33226193, 35251351, 10706082). False +ENST00000278616 NM_000051.3 472 ATM False 1 ATM, a kinase involved in DNA damage response, is inactivated in various solid and hematologic malignancies. Germline ATM mutations are a defining feature of ataxia telangiectasia syndrome, a neurodegenerative, autosomal disorder that predisposes to various cancers. ATM is a member of the protein superfamily of phosphatidylinositol 3-kinase related serine/threonine kinases (PIKKs). ATM functions as a tumor suppressor that initiates DNA damage checkpoint signaling after accumulation of DNA double-strand breaks (DSBs) or after accumulation of other forms of cellular stress (PMID: 23219553). Activated ATM can phosphorylate hundreds of substrates in order to initiate and amplify the DNA damage response (PMID: 17525332) resulting in DNA repair, cell cycle arrest and/or apoptosis. Germline homozygous/compound heterozygous loss-of-function mutations in ATM have been identified in the autosomal recessive disorder ataxia telangiectasia (A-T), a disorder that presents with a variety of neurologic conditions, lung and skin disorders, and immunodeficiency (PMID: 21792198). Patients with A-T are also predisposed to a wide variety of cancers, particularly childhood lymphomas and leukemia as well as breast cancer (PMID: 21792198), whereas heterozygous carriers are at increased risk for adult-onset breast (PMID: 27112364, 31171119, 33471974), pancreatic (PMID: 22585167, 34529012), prostate (PMID: 33436325), gastroesophageal junction (PMID: 35078243), and other cancers. Somatic mutations in ATM have been identified in lymphoid malignancies and a selection of solid tumors (PMID: 12400598, 27413114). ATM-mutant cancers are increasingly sensitive to DNA damaging agents due to deficits in DNA repair pathways, and ATM loss may result in better response to checkpoint inhibition in some cancers (PMID: 27413114, 29489427). True +ENST00000295598 NM_000701 476 ATP1A1 True ATP1A1, the catalytic subunit of the Na+/K+-ATPase complex, is frequently altered in cancer. ATP1A1 encodes the catalytic alpha1 subunit of the Na+/K+-ATPase (NKA) complex, which functions in maintaining the balance of ionic homeostasis and cellular signal transduction (PMID: 34251542). ATP1A1 binds ATP on its ATP-binding sites for the NKA complex's energy conversion to allow the transport of sodium and potassium ions across the cellular membrane (PMID: 34251542). Normal expression of ATP1A1 is dependent on different tissue types as lower and higher expression levels have been identified in various tissues. Selective inhibition of ATP1A1 in non-small cell lung cancer cell lines impairs cell proliferation and migration whereas overexpression of ATP1A1 in renal cancer cell lines impairs cell proliferation and migration, suggesting that ATP1A1 functions as both an oncogene and tumor suppressor depending on the tumor type (​​PMID: 17471453, 28484360). Overexpression of ATP1A1 has been identified in various cancer types, including non-small cell lung cancer, breast cancer and glioma (PMID: 17471453, 28529692, 18300910). In contrast, loss of ATP1A1 has been identified in renal cell carcinoma and aldosterone-producing adenoma (PMID: 28484360, 34681640). True +ENST00000369762 NM_001183.5 537 ATP6AP1 False ATP6AP1, a V-ATPase accessory protein involved in organelle acidification, is recurrently mutated in follicular lymphomas. ATP6AP1 (also VAS1, Ac45) is a vacuolar H-ATPase (V-ATPase) accessory protein (PMID: 27231034). V-ATPase is a multi-protein complex that couples ATP hydrolysis to a proton pump for the luminal acidification of organelles and secretory vesicles across membranes (PMID: 27231034). ATP6AP1, in addition to the second accessory protein ATP6AP2, guide V-ATPase into subcellular compartments such as the secretory vesicles (PMID: 22044156). The highest expression of ATP6AP1 is found in neuronal cells, neuroendocrine cells and osteoclasts (PMID: 18227071, 11983866). In addition, ATP6AP1 has roles in membrane trafficking, membrane fusion, and activation of amino acid-induced mTORC1 activation (PMID: 22736765, 26691987). ATP6AP1 is an X-linked gene and mutations in ATP6AP1 have been identified in males that have defects in glycosylation (PMID: 27231034, 29127204). Somatic ATP6AP1 frameshift and nonsense mutations have been identified in follicular lymphoma (PMID: 26691987, 25713363), suggesting that ATP6AP1 functions as a tumor suppressor. False +ENST00000276390 NM_001693.3 526 ATP6V1B2 False ATP6V1B2, a component of the V-ATPase complex, is recurrently mutated in follicular lymphoma. ATP6V1B2 is a component of the vacuolar H-ATPase (V-ATPase) complex (PMID: 27231034). V-ATPase is a multi-protein complex that couples ATP hydrolysis to a proton pump for the luminal acidification of organelles and secretory vesicles across membranes (PMID: 27231034). ATP6V1B2 encodes the non-catalytic B2 subunit of the V-ATPase complex, which predominantly functions in ATP hydrolysis and is ubiquitously expressed in most tissues (PMID: 18667600). In addition, ATP6V1B2 has roles in vacuolar fusion, T cell motility, amino acid-induced mTORC1 activation, and SIRT1-mediated regulation in adipocytes (PMID: 26177453). ATP6V1B2 mutations have been associated with dominant developmental disorders including deafness-onychodystrophy syndrome and Zimmermann-Laband syndrome (PMID: 25915598, 24913193, 28396750). Recurrent somatic mutations in ATP6V1B2 are found in patients with follicular lymphoma (PMID: 28064239, 26691987, 30720463). Loss-of-function mutations in ATP6V1B2 result in the activation of autophagy, enhanced mTOR signaling, impaired lysosomal acidification and altered amino acid sensing (PMID: 30720463). True +ENST00000350721 NM_001184.3 545 ATR False 1 ATR, a tumor suppressor involved in DNA damage repair, is mutated in various cancer types. ATR (ataxia telangiectasia and Rad3-related protein) is a serine/threonine kinase involved in the DNA damage response. ATR responds to DNA damage and single-strand DNA by activating cell-cycle checkpoint and DNA repair pathways (PMID:12791985, 20818375, 17157788). It is also involved in regulating telomere maintenance, initiation of DNA replication and meiosis (PMID: 17687332,15220931, 23824539). Germline mutations of ATR are associated with cancer predisposition and Seckel syndrome, a condition associated with central nervous system disorders (PMID: 22341969, 12640452). Somatic mutations are associated with microsatellite instability and are found in colon cancer, urothelial cancer, gastric cancer, endometrial cancer and myelomas (PMID: 11691784,16288216,17879369, 26282654,19470935). Preclinical data has shown that kinase inhibitors of ATR may enhance chemotherapy response and treatment of DNA repair-pathway-deficient cancers (PMID: 26517239, 21552262, 26312880). True +ENST00000320211 NM_130384 84126 ATRIP False ATRIP, a DNA damage checkpoint protein, is infrequently altered by deletion in cancer. ATRIP is the regulatory binding protein of the serine/threonine kinase ATR and functions in the DNA damage response (PMID: 22258451). ATRIP responds to DNA damage through interaction with replication protein A (RPA)-coated single-stranded DNA, allowing the ATRIP-ATR complex to localize to sites of DNA damage or to stressed replication forks (PMID: 12791985). The ATRIP-ATR complex is also involved in regulating telomere maintenance, initiation of DNA replication and meiosis (PMID: 17687332,15220931, 23824539). Germline truncating mutations in ATRIP are associated with Seckel syndrome, a condition associated with central nervous system disorders (PMID: 23144622). Loss of ATRIP has been identified in various cancers, including myeloma and ovarian cancer (PMID: 26282654, 19737971). True +ENST00000373344 NM_000489.3 546 ATRX False ATRX, a tumor suppressor involved in transcriptional regulation, is infrequently altered in cancer. ATRX (alpha thalassemia/mental retardation syndrome X-linked) is a chromatin regulator that functions as a member of the SWI/SNF helicase family (PMID: 20110566, 17609377). ATRX is involved in the incorporation of histone H3.3 during telomere replication (PMID: 20110566). Loss of ATRX activity results in aberrant DNA methylation, histone composition and transcription, suggesting that ATRX functions predominantly as an epigenetic regulator (PMID: 29535300). Germline mutations in ATRX result in a severe form of X-linked mental retardation often associated with alpha-thalassemia (ATRX) syndrome (PMID: 8968741). Loss-of-function mutations or reduced ATRX expression is strongly correlated with an alternate lengthening of telomeres (ALT) phenotype in tumors (PMID: 21719641). Somatic mutations have been associated with chromosomal instability and epigenetic remodeling in a variety of human cancers (PMID: 23104868, 24148618, 29535300). Patients with ATRX mutations may be increasingly sensitive to agents that target DNA repair pathways (PMID: 27657132). True +ENST00000550104 NM_002973.3 6311 ATXN2 False ATXN2, an RNA binding protein, is infrequently mutated in a diverse range of human cancers. ATXN2 is an RNA binding protein that regulates protein translation. Through interactions with poly(A) binding protein (PABP), ATXN2 regulates mRNA translation and localizes to stress granules and P-bodies, cellular components important for regulation of mRNA degradation and translation (PMID: 22508507, 15342467). In addition, ATXN2 may function to transport RNA between actively translating polysomes and stress granules (PMID: 22508507). ATXN2 also has roles in actin filament formation, secretion, receptor signaling, RNA metabolism, and cell specification (PMID: 22508507, 15342467). Abnormal expansion of the CAG repeat sequence in ATXN2, resulting in an extended polyglutamine sequence, are found in a range of neurological disorders including Spinocerebellar ataxia, Parkinson’s disease and amyotrophic lateral sclerosis (ALS) (PMID: 21562247, 29756284, 21670397, 27663142, 25098532). Somatic mutations in ATXN2 are rare in human cancers and are found infrequently in a diverse range of tumor types. True +ENST00000295900 NM_000333.3 6314 ATXN7 True ATXN7, a transcriptional regulator that mediates chromatin remodeling and deubiquitination, is recurrently altered by mutation and fusion in thyroid, colorectal and breast cancers. ATXN7 (also SCA7) is a chromatin-modifying protein that functions as a transcriptional co-activator (PMID: 16494529). ATXN7 is a component of the multi-subunit SAGA transcriptional complex that has multiple enzymatic functions including histone acetylation (PMID: 21746879) and deubiquitination (PMID: 21746879). The SAGA complex facilitates transcriptional regulation by remodeling chromatin via GCN5-mediated histone acetylation to promote general transcription factor binding to DNA (PMID: 21746879). In addition, the SAGA complex mediates targeting of the transcriptional pre-initiation complex to promoters and deubiquitination via the cofactors ATXN7L3, USP22, and ENY2 to mediate protein translation (PMID: 18206972). SAGA-dependent histone H2B deubiquitination is also critical for the DNA damage response, an activity that is especially important during class switch recombination (PMID: 21746879, 18206972). Trinucleotide repeat expansions in the coding region of the ATXN7 gene are associated with spinocerebellar ataxia type 7 (SCA7), a neurological disorder that results in macular dystrophy and progressive retinal degeneration (PMID: 9288099, 9781533, 10330346, 10640674, 3062533). In SCA7-mutant murine models and in patients with SCA7, CAG trinucleotide expansions in ATXN7 result in an abnormal polyglutamine tract (polyQ) and in nuclear accumulation of protein (PMID: 14985428). Somatic mutations in ATXN7 are found in patients with thyroid cancer and cluster predominantly in the polyglutamine domain of the protein where the germline expansions occur in SCA7 (PMID: 28584132). ATXN7 mutations are predicted to be gain-of-function and induce proliferation in thyroid cells in collaboration with the RAS oncogene (PMID: 28584132). In addition, ATNX7 fusion proteins have been found in patients with colorectal and breast cancer (PMID: 27296891). False +ENST00000312783 NM_003600.2 6790 AURKA True AURKA, an intracellular kinase, is altered by mutation, amplification or overexpression in various cancer types including breast and colorectal cancers. AURKA (Aurora kinase A) is a cell-cycle regulatory serine/threonine kinase that promotes entry into and proper progression through mitosis. AURKA is expressed in actively proliferating cells, specifically in the G2 and mitotic phases of the cell cycle, and has multiple roles in promoting cell division, including recruitment of microtubule-nucleating proteins to centrosomes to mediate spindle assembly and regulating entry into mitosis (PMID: 12884918, 16186253, 18566290). AURKA amplification has been observed in multiple tumor types, including leukemia, colorectal, and pancreatic cancers (PMID: 18820130, 9606188, 12631597). Overexpression of AURKA can promote cellular transformation and may potentiate the activity of other oncogenes, such as RAS (PMID: 15592510). Small-molecule inhibitors of AURKA (and the related Aurora B and C kinases) are currently being investigated as general inhibitors of cell proliferation and potential anti-mitotic chemotherapeutic drugs (PMID: 24965505). False +ENST00000585124 NM_004217.3 9212 AURKB True AURKB, an intracellular kinase, is infrequently altered in cancer. AURKB (Aurora Kinase B) is a cell-cycle regulatory serine/threonine kinase that promotes entry into and proper progression through mitosis. AURKB protein is expressed in proliferating cells during G2 and mitosis and phosphorylates multiple proteins to maintain genome integrity. AURKB aids in the establishment of proper chromosome-spindle attachments in the spindle assembly checkpoint and is essential for cytokinesis (PMID: 11050385,12707311, 14767480). Increased AURKB expression is seen in certain cancers, such as hepatocellular carcinomas (PMID: 20799978), but the functional implication of dysregulated AURKB expression has not been established. Forced over-expression of AURKB was reported to promote aneuploidy in fibroblast cells, suggesting a potential role in promoting chromosome instability (PMID: 12234980). False +ENST00000262320 NM_003502.3 8312 AXIN1 False AXIN1, a tumor suppressor involved in WNT signaling, is mutated at low frequencies in various cancer types. AXIN1 is a scaffolding protein that is a component of the beta-catenin destruction complex. In this complex, AXIN1 and AXIN2 provide scaffolding for the tumor suppressor APC, the kinase GSK3, and beta-catenin (PMID: 14600025), enabling beta-catenin degradation in the absence of WNT ligand binding at the plasma membrane (PMID: 9734785). AXIN proteins interact with the receptors LRP5 and LRP6 to facilitate GSK3 recruitment to the plasma membrane following WNT extracellular stimulation, leading to activation of WNT signaling and targeting of beta-catenin to the nucleus to regulate transcription (PMID: 20128690, 23169527). The activation of WNT signaling, mediated in part by AXIN proteins, can activate many pathways relevant to cancer including cellular proliferation, cell cycle progression, apoptosis, and stem cell fate decisions (PMID: 15735151, 27617575). Germline mutations in AXIN1 have been associated with gastrointestinal cancers (PMID: 25236910). Truncating somatic mutations in AXIN1 have been associated with hepatocellular carcinoma and hepatoblastomas, suggesting that AXIN1 functions as a putative tumor suppressor gene (PMID: 12101426, 10700176). True +ENST00000307078 NM_004655.3 8313 AXIN2 False AXIN2, a tumor suppressor involved in WNT signaling, is mutated at low frequencies in various cancer types. AXIN2 is a scaffolding protein that is a component of the beta-catenin destruction complex. In this complex, AXIN1 and AXIN2 provide scaffolding for the tumor suppressor APC, the kinase GSK3, and beta-catenin (PMID: 14600025), enabling beta-catenin degradation in the absence of WNT ligand binding at the plasma membrane (PMID: 9734785). AXIN proteins interact with the receptors LRP5 and LRP6 to facilitate GSK3 recruitment to the plasma membrane following WNT extracellular stimulation, leading to activation of WNT signaling and targeting of beta-catenin to the nucleus to regulate transcription (PMID: 20128690, 23169527). The activation of WNT signaling, mediated in part by AXIN proteins, can activate many pathways relevant to cancer including cellular proliferation, cell cycle progression, apoptosis, and stem cell fate decisions (PMID: 15735151, 27617575). Germline mutations in AXIN2 have been associated with gastrointestinal and colorectal cancers (PMID: 25236910, 21541676) as well as familial tooth agenesis and predisposition to colorectal cancer (PMID: 15042511). AXIN2 expression has also been shown to predict prostate cancer recurrence (PMID: 26771938). Truncating mutations in AXIN2 have been associated with colorectal cancer and are predicted to result in gain-of-function activity, however, further studies are required to confirm that these alterations are indeed activating (PMID: 11017067). True +ENST00000301178 NM_021913.4 558 AXL True AXL, a receptor tyrosine kinase, is altered by mutation, amplification or overexpression in various cancer types. AXL is a receptor tyrosine kinase (PMID: 28072762) whose primary ligand is the vitamin K-dependent growth factor GAS6 (growth arrest-specific protein 6). Activation of AXL via GAS6 requires an additional interaction with phosphatidylserine, a phospholipid that is only accessible to apoptotic cells (PMID: 28072762). AXL activates the JAK/STAT, MAPK/ERK, and PI3K/AKT signaling pathways (PMID: 18620092) leading to proliferation, survival, and chemoresistance in AXL-expressing cells (PMID: 23982172). Additionally, AXL has been shown to be essential for the epithelial-to-mesenchymal transition (EMT) and can mediate metastasis in cancer (PMID: 16585512). While somatic mutations in AXL are rare, AXL is overexpressed in many human cancers including lung, breast, pancreatic and hematopoietic cancers (PMID: 1656220). AXL overexpression has been implicated in resistance to chemotherapy and targeted agents and decreased immune response, making AXL a target for drug development (PMID: 28072762). Currently, inhibitors specifically targeting AXL or multi-targeted kinase inhibitors with good potency against AXL are under clinical development (PMID: 25337673). False +ENST00000559916 NM_004048.2 567 B2M False B2M, a tumor suppressor and regulator of the immune system, is inactivated by mutation or deletion in various cancer types including non-Hodgkin's lymphoma. B2M (beta2-microglobulin) is a component of the human leukocyte antigen (HLA) class I molecule that is expressed by all nucleated cells (PMID: 8717519). Specifically, B2M serves as the light chain of the MHC class I molecule, which functions to present peptides derived from cellular proteins to CD8+ T lymphocytes, a process critical to adaptive immune responses (PMID: 8717519). Deletion of B2M in mice results in loss of MHC class I presentation and all CD8+ T cells (PMID: 2112266). Somatic B2M loss-of-function mutations have been identified in colorectal cancer and melanoma and are predicted to result in immune evasion (PMID: 22833104). Additionally, serum levels of free, soluble B2M are increased in many hematological and solid malignancies. Various non-immunologic context-dependent functions have been ascribed to soluble B2M; these include serving as a mitogenic or pro-apoptotic paracrine factor in various tumor types (PMID: 23848204, 19056512). Elevated serum B2M is a strong prognostic indicator of poor outcomes in many hematological malignancies, particularly multiple myeloma and non-Hodgkin lymphomas, although the precise mechanism underlying this correlation is not fully understood (PMID: 8507875, 15809451, 8471438). True +ENST00000297574 79870 BAALC True BAALC, a cytoplasmic protein, is frequently overexpressed in cancer. BAALC is a highly conserved mammalian cytoplasmic protein expressed in the central nervous system and in human hematopoietic cells (PMID: 11707601). BAALC is suggested to play a role in the hematopoietic system due to its expression in early progenitor cells, however, the function of BAALC is still largely unknown (PMID: 11707601, 33968759, 26171200). Overexpression of BAALC promotes tumorigenesis through the downregulation of apoptosis and upregulation of cancer cell proliferation, invasion, migration and anchorage-dependent growth (PMID: 33968759, 22549446). BAALC overexpression has been identified in a variety of tumor types including cytogenetically normal-acute myeloid leukemia (AML) and acute lymphoblastic leukemia (PMID: 11707601, 20535151). BAALC is used as a prognostic marker for survival outcome, as high BAALC expression has been correlated with poor prognosis in patients with AML (PMID: 21869843, 26171200). False +ENST00000359435 NM_001033549.1 29086 BABAM1 False BABAM1, a protein involved in the DNA damage response, is infrequently altered in cancer. BABAM1 (also MERIT40 or NBA1) is a component of both the BRCA1-A (breast cancer type 1 susceptibility protein) and BRISC (BRCC36 isopeptidase) multiprotein complexes (PMID: 22974638, 28009280). The BRCA1-A complex recognizes ubiquitinated histones H2A and H2AX at DNA double-strand break (DSB) sites, facilitating damage-dependent BRCA1 localization and DNA repair (PMID: 19261748). BABAM1 has been implicated in the earliest stages of DNA interstrand cross-links repair (PMID: 26338419). The BRISC complex cleaves lysine 63 ubiquitinated substrates, playing a role in interferon responses and proper mitotic spindle assembly (PMID: 24075985, 26195665). Germline variants of BABAM1 have been reported to confer susceptibility to ovarian cancer (PMID: 20852633); however, somatic BABAM1 mutations appear to be rare in human cancers. False +ENST00000257749 NM_001170794.1 60468 BACH2 False BACH2, a transcription factor important in immune cell differentiation, is infrequently mutated in a diverse range of human cancers. BACH2 is a transcription factor that functions predominantly as a transcriptional repressor and mediates innate and adaptive immunity (PMID: 29625895). BACH2 is an important regulator of terminal differentiation in both B and T cells (PMID: 29669243, 29625895). In B cells, BACH2 activity is required for the formation of germinal centers, somatic hypermutation of immunoglobulin genes, plasma cell lineage commitment, negative selection of pre-B cells and class switch recombination (PMID: 29540581, 29129929, 23852341). In T cells, BACH2 expression is required for memory cell activity and BACH2 downregulation is required for effector cells to appropriately differentiate (PMID: 29669243, 29625895, 28855027). In addition, BACH2 regulates the expression of KLRG1 on the surface of CD8+ T cells in order to initiate their entry into the effector or memory pool (PMID: 29669243, 29625895). Expression of BACH2 is also required to maintain the function of alveolar macrophages in the airway and to regulate the inflammatory response (PMID: 28993481). BACH2 represses the expression of several gene programs associated with immune cell differentiation programs, cell cycle, and cytokine production (PMID: 23728300, 29540581, 29529253). The activity of BACH2 is mediated by several upstream signaling pathways, including the ERK/MAPK and mTOR pathways (PMID: 29529253, 29129929, 28993481). BACH2 also competes with BCL6 DNA binding to activate TP53-mediated checkpoint control and tumor suppression (PMID: 23852341). Germline loss-of-function mutations and polymorphisms in BACH2 are associated with autoimmune and allergic disorders such as Crohn’s disease and asthma (PMID: 28530713, 23728300). Heterozygous loss of BACH2 leads to lymphocytic defects due to transcriptional and epigenetic dysfunction (PMID: 28530713), consistent with BACH2 functioning as a haploinsufficient tumor suppressor. Somatic mutations in BACH2 are rare; however, reduced expression or promoter somatic hypermutation of BACH2 has been identified in mantle cell lymphomas and are implicated in drug resistance (PMID: 28592433). True +ENST00000460680 NM_004656.3 8314 BAP1 False BAP1 is a tumor suppressor and deubiquitinating enzyme. Germline mutations of BAP1 predispose to various cancer types, including malignant mesothelioma, uveal and cutaneous melanoma, and renal cell carcinoma. BAP1 (BRCA-associated Protein-1) is a nuclear ubiquitin hydrolase that has been implicated in several cellular processes including cell proliferation, DNA repair, chromatin regulation of gene expression, and stem cell pluripotency (PMID: 19815555, 20805357, 18757409). By deubiquitinating host cell factor-1 (HCF-1), a chromatin-associated protein that helps regulate transcription, BAP1 regulates cell proliferation (PMID: 19815555). BAP1 has been shown to regulate gene expression by forming a ternary complex with HCF-1 and the YY1 transcription factor (PMID: 20805357) and to enhance cell death by increasing progression through the G1-S checkpoint (PMID: 18757409). BAP1 loss alters class I histone deacetylase (HDAC) expression, which may result in altered therapeutic response to HDAC inhibitors in BAP1-depleted cancer cells (PMID: 25970771). Germline mutations of the BAP1 tumor suppressor gene predispose to several tumors, most commonly including uveal melanoma, mesothelioma, cutaneous melanoma, and renal cell carcinoma (PMID: 21874000, 23277170, 23849051, 32690542). Somatic BAP1 mutations are also common in these tumor types, among others (PMID: 23867514, 21642991, 23277170). True +ENST00000260947 NM_000465.2 580 BARD1 False 1 BARD1, a tumor suppressor involved in the DNA damage response, is altered by mutation in breast and ovarian cancers. BARD1 is an adaptor protein that functions as an E3 ligase when in complex with BRCA1 (PMID: 8944023, 32094664, 11573085). BRCA1 is a well-characterized tumor suppressor that functions to maintain genome integrity by repairing DNA double-stranded breaks through homologous recombination and cell-cycle checkpoint activation (PMID: 20029420, 11278247). The BARD1-BRCA1 complex is involved in diverse cellular processes including various stages of DNA repair, gene expression, replication fork maintenance and chromatin regulation (PMID: 32094664, 28976962, 17873885, 29367421, 27239795). BARD1 interacts with BRCA1, binds DNA lesions on newly replicated DNA, and adds ubiquitin molecules to lysine residues on histone H2A (PMID: 32094664, 30804502). The BARD1-BRCA1 complex then mediates the resection of DNA lesions, evicts the antagonistic repair protein 53BP1, and recruits several DNA response proteins to damaged sites, including RAD51 (PMID: 32094664, 28976962, 12832489, 27239795). Poly ADP-ribose (PAR) mediates early recruitment of the BRCA1-BARD1 complex to damaged DNA sites (PMID: 25634209). Loss of BARD1 expression in murine models of breast cancer results in similar phenotypes as BRCA1 deletion, underscoring the likelihood that they function similarly (PMID: 18443292). Germline mutations in BARD1 predispose to breast and ovarian cancer, among other cancers (PMID: 11807980, 20077502, 23334666, 25058500, 28726808, 31371347). Some BARD1 variants function as dominant-negative mutations, suggesting that BARD1 predominantly functions as a tumor suppressor (PMID: 22350409, 26738429). Somatic mutations in BARD1 are also found in human cancers and emerging data suggest that BARD1 can function as an oncogene or tumor suppressor in different cellular contexts (PMID: 18089818, 29292755, 26738429). True +ENST00000449228 NM_001127240.2 27113 BBC3 False BBC3, a pro-apoptotic protein, is infrequently altered in cancer. BBC3 (BCL2 binding component 3, also known as PUMA) is a pro-apoptotic BCL-2 family protein. BBC3 contains a BH3 (BCL-2 homology 3) domain, which allows for binding to anti-apoptotic BCL2 family members, including BCL-xL and BCL-2 (PMID: 23175245). This binding releases the pro-apoptotic factors BAK and BAX, which in turn initiate apoptosis via permeabilization of the mitochondrial membrane (PMID: 11463392, 17322918). BBC3 is a transcriptional target of TP53, but is also activated independently of TP53 in response to cellular stress; thus, BBC3 is considered both a p53-dependent and -independent pro-apoptotic factor (PMID: 14585359, 19641508). Although methylation-dependent silencing of BBC3 has been described in Burkitt lymphomas, somatic mutation of BBC3 is not commonly found in human cancers (PMID: 17267315, 18573879). However, BBC3 function can be altered as a consequence of perturbations of other factors in the apoptosis pathways, such as mutations in TP53, which abrogate the ability of TP53 to induce BBC3 expression (PMID: 21478674). BBC3 is a highly efficient effector of apoptosis, and BH3 mimetic peptides and small molecule therapeutics targeting anti-apoptotic proteins are being investigated as therapeutic options in cancers with dysregulated BBC3 activity (PMID: 17921043, 11463391, 19641508). True +ENST00000648566 NM_003921.4 8915 BCL10 False BCL10, a tumor suppressor and pro-apoptotic protein, is infrequently altered in cancer. BCL10 (B-cell CLL/lymphoma 10) is an adaptor protein involved in apoptosis and NF-kB signaling. The protein forms part of the CARD11-BCL10-MALT1 (CBM) complex, which is a regulator of NFkB signaling in lymphocytes following antigen stimulation (PMID: 25087226, 15541657). BCL10 was discovered at the breakpoint of a recurrent translocation in mucosa-associated lymphoid tissue (MALT) B-cell lymphoma and subsequent experiments showed its role in apoptosis and NFkB regulation (PMID: 9989495, 10319863). Mutations in BCL10 have been found at low frequency in lymphomas and germ cell tumors (PMID: 10582682, 10408401). True +ENST00000357195 NM_138576.3 64919 BCL11B False BCL11B, a transcription factor expressed in T cells and the central nervous system, is altered by mutation, deletion, or chromosomal rearrangement in hematopoietic malignancies. BCL11B (also RIT1) is a transcription factor that is a member of the BCL family. BCL11B is predominantly expressed in T cells and the nervous system (PMID: 23211040). The activity of BCL11B is required for T cell development including lineage commitment, proliferation, differentiation and survival of T cells (PMID: 23211040) as well as in the development of cells in the central nervous system (PMID: 28424591, 29416501). In murine models, loss of BCL11B results in unsuccessful V(D)J recombination and lack of pre-T cell receptor (TCR) presentation on the cell surface (PMID: 12717433), highlighting the importance of BCL11B in T cell biology. BCL11B functions in a transcriptional complex with GATA3 to regulate gene expression in type 2 T helper cells (Th2 cells) (PMID: 29514917). BCL11B has many additional functions including regulation of chromatin state (PMID: 29466755), binding the nuclear hormone receptor NR2F1 (PMID: 23211040), and regulation of cyclin-dependent kinase during the cell cycle (PMID: 16950772). BCL11B acts as either a transcriptional activator or repressor in a context-specific manner (PMID: 23211040). Germline mutations in BCL11B have been identified in individuals with developmental disorders and immune deficiencies (PMID: 29985992, 27959755). Somatic mutations, fusions, and deletions of BCL11B are found in patients with adult T-ALL (PMID: 26219558, 25023966, 21878675). BCL11B functions as a haploinsufficient tumor suppressor, as most alterations are hemizygous (PMID: 26219558) and reduced expression of BCL11B is associated with poor prognosis in T-ALL (PMID: 25023966). True +ENST00000333681 NM_000633.2 596 BCL2 True BCL2, an anti-apoptotic protein, is frequently altered in non-Hodgkin lymphomas. BCL2 (B-cell lymphoma 2) is a key regulator of cell apoptosis, and is part of the BCL2 family of proteins that orchestrate the intrinsic apoptotic pathway (PMID: 24355989). BCL2 is considered a pro-survival factor that inhibits BAX-mediated mitochondrial permeability, thus preventing cytochrome c release and downstream caspase 9 activation through APAF1 (PMID: 9390557, 9219694, 9390557). BCL2 is commonly linked to the immunoglobulin (Ig) heavy chain locus in follicular B-cell lymphomas via the t(14;18) chromosomal translocation (PMID:2875799). This results in robust expression of BCL2 and downstream pro-survival signals, a key step in lymphomagenesis (PMID:7632929). Progression of follicular lymphoma to a more aggressive disease state is often associated with MYC translocation, suggesting a synergy between BCL2 and MYC in cancer progression (PMID:1638027, 12015982). BCL2 is found to be translocated and overexpressed particularly in haematological malignancies, but is infrequently mutated (PMID: 3262202, 16193090). Venetoclax is a small molecule inhibitor of BCL2, and has been approved for treatment in patients with relapsed chronic lymphocytic leukemia (CLL) harboring a specific genetic alteration (PMID: 26639348). False +ENST00000307677 NM_138578.1 598 BCL2L1 False BCL2L1, a regulator of apoptosis, is altered by mutation or amplification in various cancer types including colorectal cancer. BCL2L1 (Bcl-2-like protein 1) belongs to the BCL-2 family of proteins and has a dual pro- and anti-apoptotic role ascribed to its different transcript isoforms produced by alternative splicing (PMID: 8358789). The two isoforms, BCL-XL and BCL-XS, inhibit and activate apoptosis, respectively. BCL-XL sequesters activators of apoptosis such as BID, thus blocking downstream activation of the apoptosis effector proteins BAX and BAK, which normally control mitochondrial membrane potential and the release of cytochrome C (PMID: 17115033, 20584903, 9393856). Inhibition of apoptosis by BCL-XL is overcome by caspase-mediated cleavage (PMID: 9771973, 21256112). Although the pro-apoptotic effect of BCL-XS is poorly understood, it has been shown to interact with BCL2 and BCL-XL (PMID: 10777212, 11526448). BCL2L1 is often amplified in colorectal cancers (CRC) and its expression affects anchorage-independent growth and cell proliferation, though it is not considered a driver of tumorigenesis (PMID: 22009326). Nevertheless, preclinical data has shown small molecules targeting BCL-XL may have therapeutic potential in a subset of CRCs and other cancers (PMID: 26134786, 25313317, 23824742). False +ENST00000393256 NM_138621.4 10018 BCL2L11 False BCL2L11, a tumor suppressor and pro-apoptotic protein, is altered by mutation in various cancer types. BCL2L11 (also BIM) is a pro-apoptotic tumor suppressor that is a member of the BCL2 protein family (PMID: 9731710, 9430630). BCL2L11 expression activates apoptosis by triggering the release of cytochrome c from the mitochondria. Cytochrome c release initiates a series of signaling events that result in apoptosome formation and activation of caspase-mediated programmed cell death (PMID: 19934277, 26405162, 16243507). The anti-apoptotic protein BCL2 sequesters BCL2L11; therefore, the relative levels of BCL2L11 and BCL2 regulate many cellular processes including cell survival and tissue homeostasis (PMID: 9430630, 10576740, 25176652). There are several alternatively-spliced BIM isoforms with various levels of pro-apoptotic activity (PMID: 22728771). Expression of BIM is epigenetically downregulated in several cancer types, including chronic myeloid leukemia and acute lymphoblastic leukemia (PMID: 19403302, 20647567). Furthermore, BCL2L11 activity, in addition to a BCL2L11 single nucleotide polymorphism (SNP), has been shown to be a predictor of response to tyrosine kinase inhibitors (TKIs) in several contexts (PMID: 22145099, 24223824). Thus, Bcl-2 homology 3 (BH3) mimetics may have utility in cancers that are resistant to TKIs through a BIM-dependent mechanism (PMID: 18949058). Chemoresistance mechanisms may also arise due to downregulation of BCL2L11 expression (PMID: 18174237). True +ENST00000250405 NM_004050 599 BCL2L2 True BCL2L2, a regulator of apoptosis, is infrequently altered in cancer. BCL2L2, a member of the BCL-2 protein family, encodes for a mitochondrial outer membrane protein that primarily functions to promote anti-apoptotic signaling (PMID: 11423909). BCL2L2 expression is upregulated by various signaling factors, such as MYC, CREB or p53, and repressed by microRNA (PMID: 17336089, 24070634, 29117536). In addition to apoptotic regulation, BCL2L2 is essential to spermatogenesis and is largely expressed in Sertoli cells, Leydig cells and spermatocytes (PMID: 11423909, 11420255, 10809232). Overexpression of BCL2L2 in various cancer cell lines and models suppresses cell death and induces cellular proliferation and invasion, suggesting that BCL2L2 functions predominantly as an oncogene (PMID: 12615727, 23740614, 25846734). BCL2L2 upregulation has been identified in various cancers, including non-small cell lung cancer and bladder cancer (PMID: 17459056, 21205209). Upregulation of BCL2L2 has been suggested to confer chemoresistance based on preclinical studies (PMID: 28979809, 28742199, 32005716). False +ENST00000164227 NM_005178 602 BCL3 True BCL3, an NFkB regulatory protein, is altered by translocation or overexpression in various cancer types. BCL3, an atypical IkB family member, finely regulates the classical and non-classical NFkB pro-inflammatory response by both repressing and activating NFkB signaling (PMID: 31930327, 1532257). Phosphorylation of BCL3, regulated by the MAPK and AKT pathways, promotes its nuclear localization, stabilization, and recruitment to DNA (PMID: 28689659). BCL3 promotes proliferation via myc and cyclin D, contributes to invasion and metastasis, and evades apoptosis via HDM2, DNA-dependent protein kinases, caspases, and AKT (PMID: 31930327). In cancer, BCL3 is translocated adjacent to the IGH gene forming the oncogenic t(14;19)(q32.3;q13.1) IGH-BCL3 fusion in chronic lymphocytic leukemia (PMID: 2083219, 2180580, 1532257). BCL3 overexpression is associated with poor prognosis in various cancers, including colorectal cancer, in which it has been shown to promote stemness (PMID: 20414006, 30792270). BCL3 may also play a role in immune evasion of cancer cells through upregulation of PD-L1 (PMID: 30135206). False +ENST00000232014 NM_001706.4 604 BCL6 True BCL6, a transcriptional repressor involved in immune cell development, is frequently altered by chromosomal rearrangement in lymphomas. BCL6 (B-cell CLL/lymphoma 6) is a zinc-finger transcription factor that is considered a transcriptional repressor and helps regulate genes involved in lymphocyte activation, differentiation, cell cycle progression and apoptosis (PMID: 9019154, 10981963). It also suppresses terminal differentiation of germinal center B-cells, and downregulation of BCL6 is necessary for further B-cell differentiation (PMID: 18452090, 11452114). BCL6 is a proto-oncogene that is commonly translocated in diffuse large B-cell lymphoma (DLBCL) and non-Hodgkin's lymphoma (PMID: 15202519, 8167331). This translocation, as well as BCL6 somatic mutations found in DLBCL, glioblastoma multiforme (GBM) and breast cancer, are proposed to deregulate BCL6 expression, resulting in its oncogenic potential (PMID: 25038272, 18452090, 24662818). In vitro studies have shown that inhibition of BCL6 results in reduced cell viability and increased apoptosis (PMID: 24662818). False +ENST00000261822 NM_001024808 605 BCL7A False BCL7A, a subunit component of the SWI/SNF complex, is recurrently downregulated in various types of cancer. BCL7A, a member of the BCL7 family, encodes for a subunit of the ATP-dependent chromatin remodeling switch/sucrose non-fermenting (SWI/SNF) complex (PMID: 29213114, 18809673). BCL7A functions in negatively regulating the Wnt signaling pathway and positively regulating the apoptotic pathway (PMID: 25569233). Ectopic expression of BCL7A in acute myeloid leukemia cell and xenograft models represses tumor growth and cellular proliferation, suggesting that BCL7A functions predominantly as a tumor suppressor gene (PMID: 36941700). Downregulated BCL7A has been identified as a risk factor and prognostic biomarker for various types of cancer, including glioma, non-Hodgkin lymphoma, cutaneous T-cell lymphoma and ovarian cancer (PMID: 34362400, 19336552, 15897551, 31077237). True +ENST00000234739 NM_004326.3 607 BCL9 True BCL9, a transcriptional adaptor protein, is recurrently altered by chromosomal translocations in hematologic malignancies. BCL9 is a transcriptional adaptor protein that is a regulator of WNT signaling (PMID: 11955446, 16377174). BCL9 is a nuclear protein that binds the β-catenin-TCF complex, the transcriptional coactivator complex that is downstream of the WNT signaling pathway (PMID: 11955446). BCL9 is also a member of the WNT enhanceosome, a multiprotein complex that regulates the activity of TCF/LEF-responsive enhancer genes (PMID: 28296634). As a component of the WNT enhanceosome, BCL9 recruits additional co-regulators that activate the transcriptional activity of β-catenin depending on the cellular context (PMID: 11955446, 28103279). Namely, BCL9 interacts with Pygo, a protein that binds H3K4 methylation sites on chromatin, implicating BCL9 in epigenetic regulation (PMID: 19305417, 18498752). In addition, BCL9 is a critical mediator of cell-type specific WNT-dependent transcriptional activity (PMID: 18347063, 19699733. 28174279, 30366904). BCL9-mediated WNT signaling regulates several cellular functions including migration, gene expression, mesoderm patterning, proliferation, and adhesion, among others (PMID: 15371335, 19305417, 19738061). Downregulation of BCL9 in biochemical experiments results in translocation of β-catenin from the nucleus to the cytoplasm, leading to altered gene expression (PMID: 15371335). Overexpression of BCL9 and recurrent BCL9 fusions have been identified in patients with B-cell malignancies and acute myeloid leukemia (PMID: 9490669, 10602418), suggesting that BCL9 functions as an oncogene. Inhibitors that target the β-catenin-BCL9 interaction may be efficacious in patients with increased BCL9 activity (PMID: 22914623). False +ENST00000378444 NM_001123385.1 54880 BCOR False BCOR, a transcriptional repressor, is altered in various solid and hematologic malignancies including acute myeloid leukemia. BCOR (BCL6 co-repressor) is a transcriptional repressor that is required for normal germinal center formation in B cells (PMID: 27505670). BCOR is a chromatin regulatory protein that functions in a variety of non-canonical epigenetic repressive complexes and binds the transcriptional repressor BCL6 (PMID: 27505670, 29337181). Depletion of BCOR results in loss of Polycomb protein binding at target genes, which is critical for maintaining repressed chromatin (PMID: 9337181). Additionally, the presence of RING1 and RNF2 in the BCOR complex suggests BCOR involvement in the ubiquitination of histones (PMID: 19738629). BCOR functions as a tumor suppressor that is a key regulator of early embryonic development, mesenchymal stem cell function, hematopoiesis and vertebrate laterality (PMID: 17517692, 18795143, 19578371, 10898795). Germline mutations in BCOR are responsible for the inherited oculofaciocardiodental and Lenz microphthalmia syndromes (PMID: 15004558). BCOR fusions are recurrent in soft tissue and endometrial stromal sarcomas (PMIDs: 22387997, 25176412, 24805859, 25360585), as well as in acute promyelocytic leukemia (APL) (PMID: 20807888). These fusions lead to oncogenesis by activating various anti-apoptotic pathways. BCOR has been identified as both the N-terminal and the C-terminal fusion partner depending on the type of cancer in which it is expressed, suggesting differing mechanisms for oncogenesis in these tumors (PMID: 25360585). Somatic BCOR truncating mutations have also been identified in retinoblastoma and hematologic malignancies, including acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) (PMID: 22237022, 22012066, 24047651, 25550361). True +ENST00000218147 NM_021946.4 63035 BCORL1 False BCORL1, a transcriptional repressor, is recurrently mutated in hematopoietic malignancies, astrocytomas, and intracranial germ cell tumors. BCORL1 is a transcription factor that functions to repress gene expression (PMID: 17379597). BCORL1, a homolog of the BCOR repressor, interacts with histone deacetylases to mediate transcriptional repression (PMID: 17379597). In addition, BCORL1 interacts with the CtBP corepressor and plays a role in repression of E-Cadherin, an important gene in the epithelial to mesenchymal transformation. Loss of BCORL1 results in promotion of migration and invasion in hepatocellular cancer cell lines (PMID: 26879601). BCORL1 also binds proteins in the epigenetic Polycomb Repressive 1 (PRC1) complex and mediates chromatin state changes (PMID: 27568929). Somatic mutations in BCORL1 are found in patients with adult and pediatric acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), astrocytomas and intracranial germ cell tumors (PMID: 21989985, 24047651, 24896186, 27470916, 27425854) and are predicted to be loss-of-function mutations resulting in truncation of the C-terminus of the protein. Mutations in BCORL1 are associated with age-related clonal disorders of hematopoiesis, which are hematopoietic defects that can transform to MDS or AML (PMID: 25326804, 26132940, 27084249). Overexpression of BCORL1 is also found in a subset of tumors, including in hepatocellular cancer (PMID: 26879601). BCORL1 mutations have also been shown to be relevant to vemurafenib resistance in melanoma (PMID: 29605720). True +ENST00000305877 NM_004327.3 613 BCR True BCR, a signaling molecule, is recurrently altered by chromosomal rearrangement in chronic myeloid leukemia and other hematopoietic malignancies. BCR is a signaling molecule with serine/threonine kinase activity (PMID: 23940119). BCR has been reported to function as both a guanine nucleotide exchange factor (GEF), which promotes the activation of RhoA family GTPases (PMID: 23940119), and a GTPase activating protein (GAP), which inactivates GTPase activity by stimulating the activity of the small GTP binding proteins Rac1, Rac2, and Cdc42 (PMID: 7889565). In keratinocytes, BCR promotes the formation of stress fibers and focal adhesions, an important function for cellular migration (PMID: 23940119). Loss of BCR in mice results in normal development, however; mice develop a neutrophil expansion due to an increase in reactive oxygen metabolite production (PMID: 7889565). BCR also functions as a mediator of signaling and has modular domains that serve as binding sites for GRB2, GRB10, 14-3-3 and the ABL proteins (PMID: 15719031). BCR is most commonly studied as a translocation partner in the BCR-ABL1 fusion protein (or Philadelphia chromosome), which leads to a constitutively active kinase. The BCR-ABL1 fusion protein is found in essentially all cases of chronic myeloid leukemia (CML) and a small proportion of patients with acute lymphocytic leukemia (ALL) and acute myeloid leukemia (AML). BCR-ABL1 binds signaling molecules, including SOS and GRB2, and initiates downstream signaling pathways including the PI3K/AKT and RAS/MAPK pathways (PMID: 15719031). BCR-ABL1-translocated cancers are sensitive to the kinase inhibitor imatinib, and second-generation kinase inhibitors have been identified that target drug resistance mechanisms that arise in response to imatinib (PMID: 17457302). False +ENST00000263464 NM_182962.2 330 BIRC3 True BIRC3, an anti-apoptotic protein, is altered in various cancer types. BIRC3 (baculoviral IAP repeat containing 3, or cIAP2) is a member of the inhibitor of apoptosis (IAP) family of proteins and contains catalytic ubiquitinase activity (PMID: 8548810, 20651737). BIRC3 activates the canonical NFκB signaling pathway following tumor necrosis factor (TNF) α binding to TNFR1 (TNF receptor 1). TNFR1 activation triggers assembly of a complex wherein BIRC3 mediates ubiquitination of several factors, resulting in derepression of NFκB (PMID: 20651737, 11907583). BIRC3 also activates non-canonical NFκB signaling by mediating ubiquitination of NIK (NFκB-inducing kinase) (PMID: 20651737, 11907583). In addition, BIRC3 functions as an inhibitor of apoptosis by directly ubiquitinating caspases 3 and 7 (PMID: 20651737), targeting them for degradation. BIRC3 and its homolog, BIRC2 (cIAP1), are functionally redundant in preclinical model systems, but also have non-overlapping expression patterns suggesting distinct biological functions (PMID: 20651737, 21430708). Overexpression of BIRC3 has been associated with cancer evasion from apoptosis with amplification identified in lung and breast cancer and gliomas (PMID: 12651874, 27074575, 31713298). Somatic BIRC3 truncating mutations and deletions have been identified in patients with chronic lymphocytic leukemia and associated with poor prognosis (PMID: 26837699, 22308293). The efficacy of SMAC (second mitochondria-derived activator of caspases) mimetics as single agents and in combination with proteasome inhibitors are being investigated as a therapeutic for hematological and solid cancers (PMID: 30766663, 32170726). True +ENST00000355112 NM_000057.2 641 BLM False BLM is a tumor suppressor involved in DNA repair. Germline mutations of BLM are associated with Bloom syndrome and predispose to certain cancers. BLM (also Bloom syndrome protein) is a DNA helicase that functions by unwinding double-stranded DNA intermediates during multiple cellular functions, including double-strand break repair by homologous recombination, telomere maintenance and replication (PMID: 21047263, 24606147). BLM gene expression is cell cycle regulated and BLM has been shown to interact with the E3 ubiquitin-protein ligase Mindbomb 1 (MIB1) and a highly conserved DNA topoisomerase 2β-binding protein 1 (TopBP1) (PMID: 24239288). The helicase activity of BLM is critical for preserving the fidelity of the genome, and deleterious mutations result in a strong predisposition for a broad spectrum of cancers across multiple tissue types, generally characterized as highly aggressive and occurring early in life. Germline mutations in BLM lead to the rare genetic disorder Bloom syndrome (BS), an autosomal recessive disorder characterized by severe chromosomal instability and increased cancer risk (PMID: 17407155). Heterozygous inherited deleterious mutations in BLM have been associated with an increased risk for breast cancer (PMID: 23028338) and colorectal cancers (PMID: 26358404), albeit with a moderate penetrance for the latter. Somatic mutations in BLM are rare in human cancers, however, truncating mutations in BLM have been identified in colorectal cancers with a microsatellite instability (PMID: 11532193). True +ENST00000372037 NM_004329.2 657 BMPR1A False BMPR1A is a transmembrane receptor kinase. Germline mutations of BMPR1A are associated with juvenile intestinal polyposis and Cowden syndrome. BMPR1A is a transmembrane serine/threonine kinase receptor that belongs to the transforming growth factor β (TGF β) family (PMID: 22992590). TGFß signaling controls multiple biological processes including cellular proliferation, differentiation and tissue homeostasis (PMID: 22992590, 11057902). BMPR1A functions as a type I receptor and therefore must associate with the type II receptor BMPR2 to initiate ligand binding (PMID: 22992590). BMP receptors receive signals from growth factor and cytokine BMP ligands and transduce these signals through SMAD and non-SMAD pathways to regulate cell growth, differentiation and apoptosis (PMID: 10712517, 9738456, 19762341). BMPR1A signaling also plays a role in apoptosis, osteoblast function and adipocyte differentiation (PMID: 15090551). Germline mutations of BMPR1A are found in individuals with juvenile polyposis syndrome, juvenile intestinal polyposis and Cowden syndrome (PMID: 15235019, 11536076). BMPR1A mutations are associated with increased risk of gastrointestinal polyps and colon cancer (PMID: 25389115, 21203531). True +ENST00000646891 NM_004333.4 673 BRAF True 1 BRAF, an intracellular kinase, is frequently mutated in melanoma, thyroid and lung cancers among others. BRAF is a serine/threonine kinase that plays a key role in the regulation of the mitogen-activated protein kinase (MAPK) cascade (PMID: 15520807), which under physiologic conditions regulates the expression of genes involved in cellular functions, including proliferation (PMID: 24202393). Genetic alterations in BRAF are found in a large percentage of melanomas, thyroid cancers and histiocytic neoplasms as well as a small fraction of lung and colorectal cancers. The most common BRAF point mutation is V600E, which deregulates the protein's kinase activity leading to constitutive BRAF activation, as BRAF V600E can signal as a monomer independently of RAS or upstream activation (PMID: 20179705). Other BRAF mutations have been found that affect the protein's propensity to dimerize (PMID: 16858395, 26343582, 12068308). The product of these alterations is a BRAF kinase that can activate MAPK signaling in an unregulated manner and, in some instances, is directly responsible for cancer growth (PMID: 15520807). Inhibitors of mutant BRAF, including vemurafenib and dabrafenib, are FDA-approved for the treatment of late-stage or unresectable melanoma. False +ENST00000357654 NM_007294.3 672 BRCA1 False 1 BRCA1, a tumor suppressor involved in the DNA damage response, is mutated in various cancer types. BRCA1 (breast cancer susceptibility gene 1) is a tumor suppressor gene that functions as a multifunctional ubiquitin E3 ligase. BRCA1 has been implicated in regulating diverse cellular processes including transcription, protein ubiquitination, cell cycle regulation and DNA damage response, with a particularly important role in DNA repair during homologous recombination (PMID: 22193408). BRCA1 forms protein complexes with known tumor suppressors including RAD51, BRCA2, BARD1 and PALB2; specifically, BRCA1 and BARD1 facilitate resection of DNA ends and enhance the activity of the recombinase RAD51 (PMID: 14636569, 20729832, 20930833, 20871615, 20729858, 28976962). BRCA1 was the first breast and ovarian cancer susceptibility gene identified and cloned. Germline heterozygous loss-of-function mutations result in autosomal dominant hereditary breast and ovarian cancer (HBOC) syndrome, which is associated with an increased lifetime risk of breast, ovarian, prostate, pancreatic, and other cancers (PMID: 22193408, 31171119). BRCA1 was also more recently implicated in Fanconi anemia complementation group S, a rare Fanconi anemia subtype that results from biallelic mutations in the gene (PMID: 25472942, 29133208, 29712865, 32843487). BRCA1 mutations are predicted to disrupt protein-protein interactions, which facilitate DNA repair (PMID: 1157308, 10918303). Somatic mutations in TP53 in breast tumors are seen almost exclusively with BRCA1 and BRCA2 mutations, suggesting that TP53 loss of function may be a necessary step in the tumorigenesis of BRCA-associated carcinomas (PMID: 14672397). PARP inhibitors are FDA-approved for patients with germline BRCA1-mutant ovarian and breast cancers (PMID: 25366685). True +ENST00000380152 NM_000059.3 675 BRCA2 False 1 BRCA2, a tumor suppressor involved in the DNA damage response, is mutated in various cancer types. BRCA2 (breast cancer susceptibility gene 2) is a tumor suppressor gene that functions as a DNA repair protein. BRCA2 has been implicated in regulating diverse cellular processes including transcription, cell cycle regulation, and DNA damage response, with a particularly important role in DNA repair during homologous recombination (PMID: 22193408). BRCA2 forms protein complexes with known tumor suppressors including RAD51, BRCA1, and PALB2; specifically, BRCA2 binds single-stranded DNA and loads RAD51 monomers at sites of DNA double-strand breaks (PMID: 14636569, 20729832, 20930833, 20871615, 20729858, 28976962). RAD51 requires the BRCA1-BRCA2-PALB2 complex to initiate homologous recombination (PMID: 11239455). Germline, heterozygous loss-of-function mutations result in autosomal dominant hereditary breast and ovarian cancer (HBOC) syndrome, which is associated with an increased lifetime risk of developing breast, ovarian, prostate, pancreatic, and other cancers (PMID: 15800615, 22193408, 31171119, 31343663). Biallelic BRCA2 mutations were also more recently implicated in Fanconi anemia complementation group D1 (PMID: 12065746, 34680915). Somatic mutations in TP53 in breast tumors are seen almost exclusively with BRCA1 and BRCA2 mutations, suggesting that TP53 loss of function may be a necessary step in the tumorigenesis of BRCA-associated carcinomas (PMID: 14672397). PARP inhibitors are FDA-approved for patients with germline BRCA2-mutant ovarian and breast cancers (PMID: 25366685). True +ENST00000303407 NM_007371 8019 BRD3 True BRD3, a transcriptional activator, is altered by translocation in NUT midline carcinoma. BRD3 (bromodomain containing 3) is a member of the bromodomain and extraterminal (BET) subfamily of bromodomain-containing proteins that regulate transcription through the recognition and binding of acetylated lysine residues on histones and transcription factors (PMID: 25849938, 31780938). BRD3 is an epigenetic reader (PMID: 31780938) and acts as a transcription regulator via association with the transcription factor GATA1 (PMID: 21536911). BRD3 has been shown to regulate processes such as skeletal myogenesis and erythroid maturation, among others (PMID: 28733670, 21536911). Translocations of BRD3 that fuse the gene to the 5' end of NUTM1 result in the oncogenic BRD3-NUTM1 fusion, which has been identified as a driver of NUT midline carcinoma (PMID: 25688404, 32328562). Inhibition of the BET protein family has been proposed as a therapeutic strategy across several cancer types (PMID: 25849938). False +ENST00000263377 NM_058243.2 23476 BRD4 True BRD4, a transcriptional coactivator, is altered by amplification or chromosomal rearrangement in various cancer types. BRD4 is a member of the bromodomain and extraterminal (BET) family of proteins, and is important in transcriptional activation and elongation at specific gene enhancer elements (PMID: 20871596). BRD4 binds to acetylated histone lysine motifs and helps recruit members of the transcriptional regulator complex, including P-TEFb and Mediator, which are necessary for PolII-dependent transcriptional elongation (PMID: 24751816). BRD4 has been shown to have a role in inflammation (PMID: 21068722, 25263595), viral gene expression (PMID: 16109376) and heart failure (PMID: 23911322). A subset of regulatory elements termed 'super-enhancers' are bound by high levels of BRD4 and are particularly prone to transcriptional perturbations of BRD4 inhibition (BETi) via small molecules (PMID: 24905006, 23582323). For example, BETi results in significant reduction of MYC downstream activity via its super-enhancer. As such, experimental data has shown that MYC-driven cancers are particularly sensitive to BETi, including multiple myeloma (PMID: 21889194) and medulloblastoma (PMID: 24297863). A chromosomal BRD4-NUT fusion product is a driver of disease in most cases of NUT midline carcinoma and is sensitive to BETi (PMID: 20871596). Resistance to BETi can arise due to BRD4 hyperphosphorylation in breast cancer (PMID: 26735014), and SPOP mutations, which can lead to BRD4 stabilization in prostate cancer (PMID: 28805820). False +ENST00000259008 NM_032043.2 83990 BRIP1 False 1 BRIP1 is a tumor suppressor involved in DNA repair. Germline mutations of BRIP1 are associated with Fanconi anemia and predispose to certain cancers. BRIP1 (BACH1 and FANCJ) is a member of the RecQ DEAH helicase family. DEAH helicases participate in pre-messenger RNA splicing and ribosome biogenesis (PMID: 20168331). This family of genes includes those that have been implicated in heritable human diseases, including BLM, WRN and RECQL4 (PMID: 24606147). Specifically, BRIP1 interacts with the BRCT motif-containing domain of BRCA1 (PMID: 17033622). In the HCC1937 cell line that produces BRCA1 with a truncated C-terminal, BRIP1 failed to co-immunoprecipitate with BRCA1, suggesting this domain is important for interaction with BRIP1 (PMID: 11301010). In the same study, two intact BRCT repeat units on BRCA1 were shown to be necessary for the BRCA1 and BRIP1 interaction; a mutation at K52R on BRIP1 may control the interaction of the two proteins. Germline heterozygous mutations in BRIP1 primarily predispose individuals to ovarian cancer (PMID: 21964575, 26315354, 29368626, 32359370) with controversial or inconclusive evidence for other cancer types (PMID: 11301010, 17033622, 19127258, 30099541, 33471974, 33471991). Biallelic mutations in BRIP1 are implicated in Fanconi anemia complementation group J (PMID: 16116423, 16116424, 27107905). Cell lines that are deficient in BRIP1 are sensitive to mitomycin C, a crosslinking agent (PMID: 16153896). True +ENST00000309383 NM_032430 84446 BRSK1 False BRSK1, a serine/threonine kinase, is infrequently altered in cancer. BRSK1 (Brain Specific Kinase 1, aka SAD-B) and its related isoform BRSK2 are AMP-activated protein kinase (AMPK) subfamily serine/threonine kinases that are phosphorylated by LKB1 and carry out tumor suppresive functions (PMID: 14976552). Activated BRSK1 regulates cell cycle progression by phosphorylating tubulin, which is critical for centrosome duplication (PMID: 19648910). Activated BRSK1 also phosphorylates and downregulates Wee1A and Cdc25-B/C, which regulates neuronal polarity and leads to G2/M arrest in response to UV- or MMS-induced DNA damage (PMID: 15705853, 20026642, 15150265). Truncating mutations of BRSK1 are found in MSI-high gastric and colorectal cancers (PMID: 27677186). Additionally, loss of BRSK1 expression in breast cancer has been associated with higher-grade disease (PMID: 25036402). True +ENST00000256015 NM_001731.2 694 BTG1 False BTG1, an adaptor molecule that regulates transcription factor binding, is recurrently altered by deletions and mutations in hematopoietic malignancies. BTG1 is a member of a family of proteins that regulate cell proliferation. BTG1 acts as an adaptor molecule that stimulates the activity of transcription factors including HOXB9 and RARα (PMID: 19746446). In addition, BTG1 regulates the activity of an epigenetic complex containing PRMT1, an arginine methyltransferase (PMID: 26657730). Expression of BTG1 is important for regulation of cell cycle arrest, apoptosis, and cell proliferation in a variety of cellular contexts (PMID: 26622543). Deadenylation of poyl(A) tails on mRNA is also mediated by BTG1 binding to CNOT7, allowing for regulation of mRNA turnover and decay (PMID: 19746446). BTG1 transcriptional control is important for cerebellum and pre-B cell development as demonstrated in murine models (PMID: 27036158, 26524254). Loss of BTG1 enhances the stem cell renewal capacity of hematopoietic progenitor cells and mediates the upregulation of BCL6, leading to suppression of the tumor suppressor genes TP53 and p19ARF (PMID: 29408281). Somatic BTG1 loss-of-function mutations occur in diffuse large B cell lymphomas (DLBCL) and deletions occur in B-cell precursor acute lymphoblastic leukemia (BCP-ALL) and acute lymphoblastic leukemia (ALL) (PMID: 22343534, 29407587, 27151989), suggesting that BTG1 functions as a tumor suppressor. Secondary mutations in BTG1 have also been identified in patients with chronic lymphocytic leukemia (CLL) treated with the BCL-2 inhibitor venetoclax (PMID: 29463802). True +ENST00000290551 NM_006763 7832 BTG2 False BTG2, a cell cycle transcription coregulator, is infrequently altered in cancer. BTG2, a member of the BTG/TOB gene family, is a transcription coregulator that controls cell cycle progression through either enhancing or inhibiting transcription factor activity (PMID: 9712883, 8944033). BTG2 has two highly conserved domains in the N-terminal portion of the protein, box A and box B, that allow for interaction with target molecules to regulate cell proliferation (PMID: 9712883, 8944033). BTG2 has been identified to regulate pathways that control cell growth, cell differentiation, cell death, cell migration and senescence (PMID: 23876794, 22562501, 24981574, 20020054, 15302583). Silencing miR-27a, an inhibitor of BTG2, in pancreatic cancer cell lines increases BTG2 levels and results in the inhibition of cellular proliferation, suggesting that BTG2 functions predominantly as a tumor suppressor gene (PMID: 31724333). Loss of BTG2 expression has been identified in various cancers, including breast cancer, ovarian cancer and non-small cell lung cancer (PMID: 35401805, 34485119, 35388633). True +ENST00000308731 NM_000061.2 695 BTK True R2 BTK, an intracellular kinase, is overexpressed in B-cell malignancies. BTK (Bruton’s agammaglobulinemia tyrosine kinase) is a cytoplasmic tyrosine kinase that plays an important role in B-cell activation. The B-cell receptor (BCR) activates BTK when BCR-associated tyrosine kinases (such as SYK and LYN) phosphorylate BTK at the plasma membrane (PMID: 8629002, 29861875). The main target of BTK phosphorylation is phospholipase C-γ2 (PLCγ2) which leads to the activation of downstream signaling pathways including NFAT, NFkB and MAPK pathways (PMID: 8691147, 10811867). BTK signaling is also implicated in chemokine receptor signaling in lymphocyte trafficking and in Toll-like receptor signaling in the immune response (PMID: 17239630, 23967355). Loss-of-function mutations in BTK result in X-linked agammaglobulinemia (XLA), a disorder that results in the failure of pre-B cells in the bone marrow to differentiate into mature circulating B cells (PMID: 8380905). While somatic mutations in BTK are not common, BTK signaling is critical for growth of B-cell derived malignancies such as chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), multiple myeloma (MM) and Waldenstrom's Macroglobulinemia (WM) (PMID: 24658273). BTK is also overexpressed in B-cell malignancies (PMID: 21422473, 23962569). BTK inhibition has been a successful means of therapy in hematologic malignancies. The tyrosine kinase ibrutinib targets BTK and is FDA approved for the treatment of patients with MCL, CLL, and WM (PMID: 25361916). However, acquired resistance to ibrutinib has been observed through mutations in BTK itself and in downstream effectors such as PLCγ2 (PMID: 24869598). R2 False +ENST00000287598 NM_001211.6 701 BUB1B True BUB1B, a spindle assembly checkpoint kinase, is altered in various cancers. BUB1B encodes for the BUBR1 protein, a serine/threonine kinase involved in mitosis where it is a core component of the spindle assembly checkpoint (PMID: 33207204). By inhibiting the anaphase-promoting complex/cyclosome, BUBR1 delays the onset of anaphase and mediates proper chromosome segregation (PMID: 23079597, 33207204). While the full spectrum of BUBR1 interacting partners remains to be elucidated, HDAC2 has been identified as a potential upstream regulator (PMID: 36577966). Functional studies indicate that BUBR1 interacts with multiple signaling pathways implicated in cancer progression. In hepatocellular carcinoma (HCC) cell lines, downregulating BUBR1 decreases protein expression levels of mTOR and in vitro evidence suggests that BUBR1 may activate the MTORC1 signaling pathway (PMID: 32977361). In cholangiocarcinoma cell lines, knockdown of BUBR1 decreases phosphorylated c-Jun and inhibits translocation of JNK, suggesting a potential role in the JNK-c-Jun signaling pathway (PMID: 33431813). Additionally, BUBR1 knockdown promotes apoptosis in HCC, lung adenocarcinoma and thyroid cancer cell lines, supporting its role as an oncogene (PMID: 32977361, 26000094, 35517426). BUBR1 is overexpressed in various cancers including prostate cancer, gastric adenocarcinoma, multiple myeloma, lung adenocarcinoma, thyroid cancer, HCC and sarcoma, and is often associated with less favorable prognosis (PMID: 27143916, 34620840, 26000094, 35517426, 32977361, 33872216). Overexpression of BUBR1 is also correlated with resistance to chemotherapy in vitro and in vivo (PMID: 34620840, 39043653). Biallelic pathogenic germline mutations in the BUB1B gene are associated with the cancer predisposition syndrome premature chromatid separation (mosaic variegated aneuploidy) syndrome (PMID: 15475955). False +ENST00000350061 NM_001128840 776 CACNA1D True CACNA1D, a subunit of the Cav1.3 voltage-gated calcium channel, is infrequently altered in cancer. CACNA1D encodes for the pore-forming α1-subunit of Cav1.3, an L-type voltage-gated Ca2+-channel (PMID: 21406960). Voltage-sensitive calcium channels, such as Cav1.3, function in mediating calcium ion entry into excitable cells to regulate calcium-dependent physiological processes (PMID: 29038230, 26842699, 23913004). CACNA1D directly interacts with the GABA(B) receptor to upregulate MAPK signaling pathways and regulate cellular proliferation (PMID: 22366257). The oncogenic function of CACNA1D may be tissue specific. CACNA1D overexpression and expression of CACNA1D gain-of-function alterations in prostate cancer and aldosterone-producing adenoma cell models induces increased cellular proliferation, suggesting that CACNA1D functions predominantly as an oncogene in these contexts (PMID: 36949059, 23913001, 28781648, 28584016). Amplification and activating mutations of CACNA1D have been identified in gastric cancer, prostate cancer and aldosterone-producing adenoma (PMID: 35590368, 36949059, 24054868, 23913004). Conversely, downregulation of CACNA1D has also been identified in various cancer types, including myeloma, sarcoma and renal tumors (PMID: 28781648). False +ENST00000264705 NM_001306079 790 CAD True CAD, a phosphate synthetase involved in pyrimidine synthesis, is infrequently altered in cancer. CAD encodes for a trifunctional multi-domain protein that functions primarily in pyrimidine biosynthesis through carbamoyl phosphate synthetase activity (PMID: 1967494). De novo synthesis of pyrimidine is required for cellular proliferation (PMID: 12438317). MAPK and mTORC1 phosphorylation causes CAD to become more sensitive to activation and upregulates biosynthesis of pyrimidines for increased cellular proliferation (PMID: 10659854, 23429704). Overexpression of CAD in various cancer cell lines and models induces increased cellular proliferation, suggesting that CAD functions predominantly as an oncogene (PMID: 33670206, 16155188, 32325032). Amplification of CAD has been identified in various types of cancer, including breast cancer, glioblastoma and prostate adenocarcinoma (PMID: 33186350, 31391321, 21982950). False +ENST00000316448 NM_004343.3 811 CALR True CALR, a calcium-binding protein, is altered in various solid and hematologic malignancies including myeloproliferative neoplasms. CALR, also known as calreticulin, is a calcium-binding protein located in the lumen of the endoplasmic reticulum (ER). In the ER, the CALR protein has two primary functions: molecular chaperone in the protein-folding pathway and regulator of calcium homeostasis (PMID: 25918716). As a molecular chaperone, CALR acts to prevent the aggregation and export of partially or incorrectly folded proteins from the ER to the Golgi (PMID: 16467570). The activity of CALR and its paralog CNX (calnexin) is important to ensure the quality of glycoproteins, including membrane-bound proteins, transporters and certain secreted factors (PMID: 10567207). Additionally, CALR is localized to the nucleus and inhibits the function of nuclear hormone receptors, such as the androgen and glucocorticoid receptors, suggesting a role in transcriptional regulation (PMID: 8107808, 8107809, 7556879, 9013706, 7667104). CALR also has important roles in immune regulation including folding of MHC Class I molecules and serving as an “eat me” signal on cancer cells (PMID: 25918716). Recurrent somatic mutations in CALR have been identified in patients with myeloproliferative neoplasms that lack alterations in JAK2 or MPL, suggesting a role in activation of the JAK-STAT signaling pathway (PMID: 24325356, 24325359, 25873496). Alterations in CALR commonly occur as frameshift mutations in the C-terminal region of CALR, truncating the ER-targeting domain of the protein (PMID: 26951227). CALR mutations disrupt the interaction between CALR and membrane receptors (such as MPL) and activate downstream signaling pathways (PMID: 26951227). Somatic CALR mutations are also found in familial cases of thrombocythemia or primary myelofibrosis (PMID: 24553179). False +ENST00000302345 NM_001159772 124583 CANT1 True CANT1, a UDP-preferential nucleotidase, is infrequently altered in cancer. CANT1, a member of the apyrase family, encodes for a calcium-dependent nucleotidase which hydrolyzes the UDP, GDP, UTP and GTP nucleotides with a preference for UDP (PMID: 12600208, 12234496). Alterations of CANT1 have been identified to impair endoplasmic reticulum function and proteoglycan synthesis (PMID: 19853239, 22539336). Germline mutations of CANT1 have been identified to cause dysfunction in cartilage proteoglycan synthesis and are associated with the autosomal recessive condition Desbuquois dysplasia (PMID: 21412251, 25486376,19853239, 30439444). Silencing and knockdown of CANT1 in various cancer cell lines suppresses cell proliferation, migration and invasion, suggesting that CANT1 functions predominantly as an oncogene (PMID: 31102300, 35090419, 35068336, 21435463). Amplification of CANT1 has been identified in various cancer types, including clear cell renal carcinoma and prostate cancer (PMID: 31102300, 21435463). False +ENST00000396946 NM_032415.4 84433 CARD11 True CARD11, a scaffolding protein, is altered in various cancer types including skin cancer and diffuse large B-cell lymphoma. CARD11 (caspase recruitment domain 11) is a cytoplasmic scaffold protein that functions in mediating apoptosis and NF-ĸB signaling via the CARD11/BCL10/MALT1 (CBM) complex (PMID:11278692). Upregulation of CARD11 by protein kinase C (PKC) leads to a conformational change of the protein and formation of the CBM complex, resulting in activation of NF-ĸB through the IĸB kinase (PMID: 26260210, 26212909). In mouse B-cells, CARD11 is a molecular switch defining either the occurrence of activation-induced cell death or proliferation and plasmablast differentiation (PMID: 23027925). CARD11 is an oncogene, and constitutive activation of the CBM complex is a common feature of B- and T-cell malignancies, particularly diffuse large B-cell lymphoma where gain-of-function mutations in CARD11 have been identified (PMID: 18323416). False +ENST00000327064 NM_199141.1 10498 CARM1 False CARM1, a methyltransferase, is overexpressed in various cancer types. CARM1 is a methyltransferase that modifies arginines seventeen and twenty-six of histones and other proteins. CARM1 is recruited, along with EP300 and the NCOA-family of histone acetyltransferases, to active gene promoters, playing a role in transcriptional activation via chromatin remodeling (PMID: 16497732, 19405910). CARM1 is a positive regulator of WNT/β-catenin expression, induces growth and proliferation in colon cancer cells (PMID: 21478268), and synergistically co-activates NF-kB pathway with EP300 in fibroblasts (PMID: 15616592). CARM1 is amplified in a small subset of cancers, such as neuroendocrine, prostate and ovarian tumors (cBioPortal, MSKCC, Nov 2016). False +ENST00000358485 NM_001080125.1 841 CASP8 False CASP8, a tumor suppressor and pro-apoptotic protein, is inactivated by mutation or deletion in various cancer types. CASP8 is a cysteine protease that is a member of the cysteine-aspartic acid protease (caspase) family. CASP8 functions as the main initiator caspase that mediates death receptor-induced apoptosis (PMID: 9729047). Proteolytic activation of CASP8 is induced by the formation of the death-inducing signaling complex (DISC) involving CD95 (Fas/Apo1), tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) receptors and TNF receptors (PMID: 25617598, 18073771). Upon activation, CASP8 can directly cleave other caspases, such as CASP3, or engage the mitochondrial pathway by cleavage of BID (BH3-interacting domain death agonist) (PMID: 9727492, 9501089, 10428830). Conversely, CASP8 has pro-survival activity roles in the anti-apoptotic NF-κB pathway (PMID: 11002417, 10753878, 15746428) and by inhibiting receptor-interacting protein kinase-3 (RIPK3)-dependent necroptosis (PMID: 21368763, 24476434). Other non-proteolytic functions of CASP8 have been identified in neuroblastoma and lung cancer cell lines including the promotion of cell adhesion, (PMID: 18089800, 18089778), motility (PMID: 18216014, 16618751, 18089778), metastasis (PMID: 16397500) and pyroptosis (PMID: 31723262, 31748744). Caspase-8 deficiency state (CEDS) is a rare genetic disorder that is caused by CASP8 mutations and resembles autoimmune lymphoproliferative syndrome (ALPS) (PMID: 12353035). Inactivating somatic mutations, as well as gene silencing by promoter hypermethylation of CASP8, have been observed in different cancers including hepatocellular, gastric, colorectal, central nervous system malignancies and head and neck cancers (PMID: 25631445, 28112728, 15705878, 12949717). True +ENST00000639785 NM_000388.4 846 CASR True CASR, a calcium-sensing G-protein coupled receptor, is rarely altered in cancer. CASR is a calcium-sensing dimeric G-protein coupled receptor with multifaceted signaling roles related to extracellular calcium-sensing, regulation and homeostasis (PMID: 8255296, 32117726). CASR expression is greatest in the kidneys and parathyroid glands; in the kidneys, CASR modulates calcium excretion by inhibiting its reabsorption in the distal tube, while in the parathyroid gland, CASR regulates parathyroid hormone synthesis and secretion, thereby increasing calcium reabsorption (PMID: 22192592, 23565380). These responses to changes in extracellular calcium levels are accomplished by intracellular signaling via G-proteins and beta-arrestin (PMID: 31399503, 22192592). CASR is expressed in many other tissues and has a broad range of cellular interactions and functions in addition to calcium homeostasis, including implications in cellular proliferation, differentiation, inflammation, wound healing, bone metabolism, gastrointestinal nutrient sensing and ion transport (PMID: 34663830, 23228129, 34774235, 37802982). The oncogenic function of CASR is likely tissue-specific. In cancer cells, CASR is associated with suppression of the epithelial-to-mesenchymal transition (EMT) pathway, as demonstrated in renal cell carcinoma and colon cancer cells (PMID: 37804688, 25879211). Knockdown of CASR in renal cell carcinoma in vitro and in vivo results in tumor cell migration, invasion, and increased tumor size and volume, suggesting that CASR functions predominantly as a tumor suppressor gene in this context (PMID: 37804688). However, knockdown of CASR in breast cancer cell lines inhibits proliferation and sensitizes cells to calcium-induced apoptosis, indicating that CASR may function as an oncogene in this context (PMID: 27450451, 37511437). CASR mutations are associated with various disorders, including familial hypocalciuric hypercalcemia and primary hyperparathyroidism (PHPT) (PMID: 35356007, 38021951). True +ENST00000268679 NM_005187 863 CBFA2T3 False CBFA2T3, a transcriptional corepressor, is infrequently altered in various solid tumors and is altered by chromosomal rearrangement in myeloid malignancies. CBFA2T3, a member of the myeloid translocation gene family, encodes for a transcriptional corepressor that interacts with DNA-bound transcription factors to facilitate transcriptional repression (PMID: 12559562, 15203199). CBFA2T3 contributes to the inhibition of the glycolysis pathway through transcriptional repression of glycolytic genes in the HIF-1a pathway (PMID: 23840896, 25974097). The oncogenic function of CBFA2T3 may be likely tissue specific. Ectopic expression of CBFA2T3 in breast cancer cell lines reduced colony growth, suggesting that CBFA2T3 functions predominantly as a tumor suppressor gene in that context (PMID: 12183414). Loss of CBFA2T3 has been identified in various types of cancer, including breast cancer and lung cancer (PMID: 12183414, 13680524, 34164477). CBFA2T3 has been recurrently identified in the t(16;21) (q24;q22) chromosomal translocation in the context of therapy-related myeloid malignancies and is associated with poor patient prognosis (PMID: 31040112, 32434928, 22420028, 23407549, 9596646, 23153540). CBFA2T3 fusions are suggested to promote oncogenesis of therapy-related myeloid malignancies through inhibition of all-trans-retinoic acid (ATRA)-mediated myeloid gene expression and retinoic acid receptor (RAR) target gene transcription (PMID: 32434928). True +ENST00000412916 NM_022845.2 865 CBFB False CBFB, a protein involved in transcriptional activation, is altered by chromosomal rearrangement in a subset of acute myeloid leukemia. The CBFB (core-binding factor, beta subunit) gene encodes a heterodimeric transcription factor component, that together with a core-binding factor alpha component, RUNX1/2/3 (Runt related transcription factor) proteins, forms a transcription factor complex (PMID: 8929538). CBFB is a non-DNA binding subunit that functions to enhance the DNA binding of the CBF alpha component. The CBF complex targets specific genes for activation or repression and also recruits activating or repressive cofactors such as p300 and HDACs (Histone deacetylases) (PMID: 23148227, 21059642). CBFB complexed with RUNX1 regulates important steps in hematopoiesis through processes such as cell cycle progression, differentiation and development (PMID: 11561154). With RUNX2, CBFB regulates skeletal development (PMID: 12434152, 24798493). Inversion of chromosome 16 can result in a CBFB-MYH11 (Myosin heavy chain 11) fusion gene and is associated with the M4 type of acute myeloid leukemia, and often with associated eosinophilia (PMID: 23160462). This fusion protein disrupts the CBF complex and results in a block in hematopoiesis (PMID: 20007544). CBFB may also influence solid tumor development, as mutations have been identified in breast and cervical cancer samples (PMID: 22722202, 24390348). True +ENST00000264033 NM_005188.3 867 CBL False CBL, a tumor suppressor and ubiquitin ligase, is inactivated by mutation or deletion in various cancer types including myeloid malignancies. CBL is an E3 ubiquitin-ligase and proto-oncogene that mediates degradation of receptor tyrosine kinases (PMID: 11283727, 23085373). CBL family E3 ligases selectively and negatively regulate activated receptor tyrosine kinases, including EGFR (PMID: 23085373), PDGFR (PMID: 11283727), CSF-1R (PMID: 11283727), MET (PMID: 24384534), and FLT3 (PMID: 17446348), through ubiquitylation that targets these proteins for degradation by the proteasome (PMID: 11283727). The activity of CBL is required to negatively regulate various signaling pathways, most commonly in hematopoietic and immune cells (PMID: 11857085). In addition to receptor tyrosine kinase regulation, CBL-b is also involved in T cell activation and peripheral T cell tolerance (PMID: 24875217, 17704644, 11283727). Germline mutations in CBL result in developmental delays and a predisposition for juvenile myelomonocytic leukemia (PMID: 20694012). Somatic alterations in CBL have been identified in several human cancers including myelodysplastic syndromes, lung adenocarcinoma and cutaneous melanoma (PMID: 26343386, 11857085). In BCR-ABL rearranged mutant chronic myeloid leukemia (CML), CBL expression is downregulated by the BCR-ABL fusion leading to aberrant activation of downstream signaling pathways (PMID: 11857085). True +ENST00000368666 NM_198239.1 8838 CCN6 True CCN6, a matricellular protein, is altered by deletion in breast cancer. CCN6, a member of the WNT1 inducible signaling pathway (WISP) protein subfamily and connective tissue growth factor (CTGF) family, encodes for an extracellular matrix-associated signaling matricellular protein that regulates various cellular functions including cellular adhesion, migration, proliferation, survival and differentiation (PMID: 27252383, 18775791, 18789696). CCN6 primarily functions in the musculoskeletal system and promotes bone growth and cartilage maintenance through the regulation of mitochondrial function in chondrocytes (PMID: 33644064, 27252383). Mutations of CCN6 have been associated with the musculoskeletal disorder progressive pseudorheumatoid dysplasia (PMID: 10471507, 37417608). The oncogenic role of CCN6 may be tissue-type specific. CCN6 knockdown in inflammatory breast cancer cell lines and models induces epithelial-to-mesenchymal transition and anchorage-independent growth, suggesting that CCN6 functions predominantly as a tumor suppressor gene in the context of breast cancer (PMID: 18321996, 20395207, 12082632, 39024552, 29071006). Loss of CCN6 has been identified in various cancers, including breast cancer and hepatocellular carcinoma (PMID: 30793395, 10499627). Conversely, overexpression of CCN6 in pancreatic cancer and chondrosarcoma cell lines and models induces increased cellular migration, invasion and motility, suggesting that CCN6 functions predominantly as an oncogene in these contexts (PMID: 37105075, 30237403). Amplification of CCN6 has been identified in chondrosarcoma (PMID: 30237403). True +ENST00000276014 NM_033031.2 85417 CCNB3 True CCNB3, a protein involved in cell cycle control, is recurrently altered by mutation, amplification or deletion in various cancer types. CCNB3 (Cyclin B3) is a cyclin protein involved in the positive regulation of cell cycle control. In normal cells, cyclin B3 is exclusively expressed in the testis and is only active during spermatogenesis as a meiotic cyclin thought to be linked to the transition from pre-meiotic to meiotic prophase (PMID: 12185076). In vitro studies have demonstrated that cyclin B3 is able to bind to CDK2; however, it is unable to activate the associated histone H1 kinase activity (PMID: 12185076). CCNB3 is most commonly altered by missense mutations or gene amplifications/deletions in multiple cancer types. Gene fusions with CCNB3 occur most frequently in undifferentiated sarcomas, which lead to aberrant expression of CCNB3 in the mutated cells (PMID: 22387997, 25360585). False +ENST00000227507 NM_053056.2 595 CCND1 True CCND1, a regulator of the cell cycle, is amplified in various cancer types including breast, head and neck, and bladder cancers. CCND1 (cyclin D1) is a protein that couples extracellular growth signaling to cell cycle entry through the activation of cyclin-dependent kinase 4 (CDK4) and CDK6 (PMID: 8114739). Upon forming a complex with cyclin D1, CDK4 and CDK6 phosphorylate and inactivate retinoblastoma (RB), thus leading to the induction of a gene expression program regulated by the E2F family of transcription factors that is important in the transition from G1 to S phase in the cell cycle (PMID: 12432268, 8114703). Functions of cyclin D1 include control of cell growth, proliferation, transcription, DNA repair, and migration (PMID: 21734724). Cyclin D1 is an oncogene, and is often overexpressed or amplified in numerous cancers, including breast, lung, melanoma, and oral squamous cell carcinomas (PMID: 20164920, 20029424). Cyclin D1 is not essential for entry into cell cycle progression (PMID: 15315760), however, its amplification/overexpression in human tumors is oncogenic as it allows cancer cells to proliferate independently of extracellular growth signaling cues (PMID: 23644662, 20029424). False +ENST00000261254 NM_001759.3 894 CCND2 True CCND2, a regulator of the cell cycle, is amplified in various cancer types. CCND2 (cyclin D2) is a protein that couples extracellular growth signaling to cell cycle entry through the activation of cyclin-dependent kinase 4 (CDK4) and CDK6 (PMID: 8114739). Upon forming a complex with cyclin D2, CDK4 and CDK6 phosphorylate and inactivate retinoblastoma (RB), thus leading to the induction of a gene expression program regulated by the E2F family of transcription factors that is important in the transition from G1 to S phase in the cell cycle (PMID: 12432268). Cyclin D2 is not essential for entry into the cell cycle (PMID: 15315760) and is rarely amplified or overexpressed in human cancers. However, the cyclin D2 promoter is frequently methylated with loss of protein expression observed in pancreatic, breast, and prostate cancer, suggesting that it may play a role as a tumor suppressor in certain contexts (PMID: 21734724). De novo cyclin D2 mutations can cause stabilization of the protein and may result in megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome, which is characterized by abnormalities in brain development (PMID: 24705253). False +ENST00000372991 NM_001760.3 896 CCND3 True CCND3, a regulator of the cell cycle, is amplified in various cancer types. CCND3 (cyclin D3) is a protein that couples extracellular growth signaling to cell cycle entry through the activation of cyclin-dependent kinase 4 (CDK4) and CDK6 (PMID: 8114739). Upon forming a complex with cyclin D3, CDK4 and CDK6 phosphorylate and inactivate retinoblastoma (RB), thus leading to the induction of a gene expression program regulated by the E2F family of transcription factors that is important in the transition from G1 to S phase in the cell cycle (PMID: 12432268). Cyclin D3 is not essential for entry into the cell cycle (PMID: 15315760) and is rarely amplified in human cancers (PMID: 21734724). However, the cyclin D3-CDK6 complex may play a metabolic, pro-survival role in cancer cells by inhibiting key enzymes in the glycolytic pathway (PMID: 28607489). False +ENST00000262643 NM_001238.2 898 CCNE1 True 3A CCNE1, a regulator of the cell cycle, is amplified in various cancer types. CCNE1 (cyclin E1) is a protein that regulates the activation of cyclin-dependent kinase 2 (CDK2) during the G1/S transition of the cell cycle (PMID: 1833068). The cyclin E1-CDK2 complex phosphorylates p27(Kip1) and p21, which signals for the degradation of cyclin D and promotes the expression of cyclin A, leading to progression through S phase of the cell cycle (PMID:9192873). Cyclin E1-CDK2 phosphorylates and inactivates retinoblastoma protein (RB), thus leading to the induction of a gene expression program regulated by the E2F family of transcription factors that is important in the transition from G1 to S phase in the cell cycle (PMID: 1388095). Cyclin E1-CDK2 is degraded by SCF-Fbw7, an E3 ubiquitin ligase that is commonly mutated in cancer (PMID: 11533444 ). Increased cyclin E expression in cell lines leads to quicker passage through the G1/S phase, but deletion of cyclin E or CDK2 in mice does not result in a G1/S defect (PMID: 12941272). Amplification and overexpression of cyclin E1 has been implicated in many cancers, including breast cancer, and can be indicative of poor prognosis (PMID: 12432043). False +ENST00000576892 NM_152274.4 92002 CCNQ False CCNQ, a cyclin-related gene, is altered by mutation and deletion in the germline of patients with STAR syndrome. CCNQ (also Cyclin M and CCNQ) is a cyclin-dependent kinase binding partner that is a member of the FAM58 cyclin-like family (PMID: 24218572, 28178678). CCNQ forms a heterodimeric complex with cyclin-dependent kinase 10 (CDK10), which phosphorylates the transcription factor ETS2 (PMID: 24218572). Phosphorylation targets ETS2 for degradation via the 26S proteasome leading to altered cell cycle progression and proliferation (PMID: 24218572). In addition, CCNQ activity has been associated with actin organization and ciliogenesis (PMID: 27104747). Germline loss-of-function mutations and deletions in CCNQ have been identified in patients with STAR syndrome, an X-linked hereditary condition characterized by toe syndactyly, telecanthus and anogenital and renal malformations (PMID: 18297069, 29088509). Alterations in CCNQ/cyclin M stabilize ETS2 protein levels, increase c-RAF signaling, and confer tamoxifen resistance in breast cancer cells (PMID: 24218572). Somatic mutations of CCNQ are rare in human cancer; however, CDK10/Cyclin M activity results have tumor suppressive or oncogenic functions in different cancer types (PMID: 22209942, 18242510, 29435072). True +ENST00000538922 NM_001770 930 CD19 True CD19, a transmembrane glycoprotein, is recurrently amplified in hematologic B-cell malignancies. CD19, a member of the immunoglobulin gene superfamily, encodes for the transmembrane glycoprotein coreceptor of the B-cell antigen receptor complex (BCR) found on the cell surface of B-cells (PMID: 23210908). CD19 functions as an adaptor protein to recruit cytoplasmic signaling proteins to the B-cell membrane and as a member of the CD19/CD21 complex to enhance antigen signaling for the B-cell signaling pathways (PMID: 23210908, 11418645). As a coreceptor of the BCR, CD19 mediates signals to drive B-cell survival, differentiation and proliferation (PMID: 15963789, 12496385, 16116172). Upregulation of CD19 in mouse models induces increased MYC signaling, B-cell transformation and lymphoma progression, suggesting that CD19 functions predominantly as an oncogene (PMID: 22826319, 23210908). CD19 amplification has been identified in various types of hematologic B-cell malignancies, including B-cell lymphoma, acute lymphoblastic leukemia and chronic lymphocytic leukemia (PMID: 23210908, 3257143). Individuals with B-cell malignancies expressing CD19 should be considered for immunotherapies targeting CD19. Loncastuximab tesirine, a monoclonal antibody conjugate targeting CD19, is FDA-approved for the treatment of pretreated patients with relapsed or refractory large B-cell lymphoma (PMID: 33989558). Axicabtagene ciloleucel and tisagenlecleucel, CD19-directed CAR-T cell immunotherapies, are FDA-approved for the treatment of patients with certain types of large B-cell lymphoma and relapsed or refractory follicular lymphoma, respectively (PMID: 29226797, 34921238). False +ENST00000085219 NM_001771 933 CD22 False CD22, an endocytic B-cell receptor, is infrequently altered in cancer. CD22, a member of the sialic acid-binding immunoglobulin-like lectin (Siglec) family, encodes for an endocytic receptor expressed primarily on mature B-cells (PMID: 11967115). CD22 functions as an inhibitory receptor that can physically associate with the B-cell receptor (BCR) to inhibit signaling (PMID: 22566885). CD22 contains an immunoreceptor tyrosine-based inhibitory motif (ITIM) at the cytoplasmic tail to recruit tyrosine phosphatase SHP-1 and inositol phosphatase SHIP to negatively regulate BCR signaling (PMID: 23836650, 10748054). Inhibition of BCR signaling prevents internalization and processing of antigens to present to T cells (PMID: 3157869). CD22 has been identified in blasts from patients with B-cell acute lymphoblastic leukemia; however, its oncogenic function has not yet been well characterized in biochemical studies (PMID: 20841423, 21348573). The efficacy of CD22-targeting treatments, such as monoclonal antibodies, antibody-drug conjugates, radioimmunoconjugates and CAR-T therapies, have been investigated in clinical trials in the context of B-cell lymphoid malignancies (PMID: 29296758, 21673350, 32286905). False +ENST00000381577 NM_014143.3 29126 CD274 True CD274 (also known as PD-L1) is an immune receptor ligand. Expression of PD-L1 may help predict response to immunotherapies targeted against PD-L1 and its receptor, PD-1. The CD274 gene encodes programmed death ligand 1 (PD-L1), a member of a family of co-stimulatory immune receptor ligands. PD-L1 acts to inhibit an immune response by binding to the PD-1 cell surface receptor, which is expressed by T cells, B cells and natural killer cells (PMID: 17629517). PD-L1 allows tumor cells to evade the host immune system by suppressing the T cell response. Amplification or overexpression of PD-L1 has been identified in some tumor types and can be predictive of responses to immunotherapy (PMID: 22437870, 26918453, 28652380, 27620277), suggesting that PD-L1 functions as an oncogene. Individuals with tumors expressing PD-L1 should be considered for immune checkpoint therapy. Atezolizumab, a monoclonal antibody targeting PD-L1, is FDA approved for the treatment of patients with locally advanced or metastatic urothelial carcinoma (PMID: 28424325) and metastatic non-small cell lung cancer (NSCLC) whose disease progressed during or following platinum-containing chemotherapy (PMID: 28611199). Pembrolizumab, an anti-PD-1 antibody, is considered first-line therapy for patients with non-small cell lung cancer and metastatic melanomas that express PD-L1, and may be efficacious in other tumors that express PD-L1 (PMID: 28806116). Nivolumab, an FDA-approved monoclonal antibody that targets PD-1, is also effective in tumors with high PD-L1 expression due to the blockade of the PD-1/PD-L1 interaction and activation of a robust immune response (PMID: 28806116). False +ENST00000318443 NM_001024736.1 80381 CD276 True CD276, a cell surface protein involved in the immune response, is overexpressed in various cancer types. CD276 (also B7-H3 and B7RP-2) is an immune checkpoint molecule and member of the B7 immunoglobulin superfamily of proteins (PMID: 27208063). CD276 is a transmembrane protein found in various cell types, including fibroblasts, endothelial cells and osteoclasts; however, post-transcriptional mechanisms reduce the steady-state levels of CD276 protein (PMID: 27208063). Expression of CD276 is also found on antigen-presenting cells in response to inflammation, including on dendritic and natural killer cells, which likely play important roles in T-cell mediated immune response (PMID: 27208063, 22437870, 11224528, 12925852). Loss of CD276 in murine models results in overactivation of the immune system, demonstrating that CD276 negatively regulates T-cell proliferation (PMID: 12925852). CD276 is overexpressed in a variety of human cancers and has been associated with cancer progression and immune evasion (PMID: 24892449, 22473715, 16489649, 18042703, 23940627, 21671471, 31075138). In addition, CD276 is overexpressed on the cell surface of cancer cells and dampens T-cell inhibitory responses, including in pediatric brain tumors (PMID: 32341579, 29860983). Immunotherapies targeting CD276, such as monoclonal antibodies and engineered CAR T-cell therapy, are currently under clinical investigation (PMID: 30753824, 30655315, 22615450, 29914796, 32398947). False +ENST00000324106 NM_006139.3 940 CD28 True CD28, a costimulatory receptor expressed by T cells, is infrequently altered in a diverse range of human cancers. CD28 is a costimulatory receptor required for T cell activation and survival (PMID: 27192564). CD28 is expressed predominantly on T cells and mediates various T cell processes including differentiation, survival, cytokine production, and immune homeostasis (PMID: 27192564, 29163534). The pairing of CD28 with a B7 protein presented on an antigen presenting cell enhances the activity of MHC (major histocompatibility complex)-TCR (T cell receptor signal) complexes and CD28-B7 coupling is required to initiate a T cell response (PMID: 8642283). The ligands that bind CD28 are CD86, which is constitutively expressed on antigen presenting cells, and CD80, which is upregulated after CD28-CD80 binding (PMID: 27192564, 14978077). CTLA4 and CD28 compete for the same ligands, and subsequent CD80 upregulation following CD28 stimulation may promote immune suppression (PMID: 7682233, 27192564). CD28 is expressed on other immune cells, including plasma cells and T regulatory cells, and plays a role in antibody production and the inflammatory response (PMID: 7534672, 12616483). CD28 engagement initiates several signal transduction pathways due to the association of signaling molecules with the cytoplasmic tail of CD28 (PMID: 8067997, 8025954). CD28 function is dysregulated in autoimmune disorders and cancers (PMID: 28711152, 27460989). CD28 agonists and antagonists are FDA-approved for a variety of immune-related disorders to modulate the function of T effector and T regulatory cells (PMID: 27192564). False +ENST00000369489 NM_001779.2 965 CD58 False CD58, a cell surface adhesion molecule expressed in immune cells, is recurrently altered by mutation and deletion in hematopoietic malignancies. CD58 (also LFA-3) is a cell surface ligand that functions as an immune cell adhesion molecule. CD58 binds CD2, a receptor expressed on T lymphocytes, B cells, and natural killer (NK) cells, to promote cell adhesion to target cells and to provide a stimulatory signal for T cells (PMID: 2951597, 29564225). Co-stimulation resulting from CD2-CD58 engagement results in proliferation, cytokine production and effector function in immune cells (PMID: 26041540). Antibodies targeting CD58 result in blunted immune recognition and reduced cytolysis of target cells by cytotoxic T lymphocytes and NK cells in preclinical studies (PMID: 3084649). CD58 expression is reduced in some acute lymphoblastic leukemia (ALL) and lymphomas, resulting in tumor cells lacking the necessary cell surface molecules for immune recognition (PMID: 22137796, 24413734). Somatic mutations and deletions in CD58 have been identified in diffuse large B cell lymphomas (DLBCL) and other lymphomas, contributing to immune evasion (PMID: 26194173, 22137796, 24413734, 27825110). In DLBCL, concurrent downregulation of both CD58 and HLA-1 molecules results in immune escape from T and NK cells (PMID: 22137796). True +ENST00000245903 NM_001252 970 CD70 True CD70, a transmembrane glycoprotein, is altered by amplification in various cancers. CD70, a member of the TNF ligand family, encodes for a surface antigen found on T and B lymphocytes and functions primarily as a regulator for immune responses, inflammation and cell survival through interaction with receptor CD27 (PMID: 21182090, 29046346, 32665635, 8977292). CD70 interaction with CD27 triggers signaling cascades that lead to the activation of T lymphocytes and enhance the adaptive immune system's ability to mount a response (PMID: 19556308). Dysregulation of the CD70/CD27 signaling axis has been implicated in autoimmune disorders due to aberrant T lymphocyte activation contributing to chronic inflammation and tissue damage (PMID: 16175931, 24817699). Overexpression of CD70 in leukemic cell lines and models induces tumor growth and cancer cell survival, suggesting that CD70 functions predominantly as an oncogene (PMID: 16338493, 7540066). CD70 amplification has been identified in various types of cancer, including renal cell carcinoma, glioblastoma and hematological malignancies (PMID: 16489038, 11980654, 17615291, 28031480). Clinical studies are currently investigating the efficacy of anti-CD70 immunotherapies in patients with hematological malignancies (PMID: 36779592, 36845088). False +ENST00000009530 NM_001025159 972 CD74 True CD74, an MHC class II invariant chain, is infrequently altered in cancer. CD74, a member of the major histocompatibility complex (MHC) class II family, encodes for an invariant chain that functions primarily in antigen presentation for the generation of CD4+ T-cell immune responses (PMID: 30723591). CD74 also functions as a cell surface receptor for the cytokine macrophage migration inhibitory factor, which induces a pro-inflammatory cytokine response (PMID: 32004754, 12782713). Overexpression of CD74 in various cancer cell lines and models induces xenograft tumor growth and increases actin polymerization, suggesting that CD74 functions predominantly as an oncogene (PMID: 27626171). Amplification of CD74 has been identified in various types of cancer, including gastrointestinal cancer, glioma and thyroid carcinoma (PMID: 21228923, 34540893, 25600560). CD74 expression is a potential therapeutic target with preclinical studies and clinical trials investigating the efficacy of anti-CD74 inhibitors and antibody-drug conjugates in various types of cancer (PMID: 25600560, 23427296, 22611320, 28466956, 36634212). False +ENST00000221972 NM_001783.3 973 CD79A True CD79A, a component of the B-cell receptor, is altered at low frequencies across various solid and hematologic malignancies. CD79A is a surface immunoglobulin protein that forms a complex with CD79B and composes part of the B-cell receptor (BCR) (PMID: 1439759). CD79A is expressed from an early stage of B-cell development until the final stage of maturation prior to differentiation into plasma cells (PMID: 21841126, 24146823). The CD79A/CD79B complex is important for transmitting signals generated by antigen binding to the BCR into the cell to support B-cell maturation and survival (PMID: 15186779). Following BCR-ligand interaction, CD79A and CD79B are phosphorylated and activated by SRC family kinases leading to activation of downstream oncogenic signaling cascades that affect B-cell maturation (PMID: 17114463, 15699130, 20940318, 22078222,11514602). Activating mutations in CD79A have been identified in diffuse large B-cell lymphoma, particularly the activated B-cell-like subtype (PMID: 20054396), suggesting that CD79A acts as an oncogene. Such aberrations result in increased BCR signaling and ligand-independent clustering of BCRs, resulting in enhanced B-cell survival and differentiation. Antibody-drug conjugates targeting CD79A/B and inhibitors targeting SRC activity, such as dasatinib, can reduce BCR signaling (PMID: 17374736, 20054396). False +ENST00000392795 NM_001039933.1 974 CD79B True CD79B, a component of the B-cell antigen receptor, is recurrently altered in diffuse large B-cell lymphoma. CD79B is a surface immunoglobulin that forms a complex with CD79A to form a component of the B-cell receptor (BCR) (PMID:1439759). The CD79 (Iga/Igb) complex is important for signaling from the BCR to support maturation and survival of B-cells throughout development (PMID:15186779, 8602530). The cytoplasmic portion of CD79B contains immunoreceptor tyrosine-based activation motif (ITAM) domains that become phosphorylated by SRC proto-oncogene family protein kinases. These regions serve as docking sites for signaling complex formation with kinases such as SYK (spleen tyrosine kinase) and for signal regulation (PMID: 17114463, 20940318, 22078222). Activating mutations of CD79B have been identified in diffuse large B-cell lymphoma, particularly the activated B-cell-like subtype (PMID: 20054396) suggesting that CD79B acts as an oncogene. CD79B mutations result in increased surface BCR expression, reduced BCR internalization and dampening of LYN (Lyn proto-oncogene) kinase feedback inhibition, thus resulting in increased BCR signaling. Somatic mutation in the protein's ITAM domain have also been identified and shown to affect signaling (PMID: 20054396). Germline CD79B mutation leads to agammaglobulinemia, a severe immunodeficiency syndrome with B-cell dysfunction (PMID: 17709424). Antibody-drug conjugates targeting CD79B and inhibitors targeting SRC activity, such as dasatinib, can reduce BCR signaling (PMID: 17374736, 20054396, 25925619, 28009435). False +ENST00000344548 NM_001791.3 998 CDC42 True CDC42, a small GTPase, is infrequently altered in cancer. CDC42 is a small GTPase that localizes to the plasma membrane of the cell. CDC42 can switch between active GTP-bound and inactive GDP-bound states, transducing signals to a variety of downstream effectors (PMID: 21115489). CDC42 plays a role in cell polarization, chemotaxis, migration and mitosis (PMID: 14978216, 15642749, 17038317, 26689677). In cancer, CDC42 overexpression has been associated with enhanced proliferation and invasion, suggesting an oncogenic role; however, a tumor suppressor function related to cell polarity maintenance has also been observed (PMID: 21515363). Mutations and copy number alterations of CDC42 are rare events in cancer. CDC42, as well as other Rho GTPases (e.g., Ras oncoproteins), are difficult targets for pharmacological intervention, although some CDC42-specific drugs exist (PMID: 21433396). False +ENST00000367435 NM_024529.4 79577 CDC73 False CDC73, a tumor suppressor involved in transcriptional regulation, is altered at low frequencies in various cancer types. CDC73 (also known as HRPT2) is the nuclear parafibromin protein, a component of the RNA Polymerase-associated factor (PAF1) complex which regulates transcriptional elongation, histone methylation and histone ubiquitination to modulate gene expression (PMID: 20178742, 19522828, 12667454). The PAF1 complex, composed of CDC73, CTR9, LEO1, RTF1, SKI8, and PAF1, associates with the RNA polymerase II subunit POLR2A (PMID: 19522828). CDC73 is a tumor suppressor, and germline mutations are associated with familial hyperparathyroidism-jaw tumor (HPT-JT) syndrome (PMID:12434154, 15531515), while somatic mutations are found in parathyroid carcinomas (PMID: 14585940, 12960210). The CDC73/PAF complex is also important in leukemogenesis by interacting with the MLL oncogene and controlling epigenetic regulation of proleukemogenic target genes, such as MEIS1 and BCL2 (PMID: 23900238). True +ENST00000261769 NM_004360.3 999 CDH1 False CDH1 (E-cadherin), a tumor suppressor involved in cell adhesion, is altered by mutation or deletion in various cancer typess, most frequently in breast and esophagogastric cancers. CDH1, also known as E-cadherin, is a calcium-dependent transmembrane glycoprotein that is mainly expressed in epithelial cells and functions in cell-cell adhesion, signaling cascades and epithelial-to-mesenchymal transition (EMT) (PMID: 18726070). The extracellular portion of E-cadherin facilitates homophilic cell-to-cell adhesion by binding to cadherins on adjacent cells, while the intracellular domain is tethered to the actin cytoskeleton through interactions with catenins and functions to activate signaling cascades that play a role in the EMT (PMID:7885471, 2788574). The transcription factor SNAIL, a key regulator of the EMT during embryonic development, represses expression of the E-cadherin gene in tumor cell lines (PMID: 10655586, 10655587). Lack of E-cadherin function/expression enables cancer progression by altering cellular morphology, decreasing cellular adhesion, and increasing cellular motility (PMID: 10439038, 2070412, 9515965). Along with point mutations and loss of heterozygosity (LOH), epigenetic silencing by hypermethylation of the CDH1 promoter has been associated with the loss of E-cadherin gene expression during cancer progression (PMID: 7543680). Individuals with a germline CDH1 mutation have an increased risk of developing diffuse gastric cancer and lobular breast cancer (PMID: 11729114, 31171119, 32758476). Loss of E-cadherin has also been demonstrated in a variety of sporadic cancer types including gastric cancer, colorectal cancer, and esophageal cancer (PMID: 11313896, 22716209, 21373750). True +ENST00000268603 NM_001797 1009 CDH11 True CDH11, a cadherin protein, is infrequently altered in cancer. CDH11, a member of the cadherin superfamily, encodes for a type II classical cadherin that functions in calcium-dependent cell-cell adhesion (PMID: 7583005). CDH11 activates the WNT signaling pathway to promote cellular proliferation through the upregulation and anchoring of β-catenin (PMID: 30691241, 25787991). Overexpression of CDH11 in breast cancer cell lines induces cellular proliferation, migration and invasion, suggesting that CDH11 functions predominantly as an oncogene (PMID: 29296180, 24681547, 30691241). CDH11 amplification has been identified in various types of cancer, including breast cancer and distant bone metastases (PMID: 28101202, 18708358, 24587095). False +ENST00000269141 NM_001792 1000 CDH2 True CDH2, a cadherin protein, is infrequently altered in cancer. CDH2, a member of the cadherin superfamily, encodes for a classical cadherin that functions in calcium-dependent cell-cell adhesion (PMID: 2831236). CDH2 upregulates the β-catenin and NOTCH signaling pathways to regulate neurogenesis and maintain stemness of radial glia progenitor cells (PMID: 20230753, 24715457). Overexpression of CDH2 in various cancer cell lines and models induces cellular proliferation, migration, invasion, tumor growth and epithelial mesenchymal transition, suggesting that CDH2 functions predominantly as an oncogene (PMID: 10684258, 8978829, 35574323). CDH2 amplification has been identified in various types of cancer, including breast cancer, thyroid cancer, colorectal cancer and ovarian cancer (PMID: 10684258, 8978829, 35756646, 35574323). False +ENST00000614565 NM_001794 1002 CDH4 True CDH4, a cadherin protein, is infrequently altered in cancer. CDH4, a member of the cadherin superfamily, encodes for a classical cadherin that functions in calcium-dependent cell-cell adhesion (PMID: 1712604). CDH4 is primarily expressed in the brain and functions in neurogenesis and segmentation of the central nervous system through its adhesive properties (PMID: 33833667). Overexpression of CDH4 in various cancer cell lines induces cellular proliferation, migration, self-renewal and invasion, suggesting that CDH4 functions predominantly as an oncogene (PMID: 37237299, 29610525). CDH4 amplification has been identified in various types of cancer, including breast cancer, osteosarcoma and glioblastoma (PMID: 22820501, 29610525, 31426573). False +ENST00000447079 NM_016507.2 51755 CDK12 False 1 CDK12, a cyclin dependent kinase, is recurrently mutated in metastatic prostate and serous ovarian cancers. CDK12 (Cyclin-dependent kinase 12) is a kinase involved in the regulation of the cell cycle and the regulation of transcriptional elongation of many DNA-damage-response genes (PMID: 11683387, 22012619). Recurrent inactivating CDK12 mutations in metastatic prostate and serous ovarian cancers have been observed (PMID: 28843286, PMID: 26787835). CDK12 interacts with and phosphorylates the C-terminal domain (CTD) of RNA polymerase II (RNAP) in vitro (PMID: 11683387) and complexes with Cyclin K to maintain genomic stability via regulation of the expression of DNA damage response genes, such as BRCA1, ATR, FANCI and FANCD2. Loss of the CDK12/cyclin K complex renders HEK293 cells sensitive to various DNA damaging agents, including camptothecin, etoposide and mitomycin C (PMID: 22012619, 24662513). CDK12 is one of the most frequently somatically mutated genes in ovarian cancer (PMID: 21720365), which is consistent with its role in the maintenance of genomic stability. The genomic location of CDK12, is adjacent to that of ERBB2, and while there is some laboratory data that associates an amplification of CDK12 to a tumorigenic phenotype (PMID: 28187285, 27880910, 28334900), it is likely that CDK12 amplification is a passenger event in this context, co-occurring with ERBB2 amplification in breast and gastric cancers (PMID: 20932292, 21097718, 26658019). True +ENST00000257904 NM_000075.3 1019 CDK4 True 4 CDK4, an intracellular kinase, is altered by amplification or mutation in various cancer types including soft tissue sarcomas and gliomas. CDK4 (cyclin-dependent kinase 4) is a serine/threonine kinase that regulates the cell cycle G1 to S phase transition. Upon mitogen stimulation, CDK4 forms a complex with cyclin D and cyclin-dependent kinase 6 (CDK6), which leads to activation of the kinases (PMID: 12432268). The active CDK4/CDK6 complex then phosphorylates and inactivates retinoblastoma (RB), thereby inducing the gene expression program regulated by the E2F family of transcription factors, which is important in cell cycle progression. CDK4/6 are in turn negatively regulated by p16INK4a (CDKN2A), which binds to the catalytic domains of the kinases and interferes with cyclin D and ATP binding (PMID: 9751050, 11124804). Amplification and overexpression of CDK4 occur in sarcomas, glioblastoma and breast cancers (PMID: 8221695, 8044775, 8586464, 9916925). CDK4/6 inhibitors have shown clinical efficacy in certain solid tumors, including breast and non-small cell lung cancer (PMID: 27959613, 27217383). Furthermore, CDK4/6 inhibition can trigger anti-tumor immunity by promoting cytotoxic T-cell-mediated clearance of tumor cells (PMID: 28813415). False +ENST00000265734 NM_001145306.1 1021 CDK6 True CDK6, an intracellular kinase, is amplified in various cancer types. CDK6 (cyclin-dependent kinase 6) is a serine/threonine kinase that regulates the cell cycle G1 to S phase transition. Upon mitogen stimulation, CDK4 forms a complex with Cyclin D and cyclin-dependent kinase 4 (CDK4), which leads to activation of the kinases (PMID: 12432268). The active complex then phosphorylates and inactivates retinoblastoma (RB), thus leading to the induction of a gene expression program regulated by the E2F family of transcription factors, which is important in cell cycle progression (PMID: 12432268). CDK4/6 are in turn negatively regulated by p16INK4a (CDKN2A), which binds to the catalytic domains of the kinases and interferes with cyclin D and ATP binding (PMID: 9751050, 11124804). Amplification and overexpression of CDK6 occur in several cancer types, such as esophageal carcinoma, leukemia and lymphoma (PMID:24423610, 9422538, 16782810). CDK4/6 inhibitors have shown clinical efficacy in certain solid tumors, including breast and non-small cell lung cancer (PMID: 27959613, 27217383). Furthermore, CDK4/6 inhibition can trigger anti-tumor immunity by promoting cytotoxic T-cell-mediated clearance of tumor cells (PMID: 28813415). False +ENST00000381527 NM_001260.1 1024 CDK8 True CDK8, an intracellular kinase, is amplified in various cancer types. CDK8 (cyclin-dependent kinase 8) is a serine/threonine kinase that is an important regulator of DNA transcription and cell cycle progression. CDK8 associates with Cyclin C (CCNC), Med12 and Med13 to form a module that associates with the Mediator complex, which is involved in the regulation of DNA transcription (PMID: 7568034). CDK8 associates and phosphorylates the c-terminal domain of RNA polymerase II, and thus plays an important role in transcriptional elongation (PMID:10023686, 11278802). CDK8 is a positive regulator of oncogene-induced proliferation and enables efficient transcriptional elongation through recruitment of pTEF-B and BRD4 to oncogenic genes (PMID: 20098423). However, CDK8 has been shown to restrain Mediator-dependent super-enhancer driven transcription in acute myeloid leukemia (AML) (PMID: 26416749), and thus may have different roles in certain oncogenic contexts. CDK8 is amplified in a large number of colorectal cancers and was specifically shown to modulate beta-catenin activity in this context (PMID: 18794900). False +ENST00000244741 NM_078467.2 1026 CDKN1A False CDKN1A, a tumor suppressor and cell cycle regulator, is altered in various cancer types and is recurrently mutated in bladder cancer. The CDKN1A gene encodes the p21 (WAF1) protein, which is a member of the Cip/Kip family of cyclin-dependent kinase (CDK) inhibitors. p21 inhibits the cyclin-dependent kinases CDC2 and CDK2, leading to G1 phase cell cycle arrest. p21 expression is upregulated by DNA damage through a p53-dependent mechanism (PMID: 8242752). Moreover, activation of the PI3K/AKT mitogenic signaling pathway results in phosphorylation and localization of p21 to the cytoplasm where it can no longer access its CDK targets, leading to enhanced cell proliferation. p21 may play a role in repair of DNA damage through interactions with DNA polymerase accessory factors. Loss of p21 can lead to chromosomal aneuploidy, implying a role in mitotic regulation. p21 expression is tightly regulated at both the transcriptional and protein levels: tumor suppressors and oncoproteins modulate transcription of CDKN1A while post-translational p21 modification regulates proteasomal degradation and subcellular localization (PMID: 9296497, 10319992). The majority of p21 alterations in cancer are truncating, concurrent with its role as a tumor suppressor, and p21 knockout mouse models display an increased incidence of a variety of cancers as compared to mice with intact p21 expression (PMID: 7664346, 12810620). p21 also exhibits anti-apoptotic activity in certain contexts, suggesting that it also possesses an oncogenic role. Inhibitors targeting the checkpoint kinase Chk1 in combination with chemotherapy have been found to have anti-tumor activity in bladder cancer (PMID: 25349305). True +ENST00000228872 NM_004064.3 1027 CDKN1B False CDKN1B, a tumor suppressor and cell cycle regulator, is altered in various cancer types. CDKN1B (cyclin-dependent kinase (CDK) inhibitor 1B), also called p27 or KIP1, is a member of the Cip/Kip protein family and helps control cell cycle progression, proliferation, motility, and apoptosis (PMID: 18354415). The p27 protein is ubiquitously expressed and located both in the nucleus and in the cytoplasm (PMID: 8033212). Nuclear p27 functions as a tumor suppressor by controlling cell cycle progression from G1 to S phase, specifically by inhibiting the binding of cyclins A and E to CDK2 (PMID: 18354415). Conversely, cytoplasmic p27 may have a pro-oncogenic role by stimulating cell migration through mechanisms largely independent of its CDK-inhibiting function (PMID: 15573116, 17909030). The activity of p27 is largely regulated by protein degradation, and proteolysis is triggered by its CDK-dependent phosphorylation and subsequent ubiquitination by SCF complexes (PMID: 16633365). Germline mutations in p27 can cause a multiple endocrine neoplasia (MEN) syndrome (PMID: 17030811). Low p27 levels due to increased protein degradation are prevalent in several different types of epithelial tumors, such as cancers of the upper gastrointestinal tract, skin, hematopoietic malignancies, gliomas, and sarcomas, and are commonly correlated with aggressive tumor growth and poor clinical outcome (PMID: 15573116, 10699961). True +ENST00000440480 NM_001122630.2 1028 CDKN1C False CDKN1C, a cyclin-dependent kinase inhibitor, is infrequently altered in cancer. CDKN1C encodes for a cyclin-dependent kinase inhibitor that primarily functions in the negative regulation of cellular proliferation (PMID: 7729684). CDKN1C inhibits G1-phase cell cycle progression through tight-binding inhibition of cyclin complexes cyclin E-CDK2, cyclin D2-CDK4 and cyclin A-CDK2 (PMID: 7729684). CDKN1C undergoes gene imprinting to silence the paternally-inherited allele through methylation, allowing the maternally-inherited allele to be the active copy (PMID: 16575194). Germline mutations and disruptions in the genomic imprinting of CDKN1C have been associated with the growth disorders Beckwith-Wiedemann syndrome and intrauterine growth restriction, metaphyseal dysplasia, adrenal hypoplasia congenita and genital anomalies (IMAGe) syndrome (PMID: 26077438, 22634751). CDKN1C knockdown in various cancer cell lines and models induces cellular proliferation, migration and invasion, suggesting that CDKN1C functions predominantly as a tumor suppressor gene (PMID: 18483241, 26271467, 29428729). CDKN1C downregulation has been identified in various types of cancer, including breast cancer and esophageal cancer (PMID: 29428729, 15007390, 38822599, 34464504). True +ENST00000304494 NM_000077.4 1029 CDKN2A False 4 The CDKN2A gene encodes two proteins, p16INK4A and p14ARF, that regulate the cell growth and survival. CDKN2A is altered by mutation and/or deletion in a broad range of solid and hematologic cancers. The CDKN2A gene encodes two unique proteins, p16(Ink4a) and p14(ARF), which are important in regulating cell cycle progression (PMID: 8521522). p16(Ink4a) is a cyclin-dependent kinase (CDK) inhibitor, which inhibits CDK4 and CDK6 by preventing their binding to cyclins. This activates the retinoblastoma (Rb) family of proteins, which blocks the G1 to S-phase transition and can result in cell cycle arrest or quiescence (PMID: 15878778, 22025288). p14(ARF) is an inhibitor of MDM2-mediated degradation of the tumor suppressor p53, thus enhancing p53-dependent transactivation and apoptosis (PMID: 9529249). Deletion of CDKN2A in murine models results in the generation of spontaneous tumors, consistent with its role as a tumor suppressor (PMID: 8620534). The CDKN2A locus is also frequently mutated or epigenetically silenced in numerous cancer types, including lymphoma, melanoma, pancreatic cancer, and lung cancer (PMID: 27428416). Furthermore, germline mutations in CDKN2A can lead to familial pancreatic cancers (PMID: 12454511). True +ENST00000276925 NM_004936.3 1030 CDKN2B False CDKN2B, a tumor suppressor and cell cycle regulator, is inactivated by mutation or deletion in various cancer types. CDKN2B (cyclin-dependent kinase (CDK) inhibitor 2B), also known as p15 or INK4B, is a cyclin-dependent kinase (CDK) inhibitor that helps regulate cell cycle progression. p15 inhibits CDK4 and CDK6 by preventing their binding to cyclins. This activates the retinoblastoma (Rb) family of proteins, which blocks the G1 to S-phase transition and can result in cell cycle arrest or quiescence (PMID: 9031081). CDKN2B expression has also been shown to regulate TGFβ-mediated cell cycle arrest (PMID: 8078588). Germline mutations in CDKN2B can result in a predisposition to renal cell carcinoma (PMID: 25873077). Deletion of CDKN2B in murine models can result in tumor progression, consistent with its role as a tumor suppressor (PMID: 14681685) and it is frequently deleted, hypermethylated, or mutated in a variety of tumors (PMID: 9479825). True +ENST00000262662 NM_078626.2 1031 CDKN2C False CDKN2C, a tumor suppressor and cell cycle regulator, is infrequently altered in cancer. CDKN2C (cyclin-dependent kinase inhibitor 2C), also known as p18 or INK4C, is a cyclin-dependent kinase (CDK) inhibitor that helps regulate cell cycle progression. p18 inhibits CDK4 and CDK6 by preventing their binding to cyclins. This activates the retinoblastoma (Rb) family of proteins, which blocks the G1 to S-phase transition and can result in cell cycle arrest or quiescence (PMID: 9031081). Regulation of cell division by p18 is important for B-cell, muscle and cerebellar development (PMID: 21163929, 9528803, 16864777). Consistent with its role as a tumor suppressor, deletions and mutations of p18 are found in multiple cancer types including multiple myeloma, lymphoma, glioblastoma, meningiomas and pituitary cancer (PMID:16960149, 18829482, 18381405, 11485924, 18973139). True +ENST00000498907 NM_004364.3 1050 CEBPA False CEBPA, a tumor suppressor and transcription factor, is recurrently altered by mutation in acute myeloid leukemia. CEBPA is a transcription factor that is a member of the basic region leucine zipper (bZIP) protein family (PMID: 25753223). CEBPA exists as two isoforms (p42 and p30) and binds DNA as a homodimer or heterodimer (as a p42/p30 heterodimer or in complex with other transcription factors, such as AP-1) to activate transcription (PMID: 25753223, 18026136). Through interactions via the transactivation domain, CEBPA can help recruit RNA polymerase II, coactivators such as CBP (Creb binding protein)/p300, and chromatin-modifying complexes such as SWI/SNF (switch/sucrose nonfermentable) (PMID: 12857754, 14660596). CEBPA functions as a regulator of cellular identity and coordinates the differentiation of diverse cell types including hematopoietic, adipose, and epithelial cells (PMID: 7652557, 23160954, 12757710). In hematopoiesis, CEBPA is important for the development of the myeloid lineage and granulocytic differentiation by regulating specific growth factor receptors and cell cycle arrest (PMID: 25753223). Loss of CEBPA in several cell types results in aberrant gene expression changes and cancer progression (PMID: 17638888). CEBPA mutations are found in acute myeloid leukemia (AML) and in inherited AML predisposition syndromes (PMID: 11242107, 12351377, 25311743, 23560626). N-terminal alterations result in the exclusive expression of the CEBPA p30 isoform and commonly co-occur with biallelic C-terminal mutations that disrupt CEBPA homodimerization (PMID: 31309149). The presence of a mutation in the bZIP region, regardless of monoallelic or biallelic status, is predictive of a favorable outcome in patients with AML (PMID: 33951732, 34320176, 34448807, 19171880). True +ENST00000335756 NM_001809.3 1058 CENPA False CENPA, a histone variant in centromere-associated chromatin, is altered by amplification and overexpression in various cancer types. CENPA is a histone variant that replaces the canonical histone H3 protein in nucleosomes at centromeres (PMID: 3558482, 20739937, 21478274, 16622419). Centromeric chromatin has distinct properties including flexible histone tails, which preclude the binding of histone H1, a histone molecule important in heterochromatin formation (PMID: 27499292, 32516549). CENPA is only present at centromeres and is essential for the correct assembly of proteins at the kinetochore, for centromere activity, and for chromosome segregation (PMID: 12906131, 10655499, 15870271, 27499292). Impaired kinetochore assembly and centromere activity can lead to aneuploidy and the development of cancer (PMID: 15380953). In addition, CENPA controls epigenetic mechanisms important for centromere organization, DNA replication, and cell division (PMID: 17339380, 9024683). Overexpression of CENPA is found in many cancer types including hepatocellular carcinoma, prostate cancer, colorectal cancer, and glioblastoma, among others (PMID: 17535684, 12839935, 26295306, 32371391). Amplification and overexpression of CENPA is a marker of poor prognosis, including in patients with breast cancer and osteosarcoma (PMID: 17970049, 24213134, 24440098, 24676531, 22369099). Somatic mutations in CENPA have been identified; however, these alterations have not been functionally validated (PMID: 31337617). Downregulation of CENPA contributes to methotrexate resistance and doxorubicin-induced senescence induced by low doses of doxorubicin in cancer cell lines (PMID: 26337976, 15870702). False +ENST00000394196 NM_001271 1106 CHD2 False CHD2, a chromodomain helicase, is frequently altered in chronic lymphocytic leukemia. CHD2, a member of the chromodomain helicase DNA-binding (CHD) family, encodes for a chromodomain helicase that functions in chromatin remodeling (PMID: 9326634, 25384982). CHD2 is composed of two chromodomains at the N-terminus that serve an autoinhibitory role for DNA-binding and ATPase activities (PMID: 25384982). CHD2 modifies chromatin through remodeling to regulate gene expression related to cellular development and differentiation (PMID: 25621013, 28549158). Expression of inactivating CHD2 mutations in cancer cell lines induces increased activation of signaling pathways associated with DNA modification processes, suggesting that CHD2 functions predominantly as a tumor suppressor gene (PMID: 26031915). Loss of CHD2 function has been identified in chronic lymphocytic leukemia, breast implant-associated anaplastic large-cell lymphoma and B-cell prolymphocytic leukemia (PMID: 26031915, 31774495, 31527074). True +ENST00000544040 NM_001273 1108 CHD4 True CHD4, a helicase, is infrequently altered in cancer. CHD4, a member of the SNF2/RAD54 helicase family, encodes for a helicase that functions in remodeling nucleosome structure through the ATPase/helicase domain of the protein (PMID: 8843877). CHD4 is a core component of the nucleosome remodeling and deacetylase (NuRD) complex, which regulates chromatin structure, gene expression and cell cycle progression (PMID: 11410659, 20693977). CHD4 has also been identified to regulate cellular processes independent of the NuRD complex, which include DNA-damage response, cell cycle progression and signal transduction, through binding to histone H3 with the PHD finger motifs of CHD4 (PMID: 15189737, 20805324, 22749909). Knockdown of CHD4 in various cancer cell lines and models inhibits cellular proliferation and invasion and decreases tumor metastasis, suggesting that CHD4 functions predominantly as an oncogene (PMID: 32070428, 32228507, 36681835). Amplification of CHD4 has been identified in various cancers, including colorectal cancer, uterine serous carcinoma and oral cancer (PMID: 33994851, 23359684, 28683324). CHD4 has been identified to modulate sensitivity to platinum treatment, and suppression of CHD4 is suggested to confer sensitivity (PMID: 34161330, 36603431). False +ENST00000428830 NM_001274.5 1111 CHEK1 False 1 CHEK1, an intracellular kinase, is overexpressed in various solid and hematologic malignancies. CHEK1 (Checkpoint Kinase 1) is a serine/threonine kinase that plays an integral role in the DNA damage checkpoint pathway and prevents damaged cells from continuing through the cell cycle. In response to DNA damage, CHEK1 is activated by the kinases ATR and ATM via phosphorylation (PMID: 12781359). Once activated, CHEK1 acts as an effector kinase, mediating downstream signaling that leads to a diverse range of cellular responses, including cell cycle checkpoint activation, cell cycle arrest, DNA repair and/or apoptosis and replication fork stability (PMID: 23508805). In particular, activated CHEK1 maintains the cyclin B1-CDK1 complex in an inactive cytoplasmic state, which prevents the G2/M transition and prevents mitotic segregation of damaged chromatids (PMID: 21532626). Though CHEK1 mutations are extremely rare (PMID: 12781359) CHEK1 is frequently over-expressed in a variety of tumors, including breast (PMID: 17638866), non-small cell lung cancer (PMID: 24418519 ), and nasopharyngeal cancers (PMID: 15297395). True +ENST00000404276 NM_007194.3 11200 CHEK2 False 1 CHEK2, a tumor suppressor and intracellular kinase, is altered in various cancer types. Germline mutations of CHEK2 are associated with an increased risk of certain cancers including breast, prostate and colorectal cancers. CHEK2 (Checkpoint Kinase 2) is a serine/threonine kinase that plays an integral role in the DNA damage checkpoint pathway and prevents damaged cells from continuing through the cell cycle. In response to DNA damage, CHEK2 is activated by the kinases ATR and ATM via phosphorylation (PMID: 12781359). Once activated, CHEK2 acts as an effector kinase, mediating downstream signaling that leads to a diverse range of cellular responses, including cell cycle checkpoint activation, cell cycle arrest and DNA repair and/or apoptosis (PMID: 25404613). CHEK2 also plays an important role during mitosis by maintaining chromosomal stability (PMID: 24798733, 20364141). Given its role in maintaining genomic stability, CHEK2 alterations are found in a range of cancers including glioblastoma, breast, ovarian, prostate, colorectal, gastric, thyroid, and lung cancer (PMID: 23296741, 24713400, 25583358, 12052256, 15125777). Germline mutations in CHEK2 have been associated with an increased risk of breast, colorectal, and prostate cancers (PMID: 21701879, 12533788, 17106448). True +ENST00000398235 NM_001039690 54921 CHTF8 False CHFT8, a component of the CTF18 replication factor C complex involved in DNA synthesis and repair, is altered by deletion in cancer. The CHTF8 gene, also known as DERPC, encodes the CTF8 subunit of the CTF18 replication factor C (RFC) complex, a proliferating cell nuclear antigen loader that functions in sister chromatid cohesion (PMID: 20826785). CTF8, along with the subunits CTF18 and DCC1, form a trimeric complex to mediate binding to DNA polymerase ε to promote polymorphic modulation of DNA synthesis (PMID: 20826785). Deletion of CHTF8 by itself and in combination with the other subunits of the RFC complex in yeast demonstrate severe defects in sister chromatid cohesion and G2/M cell cycle accumulation (PMID: 11389843). In vitro studies with prostate tumor cell lines and kidney embryonic cell lines demonstrate that CHTF8 expression is significantly reduced in prostate and renal cancer, respectively (PMID: 12477976). Similarly, overexpression of CHTF8 in prostate tumor cell lines demonstrates prostate cancer growth suppression as measured by inhibition of colony growth (PMID: 12477976). True +ENST00000575354 NM_015125.3 23152 CIC False CIC, a tumor suppressor and transcriptional repressor, is recurrently altered by mutation, deletion, and translocation, most frequently in oligodendrogliomas. CIC (also Capicua) is a transcriptional repressor that is a member of the high mobility (HMG)-box protein family (PMID: 32073140). CIC is expressed in a variety of tissues and is a critical regulator of patterning, differentiation, and signaling (PMID: 10652276, 32073140). Chromatin modifiers, such as the Sin/HDAC3 histone deacetylase complex, are recruited to sites bound by CIC to inhibit gene expression of target genes (PMID: 29844126). CIC exists in diverse protein complexes including with ATXN1, which directly binds CIC and modulates its transcriptional repressor activity (PMID: 17190598). The CIC-ATXN1 complex regulates the expression of several transcription factors, including members of the ETS protein family (PMID: 27869830). Loss of CIC expression results in the derepression of ETS transcriptional regulators, such as ETV4, which can activate extracellular remodeling programs and metastasis (PMID: 27869830, 22014525). In addition, CIC is a negative regulator of receptor tyrosine kinase (RTK) and MAPK signaling pathways and acts as a transcriptional repressor in the absence of RTK signaling (PMID: 11714680, 11861482, 29844126, 28178529). CIC is recurrently mutated in oligodendrogliomas, including in 1p/19q-deleted cancers (PMID: 21817013, 22869205, 22588899). Somatic mutations and deletions have also been found in various other cancer types, including in lung and gastric cancers (PMID: 25079317, 27869830). Chromosomal translocations that produce chimeric CIC proteins fused to several partner proteins, including DUX4 or FOXO4, occur in aggressive round cell sarcomas and result in aberrant CIC-mediated transcriptional activation (PMID: 19837261, 25007147, 21813156). True +ENST00000324288 NM_000246.3 4261 CIITA False CIITA, a transcriptional coactivator in immune cells, is recurrently altered by deletion, mutation and chromosomal rearrangement in lymphomas. CIITA is a transcriptional coactivator that functions as a master regulator of the genes that encode the major histocompatibility complex class II (MHC class II) proteins (PMID: 24391648). MHC class II proteins present extracellular peptides on the surface of antigen presenting cells to display these peptides to the immune system. CIITA is constitutively expressed in cell types that express MHC class II molecules, including dendritic cells, macrophages and B cells (PMID: 25324123). CIITA and MHC class II expression can be induced in other immune cell types by IFNγ and stimulation with other cytokines (PMID: 25324123). CIITA has multifaceted roles in transcriptional regulation including replacement of the TFIID component in the general transcriptional complex as well as acetyltransferase and kinase activity, which are necessary for the transcription of MHC class I and class II genes (PMID: 24391648). CIITA requires the DNA binding proteins CREB, RFX, and NF-Y to serve as a binding scaffold (PMID: 16730065). Germline mutations in CIITA have been identified in patients with bare lymphocyte syndrome type II, an immune deficiency that leads to a loss of MHC class II protein surface expression (PMID: 7749985). Rearrangements involving CIITA are found in patients with B cell and Hodgkin lymphoma (PMID: 21368758). CIITA fusion proteins cause downregulation of MHC class II expression and overexpression of ligands for PD-1, a receptor that mediates immune suppression (PMID: 21368758). Somatic CIITA loss-of-function mutations and deletions have been associated with some lymphomas, suggesting that CIITA functions as a tumor suppressor (PMID: 28479318, 26599546, 26549456). True +ENST00000427926 NM_007098 8218 CLTCL1 False CLTCL1, a clathrin heavy chain, is infrequently altered in cancer. CLTCL1, a member of the clathrin heavy chain family, encodes for the CHC22 clathrin heavy chain and functions in intracellular trafficking of the GLUT4 glucose transporter (PMID: 26068709). Intracellular trafficking of GLUT4 is triggered in response to insulin, and CLTCL1-dependent GLUT4 trafficking has been identified to occur in compartments within muscles and adipocytes (PMID: 19478182). CLTCL1 downregulation and fusions have been identified in breast cancer and ALK-positive lymphoma; however, the oncogenic function of the protein has not yet been well characterized in biochemical studies (PMID: 22496928, 10807789). False +ENST00000338099 NM_001099642.1 55783 CMTR2 False CMTR2, an RNA cap methyltransferase, is recurrently altered by mutation in non-small cell lung cancer. CMTR2 (also FTSJD1 and HMTR2) is an RNA methyltransferase that modifies the 5’ cap structures of messenger RNA (mRNA). CMTR2 catalyzes the transfer of a methyl group to the 2'-O-ribose on the second nucleotide in the mRNA (cap2) (PMID: 24402442, 21310715). The 5’ cap of mRNA is modified by methylation on both the first and second nucleotide, which is important for effective processing, translation initiation, gene expression, splicing, and stability of mRNA (PMID: 24402442, 15525712). In addition, 2'-O-ribose methylation is important for immune recognition of mRNA transcripts in the host cell (PMID: 21217758). Cap2 methylation occurs on fifty percent of mRNA transcripts, while methylation of the first nucleotide is ubiquitous of all mRNA (PMID: 1057180, 21310715). Somatic loss-of-function mutations in CMTR2 are found in patients with lung squamous cell carcinoma (PMID: 24402442). CMTR2 variants are predominantly truncating mutations, suggesting that CMTR2 may function as a tumor suppressor (PMID: 24402442). True +ENST00000373855 NM_007018.6 11064 CNTRL False CNTRL, a centrosomal protein, is infrequently altered in cancer. CNTRL encodes for a centrosomal protein that functions in the maturation of the centrosome and a subunit that allows the centrosome to function as a microtubule organizing center (PMID: 11956314). CNTRL regulates cell cycle progression into S-phase and cytokinesis within the mother centriole (PMID: 12732615). CNTRL fusions and upregulated expression have been identified in stem cell myeloproliferative disorders, acute myeloid leukemia and esophageal squamous cell carcinoma; however, the oncogenic function of the gene has not yet been well characterized in biochemical studies (PMID: 10688839, 21403647, 33491601, 32227267). False +ENST00000225964 NM_000088 1277 COL1A1 True COL1A1, a collagen type I alpha 1 chain, is infrequently altered in cancer. COL1A1 encodes for the type I collagen pro-alpha1(I) chain which functions in crosslinking with pro-alpha2(I) chains (COL1A2) and other pro-alpha1(I) chains to create collagen type I within connective tissues (PMID: 3468512, 27894325). Collagen type I interacts with various signaling pathways, including integrins and DDR1, to regulate extracellular matrix production, cellular proliferation and survival (PMID: 32500940, 20093046). Overexpression of COL1A1 in various cancer cell lines and models induces cellular proliferation, migration and invasion, suggesting that COL1A1 functions predominantly as an oncogene (PMID: 29393423, 28482162, 29906404). COL1A1 amplification has been identified in various types of cancer, including breast cancer, gastric cancer and colorectal cancer (PMID: 29906404, 27894325, 29393423). Upregulated expression of COL1A1 has been associated with increased chemoresistance in pancreatic, lung and ovarian cancers (PMID: 27390605, 33680916, 29414301, 34475986). False +ENST00000380518 NM_001844 1280 COL2A1 False COL2A1, a collagen type II alpha 1 chain, is frequently altered in chondrosarcoma. COL2A1 encodes for the type II collagen pro-alpha1(I) chain that functions in crosslinking with two other pro-alpha1(II) chains to create collagen type II within connective tissues (PMID: 7806485). Collagen type II interacts with various signaling pathways such as integrins and RhoA to regulate chondrogenesis and synthesis of the extracellular matrix (PMID: 19624244, 15895462, 26879681). COL2A1 loss-of-function mutations in chondrosarcoma models induce hypertrophic differentiation of chondrocytes, suggesting that COL2A1 functions predominantly as a tumor suppressor gene (PMID: 30854241, 12917109). Inactivating mutations of COL2A1 have been frequently identified in chondrosarcoma (PMID: 23770606, 33147331, 31604924). True +ENST00000367669 NM_022457.5 64326 COP1 True COP1, an E3 ubiquitin-protein ligase, is frequently altered in various cancers. COP1 encodes an E3 ubiquitin-protein ligase that targets both oncogenic and tumor suppressive substrates for ubiquitination and degradation, including c-Jun, p53, ETS factors, β-catenin, CEBPA and p27 (PMID: 27534417, 22673153, 21572435, 34582788, 28611108). The role of COP1 in cancer is context-dependent, and can involve apoptosis, the cell cycle, DNA repair, cell proliferation, transformation and tumor progression (PMID: 21135113). The oncogenic and tumor-suppressive role of COP1 expression has been demonstrated experimentally in vitro and in vivo (PMID: 20959491, 21572435, 21403399, 21403396). Loss of COP1 in wild-type mice suppresses tumor growth and prolongs survival through tumor microenvironment reprogramming and immune response (PMID: 34582788). COP1 is commonly overexpressed in several tumor types, including gastric cancer, hepatocellular carcinoma, breast cancer and ovarian adenocarcinoma, and is associated with poor overall survival (PMID: 23091414, 15492238). Conversely, low COP1 mRNA and protein levels are associated with a less favorable prognosis in renal cell carcinoma, gastric cancer and triple-negative breast cancer (PMID: 27278120, 23933908, 25884720). True +ENST00000231948 NM_016302.3 51185 CRBN False CRBN, a ubiquitin ligase, is recurrently altered by mutation or downregulation in multiple myelomas. CRBN (also cereblon) is a ubiquitin ligase that targets various protein substrates for degradation. CRBN forms a complex with DDB1, CUL4A and ROC1 to coordinate the ubiquitination and degradation of protein substrates via the proteasome (PMID: 16964240). IKZF1 and IKZF3, two lymphoid transcription factors, are key CRBN degradation targets in multiple myeloma cells (PMID: 24292625). Other CRBN degradation targets have been identified including GPST1, a translation termination factor (PMID: 27338790). CRBN has been shown to activate protein synthesis through inhibition of AMPK via the mTOR pathway (PMID: 24993823) and regulate potassium channels in neuronal cells (PMID: 15194823). Germline mutations in CRBN have been identified in individuals with intellectual disorders (PMID: 15557513). Expression of CRBN is required for the sensitivity of multiple myeloma cells to immunomodulatory drugs including thalidomide, lenalidomide, and pomalidomide (PMID: 21860026, 22552008). Somatic CRBN loss-of-function mutations or reduced expression of CRBN are found in patients with multiple myeloma that are refractory to immunomodulatory drugs (PMID: 23480694, 27458004). Specific protein degraders have been developed leveraging the ability of CRBN to bind thalidomide derivatives and target a variety of substrates for degradation (PMID: 25999370). True +ENST00000432329 NM_134442.3 1385 CREB1 True CREB1, a transcription factor, is rarely altered by chromosomal rearrangements in soft tissue sarcomas. CREB1 is a leucine zipper transcription factor that is induced and binds to cAMP-inducible promoters. The protein is activated via phosphorylation by several kinases, such PKA, and dimerizes and binds to cAMP-responsive elements within promoters across the genome (PMID: 15982754). CREB1 has been shown to be required for neuronal development, specifically within sensory and sympathetic neurons, as well as axon extension (PMID: 11988169, 11967539). CREB-dependent signaling pathways are also required for peripheral neuron development and survival. Additionally, signaling pathways activated by CREB1 have been shown to be involved in learning, memory, mood, and addiction (PMID: 19286560, 11889468, 15999345, 9856954). Recently, CREB1 has been shown to be important in late-stage lung development (PMID: 27150575) and survival and development of immune cell function (PMID: 21084670). False +ENST00000262367 NM_004380.2 1387 CREBBP False CREBBP, a tumor suppressor and transcriptional co-activator, is frequently inactivated in hematologic malignancies. CREBBP (CREB binding protein) is a transcriptional co-activator with intrinsic histone acetyltransferase (HAT) activity; it is closely homologous to the co-activator EP300 (PMID: 8004670, 18273021). As a co-factor, CREBBP binds to DNA binding proteins where it functions as a scaffold to recruit a range of transcription complex components (PMID: 9215639, 9445474). CREBBP itself can recruit the basal transcriptional machinery, and through its HAT activity acetylate lysine tails to modify chromatin into a more open conformation for active transcription (PMID: 8576192,8967953). The HAT activity of CREBBP is also active on non-histone proteins, including tumor suppressors such as p53 and tissue-specific transcription factors such as GATA1 (PMID: 9830059, 9859997). In leukemias, CREBBP can be disrupted by translocations that fuse the HAT domain with the MOZ/KAT6A (lysine acetyltransferase 6a) protein t(8;16) (PMID: 9447825). Somatic mutations of CREBBP have been found in leukemia, lymphoma and solid tumors including small-cell lung cancer, squamous carcinoma and bladder cancer (PMID: 24670651, 21796119, 21390130, 25151357, 21390130). Most CREBBP mutations are truncating and commonly co-occur with loss of the wildtype allele, suggesting that CREBBP is a tumor suppressor. Inherited mutations can result in the Rubinstein-Taybi syndrome with stereotypical facial and digit abnormalities along with neurological deficits (PMID:7630403). CREBBP-mutated tumors are dependent on EP300 activity and inhibitors targeting EP300 are efficacious in CREBBP-mutated cell line and mouse models (PMID: 26603525). True +ENST00000354336 NM_005207.3 1399 CRKL True CRKL, an adapter protein, is overexpressed in various cancer types. CRKL is an adaptor protein that facilitates signal transduction from kinases to downstream targets (PMID:10648385). It is a target of the BCR-ABL translocation kinase and enhances transformation in CML (chronic myelogenous leukemia) (PMID:20807813). CRKL can activate the Ras, Rac, and Jun kinase signaling pathways (PMID:12393632, 11443118, 10514505). Pathway activation mediates diverse cellular processes involved in cancer including cell proliferation, EMT (epithelial to mesenchymal transition), and invasion (PMID:26044596, 25661331,25318601). CRKL amplification has been identified in lung carcinomas and gastric cancer (PMID:22591714, 22586683). Amplification can be a means of acquired resistance to targeted therapy in EGFR lung cancer (PMID:22586683). False +ENST00000381566 NM_022148.4 64109 CRLF2 True CRLF2, a cytokine receptor, is recurrently altered by chromosomal rearrangement in B-cell acute lymphoblastic leukemia. CRLF2 is a type I cytokine receptor that signals through the pro-oncogenic JAK-STAT pathway, which regulates processes such as proliferation and development of the hematopoietic system (PMID: 20807819). In order to signal, CRLF2 heterodimerizes with the IL7RA (interleukin 7 receptor), thus forming the receptor for thymic stromal lymphopoietin (TSLP), a cytokine that mediates B-cell precursor proliferation and survival (PMID: 9916685). CRLF2 is expressed on T cells, dendritic cells, monocytes, and basophils (PMID: 11418668). Its activation is linked to a Th2 response, can lead to eosinophilia, and is implicated in reactivity and airway remodeling for asthma, in atopic dermatitis, and in immunity against helminth infections (PMID: 24167583, 26288354, 21841801, 23024277 ). Rearrangement of the gene is seen in precursor B-cell acute lymphoblastic leukemia (PMID: 25207766, 22897847, 19838194). Rearranged receptor can signal through the JAK-STAT and PI3K-MTOR pathways and lead to transformation (PMID: 22685175, 19838194). False +ENST00000438362 NM_001242891.1 7812 CSDE1 False CSDE1, an RNA-binding protein, is altered by mutation in various cancer types, including neuroendocrine tumors. CSDE1 (also UNR) is an RNA-binding protein that regulates RNA stability and protein homeostasis (PMID: 31987048, 29422612). CSDE1 forms complexes with diverse partner proteins to positively or negatively regulate cap-dependent translation, cap-independent translation, and mRNA transcript stability (PMID: 17086213, 31987048). The binding of CSDE1 regulates numerous mRNA targets, including poly(A) binding protein (PABP), MYC and FOS (PMID: 16356927, 31027221). Because CSDE1 is involved in numerous RNA regulatory protein complexes, CSDE1 modulates a variety of cellular processes including apoptosis, neuronal development, cell cycle progression, invasion and sex chromosome dosage compensation (PMID: 31579823, 24012837, 17159903, 11313462). In addition, CSDE1 regulates processes important in protein translation including deadenylation (PMID: 11051545, 15314026). Loss-of-function mutations in CSDE1 have been implicated in autism spectrum disorder (PMID: 31579823). Deletions and loss-of-function alterations have been identified in patients with rare neuroendocrine tumors, including pheochromocytomas and paragangliomas (PMID: 28162975). In addition, CSDE1 may function as an oncogene or tumor suppressor in several cancer types (PMID: 31027221, 27908735, 28162975, 29422612). False +ENST00000286301 NM_005211.3 1436 CSF1R False CSF1R, a cytokine receptor, is altered in various cancer types. CSF1R is a membrane protein that acts as a receptor for colony-stimulating factor 1 (CSF1), a cytokine that regulates the production, differentiation, and function of macrophages. CSF1R-mediated signaling is an important regulator of innate immunity. Co-expression of CSF1R and the ligand CSF1 can lead to tumorigenic activity in cancer cells independent of CSF1R overexpression or amplification, suggesting that CSF1R acts as an oncogene (PMID: 22096574). However, loss-of-function CSF1R mutations and splice variants have also been associated with a predisposition for myeloid malignancies (PMID: 18971950). Kinase inhibitors and neutralizing antibodies that target CSF1R have been shown to effectively target CSF1/CSF1R signaling, resulting in a reduction in the number of tumor-associated macrophages. Experimental data suggest that CSF1/CSF1R blockade could improve the efficacy of immunotherapies by enhancing activation of T cells in the tumor microenvironment. (PMID: 25082815, 22186992, 27199435, 24056773). False +ENST00000361632 NM_000760.3 1441 CSF3R True CSF3R, a transmembrane receptor, is frequently mutated in chronic neutrophilic leukemia and atypical chronic myeloid leukemia. CSF3R (also G-CSF) is a transmembrane receptor for cytokine colony-stimulating factor 3. Activation of the receptor is associated with the increased production of neutrophilic granulocytes and has been used clinically to shorten recovery time for chemotherapy and to mobilize hematopoietic stem cells into the periphery for stem cell collection (PMID: 7521686, 3311216, 7534140). Signaling from the receptor is mediated by JAK (Janus kinase) and SRC (SRC proto-oncogene) family of kinases with downstream activation of STAT, PI3K, and MAPK signaling cascades (PMID:7579336, 9590246) and inhibition mediated through the SOCS (Suppressor of Cytokine Signaling) proteins and tyrosine phosphatases (PMID:12133942, 9590246). Loss of function mutations can lead to severe congenital neutropenia (PMID:10449521, 24753537). Activating mutations can cause receptor dimerization independent of ligand with mutations near the juxtamembrane region, or truncate the receptor leading to altered signal transduction (PMID:23739288, 8246993). These mutations have been found in myeloid disorders such as chronic neutrophilic leukemia, atypical chronic myeloid leukemia and acute myeloid leukemia (PMID: 7542747, 23656643). Solid tumors have been shown to express CSF3R that may be important for disease phenotype or transformation (PMID:16912178, 25908586). False +ENST00000264010 NM_006565.3 10664 CTCF False CTCF, a tumor suppressor and chromatin binding factor, is mutated in various cancers, most frequently in endometrial cancer. CTCF is a versatile regulator of gene transcription that binds DNA with different combinations of its eleven highly conserved zinc finger (ZF) domains. CTCF can recruit histone acetyltransferases (HATs) or histone deacetylases (HDACs), along with other cofactors, and activate or repress transcription, respectively (PMID: 11525835,10734189). The c-MYC oncogene is a well-known CTCF target, which acts in this context as a transcriptional repressor (PMID: 8649389). CTCF also acts as an insulator, playing a role in high order chromatin structural organization and long-range genomic interactions (PMID: 23498937), typically isolating enhancers from promoters which ultimately results in inhibition of gene transcription (PMID: 19846290, 25002401). Insulation is achieved by CTCF-mediated modification of epigenetic marks, such as H3K27me3 removal (PMID: 25294833). CTCF binding prevents CpG methylation and vice versa (PMID: 20591991, 25703332). While complete loss of CTCF is embryonically lethal, CTCF haploinsufficiency has been demonstrated to alter global methylation patterns, predispose mice to a range of cancers and is associated with shortened overall lifespan (PMID: 24794443). Mutations in the CTCF gene usually result in a truncated protein, and they are mainly found in carcinomas of the endometrium (15%), digestive tract (colon and stomach, around 5%) and breast (cBioPortal, MSKCC, March 2015). In addition, both CTCF loss and overexpression lead to global effects in expression profiles. True +ENST00000574322 NM_001143775.2 23399 CTDNEP1 False CTDNEP1, a serine/threonine protein phosphatase, is recurrently altered by mutation or reduced expression in medulloblastoma. CTDNEP1 (C-terminal domain nuclear envelope phosphatase 1), also known as Dullard, is a noncanonical serine/threonine protein phosphatase. CTNEP1 is a member of the C-terminal domain phosphatases (CTDPs), a group of seven phosphatases named for the CTD of RNA polymerase II (RNAPII) which is dephosphorylated by one member of the family, CTD phosphatase 1 (CTDP1) (PMID: 38776370, 37374122, 19215094). CTDNEP1 contributes to the regulation of endoplasmic reticulum (ER) and nuclear envelope (NE) membrane biogenesis through the dephosphorylation of lipin-1, a phosphatidic acid phosphatase that associates with the ER and regulates membrane lipid metabolism (PMID: 17420445, 34852214, 37873275, 37374122, 38776370, 23426360). CTDNEP1 binds and interacts with NEP1R1 (nuclear envelope phosphatase 1 regulatory subunit 1), and together this complex functions in maintaining the morphology and regulating the expansion of the ER membrane as well as regulating nuclear pore complex insertion (PMID: 38776370, 38045299). Through interaction with other proteins, CTDNEP1 plays a role in maintaining proper nuclear architecture, nuclear positioning and centrosome reorientation and in regulating cell migration (PMID: 37374122, 36318477, 33567288). Additionally, CTDNEP1 plays an important role in neural induction during embryogenesis by functioning as a negative regulator of bone morphogenetic protein (BMP) signaling through dephosphorylation and degradation of BMP receptors (PMID: 25155999, 37374122, 17141153). Similarly, CTDNEP1 has been found to negatively regulate TGF-ꞵ signaling. CTENDP1 is recurrently mutated in aggressive MYC-driven medulloblastoma, where reduced levels of CTDNEP1 have been shown to lead to MYC activation and tumor progression, thus supporting CTNEDP1's role as a tumor suppressor gene (PMID: 36765089). True +ENST00000648405 NM_005214.4 1493 CTLA4 True CTLA4, a transmembrane receptor, is infrequently altered in cancer and is a promising target for immune blockade therapies. CTLA4 (cytotoxic T-lymphocyte-associated antigen-4) is a transmembrane immunoglobulin receptor that blocks activation of T-lymphocytes (PMID: 9653097). CTLA4 binds to ligand B7-1 and B7-2, present on antigen presenting cells (PMID: 7543139). Binding of these ligands prevents their binding to CD28, the co-stimulatory molecule on T-cells and transduces an inhibitory signal within the T-cell (PMID: 11244047). Germline mutations in CTLA4 lead to immune dysregulation, hyper-activated T-cells and loss of normal circulating B-cells (PMID: 25213377). Polymorphisms and mutations in CTLA4 are associated with autoimmune diseases, including thyroid disorders and diabetes (PMID: 25695113, 25329329). Inhibition of CTLA4 has been employed in immune therapy of cancer by allowing activation of tumor-specific T-cells (PMID: 20525992). Ipilimumab, a monoclonal antibody that targets CTLA4, is FDA approved for the treatment of metastatic melanoma and functions by inhibiting immune system tolerance. Combination treatments with other immunotherapy treatments, including nivolumab, are currently under investigation (PMID: 28087644). False +ENST00000302763 NM_001903 1495 CTNNA1 False CTNNA1, a cytoplasmic adhesion protein, is infrequently altered in cancer. CTNNA1 encodes for a catenin which functions in association with a variety of cadherins to promote cell-adhesion (PMID: 11997091). The intracellular adhesion function of CTNNA1 is regulated through a dual-kinase mechanism located on the carboxy-terminal region and phospho-linker region of the protein (PMID: 25653389). CTNNA1 forms part of the E-cadherin/catenin multiprotein complex and promotes adhesion junction through interaction between other catenins and the actin cytoskeleton (PMID: 34425242, 9819562). Inactivation of CTNNA1 in various types of cancer cell lines and models induces cellular invasiveness and tumor metastasis, suggesting that CTNNA1 functions predominantly as a tumor suppressor gene (PMID: 33057364, 17223851, 29484367, 33364826). Downregulation of CTNNA1 has been identified in various types of cancer, including bladder cancer, acute myeloid leukemia and breast cancer (PMID: 18190825, 25177364, 22080244). True +ENST00000349496 NM_001904.3 1499 CTNNB1 True CTNNB1 (β-catenin), a transcriptional activator, is recurrently mutated in various cancers including endometrial and hepatocellular cancers. CTNNB1 (also β-catenin) is a transcriptional activator involved in the WNT signaling pathway (PMID: 22682243, 22617422). In the absence of WNT ligands, β-catenin is sequestered in the cytosol by its interaction with the APC/AXIN destruction complex. This destruction complex includes GSK3β, a kinase responsible for phosphorylating key β-catenin residues and targeting β-catenin for degradation. Engagement of WNT receptors by WNT ligands results in disruption of the APC/AXIN destruction complex, freeing β-catenin to transit into the nucleus and mediate target gene activation by interaction with transcription factors of the TCF/LEF family. Important transcriptional targets of β-catenin/TCF include Cyclin D1 and MYC (PMID: 10201372, 9727977). β-catenin also influences cell-cell adhesion and cell migration (PMID: 15001769). Somatic gain-of-function mutations in CTNNB1 result in aberrant accumulation of the β-catenin protein and are prevalent in a wide range of solid tumors, including uterine/endometrial carcinoma (PMID: 9721853, 23636398), ovarian (PMID: 19349352, 20942669), hepatocellular carcinoma (PMID: 22634756, 23788652), and colorectal carcinoma (PMID: 22810696), among others. Cancers with CTNNB1 mutations are presumed to be resistant to pharmacologic inhibition of upstream components of the WNT pathway, instead requiring direct inhibition of β-catenin function (PMID: 19351922, 22682243). False +ENST00000361367 NM_014633.4 9646 CTR9 False CTR9, a component of the PAF1 complex involved in RNA polymerase II regulation, is recurrently altered by mutation in Wilms tumor. CTR9 is an adaptor protein that is a component of the transcriptional regulatory PAF1 complex (PAF1c) (PMID: 20060942). CTR9 binds the multimeric PAF1c, which is also composed of the proteins PAF1, LEO1, CDC73, RTF1, and WDR61 (PMID: 25099282, 11884586, 30228257). PAF1c binds RNA polymerase II (Pol II) via the C-terminal domain (CTD) in the unphosphorylated state and dynamically regulates transcription at various stages including initiation, termination, elongation, and polyadenylation (PMID: 25099282, 11884586). In addition to regulating the activity of Pol II, PAF1c and CTR9 function to recruit transcription factors, histone remodelers, and processing factors to chromatin, thereby regulating gene expression via various layers of regulation (PMID: 20060942). The activity of CTR9 and PAF1c coordinate the appropriate placement of histone marks, allowing for regulation of chromatin remodeling (PMID: 22982193). The PAF1c complex also mediates the eviction of Pol II from chromatin in response to DNA damage, implicating the transcriptional complex in mediating genome instability (PMID: 26798134). PAF1c function is ubiquitously expressed to coordinate gene expression; however, PAF1c activity is particularly important during development (PMID: 17721442) and for the maintenance of embryonic stem cell identity (PMID: 19345177). Germline mutations in CTR9 are found in patients with Wilms’ tumor, a childhood renal cancer (PMID: 25099282). CTR9 alterations are predominantly heterozygous and alter CTR9 splicing, likely leading to protein truncation and loss of activity, suggesting that CTR9 acts predominantly as a tumor suppressor (PMID: 25099282, 29292210). However, in breast cancer, CTR9 expression is associated with increased transcription of oncogenic genes and proliferation, demonstrating a context-specific growth-promoting role of CTR9 (PMID: 26494790, 27829357). True +ENST00000264414 NM_003590.4 8452 CUL3 False CUL3, an E3 ubiquitin ligase component, is altered by mutation in non-small cell lung cancer. CUL3 is an E3 ubiquitin ligase that is a member of the cullin protein family (PMID: 27200299). Cullins, such as CUL3, associate with RING domain proteins to form E3 ligase complexes, which covalently attach ubiquitin to target proteins for subsequent degradation by the 26S proteasome (PMID: 15071497). CUL3 functions as a scaffolding protein with BTB-domain adaptor proteins to bring target substrates in proximity to the catalytic RING domain (PMID: 17120193). CUL3 is also involved in many cellular processes including the maturation of endosomes associated with lysosomal degradation, inflammation, proliferation, and cell cycle progression (PMID: 22219362, 30872636, 27200299). In addition, CUL3 interacts with several substrate adaptors that are altered in cancer including KEAP1, KLHL20, and SPOP (PMID: 27200299). A prominent example is KEAP1, which recruits the oxidative stress signaling factor NRF2 to the CUL3-containing E3-ubiquitin ligase complex for degradation (PMID: 19321346, 19638449, 23365135). Germline mutations in CUL3 are found in patients with Gordon’s syndrome, which is characterized by hypertension (PMID: 23689903). Somatic loss-of-function mutations in CUL3 have been identified in patients with non-small cell lung cancer (PMID: 31548347). These alterations disrupt the degradation of NRF2 and subsequently upregulate the oxidative stress response via KEAP1 and NRF2, leading to cancer progression (PMID: 19321346, 19638449, 23365135). True +ENST00000375440 NM_001008895 8451 CUL4A True CUL4, a ubiquitin ligase component of an E3 ubiquitin-protein ligase complex, is infrequently altered in cancer. CUL4 encodes for the ubiquitin ligase component of the cullin-RING-based E3 ubiquitin-protein ligase complex (PMID: 15811626, 16678110). The cullin-RING-based E3 ubiquitin-protein ligase complex mediates ubiquitination of target proteins in response to DNA damage and regulates histone methylation (PMID: 15448697, 16678110, 17041588). Overexpression of CUL4 in various cancer cell lines and models induces metastasis, tumor growth and cellular proliferation, suggesting that CUL4 functions predominantly as an oncogene (PMID: 28576144, 25413624, 28223829). CUL4 amplification has been identified in various types of cancer, including lung cancer, prostate cancer, breast cancer and ovarian cancer (PMID: 34119472, 22422151, 24305877). CUL4 expression is a potential therapeutic target with preclinical studies investigating the efficacy of anti-CUL4 inhibitors in various types of cancer (PMID: 28677427, 33602808). CUL4 is suggested to confer chemoresistance in ovarian cancer by inhibiting BIRC3 expression (PMID: 30718461). False +ENST00000292535 NM_181552.3 1523 CUX1 False CUX1, a transcription factor, is frequently altered in several cancers types by deletion, mutation or translocation. CUX1 (also CUTL1) is a transcription factor that regulates gene expression in a variety of cellular contexts (PMID: 18313863). The CUX1 protein has several alternative spliced protein isoforms which exhibit distinct DNA binding and transcriptional properties (PMID: 12429822). One isoform of CUX1 can function as either a transcriptional repressor or activator, while another is critical in base excision repair (PMID: 25190083). CUX1 also binds at enhancer sites with cohesin and regulates higher-order chromatin structure (PMID: 28369554). In addition, CUX1 regulates key cellular functions including cell cycle, proliferation, migration, neutrophil maturation, DNA damage and TGF-β-mediated signaling (PMID: 11438745, 22319212, 28147323, 18313863). Loss of CUX1 in preclinical models results in various gene expression changes, including de-repression of the PI3K pathway inhibitor PIK3IP1, leading to hematopoietic abnormalities (PMID: 29592892). CUX1 is recurrently deleted in uterine leiomyomas, acute myeloid leukemia and myelodysplastic syndromes (PMID: 9178912, 23212519, 25645650). Deletion of CUX1 occurs in the commonly deleted 7q region and is typically heterozygous, suggesting that CUX1 functions as a haploinsufficient tumor suppressor (PMID: 23212519, 25645650). Somatic loss-of-function mutations and fusion proteins involving CUX1 are also found in a range of human cancers, namely hematopoietic malignancies (PMID: 21674579). While CUX1 can function as a tumor suppressor in some cancer types, increased expression of CUX1 is also transforming in preclinical models and overexpression of CUX1 has been linked to poor prognosis in several human cancers (PMID: 25190083). True +ENST00000241393 NM_003467.2 7852 CXCR4 True CXCR4, a chemokine receptor, is altered in various solid and hematologic malignancies including lymphoplasmacytic lymphoma. CXCR4 is a chemokine receptor specific to the stromal-derived factor CXCL12, a molecule with potent chemotactic activity for lymphocytes (PMID: 20484021). Through autocrine and paracrine interactions, the CXCR4-CXCL12 signaling axis promotes cancer cell proliferation, survival, motility and drug resistance (PMID: 20484021). Expression of CXCR4 in cancer cells has been linked to metastasis to tissues containing high levels of CXCL12, like the bone, lungs, liver and lymph nodes (PMID: 21866172, 20484021, 17891505, 11242036). The CXCR4-CXCL12 axis also induces angiogenesis in several malignancies through hypoxia-induced CXCR4 expression and recruitment of endothelial progenitor cells to tumors (PMID: 15180966, 15882617, 21618540). Germline mutations in CXCR4, including activating C-terminal truncating mutations, cause WHIM syndrome, an immunodeficiency disorder characterized by neutropenia (Abstract: Cao et al. Abstract# 2715, ASH 2012. http://www.bloodjournal.org/content/120/21/2715)(PMID: 24553177, 24711662). Somatic alterations in CXCR4 are found in Waldenström macroglobulinemia (PMID: 24553177), but are rare in other cancers; elevated expression of CXCR4 is a poor prognostic marker in many cancers, including breast, ovarian, melanoma and prostate cancers (PMID: 25669980). Inhibitors of the CXCL4-CXCL12 axis are in several Phase I/II clinical trials for stem cell mobilization and HIV research; these inhibitors have not yet been evaluated in the context of cancer (PMID: 24141062). False +ENST00000398568 NM_001042355.1 1540 CYLD False CYLD is a tumor suppressor and deubiquitination enzyme that negatively regulates the NF-κB pathway. Germline mutations of CYLD are associated with Brooke-Spiegler syndrome, familial cylindromas, multiple familial tricoepithelioma, and spiradenomas. CYLD is a deubiquitinating enzyme that removes lysine-63-linked ubiquitin marks. It negatively regulates NF-κB signaling by deubiquitinating upstream regulators such as TRAF2 and TRAF6 (PMID: 12917689, 12917691). CYLD has a tumor suppressor role, principally via NF-κB pathway inhibition and enhancement of apoptosis (PMID: 12917690). Despite its recognized tumor suppressor role, CYLD also modulates microtubule dynamics and plays roles in cell migration and angiogenesis (PMID: 18222923, 20194890). CYLD is involved in other physiological processes, such as immune response, inflammation, cell cycle progression, spermatogenesis and osteoclastogenesis (PMID: 19373246). CYLD is mutated at low frequencies in various tumors. Around 25% of CYLD alterations are truncating mutations (cBioPortal, MSKCC, Jan. 2017). Germline mutations in CYLD gene have been associated with cylindromatosis, multiple familial trichoepithelioma, and Brooke-Spiegler syndrome (PMID: 26370355, 20502185, 16307661, 26329847). True +ENST00000396402 NM_000103.4 1588 CYP19A1 True CYP19A1, an enzyme that controls estrogen biosynthesis, is altered by mutation and amplification in aromatase inhibitor-resistant ER+ breast cancers. Germline mutations in CYP19A1 are found in aromatase excess and deficiency syndromes. CYP19A1 (also aromatase) is an enzyme that is a member of the cytochrome P450 superfamily (PMID: 11826265). CYP19A1 mediates the conversion of androgen precursors into estrogens, a hormone that functions in reproductive processes as well as in lipid and carbohydrate metabolism (PMID: 11826265). Estrogens bind to estrogen receptors (ER), which dimerize in the nucleus to regulate ER-responsive transcription and chromatin states (PMID: 29259445, 29775582, 22049316). The expression of CYP19A1 is highly context-dependent and is controlled by ten distinct tissue-specific promoters (PMID: 23340254). CYP19A1 is predominantly produced in the ovary in premenopausal, non-pregnant women; however, CYP19A1 production shifts to peripheral tissues, such as adipose, bone and skin tissues, following menopause (PMID: 11826265). Germline mutations in CYP19A1 result in aromatase excess and deficiency syndromes, which can result in early puberty, breast hypertrophy, and abnormal virilization (PMID: 12736278, 8530621). Patients with ER+ (estrogen receptor-positive) breast cancers may receive adjuvant endocrine therapy which may include aromatase inhibitors such as letrozole, exemestane, and anastrozole (PMID: 14668813). Several mechanisms of aromatase-based resistance have been identified, including amplification and mutation of CYP19A1 in patients with ER+ breast cancers (PMID: 14668813, 28112739, 24242068). CYP19A1 activity has also been implicated in several other hormone-positive cancers including endometrial cancers and cholangiocarcinomas (PMID: 27067638, 30284180). False +ENST00000282018 NM_020377.2 57105 CYSLTR2 True CYSLTR2, a G-protein-coupled receptor, is recurrently altered in uveal melanoma. CYSLTR2 is a G-protein coupled receptor (GPCR) that is a member of the rhodopsin-like GPCR family (PMID: 16776669, 13679572). CYSTLTR2 is activated by cysteinyl leukotrienes (CysLTs), which are inflammatory lipid mediators that are involved in allergic processes (PMID: 16776669, 13679572). Activation of Gαq proteins (such as GNAQ and GNA11) by CYSLTR2 promotes Gαq-mediated GDP/GTP exchange and binding to phospholipase C β (PLCB4), resulting in PIP2 cleavage (PMID: 27089179). Following PIP2 cleavage, the second messenger proteins diacylglycerol (DAG) and inositol triphosphate (IP3) activate calcium release (PMID: 27089179). CYSLTR2-mediated signaling promotes the activation of a variety of downstream pathways, including PKC, MAPK, and PI3K signaling, which promote several cellular processes such as endothelial permeability (PMID: 15545522, 25839425, 30559191). Overexpression of CYSLTR2 has been reported in several cancer types including colon cancer (PMID: 28402256, 21203429, 23829413). Recurrent somatic mutations in CYSLTR2 are found in patients with uveal melanoma and other related tumor types (PMID: 27089179, 31671564, 29476293, 27934878). These alterations promote ligand-independent activation of CYSLTR2, resulting in pigmentation defects and melanocytic phenotypes (PMID: 27089179). False +ENST00000266000 NM_001141970.1 1616 DAXX False DAXX, a transcriptional co-repressor, is inactivated in various cancers including pancreatic neuroendocrine tumors. DAXX (death domain-associated protein) is a protein involved in transcriptional regulation and apoptosis (PMID: 16406523, 9215629). DAXX accumulates in both the nucleus and the cytoplasm; in the nucleus, DAXX associates with the promyelocytic leukemia (PML) nuclear body and with ATRX-positive heterochromatic regions. In the cytoplasm, DAXX has been reported to interact with various proteins involved in cell death regulation. The proteins encoded by ATRX and DAXX interact with one another and play multiple cellular roles, including chromatin remodeling at telomeres, where they are required for the incorporation of the histone variant H3.3 (PMID:12953102, 21047901, 20651253, 21029860). DAXX is frequently altered in pancreatic neuroendocrine tumors (PanNETs) (PMID: 21252315). True +ENST00000233078 NM_018959.3 26528 DAZAP1 False DAZAP1, an RNA binding protein, is recurrently altered by rearrangement in acute lymphoblastic leukemias. DAZAP1 is an RNA binding protein that is a member of the Musashi protein family (PMID: 19285026, 21576381). DAZAP1 is highly expressed in the testes and functions as an important regulator of spermatogenesis and development (PMID: 15700540, 18669443, 16772659, 28575377). Several cellular processes related to mRNA stability and protein translation are regulated by DAZAP1 (PMID: 19285026, 21576381). Localization of DAZAP1 is controlled by active transcription and MAPK-directed phosphorylation, and DAZAP1 has been shown to have nuclear shuttling and mRNA transport activities (PMID: 16772659, 15700540, 16848763). DAZAP1 interacts with the mRNA processing enzymes hnRNPA1 and hnRNPA2 to control splicing (PMID: 29505834, 18391021, 18391021, 21858080, 24452013). In addition, the association of DAZAP1 with DAZ, a gene on the Y chromosome and expressed in germ cells, has been implicated in the regulation of translation (PMID: 16848763). Recurrent translocations with DAZAP1 and the partner protein MEF2D are found in B-cell precursor acute lymphoblastic leukemia (B-ALL) (PMID: 28778863, 30630978) and are associated with poor patient outcome (PMID: 27507882, 27824051). MEF2D-DAZAP1 fusion proteins demonstrate oncogenic activity by increasing MEF2D transcriptional activity, HDAC9 expression, and cellular transformation (PMID: 15182431, 27507882, 27824051). HDAC inhibition may be efficacious in patients with MEF2D translocations (PMID: 27507882). False +ENST00000292782 NM_020640.2 54165 DCUN1D1 True DCUN1D1, a component of an E3 ligases complex, is amplified in squamous cell carcinomas. DCUN1D1 (also SCCRO and DCN1) is a component of E3 ligase complexes that mediate neddylation (PMID: 18826954, 31898237). Neddylation is a cellular process that places a ubiquitin-like modification (NEDD8) on E3 ligase-associated substrate proteins via cullin protein scaffolding (PMID: 18826954). DCUN1D1 binds to cullin-RING E3 ligase complexes in the cytoplasm and coordinates nuclear translocation, promoting the optimal transfer of NEDD8 from the E2 complex to cullin-associated substrates (PMID: 28581483, 31898237). DCUN1D1 activity is implicated in the regulation of a variety of proteins, including the activation of the VHL E3 ligase and other cullin ubiquitin ligases (PMID: 26743088, 23201271, 23401859). In addition, DCUN1D1 can relieve the negative inhibition of CAND1, a protein that binds unneddylated cullin-RING complexes (PMID: 25349211). Overexpression of DCUN1D1 is found in cancer, including in non-small cell lung cancer, and may be associated with a poorer prognosis (PMID:22500162, 27285984, 25411243). Amplification of DCUN1D1 is observed in squamous cell carcinomas and is associated with cancer progression (PMID:17018598, 23908357). Inhibitors of enzymes in the neddylation pathway are currently in clinical development (PMID: 26675347, 26423795, 28581483). False +ENST00000256996 NM_000107 1643 DDB2 False DDB2, a DNA damage repair factor involved in the nucleotide excision repair (NER) pathway, is altered by mutation or deletion in squamous cell carcinoma. DDB2 encodes for a DNA binding protein which primarily functions as a subunit of the UV-DDB complex and DCX (DDB1-CUL4-X-box) complexes for DNA repair and protein ubiquitination (PMID: 16223728, 11564859, 10585395, 32789493). DDB2 is essential for the recognition and repair of UV-induced DNA damage as the protein initiates the nucleotide excision repair (NER) pathway on sites of UV damage (PMID: 14751237, 32789493, 11278856). DDB2 has been identified to function in the ubiquitination of histones H2A, H3 and H4 at sites of UV-induced DNA damage to promote subsequent DNA repair (PMID: 16473935). The DCX complex functions in promoting reversible ubiquitination of DNA damage repair factor XPC to promote NER (PMID: 15882621). Germline mutations of DDB2 are associated with the autosomal recessive disease xeroderma pigmentosum, resulting in a decreased ability to repair DNA damage caused by UV rays (PMID: 37142601). Knockdown of DDB2 in various cancer cell lines and models induces epithelial-to-mesenchymal transition, tumorigenesis and cellular proliferation, suggesting that DDB2 functions predominantly as a tumor suppressor gene (PMID: 36568213, 26205499, 15558025). Downregulation of DDB2 has been identified in various types of cancers, including squamous cell carcinoma (PMID: 33276309, 27499003, 32722430). Loss of DDB2 has been suggested to be associated with increased chemoresistance (PMID: 36568213, 35707599). True +ENST00000346473 NM_001195057.1 1649 DDIT3 False DDIT3, a transcription factor, is infrequently mutated by chromosomal rearrangements in various types of sarcomas. DDIT3 (CHOP) is a member of the CCAAT/enhancer-binding protein (C/EBP) family of transcription factors and is involved in negative regulation of adipocyte differentiation (PMID: 7805034). In normal cells, DDIT3 expression and activity is induced by cellular ER stress, specifically DNA damage and irradiation exposure. Overexpression of DDIT3 from ER stress can ultimately lead to activation of apoptotic pathways (PMID: 11121490, 1617653, 8754828, 14685163) due to a decrease in Bcl-2 expression and subsequent translocation of Bax from the cytosol to the mitochondria (PMID: 14685163). Translocations of DDIT3 such as the EWSR1-DDIT3 fusion and the FUS-DDIT3 fusion are found in liposarcomas, which abolish the ability of DDIT3 to arrest cell growth leading to aberrant cellular proliferation (PMID:24790523, 24320889). False +ENST00000367921 NM_006182.2 4921 DDR2 True DDR2, a receptor tyrosine kinase, is mutated at low frequencies in various cancers. DDR2 (Discoidin Domain Receptor 2) is a receptor tyrosine kinase that mediates several downstream signaling pathways. When the extracellular discoidin domain of the receptor is bound by its cognate ligand, collagen, autophosphorylation of the DDR2 intracellular kinase domain is initiated, which results in activation of several downstream signaling pathways, such as the MAPK and PI3K pathways. Activation of these pathways promotes cellular migration, differentiation, proliferation and survival (PMID: 16186108, 17703188, 16626936). DDR2 activation or expression has been implicated in metastasis of various cancer types, such as colorectal cancer, melanoma and breast cancer (PMID: 22071959, 21735168, 21701781, 23644467, 25130389) through mechanisms that are not yet fully understood. Somatic gain-of-function mutations in DDR2 have been identified in squamous cell lung cancers (PMID: 22768234, 22328973) and at lower frequencies in other cancers. Clinical responses to targeted therapy with dasatinib have been reported in patients with squamous cell lung cancer with DDR2 mutations (PMID: 22328973). False +ENST00000478993 NM_001356.4 1654 DDX3X False DDX3X, an RNA helicase, is recurrently altered by mutations in several cancer types, including medulloblastoma and chronic lymphocytic leukemia. DDX3X (also DDX) is an RNA helicase that is a member of the DEAD box protein family. DDX3X is implicated in a variety of cellular functions that regulate RNA structure including RNA transport, translation initiation, splicing, ribosome, and spliceosome assembly (PMID: 17667941, 27180681). In addition, DDX3X mediates cell cycle control by regulating translational initiation of key cell cycle proteins, including Cyclin E1 (PMID: 20837705) and hypoxia-inducible genes, including HIF-1α (PMID: 21448281). Germline mutations in DDX3X are found in patients with intellectual disabilities (PMID: 28135719, 26235985). Somatic loss-of-function mutations in DDX3X are found in patients with medulloblastoma, chronic lymphocytic leukemia, mesothelioma and head and neck cancers (PMID: 22150006, 22722829, 22820256, 21798893, 26928227, 26192917), suggesting that DDX3X predominantly functions as a tumor suppressor. DDX3X is commonly mutated in tumor types with altered WNT signaling and has been implicated as a transcriptional regulator of WNT responsive genes (PMID: 22820256). Expression of DDX3X has been linked to a cancer stem cell population and may mediate resistance to EGFR tyrosine kinase inhibitors (PMID: 25343452). Small molecule inhibitors targeting DDX3X are under preclinical investigation (PMID: 25820276). True +ENST00000505374 NM_024415.2 54514 DDX4 True DDX4, an RNA helicase, is altered by overexpression in ovarian cancers. DDX4 (also VASA) is an RNA helicase that is a member of the DEAD box protein family (PMID: 28612512). Expression of DDX4 is localized predominantly in migratory primordial germ cells, and DDX4 is important for embryonic patterning and germline specification (PMID: 10920202, 11178242, 11178242). More specifically, DDX4 may be a marker of oocyte precursor cells (PMID: 26444630, 22366948, 29725036); however, this result is controversial (PMID: 32123174). DDX4 interacts with the general translation factor eIF5B and mediates translation of many mRNAs involved in germline specification and maintenance (PMID: 10920202, 16630817, 28612512). The eIF5B-DDX4 interaction facilitates ATP hydrolysis and specific RNA unwinding functions, which may be suitable for RNAs with specific structures (PMID: 16630817). Transient DDX4 expression has also been found in the context of regeneration in somatic cells or during wound healing (PMID: 27179696). The activity of DDX4 is also implicated in the transport of PIWI RNAs to the cytoplasm in germ cells, which is important for the suppression of transposable elements (PMID: 28612512, 23587717). DDX4 expression has been found in ovarian cancer cell lines and tissues (PMID: 27179696, 29963162, 29078734, 28245464). Overexpression of DDX4 in cell lines results in aberrant cell cycle progression, resulting in increased cellular proliferation (PMID: 28612512, 29963162). These abnormal proliferative cellular functions have been associated with dysregulation of PIWI, CCNB1 and E2F1 during cell cycle progression in loss-of-function studies (PMID: 28612512). In addition, DDX4 has been found to bind mitotic spindles in cancer cells and has a role in mediating cellular migration (PMID: 28612512). False +ENST00000330503 NM_016222.4 51428 DDX41 False DDX41, an RNA helicase involved in innate immunity, is recurrently altered by mutation in hematopoietic malignancies. Germline mutations of DDX41 predispose to myelodysplastic syndromes and acute myeloid leukemia. DDX41 is an RNA helicase that is a member of the DEAD-box protein family (PMID: 27502187). RNA helicases have diverse cellular functions including roles in RNA metabolism, immune response and viral infection (PMID: 27502187). In dendritic cells, DDX41 functions as a DNA sensor that recognizes double-stranded DNA or cyclic diguanylate monophosphate (c-di-GMP), which are byproducts released during viral or bacterial infection (PMID: 27502187, 21892174). DDX41 activity regulates the STING pathway, which is important in innate immunity (PMID: 27502187, 28602976, 27721487, 25704810, 23142775). The STING pathway activates type I interferon responses mediated by TBK, IRF1, and NFKB, which are critical for mounting an appropriate response to DNA viruses (PMID: 27502187, 27721487, 25609843). In addition to the role of DDX41 in innate immunity, DDX41 associates with spliceosome proteins and has been implicated in mRNA processing and splicing (PMID: 25920683). Germline, hypomorphic mutations in DDX41 are found in families with a predisposition for hematopoietic malignancies such as myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) (PMID: 26712909, 25920683, 31713024, 31484648). DDX41 mutations found in familial carriers predispose individuals to acquire a secondary somatic mutation on the other DDX41 allele, suggesting that DDX41 likely functions as a tumor suppressor (PMID: 26712909). In addition, individuals with a 5q deletion, a recurrent genetic event in myeloid malignancies, exhibit haploinsufficient expression of DDX41 (PMID: 25920683). DDX41 alterations commonly occur in the ATP binding domain, consistent with the importance of ATP binding in DNA sensing (PMID: 27721487). Lenalidomide sensitivity has been reported in patients with DDX41-mutant myeloid malignancies (PMID: 31400013, 25920683). True +ENST00000225792 NM_004396 1655 DDX5 True DDX5, a DEAD-box RNA helicase, is infrequently altered in cancer. DDX5, a member of the DEAD-box family, encodes for an RNA helicase that functions in the regulation of cellular processes through remodeling RNA secondary structures during transcription and pre-mRNA maturation (PMID: 32376686). DDX5 interacts with various different genes, including TP53 and CTCF, to mediate transcriptional regulation in response to DNA damage (PMID: 22986526, 20966046). DDX5 activates signaling pathways, including the WNT, AKT and mTOR pathways, to regulate cell proliferation, cell cycle control and glucose metabolism (PMID: 28411202). Overexpression of DDX5 in various cancer cell lines and models induces cellular proliferation and tumorigenesis, suggesting that DDX5 functions predominantly as an oncogene (PMID: 28216662, 26212035, 22750847). DDX5 amplification has been identified in various types of cancer, including breast cancer and non-small cell lung cancer (PMID: 22750847, 26212035). DDX5 expression is a potential therapeutic target with preclinical studies investigating the efficacy of anti-DDX5 inhibitors in various types of cancer (PMID: 27148684, 28244855). False +ENST00000652689 NM_003472.4 7913 DEK True DEK, a DNA binding and chromatin regulatory protein, is recurrently altered by chromosomal rearrangement in acute myeloid leukemia. DEK is a nuclear protein with roles in DNA binding and chromatin regulation (PMID: 25524609). DEK is ubiquitously expressed and modifies chromatin by altering the superhelical density of DNA, introducing positive supercoils to alter DNA structure (PMID: 11997399, 10837023). DEK also interacts with the chromatin-modifying enzyme p300 and PCAF in order to maintain heterochromatin state and influence gene expression (PMID: 16696975, 21460035). In addition to regulating epigenetic state, DEK facilitates cellular proliferation by resolving conditions of DNA replication stress at the replication fork (PMID: 25347734). DEK forms a complex with the DNA repair protein RAD51 and is a critical mediator of non-homologous end joining (NHEJ) (PMID: 28317934). Loss of DEK expression results in genome instability and sensitivity to DNA damaging agents (PMID: 28317934). DEK is also required for other cellular functions including mRNA splicing, apoptosis, and chemoresistance, among others (PMID: 19679545, 28317934). DEK is overexpressed in several tumor types including breast cancer, colorectal cancer, small cell lung cancer, among others, and increased DEK expression is linked to poor patient prognosis (PMID: 25197373, 23902796, 21663673, 25544761, 24608431). Recurrent DEK rearrangements are found in patients with acute myeloid leukemia which result in increased DEK expression, suggesting that DEK functions predominantly as an oncogene (PMID: 25524609). False +ENST00000393063 NM_177438.2 23405 DICER1 False DICER1 is a tumor suppressor and an endoribonuclease. Germline mutations in DICER1 predispose to various cancer types, including pleuropulmonary blastoma, rhabdomyosarcoma, cystic nephroma, ovarian Sertoli-Leydig cell tumor and endocrine tumors. DICER1 is an endoribonuclease that catalyzes the cleavage of large RNA molecules into silencing RNAs or microRNAs. In addition, DICER1 loads siRNA onto the Argonaute protein and mediates the binding of co-factors to initiate RNA-induced silencing (PMID: 25176334). In this way, DICER1 plays a pivotal role in the post-transcriptional regulation of gene expression (PMID: 25176334). Germline mutations in DICER1 are associated with DICER1-related disorders, a familial tumor susceptibility syndrome that confers increased risk most commonly for pleuropulmonary blastoma (PPB), cystic nephroma (CN), rhabdomyosarcoma (RMS), multinodular goiter, ovarian Sertoli-Leydig cell tumor and other neoplastic conditions (PMID: 19556464, 21266384, 21882293, 24761742). The majority of germline mutations in DICER1 are nonsense, frameshift, or splice-site mutations leading to premature protein truncation and loss of protein function (PMID: 21266384, 19556464, 25176334). Somatic DICER1 mutations have also been identified, predominantly affecting the region of the protein that mediates the interaction of DICER1 with miRNAs (PMID: 25176334). DICER1 has been identified as a haploinsufficient tumor suppressor gene (PMID: 19903759, 20019750), as monoallelic but biallelic loss of DICER1 causes tumor formation. Consistent with the role of DICER1 as a tumor suppressor, reduced expression of DICER1 correlates with a poor outcome in lung, breast, skin, endometrial and ovarian cancer (PMID: 15723655, 19092150, 19782670, 20210522, 20832293). True +ENST00000377767 NM_014953.3 22894 DIS3 False DIS3, the catalytic subunit of the RNA exosome complex, is recurrently mutated in several cancer types including multiple myeloma. DIS3 (also Rrp44) is an exoribonuclease that is a member of the RNase II/RNB protein family (PMID: 31342438). DIS3 is the catalytic subunit of the RNA exosome complex, which coordinates 3’ to 5’ degradation of RNA (PMID: 20531389, 21289487). The exosome complex prominently participates in RNA processing and quality control pathways (PMID: 21289487). In addition, DIS3 regulates the maturation of many RNA targets, including the tumor suppressor let-7 miRNAs, which control the translation of oncogenes such as MYC and RAS (PMID: 25925570, 26305418). Recurrent familial and somatic mutations of DIS3 have been found in patients with multiple myeloma (PMID: 21430775, 24434212, 22573403, 25521164, 23396385, 22237025, 30967618). These DIS3 loss-of-function mutations have been shown to interfere with the exonucleolytic activity, causing defects in RNA processing, cellular proliferation, and protein translation (PMID: 24150935). In contrast, DIS3 amplification and overexpression have been detected in several cancer types, including colon cancer and melanoma, suggesting that the consequence of DIS3 alteration may be context-specific (PMID: 23319804, 24478024, 21343389). True +ENST00000373970 NM_012242.2 22943 DKK1 False DKK1, a negative regulator of WNT signaling, is overexpressed or downregulated in various cancer types. DKK1 is an extracellular ligand that is a member of the Dickkopf protein family (PMID: 28979801, 17143291). DKK1 functions as a negative regulator of the WNT signaling pathway by binding to LRP5/6 co-receptors and precluding WNT-mediated activation of downstream signaling (PMID: 28979801, 17143291, 23258168). WNT signaling is a critical developmental pathway with roles in determining cell fate, tissue identity and polarity (PMID: 28218291). DKK1-mediated antagonism of WNT blocks Frizzled receptor binding to LRP5/6 and results in the activation of the β-catenin destruction complex (containing APC, GSK3β and AXIN), which targets β-catenin for degradation (PMID: 23258168). In the absence of WNT signaling, TCF and LEF transcription factors form a repressive complex, leading to inhibition of β-catenin target genes (PMID: 24316024, 23258168). DKK1 also binds to the receptors Kremen1 and Kremen2 to remove the LRP6 co-receptor from the plasma membrane (PMID: 12050670). In addition, DKK1 is involved in the regulation of many cellular functions including developmental patterning, apoptosis, angiogenesis and invasion (PMID: 22807036, 27608843, 28979801, 11702953, 31568519). Somatic mutations in DKK1 in human cancers are relatively uncommon; however, DKK1 is found to be downregulated or overexpressed in distinct cancer subtypes (PMID: 25144498, 18331598, 26101916, 24916146). DKK1 is also an important regulator of bone metastasis (PMID: 28892080). Therefore, DKK1 may have roles as either a tumor suppressor or oncogene depending on the specific cellular context. False +ENST00000285311 NM_014421.2 27123 DKK2 False DKK2, a negative regulator of WNT signaling, is overexpressed or downregulated in various cancer types. DKK2 is an extracellular ligand that is a member of the Dickkopf protein family (PMID: 28979801, 17143291). DKK2 functions as both a positive and negative regulator of the WNT signaling pathway by binding to LRP5/6 co-receptors (PMID: 24316024, 23258168,12527209). WNT signaling is a critical developmental pathway with roles in determining cell fate, tissue identity and polarity (PMID: 28218291). DKK2-mediated antagonism of WNT blocks Frizzled receptor binding to LRP5/6 and results in the activation of the β-catenin destruction complex (containing APC, GSK3β and AXIN), which targets β-catenin for degradation (PMID: 23258168). In the absence of WNT signaling, TCF and LEF transcription factors form a repressive complex, leading to inhibition of β-catenin target genes (PMID: 24316024, 23258168). DKK2 binds the receptor Kremen2 to remove the LRP6 co-receptor from the plasma membrane; however, even in the absence of Kremen2, DKK2 can activate WNT signaling (PMID: 12527209). DKK2 has also been implicated in the regulation of immune evasion via WNT-independent mechanisms (PMID: 29431745). In addition, DKK2 is involved in the regulation of many cellular functions including developmental patterning, apoptosis, angiogenesis and invasion (PMID: 27431620, 19755393, 21540552, 28979801). Somatic mutations in DKK2 in human cancers are relatively uncommon; however, DKK2 is found to be downregulated or overexpressed in distinct cancer subtypes (PMID: 22964660, 19755393, 24809435, 23204234, 19659606, 27431620) suggesting it may have roles as either a tumor suppressor or oncogene depending on the specific cellular context. False +ENST00000326932 NM_001018057.1 27122 DKK3 False DKK3, a negative regulator of WNT signaling, is overexpressed or downregulated in various cancer types. DKK3 is an extracellular ligand that is a member of the Dickkopf protein family (PMID: 28979801, 17143291). Dickkopf proteins predominantly function as negative regulators of the WNT signaling pathway by binding to WNT pathway signaling receptors, such as LRP5/6 (PMID: 24316024, 23258168,12527209). WNT signaling is a critical developmental pathway with roles in determining cell fate, tissue identity, and polarity (PMID: 28218291). Unlike other DKK proteins, the exact role of DKK3 in WNT signaling is not well established. DKK3 interacts with Kremen1 and Kremen2 receptors, which have roles in LRP5/6 internalization, suggesting that DKK3 potentiates WNT activity (PMID: 20370576). DKK3-mediated antagonism of WNT would result in the activation of the β-catenin destruction complex (containing APC, GSK3β and AXIN), which targets β-catenin for degradation (PMID: 23258168). In the absence of WNT signaling, TCF and LEF transcription factors form a repressive complex, leading to inhibition of β-catenin target genes (PMID: 24316024, 23258168). In addition, DKK3 is involved in the regulation of many cellular functions including developmental patterning, apoptosis, immune response, and invasion (PMID: 21268126, 25573172, 28738084, 26278164). Somatic mutations in DKK3 in human cancers are relatively uncommon; however, DKK3 is found to be downregulated or overexpressed in distinct cancer subtypes (PMID: 27801786, 27467270, 27788486, 26093488). False +ENST00000220812 NM_014420.2 27121 DKK4 False DKK4, a negative regulator of WNT signaling, is overexpressed or downregulated in various cancer types. DKK4 is an extracellular ligand that is a member of the Dickkopf protein family (PMID: 28979801, 17143291). DKK4 functions as a negative regulator of the WNT signaling pathway by binding to LRP5/6 co-receptors and precluding WNT-mediated activation of downstream signaling (PMID: 24316024, 23258168). WNT signaling is a critical developmental pathway with roles in determining cell fate, tissue identity and polarity (PMID: 28218291). DKK4-mediated antagonism of WNT blocks Frizzled receptor binding to LRP5/6 and results in the activation of the β-catenin destruction complex (containing APC, GSK3β and AXIN), which targets β-catenin for degradation (PMID: 23258168). In the absence of WNT signaling, TCF and LEF transcription factors form a repressive complex, leading to inhibition of β-catenin target genes (PMID: 24316024, 23258168). DKK4 also binds to the receptors Kremen1 and Kremen2 to remove the LRP6 co-receptor from the plasma membrane (PMID: 12527209). In addition, DKK4 is involved in the regulation of many cellular functions including developmental patterning, apoptosis, angiogenesis and invasion (PMID: 27272409, 23958302). Somatic mutations in DKK4 in human cancers are relatively uncommon; however, DKK4 is found to be downregulated or overexpressed in distinct cancer subtypes (PMID: 22216841, 17675336, 29904276, 21994129, 26880586, 19059704) suggesting it may have roles as either a tumor suppressor or oncogene depending on the specific cellular context. False +ENST00000254322 NM_006145.1 3337 DNAJB1 False DNAJB1, a subunit of the heat shock factor 40 (HSP40) complex, is recurrently altered by chromosomal rearrangement in fibrolamellar hepatocellular carcinoma. DNAJB1 (DNAJ (Hsp40) homolog, subfamily B, member 1) is a member of the HSP40 protein family and has been linked to several cellular processes, such as the proteasome pathway, endoplasmic reticulum (ER) stress and virus infection (PMID:19340594, 22075554, 23400395, 21698289). DNAJB1 interacts with HSP70 and induces its ATPase activity, which stimulates the association between HSP70 and Hsc70-interacting protein (HIP) (PMID: 24309468). A seminal feature of DNAJB1 is the presence of the DNAJB1-PRKACA chimeric transcript in fibrolamellar hepatocellular carcinoma (FLHCC) tumors. Numerous independent studies have confirmed the presence of the fusion gene in 80-100% of FLCs tumor samples (PMID: 25557953, 25698061, 25605237, 25122662, 24578576, 26489647). The fusion encodes a chimeric protein that couples a segment of DNAJB1, with the catalytic domain of protein kinase A (PKA) that confers constitutive kinase activity. Although analyses of a wider array of cancer types are required to more definitively establish the specificity of DNAJB1-PRKACA to FLCs, the current evidence suggests that DNAJB1-PRKACA may be a tissue biomarker for FLCs and if the chimeric protein is secreted into circulation, it may also serve as a plasma biomarker. False +ENST00000355667 NM_001005360 1785 DNM2 True DNM2, a GTPase, is infrequently altered in cancer. DNM2, a member of the dynamin superfamily, encodes for a GTPase that functions in clathrin-independent and -dependent endocytosis and intracellular membrane trafficking (PMID: 20858595). DNM2 regulates the T-cell receptor-mediated signaling pathways and T-cell activation through interaction with VAV1 (PMID: 15696170). Overexpression of DNM2 in various cancer cell lines and models induces cellular proliferation, migration and invasion, suggesting that DNM2 functions predominantly as an oncogene (PMID: 27885263, 21841817). DNM2 amplification has been identified in various types of cancer, including acute lymphoblastic leukemia, prostate cancer and breast cancer (PMID: 27885263, 24402972, 33250680). DNM2 expression is a potential therapeutic target with preclinical studies investigating the efficacy of anti-DNM2 inhibitors in various types of cancer (PMID: 20571068, 21750222). False +ENST00000340748 NM_001379.2 1786 DNMT1 True DNMT1, a DNA methyltransferase, is infrequently altered in various cancer types. DNMT1 is a DNA methyltransferase that mediates the transfer of methyl groups to CpG sites in DNA (PMID: 21163962, 29033456). DNA methylation at gene promoters predominantly results in gene repression by precluding the binding of important transcriptional machinery (PMID: 23400093). DNMT1 preferentially methylates hemimethylated DNA, namely daughter strands that are newly generated during the cell cycle (PMID: 21163962). DNMT1 plays an important role in a number of physiologic processes such as X chromosome inactivation, genomic imprinting, chromosomal stability, and repression of retrotransposon expression. DNMT1 mutations are rarely found in human cancers; however, DNMT1 overexpression has been observed in colon cancer (PMID: 2014266, PMID: 10463569), gastric cancer (PMID: 14742272), breast cancer (PMID: 14555514), bladder cancer (PMID: 14634451), and acute and chronic myelogenous leukemia (PMID: 11222358). Increased activity of DNMT1 can lead to altered DNA methylation and abnormal transcriptional silencing (PMID: 29033456). The DNMT1 inhibitor azacytidine is FDA-approved for the treatment of patients with specific myelodysplastic syndrome (MDS) subtypes and chronic myelomonocytic leukemia (PMID: 15897554) and may have efficacy in patients with mutations in other epigenetic modifiers that impact DNA methylation state (PMID: 28193779). False +ENST00000264709 NM_022552.4 1788 DNMT3A False DNMT3A, a tumor suppressor and DNA methyltransferase, is recurrently mutated in acute myeloid leukemia and other hematologic malignancies. DNMT3A is a DNA methyltransferase that is responsible for establishing de novo genomic DNA methylation at CpG sites. DNA methylation at gene promoters predominantly results in gene repression by precluding the binding of important transcriptional machinery (PMID: 23400093). DNMT3A functions in concert with another de novo methyltransferase, DNMT3B, and a maintenance methyltransferase DNMT1, assisted by non-catalytic subunit DNMT3L (PMID: 21243710). CpG methylation is important for maintaining epigenetic tissue-specific gene expression patterns, genomic imprinting, X-chromosome inactivation, silencing of parasitic DNA sequences and genome integrity (PMID: 12359337, 15215868). Germline mutations in DNMT3A result in Tatton-Brown-Rahman overgrowth syndrome, a disorder associated with intellectual disability (PMID: 24614070), and overexpression has been linked to melanoma and hepatocellular carcinoma (PMID: 24589714). DNMT3A is recurrently mutated in de novo acute myeloid leukemia (AML) (up to 30% of all cases) (PMID: 21067377, 21399634, 22417203, 23634996), and at lower frequencies in secondary acute myeloid leukemia (PMID: 21993668), myeloproliferative neoplasms (PMID: 21537334), myelodysplastic syndromes (PMID: 21415852, 21519343) and in T-cell acute lymphoblastic leukemia (T-ALL) (PMID: 23341344, 23603912, 23687089). Cancers with enhanced activity of DNMT3A may be sensitive to DNA methyltransferase inhibitors (PMID: 29033456). True +ENST00000328111 NM_006892.3 1789 DNMT3B False DNMT3B, a DNA methyltransferase, is altered by mutation or amplification in various cancer types. DNMT3B is a DNA methyltransferase that is responsible for establishing de novo genomic DNA methylation at CpG sites (PMID: 21243710). DNA methylation at gene promoters predominantly results in gene repression by precluding the binding of important transcriptional machinery (PMID: 23400093). DNMT3B functions in concert with another de novo methyltransferase, DNMT3A, and a maintenance methyltransferase DNMT1, assisted by non-catalytic subunit DNMT3L (PMID: 21243710). CpG methylation is important for maintaining epigenetic tissue-specific gene expression patterns, genomic imprinting, X-chromosome inactivation, silencing of parasitic DNA sequences and genome integrity (PMID: 12359337, 15215868). Germline biallelic mutations in DNMT3B are associated with ICF (immunodeficiency, centromeric instability and facial abnormalities) syndrome (PMID: 10647011, 16501171). Rare mutations in the DNMT3B gene have been identified and dysregulated expression of DNMTs and/or aberrant DNA methylation patterns are found in various cancer types (PMID: 21941284, 22037554, 22895193). Cancers with enhanced activity of DNMT3B may be sensitive to DNA methyltransferase inhibitors (PMID: 29033456). True +ENST00000398665 NM_032482.2 84444 DOT1L True DOT1L, a histone methyltransferase, is infrequently mutated in various cancer types. DOT1L is a histone H3K79 methyltransferase, methylating the histone 3 lysine 79 residue (PMID:12123582). H3K79 methylation is associated with DNA damage response to double strand breaks (PMID:15525939). This modification has also been implicated in diverse cellular and developmental processes including cell division, embryonic development, meiosis, and hematopoiesis (PMID:21724828, 24526115). H3K79 methylation modifies chromatin structure and can promote active transcription (PMID:18285465). In leukemias, this modification promotes active transcription by preventing the binding of the inhibitory Sirtuin1 (SIRT1) complex (PMID:25822366). In mixed lineage leukemia (MLL) translocation leukemias, DOT1L was shown to be important for the transformation activity of the MLL fusion protein, and inhibitors of DOT1L have been employed in the treatment of this subset of leukemias (PMID:18977325, 15851025, 21741596). In breast cancer, DOT1L has been shown to cooperate with a c-Myc-p300 complex to promote epithelial to mesechymal transition and clinically is associated with more aggressive disease (PMID:26199140). Mutations in DOT1L have been identified in large-scale sequencing efforts of solid tumors including colon, small cell lung cancer, and squamous head and neck cancer (PMID:22810696, 26168399, 25056374). False +ENST00000370192 NM_000110 1806 DPYD False DPYD, a pyrimidine catabolic enzyme, is infrequently mutated in cancer. DPYD encodes for dihydropyrimidine dehydrogenase, which is the rate-limiting factor in uracil and thymidine catabolism (PMID: 36172669). Deletions in the gene result in loss of the enzyme’s activity, which has been associated with delayed motor skill development, seizures, and intellectual disability linked to congenital thymine-uraciluria (PMID: 36661700, 35607723). Loss of the gene also increases the risk of toxicity in cancer patients receiving 5-fluorouracil chemotherapy (PMID: 35607723, 36172669, 36757428,36661700). 5-fluorouracil and its oral prodrugs capecitabine and tegafur are used in the treatment of several cancers including colon, stomach, and breast (PMID: 36757428, 36661700, 36172669). Decreased dihydropyrimidine dehydrogenase activity increases exposure to both 5-fluorouracil and its cytotoxic metabolites, resulting in adverse events (PMID: 36757428, 35607723). False +ENST00000344624 NM_013235.4 29102 DROSHA False DROSHA, a ribonuclease involved in microRNA biogenesis, is mutated or amplified at low frequencies in various cancers. DROSHA is an RNA-specific endoribonuclease III involved in the initial steps of microRNA (miRNA) biogenesis. DROSHA, forming a complex with DGCR8, cleaves the double-stranded stem-loop structured pri-miRNA into pre-miRNA, which is subsequently exported to the cytosol where it can be further processed, ultimately leading to specific mRNA silencing (PMID: 14508493, 19239886, 23654304). DROSHA has been reported to be both up- and downregulated in several cancers, suggesting tissue-specific mechanisms in tumorigenesis (PMID: 20832293, 21559780, 20210522). Somatic mutations in DROSHA are found in a small proportion of cancers including in pediatric Wilm’s tumors (PMID: 25670083, 25190313) and DROSHA amplifications have been identified in lung adenocarcinoma (PMID: 26156018). DROSHA mutations are predicted to function through a dominant negative mechanism and globally inhibit miRNA biogenesis (PMID: 25670083). False +ENST00000257600 NM_004416.2 1840 DTX1 False DTX1, a ubiquitin E3 ligase and transcriptional regulator, is recurrently altered by mutation in lymphomas. DTX1 (also Deltex-1) is an E3 ubiquitin ligase that also functions as a transcriptional regulator (PMID: 12670957). DTX1 ubiquitinates substrates, including MEKK1 and C-FLIP, and targets them to the proteasome for degradation (PMID: 15684388, 29374180). High expression of DTX1 is found in germinal center B cells, marginal zone B cells, lymphoid cells and the nervous system (PMID: 22891273, 15684394, 26714454). The activity of DTX1 is important for regulation of T cell anergy and FOXP3 activity in regulatory T cells (PMID: 25695215, 19592273). In addition, DTX1 functions as a transcriptional regulator of Notch in association with the coactivator p300 to inhibit neural progenitor (PMID: 11564735, 14567914), B, NK, and T cell differentiation (PMID: 15187027, 27048872). The mechanism by which DTX1 regulates NOTCH signaling is not fully delineated; however, DTX1 may inhibit NOTCH by targeting the receptor for endosomal recycling (PMID: 29440432) and DTX1 itself is a target of NOTCH transcriptional regulation (PMID: 9056690). Somatic DTX1 mutations are found in patients with splenic marginal zone lymphoma (PMID: 22891273) and diffuse large B cell lymphomas (PMID: 25171927). These DTX1 alterations are predicted to disrupt Notch signaling and contribute to abnormal hematopoietic differentiation (PMID: 22891273, 25171927). DTX1 expression is also downregulated in several tumor types, including head and neck cancers (PMID: 28146432). True +ENST00000344450 NM_020185.4 56940 DUSP22 False DUSP22, a protein phosphatase, is recurrently altered by chromosomal rearrangement in anaplastic large cell lymphoma. DUSP22 (also JKAP, JSP-1) is a dual-specificity phosphatase with several roles in the regulation of downstream signaling pathways. Dual-specificity phosphatases can dephosphorylate phosphotyrosine and phosphoserine/threonine residues within the same substrate (PMID: 19228121). DUSP22 inhibits T-cell receptor signaling by dephosphorylating and inactivating MAPK and ERK2 (PMID: 11733513) In addition, DUSP22 is a negative regulator of focal adhesion kinase (FAK) and is an inhibitor of cell migration via reduced FAK activity (PMID: 20018849). DUSP22 can also positively regulate downstream signaling pathways; for example, DUSP22 binds JNK and activates the JNK pathway (PMID: 11717427, 27711255). Because DUSP22 has been implicated in the regulation of several signaling pathways, DUSP22 is thought to be involved in mediating various cellular functions including cell proliferation, cell death, chemotaxis and T-cell receptor signaling (PMID: 24714587, 28725226, 27711255, 28017968). Fusion proteins including DUSP22 are found in anaplastic large cell lymphomas negative for ALK-rearrangements (PMID: 21030553, 24805854, 26104084). These alterations are predicted to disrupt DUSP22 activity, suggesting that DUSP22 functions as a tumor suppressor (PMID: 27626696). True +ENST00000240100 NM_001394.6 1846 DUSP4 False DUSP4, a protein phosphatase, is deleted in a small subset of prostate and lung cancers. DUSP4 is a protein tyrosine/threonine phosphatase that regulates the mitogen-activated protein kinase (MAPK)/ERK pathway. DUSP4 negatively regulates the MAPK/ERK pathway by dephosphorylating ERK1/2 (PMID: 7535768). In addition, DUSP4 dephosphorylates substrates in the JNK pathway and mediates crosstalk between the JNK/JUN and MAPK/ERK pathways (PMID: 29795445). DUSP4 itself is a transcriptional target of MAPK-activated ERK1/2, and in turn inhibits ERK1/2 through a negative feedback mechanism, thus tempering MAPK-induced cell growth and proliferation (PMID: 22430215). DUSP4 expression has been found to be up- or downregulated in several cancer types; however, somatic mutations in DUSP4 are rare and have not yet been functionally characterized (PMID: 22965873, 22430215). DUSP4 loss has been associated with resistance to MEK inhibition, resulting in activation of associated signaling pathways (PMID: 29795445). True +ENST00000346618 NM_001949.4 1871 E2F3 True E2F3, a transcription factor that regulates the cell cycle, is altered by amplification and overexpression in a variety of cancer types. E2F3 (E2F transcription factor 3) is a member of the E2F family of transcription factors. E2F3 is related to E2F1 and E2F2 with which it shares similar DNA-binding, RB protein-binding, dimerization, and transcriptional activation domains (PMID: 8246996). E2F1-3 also bind induce transcription from to the same E2F recognition motifs in vitro and associate with RB. (PMID: 8246996). Additionally, E2F1-3 are considered inducers of gene expression and their transcription and proteasomal degradation are controlled in a cell cycle-dependent manner as opposed to the constitutively expressed transcriptional repressors E2F4-6 (PMID: 12748276). E2F proteins play overlapping roles in various processes, including DNA replication, progression through from G1 to S stages of the cell cycle, and cell-fate determination but they also appear to have certain distinct functions (PMID: 12748276, 9679057). The RB/E2F axis is considered a pivotal in activating DNA replication and G1/S transition in a manner dependent on RB's inhibitory effect on E2F proteins (PMID: 8246996, 11257102, 9365528). E2F3-specific activity includes TFE3 binding and DDX5 induction, mediation of MYC-induced transition to S phase (together with E2F2), and induction of specific target genes (PMID: 12748276, 10733529, 11511364) E2F3-deficient mice exhibit impaired growth and cell proliferation (PMID: 10733529). Amplification and subsequent overexpression of E2F3 has been observed in prostate and bladder cancer as well as lung cancer and metastatic urothelial carcinoma (PMID: 14716298, 15122326, 18037967, 16953223, 16938365, 15184867, 16909110, 24476821, 25886454). Also, E2F3 appears to be a target for the ETS fusions in certain cancers (PMID: 23940108). False +ENST00000313708 NM_024007 1879 EBF1 False EBF1, a transcription factor for B-cell development, is infrequently altered in cancer. EBF1 encodes for a transcription factor that regulates various processes associated with B-cell lymphopoiesis, transcription and activation (PMID: 20451411). EBF1 and PAX5 work synergistically to regulate B-cell expansion and lineage commitment via a MYC-dependent regulatory loop and other feedback loops (PMID: 33619557, 17101802). The oncogenic function of EBF1 may be tissue-specific. Knockdown of EBF1 in various cancer cell lines induces increased TERT promoter activity, cellular viability and cellular proliferation, suggesting that EBF1 functions predominantly as a tumor suppressor gene in these tissue-specific contexts (PMID: 32364535, 28555080). Downregulation of EBF1 has been identified in various cancer types, including acute lymphoblastic leukemia, colorectal cancer, gastric cancer, and cholangiocarcinoma (PMID: 17344859, 32676457, 29169115, 32364535). Conversely, overexpression of EBF1 in acute myeloid leukemia and breast cancer cell lines induces cellular proliferation, cellular migration, the inhibition of apoptosis and cell cycle progression, suggesting that EBF1 functions predominantly as an oncogene in these tissue-specific contexts (PMID: 35867755)(Abstract: Zhou et al. Abstract# 11486, Blood 2022. https://ashpublications.org/blood/article/140/Supplement%201/11486/490703/EBF1-Promotes-Cell-Proliferation-Migration-and). False +ENST00000270517 NM_016581 51295 ECSIT True ECSIT, a cytosolic adaptor protein, is infrequently altered in cancer. ECSIT is an adaptor protein that functions in the assembly of the mitochondrial complex I (PMID: 17344420). Mitochondrial complex I is the largest subunit of the respiratory chain, functioning in the electron transfer from NADH to ubiquinone as a proton pump for ATP synthesis (PMID: 13771349). ECSIT is directed by an N-terminal targeting sequence to localize to the mitochondria, allowing for interaction with chaperone protein NDUFAF1 and subsequent assembly and stabilization of mitochondrial complex I (PMID: 17344420). Other functions for ECSIT include activation of the inflammatory response through the Toll signaling pathway and embryonic development through the BMP signaling pathway (PMID: 10465784, 14633973). Overexpression of ECSIT in breast cancer cell lines and xenograft mouse models increases cell proliferation, migration and invasion, suggesting that ECSIT functions primarily as an oncogene (PMID: 35571656). Amplification of ECSIT has been identified in breast cancer and ovarian cancer (PMID: 35571656, 35131872). False +ENST00000367682 NM_001077706.2 345930 ECT2L False ECT2L, a protein of unknown function, is altered by mutation in T-cell precursor lymphoblastic leukemia. ECT2L is a protein with unknown function that shares sequence homology with RhoGEF proteins (PMID: 28541439). GEF (guanine nucleotide exchange factors) activate GTPases, which are enzymes that cycle between a GTP-bound active conformation and a GDP-bound inactive conformation. GTPases regulate downstream signaling pathways and are involved in a variety of cellular functions including proliferation, cell adhesion, and cell cycle progression, among others (PMID: 27301673). Additional functional work is required to determine the exact cellular function of ECT2L. Somatic mutations in ECT2L are found in patients with T-cell precursor acute lymphoblastic leukemia (PMID: 22237106). ECT2L alterations predominantly occur as missense, nonsense, and splice site mutations (PMID: 22237106), suggesting that ECT2L acts as a tumor suppressor. True +ENST00000263360 NM_003797.3 8726 EED False EED, a transcriptional repressor, is altered in malignant peripheral nerve sheath tumors and hematologic malignancies. EED (Embryonic Ectoderm Development) is a component of the Polycomb Repressive Complex 2 (PRC2) which is responsible for transcriptional repression by catalyzing di- and tri-methylation of Histone H3 lysine 27 (H3K27) (PMID: 16630818). The EED-EZH2 interaction is necessary for the histone methyltransferase activity of PRC2 (PMID: 23974116), which is important in regulating development and expression of cell identity genes, including the HOX cluster of genes (PMID: 16625203). EED interacts with the PRC1 complex to mediate histone H2A ubiquitination (PMID: 24457600), and germline mutations have been identified with an over-growth syndrome (PMID: 25787343). EED is mutated in malignant peripheral nerve sheath tumors, T-cell precursor acute lymphoblastic leukemia, and myeloid neoplasms (PMID: 25240281, 22237106, 23486531). Loss of PRC2 function can cooperate with Ras pathway signaling in cellular transformation and may sensitize tumor cells to bromodomain inhibitors (PMID: 25119042). True +ENST00000308874 NM_201446.2 51162 EGFL7 True EGFL7, a secreted pro-angiogenic factor, is infrequently mutated in various cancer types. EGFL7 (EGF-like-domain, multiple 7) is a signaling protein involved in EGFR signaling (PMID: 22160377). It is a secreted factor expressed in the endothelium during embryonic and neonatal development and has a proposed role in vasculogenesis and neural stem-cell renewal (PMID: 15085134, 19503073, 15085134, 22160377). EGFL7 expression has also been detected in adult human tissues (PMID: 18556249). Its role in cancer is unclear, but its ability to modulate angiogenesis and immune responses has been proposed to influence tumorigenesis (PMID: 22037871). Elevated expression of EGFL7 has been found in human tumors, including glioma, hepatocellular carcinomas, breast cancer and suggesting a potential role as a biomarker (PMID: 19503073, 19824075, 26328008, 23558933, 23404186). False +ENST00000275493 NM_005228.3 1956 EGFR True 1 R2 EGFR, a receptor tyrosine kinase, is altered by amplification and/or mutation in lung and brain cancers among others. EGFR (Epidermal Growth Factor Receptor) is a transmembrane receptor that is activated by EGF family extracellular ligands (PMID: 24691965). EGFR is a member of the ErbB family of receptors, including the receptors ERBB2, ERBB3, and ERBB4. Binding of EGFR by its ligands, including EGF ligands and transforming growth factor alpha (TGFα), activates downstream signaling pathways including the canonical MAPK and PI3K/AKT/mTOR signaling cascades (PMID: 22239438). EGFR can homodimerize or heterodimerize with other ErbB family members to initiate signaling (PMID: 25621509). Activation of EGFR-mediated signaling ultimately results in cellular proliferation, migration, and differentiation (PMID: 18045542). While EGFR usually is expressed at low levels in normal adult tissues, hyperactivation of this receptor by somatic mutations and/or amplification of the EGFR gene is found in many cancer types such as lung, brain, colorectal and head and neck cancer (PMID: 10880430, 17318210). In lung cancer, activating mutations in EGFR result in a constitutively activated form of the receptor that is sensitive to EGFR tyrosine kinase inhibition (PMID: 15329413). Tyrosine kinase inhibitors targeting EGFR, including afatinib, erlotinib, and gefitinib, have been approved for first-line treatment of non-small cell lung cancer patients (PMID: 14977817, 24868098, 26039556, 25963089). Second site resistance mutations in EGFR can occur in cancers previously treated with these inhibitors (PMID: 29068003). Osimertinib is a second-line tyrosine kinase inhibitor that has been FDA approved for relapsed patients with non-small cell lung cancer with the EGFR resistance mutations T790M, L858R, and exon 19 deletions (PMID: 27923840). Additionally, copy number amplification of the EGFR gene result in receptor overexpression in several cancer types, including brain and colorectal cancers, and these cancers may also be sensitive to EGFR inhibition (PMID: 11426640). R2 False +ENST00000239938 NM_001964.2 1958 EGR1 False EGR1, a transcription factor, is recurrently altered by mutation in lymphomas. EGR1 is a transcription factor that belongs to the EGR family of zinc finger proteins (PMID: 16138117). EGR1 stimulates the transcriptional activity of several key tumor suppressor genes including TGFβ1, PTEN, TP53, and fibronectin (PMID: 16138117). The activity of EGR1 is required to mediate several cellular functions induced by these tumor suppressors including growth control, differentiation, cell attachment and apoptosis (PMID: 16138117). EGR1 is also implicated in immune regulation; EGR1 expression is upregulated after T cell stimulation and mediates B cell development (PMID: 19915002, 18802061). In addition, EGR1 regulates the activity of CBP/p300 transcription coactivators in prostate cells (PMID: 15225550). Loss of EGR1 in preclinical models results in transformation, hematopoietic defects and increased tumor formation in murine models (PMID: 17420284). EGR1 expression has been found to be reduced in a variety of tumor types, suggesting that EGR1 functions as a tumor suppressor (PMID: 9212230). Somatic mutations in EGR1 are found in follicular lymphoma, chronic lymphocytic leukemia, B-cell lymphoma, and splenic marginal zone lymphomas (PMID: 24362818, 22158541, 22891273, 24145436). EGR1 alterations typically occur in the N-terminus and are predicted to be loss-of-function (PMID: 24362818). Conversely, EGR1 expression is overexpressed in prostate cancer and may function as an oncogene in that context (PMID: 12833142, 16138117). True +ENST00000242480 NM_000399.5 1959 EGR2 False EGR2, a zinc-finger transcription factor, is altered in various cancer types. EGR2, a member of the early growth response (EGR) protein family, encodes a zinc-finger transcription factor that plays a crucial role in processing signals that regulate senescence, apoptosis and immune response (PMID: 11494141, 12687019, 28687085, 33547862). EGR2 plays a key role in the PTEN-induced apoptotic pathway, promoting apoptosis in various cancer cell lines by the direct transactivation of the mitochondrial proteins BNIP3L and BAK (PMID: 11494141, 12687019). EGR2 is also essential for anti-tumor immune system response by regulating the proliferation and survival of CD8+ tumor-infiltrating lymphocytes (TILs) (PMID: 36342511). Mutations in EGR2 are associated with demyelinating neuropathies such as Charcot-Marie-Tooth disorder (PMID: 22327514, 33547862, 12687019). In chronic lymphocytic leukemia, patients with EGR2 missense mutations have an unfavorable prognosis, potentially linked to dysregulated B-cell receptor signaling and hypomethylation of transcription factor binding sites (PMID: 27890934). EGR2 expression is negatively regulated by SFRP1 (secreted frizzled related protein 1), as loss of SFRP1 in epithelial cells enhances TGF-β-mediated EGR2 expression (PMID: 28687085). EGR2 expression is downregulated in breast and ovarian cancer and loss of function mutations in various cancer cell lines and models result in increased cellular proliferation and tumor growth (PMID: 34178038, 11494141). True +ENST00000379607 NM_001412.3 1964 EIF1AX False EIF1AX, a translation initiation factor, is most frequently altered by mutation in uveal melanomas and papillary thyroid carcinomas. EIF1AX (eukaryotic translation initiation factor 1A, X-linked) is a eukaryotic translation initiation factor. EIF1AX triggers the transfer of the methionyl initiator tRNA (Met-tRNAi)-eIF2-GTP ternary complex to the 40S ribosomal subunit (PMID: 16193068). This complex creates the 43S pre-initiation complex which binds to the capped 5'-end of mRNA and subsequently reads the mRNA until it finds the first AUG codon (PMID: 23873042). Mutations in EIF1AX have been observed in uveal melanomas with disomy 3 and are associated with an increased risk of metastasis (PMID: 23793026, 24970262). EIF1AX mutations have also been identified in some cases of papillary thyroid carcinoma and leptomeningeal melanocytic neoplasms (PMID: 25417114, 26769193). Alterations of the EIF1AX gene are predominantly missense mutations that alter the protein's highly conserved N-terminus, which is critical for the initiation of protein translation (PMID: 23793026, 16193068, 24970262). False +ENST00000424014 NM_001414 1967 EIF2B1 False EIF2B1, a subunit of the EIF2B guanine nucleotide exchange factor complex, is infrequently mutated in cancer. EIF2B1 is a subunit of EIF2B, a five-subunit guanine nucleotide exchange factor that plays a key role in mRNA translation regulation (PMID: 29425030, 18974117). The EIF2B five subunit complex is composed of EIF2B1, EIF2B2, EIF2B3, EIF2B4 and EIF2B5, which encode for the α, β, γ, δ and ε subunits, respectively (PMID: 29425030). EIF2B functions as the nucleotide exchange factor for the GTPase EIF2, which initiates translation by bringing methionyl-tRNA to the ribosome (PMID: 29425030). EIF2B complex activity is inhibited when EIF2 is phosphorylated by stress-induced kinases (PMID: 29425030). EIF2B1, along with subunits EIF2B2 and EIF2B4, forms the regulatory subcomplex of EIF2B (PMID: 24811713). EIF2B2 and EIF2B4 have been identified as essential to the translation initiation and nucleotide exchange activity with EIF2, whereas EIF2B1 is required for inhibiting translation (PMID: 29036434). EIF2B1 mutations disrupt the ability of EIF2B to sense phosphorylated EIF2, resulting in increased endoplasmic reticulum stress (PMID: 31882561). The stress conditions have been identified as a cause for patient liver dysfunction and leukoencephalopathy due to unregulated unfolded protein response and cell death (PMID: 31882561, 25761052). True +ENST00000220849 NM_001568 3646 EIF3E False EIF3E, a subunit of the EIF3 complex, is infrequently altered in cancer. EIF3E encodes for a subunit of the eukaryotic translation initiation factor 3 (EIF3) complex, which functions in the initiation of protein synthesis (PMID: 17581632). EIF3E regulates various cellular processes including cellular proliferation, DNA damage response repair and protein degradation through the regulation of translation and binding to other multiprotein complexes (PMID: 25849773, 22508697, 17324924). The oncogenic function of EIF3E may be tissue-specific. Overexpression of EIF3E in various cancer cell lines induces cellular proliferation, cellular invasion and tumor growth, suggesting that EIF3E functions predominantly as an oncogene in these tissue-specific contexts (PMID: 20453879, 25400724). EIF3E amplification has been identified in various types of cancer, including breast cancer, glioblastoma, colon cancer and oral cancer (PMID: 20453879, 24481065, 25400724, 25123227). Conversely, loss of EIF3E in other cancer cell line studies has shown induction of cellular senescence, increased mTORC1 signaling and epithelial-to-mesenchymal transition, suggesting that EIF3E also has tumor suppressive functions in these tissue-specific contexts (PMID: 33868586, 22907435). EIF3E downregulation has been identified in breast cancer and non-small cell lung cancer (PMID: 22907435, 15867213). Preclinical studies of breast cancer cells suggest that loss of EIF3E confers resistance to PARP inhibition (PMID: 33868586). False +ENST00000323963 NM_001967.3 1974 EIF4A2 True EIF4A2, a translation initiation factor, is infrequently altered in cancer. EIF4A2 (eukaryotic translation initiation factor 4A2) is a translation initiation factor required for binding of mRNA ribosomal subunits. EIF4A2 is one of three mammalian isoforms of EIF4A (EIF4A1-3) which are mRNA-dependent ATPases and RNA helicases and members of the DEAD-box family of proteins, a group of proteins named after their shared motifs with roles in various cellular processes (PMID: 10872469, 2563148). More specifically, EIF4A2 is an essential factor in the binding of mRNA to the 43S pre-initiation complex, a rate-limiting step and main target of translational control, in which EIF4A2 unwinds mRNA secondary structure to enable the ribosome to bind to a single-stranded molecule (PMID: 10872469). EIF4A2 and EIF4A1 are highly similar in sequence and function but appear to be expressed in spatiotemporally distinct patterns (PMID: 3046931, 8521730). EIF4A2 has also been implicated in micro-RNA-mediated gene regulation (PMID: 23559250). Downregulation of EIF4A2 expression has been observed in non-small cell lung cancer and correlates with poor prognosis, but mutations in EIF4A2 are rare in human tumors (PMID: 23867391). False +ENST00000280892 NM_001130678.1 1977 EIF4E True EIF4E, a translation initiation factor, is overexpressed in various cancer types. EIF4E (eukaryotic translation initiation factor 4E ) is a component of the eukaryotic translation initiation factor 4F (eIF4F) complex. The eIF4F complex additionally consists of an EIF4A isoform and EIF4G and directs the ribosome to the 5' 7-methylguanosine cap of mRNAs in what is considered a rate-limiting step of translation (PMID: 291969, 3469651). As a vital part of translation initiation, EIF4E controls cellular size and is thought to be a direct target of mTOR, which can phosphorylate the translational repressor 4EBP1, allowing for EIF4E to enter the eIF4F complex (PMID: 12080086). Overexpression of EIF4E has been detected in tumors of the breast, bladder, colon, lung, and cervix and can cause malignant transformation in in vitro studies (PMID: 9330633, 9285563, 8244582, 7829225, 25986608, 10638984, 11401917, 12374671, 16260273, 16280668, 20049173). Furthermore, EIF4E exhibits oncogenic traits in a mouse model of lymphoma and is implicated in drug resistance both in contexts of mTOR, BRAF, and MEK targeting (PMID: 15029198, 16103051, 25079330, 25422161, 25615552). Thus, EIF4E is considered a therapeutic target in certain tumor types on the principles that translational control often is deregulated in cancer cells and that PI3K and mTOR signaling and MAPK-interacting kinases (MNKs) are involved in this process (PMID: 22474009, 25743081, 25425688). A variant in the promoter region of EIF4E has been identified in two families with autistic children (PMID: 19556253). False +ENST00000359651 NM_004433.4 1999 ELF3 True ELF3, a transcriptional activator, is altered by mutation or amplification in various cancer types. ELF3 is a member of the ETS-family of transcription factors. ELF3 binds ETS-consensus sequences present in many gene promoters, either activating or repressing their transcription in physiological conditions (PMID: 21548782, 10773884). ELF3 both activates NF-κB-mediated inflammatory pathways and represses androgen receptor signaling in prostate cancers, leading to cancer progression and increased cell migration, respectively (PMID: 23687337, 23435425). ELF3 regulates β-catenin transcription in colorectal cancer (PMID: 24874735). and plays an important role in the mammary gland (PMID: 10959418). Amplification of ELF3 is a frequent events in breast cancer (cBioPortal, MSKCC, Nov 2016), and oncogenic inactivating mutations in ELF3 have also been identified in ampullary cancers (PMID: 26806338). True +ENST00000308167 NM_001127197 2000 ELF4 True ELF4, a transcription factor, is infrequently altered in cancer. ELF4 encodes for a transcription factor that functions in the transcriptional activation of the hematopoietic growth factor genes CSF2, IL-3, IL-8 and PRF1 (PMID: 16530702, 8895518, 10207087, 14625302, 14976184). ELF4 regulates innate immunity by promoting the development of natural killer cells and CD8+ T-cells and suppressing the inflammatory response of macrophages, Th17 cells and various pro-inflammatory cytokines (PMID: 34326534, 35266071). The oncogenic function of ELF4 is likely tissue-specific. Overexpression of ELF4 in various cancer cell lines and models induces cellular proliferation, colony formation and tumor growth, suggesting that ELF4 functions predominantly as an oncogene in these contexts (PMID: 17213815, 36923538). ELF4 amplification has been identified in various types of cancer, including acute myeloid leukemia and esophageal adenocarcinoma (PMID: 33836003). Conversely, overexpression of ELF4 in lung adenocarcinoma, squamous cell carcinoma and endometrial carcinoma cell lines suppressed cellular growth and invasiveness, suggesting that ELF4 may have tumor suppressive function in these tissue-specific contexts (PMID: 12438253, 26921333). False +ENST00000357992 NM_001973 2005 ELK4 True ELK4, a transcription factor, is infrequently altered in cancer. ELK4, a member of the ETS transcription factor family and ternary complex factor subfamily, encodes for a transcription factor that functions in regulating various cellular processes such as proliferation and homeostasis through transcriptional activation and repression (PMID: 20637912, 37529050, 24758171). ELK4 regulates the KDM5A-PJA2-KSR1 axis through transcriptional activation of KDM5A to promote macrophage M2 polarization (PMID: 34372882). Overexpression of ELK4 in gastric cancer and melanoma cell lines and xenograft models induces increased cellular proliferation, migration and invasion through M2 polarization of macrophages, suggesting that ELK4 functions predominantly as an oncogene (PMID: 34372882, 26028036). ELK4 amplification has been identified in various types of cancer, including gastric cancer, glioma and breast cancer (PMID: 34663788, 21846680, 16457699). False +ENST00000262809 NM_006532 8178 ELL True ELL, an elongation factor, is altered by chromosomal translocations in hematological malignancies. ELL encodes for an elongation factor that functions in increasing the catalytic rate of RNA polymerase II through suppression of transient pausing (PMID: 8596958). ELL co-localizes with transcription factor regulators EAF1 and EAF2 within the nucleus to promote elongation activity (PMID: 16006523). Overexpression of ELL in RAT1 fibroblast cells induces anchorage-independent cellular growth and decreased dependence on growth factors, suggesting that ELL functions predominantly as an oncogene (PMID: 9478981). ELL has been identified as a recurrent fusion partner with the gene KMT2A (also known as MLL) in acute myeloid leukemia and other hematological malignancies (PMID: 10995463, 26185637, 26949571, 33608309). False +ENST00000237853 NM_012081.6 22936 ELL2 True ELL2, a transcription elongation factor, is altered in various cancer types. ELL2, an elongation factor for RNA polymerase II (RNA Pol II), is a member of the eleven-nineteen lysine-rich (ELL) family (PMID: 31511829, 28870994, 32606936). The ELL family proteins are part of the transcription super elongation complex (SEC) which enhances the catalytic rate of RNA Pol II transcription by suppressing transient pausing along the DNA strand, thereby facilitating the transcription process (PMID: 31511829, 28870994, 32606936). ELL2 cooperates in the SEC with positive transcription elongation factor b (P-TEFb), ELL-associated factors (EAFs), AFF family members (AFF1-4) and YEATS domain-containing protein family members (AF9 or ENL) (PMID: 28858629, 28870994, 29179998). ELL2 is also a component of the little elongation complex (LEC), which is involved in RNA Pol II transcription of small nuclear RNA genes (PMID: 31511829, 28870994). ELL2 plays a role in the differentiation of plasma cells where it is highly expressed and contributes to plasma cell immunoglobulin secretion by stimulating alternative RNA processing linked to histone methylation (PMID: 28903037, 28858629, 28870994). Likely due to its role in differentiation, reduced ELL2 expression in plasma cells has been documented in patients carrying the multiple myeloma risk allele at 5q15 (PMID: 29695719, 28903037). The consequence of ELL2 expression in other tissues is mixed. Increased ELL2 expression is associated with glioblastoma progression and poor prognosis (PMID: 28531325). ELL2 is highly expressed in the prostate and functions as an androgen response gene (PMID: 28870994). In patients with androgen receptor (AR)-positive prostate adenocarcinoma, ELL2 has been observed to be downregulated, while in patients with AR-negative neuroendocrine prostate cancer ELL2 is upregulated (PMID: 28870994, 29179998, 32606936). True +ENST00000252034 NM_000501 2006 ELN True ELN, an extracellular matrix protein, is infrequently altered in cancer. ELN encodes for the structural subunit tropoelastin, the soluble precursor of the structural protein elastin that functions as a major component in the elastic fibers that support connective tissues (PMID: 16982180, 21368178). ELN is an extracellular matrix protein and provides dynamic structural support for elasticity in all tissues (PMID: 23273220). Protease-driven elastin degradation can occur during cancer progression at the extracellular matrix and lead to the generation of bioactive fragments and elastin-derived peptides, which further promote tumorigenesis through promoting chemotaxis and cellular proliferation (PMID: 18076073, 20959825, 12244048). Expression of ELN and elastin-derived peptides in various types of cancer cell lines and models induces epithelial-to-mesenchymal transition and increases cellular invasion, migration and proliferation, suggesting that ELN functions predominantly as an oncogene (PMID: 32171282, 30186741, 20959825). ELN amplification has been identified in various types of cancer, including gastric cancer and colorectal cancer (PMID: 36226731, 22606006, 32171282). False +ENST00000284811 NM_005648.3 6921 ELOC False ELOC encodes a protein that is a component of the VHL ubiquitination complex. A hotspot mutation of ELOC is associated with a distinct subtype of renal cell carcinoma. The ELOC (transcription elongation factor B polypeptide 1) gene encodes the elongin C protein, a subunit of the transcription factor B protein complex which activates RNA elongation during transcription (PMID: 7660129). ELOC is also part of the elongin BC complex, which functions as an E3 ubiquitin ligase and includes the Von-Hippel Landau (VHL) tumor suppressor, TCEB2 (elongin B), CUL2 or CUL5 and RBX1 (PMID: 25298778). Under normoxic conditions, this complex targets the hypoxia inducible factor, HIF1A, for ubiquitination and degradation, thus preventing a hypoxic response (PMID: 23797736). However, dysregulation of this complex, including inactivation of VHL or ELOC, can lead to HIF1A accumulation and a pseudohypoxic response, even under normoxic conditions (PMID: 25298778). ELOC-mutated renal carcinomas are molecularly distinct from conventional clear cell renal cell carcinomas, and lack both VHL mutations and chromosome 3p loss (PMID: 25676555, 23797736). False +ENST00000334736 NM_020193 56946 EMSY True EMSY, a BRCA2-associated transcriptional repressor protein, is altered by amplification in breast cancer and ovarian cancer. EMSY encodes for a transcriptional repressor nuclear protein that associates with BRCA2 and functions in DNA damage response and chromatin remodeling (PMID: 16615912, 17940002). EMSY associates to BRCA2 by binding with the ENT domain and suppresses the activation domain of BRCA2 (PMID: 15978617). EMSY represses the transcription of interferon-stimulated genes (PMID: 23117821). Overexpression of EMSY in breast cancer and ovarian cancer models induces chromosomal instability and mimics BRCA2 loss-of-function mutations, suggesting that EMSY functions predominantly as an oncogene (PMID: 14651845, 21409565, 16145051, 21735447). EMSY amplification has been identified in breast and ovarian cancers (PMID: 21735447, 14651845). False +ENST00000263253 NM_001429.3 2033 EP300 False EP300, a tumor suppressor and histone acetyltransferase, is inactivated in various cancer types. EP300 (p300; E1A-binding protein) is a transcriptional co-activator with histone acetyltransferase (HAT) activity that is homologous to the co-activator CREBBP. EP300 activates transcription by opening chromatin at gene promoters, recruiting transcriptional machinery and acting as a co-factor to recruit transcription factors (PMID: 15186775, 24480624, 11050151, 23474763, 15691758). The HAT activity of EP300 can also regulate the expression of other proteins, including the tumor suppressor p53 and tissue-specific transcription factors like GATA1 (PMID: 9830059, 9859997). Fusion proteins that include the EP300 HAT domain have been identified in rare cases of acute lymphoblastic leukemias (PMID: 25943178). Somatic mutations in EP300 are found in leukemia, lymphoma and solid tumors including small-cell lung cancer, cervical cancer and bladder cancer (PMID: 21390126, 22941188, 24390348, 21822268). EP300 mutations are commonly truncating and often co-occur with loss of the wildtype allele, suggesting that EP300 functions as a tumor suppressor. Small molecule inhibitors targeting EP300 have been found to be efficacious in preclinical and mouse studies (PMID: 26731516). True +ENST00000389561 NM_015409.3 57634 EP400 False EP400, a chromatin remodeling protein, is infrequently altered by mutation in bladder cancer and lymphomas. EP400 is a chromatin remodeling ATPase that functions as a subunit in the TIP60 histone acetyltransferase complex (PMID: 18614019). The TIP60-EP400 chromatin remodeling complex binds at gene promoters and facilitates histone acetylation in order to regulate gene expression and epigenetic state (PMID: 18614019). EP400 is bound at promoters and enhancers enriched with H2AZ and H3.3 histone variants (PMID: 26669263). Loss of EP400 expression results in depletion of H2AZ and H3.3 transcription and deposition on chromatin (PMID: 26669263). EP400 also preferentially binds to H4Kme3-modified histones and regulates the transcription of those genes (PMID: 26814966). Due to the global regulation of gene expression and chromatin state, EP400 activity is required for embryonic stem cell maintenance, regulation of cell cycle, and the DNA damage/repair pathways (PMID: 18614019, 15655109, 27814680). In MYC-altered lymphomas, there is evidence that alternative splicing events occur at EP400 (PMID: 25970242). Somatic mutations in EP400 are infrequent in human cancers; however, alterations have been identified in bladder cancer and childhood lymphoblastic leukemia (PMID: 26625313, 23508829). True +ENST00000263734 NM_001430.4 2034 EPAS1 False EPAS1, a hypoxia-related transcription factor, is mutated or amplified in a small subset of human cancers. EPAS1 (also HIF2α) is a transcription factor that regulates gene expression in conditions of oxygen deficiency (PMID: 11301389). HIF2α binds the hypoxia response element (HRE) present in the promoter of genes that are regulated in the context of reduced oxygen (hypoxia), such as the vascular endothelial growth factor (VEGF) gene (PMID: 11301389). Under normal oxygen conditions, HIF2α is hydroxylated and recognized by the tumor suppressor VHL, leading to ubiquitination and degradation via the proteasome (PMID: 18498744). Under hypoxic conditions, HIF2α escapes degradation and activates genes involved in the hypoxia response, including genes involved in angiogenesis, glycolysis, apoptosis, proliferation and growth (PMID: 22089927, 14645546). HIF2α activity has been implicated in angiogenesis and oncogenesis in neuroendocrine tumor models (PMID: 23533246, 26432405). Gain-of-function EPAS1 mutations are found in pheochromocytomas and paragangliomas, which are rare neuroendocrine tumors where conditions of pseudo-hypoxia occur (PMID: 22931260, 24741025, 23418310). Although HIF inhibitors have been proposed for cancer treatment, the complex and often contradictory roles of these factors suggest careful evaluation (PMID: 22169972). False +ENST00000263735 NM_002354.2 4072 EPCAM False EPCAM, a transmembrane glycoprotein, is overexpressed in various cancer types. EPCAM (epithelial cell adhesion molecule) is a type I transmembrane glycoprotein that is expressed on normal epithelial cells and has important roles in cell signaling, migration, proliferation and differentiation. It functions as a transmembrane glycoprotein that specifically mediates epithelial-specific intercellular cell adhesion (PMID: 21576002). Germline deletions in the EPCAM gene cause Lynch syndrome via epigenetic silencing of MSH2 (MutS protein homolog 2), leading to a predisposition to primarily colorectal and endometrial cancers (PMID: 19098912). EpCAM is also overexpressed in certain types of solid tumors, though its role in this setting is not fully understood. The bi-specific antibody catumaxomab targets both EpCAM and the T-cell antigen CD3 in an attempt to recruit and activate immune effector cells at the tumor site (PMID: 11588051) and is approved for malignant ascites in patients with EPCAM-positive cancers (PMID: 20473913). True +ENST00000336596 NM_005233.5 2042 EPHA3 False EPHA3, a receptor tyrosine kinase, is altered in various cancer types including skin and lung cancers. EPHA3 (ephrin receptor A3) is a receptor tyrosine kinase that preferentially binds glycosylphosphatidylinositol (GPI)-anchored ephrins resulting in activation of downstream signaling pathways that control cell adhesion, cell migration, cells spreading and proliferation (PMID: 11870224). EPHA3 is highly expressed during embryonic development (PMID: 10197531, 9883737, 25391995) and is overexpressed in various cancer types, including sarcoma, leukemia, glioblastoma and hepatocellular cancer (PMID: 25391995, 23410976, 28415715, 2792259 ). EPHA3 loss-of-function mutations have been identified in various cancer types including lung cancer, melanoma and non-melanoma skin cancers resulting in decreased EPHA3 signaling and enhanced cellular proliferation (cBioPortal, MSKCC, Sept. 2017) (PMID: 22829656, 22242939). True +ENST00000273854 NM_004439.5 2044 EPHA5 False EPHA5, a receptor tyrosine kinase, is altered in various cancer types including skin and lung cancers. EPHA5 is a member of the Eph receptor tyrosine kinase family. Unique from its family members, EPHA5 is almost exclusively expressed in the nervous system—specifically in cortical neurons, cerebellar Purkinje cells and pyramidal neurons of the cortex and hippocampus (PMID: 10375373, 7898646, 9191074). EPHA5 plays a major role in brain development, from neurogenesis to plasticity (PMID: 19326470, 20824214, 9530499, 9698392, 9321686). In addition to its role in the nervous system, EPHA5 mediates communication between pancreatic islet cells, thereby regulating glucose-stimulated insulin secretion (PMID: 17448994). Downregulation of EPHA5 due to promoter methylation has been observed in both breast and prostate cancer, and it has been suggested that EPHA5 might represent a biomarker for diagnosis and prognosis of these tumor types (PMID: 19733895, 25609195). Aberrant methylation of the EPHA5 promoter was observed in 91% of cases of acute lymphoblastic leukemia, in particular in older patients (PMID: 23757320). Increased expression and somatic mutations of EPHA5 have been observed in ovarian cancer, pancreatic ductal adenocarcinoma and lung cancer, among others (PMID: 25623065, 19949912, 19956396, 25634010). False +ENST00000369303 NM_004440.3 2045 EPHA7 True EPHA7, a receptor tyrosine kinase, is altered by mutation or deletion in various cancer types, most frequently in skin cancers. EPHA7 (ephrin receptor A7) is a part of the subfamily of the protein-tyrosine kinase family and preferentially binds glycosylphosphatidylinositol (GPI)-anchored ligands. EPHA7 is composed of one tyrosine kinase domain and an extracellular domain that contains a ligand-binding domain, a cysteine-rich domain, and two fibronectin type III repeats (PMID 10197531, 9883737). EPHA7 structurally resembles other members of the Eph family and is associated with promoting cellular transformation, invasion, and proliferation through the JAK2 signaling pathway (PMID: 24003208, 20179713, 22862837). Differential expression levels of EPHA7 and diverse roles in carcinogenesis have been shown in various cancer types (PMID: 26160986). Studies have shown overexpression of EPHA7 in glioblastoma, breast, and gallbladder adenocarcinoma, which promotes cell proliferation and migration through the FGFR1 signaling pathway and is correlated with poor prognosis (PMID 18790757, 15147954, 18366728). Other studies have shown downregulation of EPHA7 by hypermethylation in gastric, colorectal, esophageal squamous cell and prostate cancers, as well as in follicular lymphomas; and its association with tumor progression (PMID 17669470, 16007213, 26160986, 18821581, 29022918, 22036564). True +ENST00000398015 NM_004441.4 2047 EPHB1 True EPHB1, a receptor tyrosine kinase, is altered by mutation in various cancer types. EPHB1 is a transmembrane receptor tyrosine kinase that is a member of the ephrin (EPH) protein family (PMID: 31297055). EPH receptors bind to ephrin ligands on adjacent cells, resulting in cell interaction-dependent bidirectional signaling, which activates forward signaling in cells expressing the EPH receptor and reverse signaling in ligand presenting cells (PMID: 31297055). EPHB1 is a marker of venous endothelial cells and has been found to mediate signaling in a variety of contexts including in cell positioning of colorectal cells (PMID: 12408869, 21235905). EPHB signaling has been implicated in a variety of other cellular processes including immune regulation, epithelial integrity, invasion, cell shape, cellular proliferation and axon guidance (PMID: 12408869, 18424888, 31297055, 26790531, 23669443, 21514363). Differential EPHB1 signaling has been associated with inflammatory intestinal disorders, such as Crohn’s disease (PMID: 15996027). The oncogenic function of EPHB1 is likely tissue-specific. Somatic mutations in EPHB1 are found in patients with metastatic colorectal cancer (PMID: 12408869). These mutations are predicted to be loss-of-function and disrupt epithelial cell adhesion and cellular compartmentalization, leading to metastatic progression (PMID: 12408869). Reduced expression of EPHB1 has also been detected in a variety of cancers including colorectal, gastric, and ovarian cancer, among others (PMID: 18931529, 18424888). Knockdown of EPHB1 in various cell models suppresses cellular proliferation and migration, suggesting that EPHB1 functions predominantly as an oncogene in these contexts (PMID: 25879388, 32368295). Amplification of EPHB1 has been identified in various types of cancer, including lung cancer and gastric cancer (PMID: 32368295, 24716914, 32509099). True +ENST00000358173 NM_004444 2050 EPHB4 True EPHB4, a transmembrane receptor kinase, is infrequently altered in cancer. EPHB4, a member of the ephrin family of receptors, encodes for a transmembrane receptor kinase that functions primarily in regulating angiogenesis, erythropoiesis and vasculogenesis (PMID: 10518221, 16424904, 10603345). EFNB2 binds to EPHB4 to activate the bi-directional ephrin signaling pathway and triggers a signaling cascade for cellular motility by either attracting or repelling cells (PMID: 31949258). Overexpression of EPHB4 in various cancer cell lines and models induces increased cellular survival and tumor growth, suggesting that EPHB4 functions predominantly as an oncogene (PMID: 16816380, 29296810, 15153337, 26073592). Amplification of EPHB4 has been identified in various types of cancer, including breast cancer, lung cancer and esophageal squamous cell cancer (PMID: 16816380, 31934189, 31885720). False +ENST00000222139 NM_000121.3 2057 EPOR True EPOR, a cytokine receptor, is recurrently altered by chromosomal rearrangement in familial erythrocytosis and acute lymphoblastic leukemia. EPOR is a type I cytokine receptor that binds erythropoietin (EPO) (PMID: 17721432, 17124066). EPO initiates red blood cell production by binding EPOR, which is expressed predominantly on erythroid progenitors (PMID: 21307776). EPO-engagement of EPOR results in activation of the non-receptor tyrosine kinase JAK2, leading to the recruitment and phosphorylation of downstream effectors, such as STAT3 and STAT5 (PMID: 17721432, 17124066). Subsequent phosphorylation of STAT proteins enables the translocation of these signaling molecules to the nucleus to activate transcription (PMID: 17721432). EPO-mediated activation of JAK-STAT signaling regulates several cellular functions including proliferation, erythroid differentiation, and apoptosis (PMID: 12239135). Mice lacking expression of EPOR have defective primitive and definitive erythropoiesis, resulting in embryonic lethality (PMID: 23894012, 12239135). Germline EPOR gain-of-function mutations have been identified in patients with familial erythrocytosis and congenital polycythemia (PMID: 8506290, 7795221, 24115288, 27982410). Recurrent EPOR fusion proteins are found in patients with acute lymphoblastic leukemia that results in truncated, active EPOR molecules (PMID: 22897847, 28972016, 26859458, 27870571). Expression of truncated EPOR proteins in hematopoietic assays results in EPO hypersensitivity and transformation (PMID: 26859458). EPOR alterations result in hyperactive JAK-STAT signaling and sensitivity to small molecule JAK2 inhibition (PMID: 26859458). False +ENST00000269571 NM_004448.2 2064 ERBB2 True 1 ERBB2, a receptor tyrosine kinase, is altered by mutation, amplification and/or overexpression in various cancer types, most frequently in breast, esophagogastric and endometrial cancers. ERBB2 (also HER2) is a transmembrane receptor that is a member of the ERBB family of receptor tyrosine kinases, including EGFR, ERBB3, and ERBB4. ERBB2 does not directly bind its own ligand; instead, it potentiates the activity of other ligand-bound ERBB receptors by binding to them (PMID: 12620236). ERBB2 can heterodimerize with any of the other EGFR family receptors (PMID: 10220407, 9130710) initiating downstream signaling activation of several pathways including the MAPK and PI3K/AKT/mTOR signaling cascades (PMID: 22239438, 12853564). ERBB2 can also homodimerize and initiate MAPK, SRC, PI3K and STAT signaling (PMID: 22785351). Activation of ERBB2-mediated signaling ultimately results in cellular proliferation, migration, and differentiation (PMID: 18045542). ERBB2 is activated by gene amplification and overexpression in a range of human cancers including breast, gastric, and endometrial tumors, among others (PMID: 19536107, 24656976). ERBB2 gene amplification in human breast cancers is associated with poor overall survival and time to tumor recurrence (PMID: 3798106, 23000897,9552035, 9469329). Amplified ERBB2 heterodimerizes with ERBB3 to activate oncogenic signaling and drives tumorigenesis in breast cancer (PMID:12853564, 23204226, 12124352, 18632642). Somatic mutations in ERBB2 have been identified in a series of tumors including lobular breast, lung adenocarcinoma, and gastric cancers, among others, with recurrent hotspot alterations in both the extracellular and kinase domains (PMID: 23000897, 23220880, 22908275). Preclinical and clinical studies have demonstrated that many of these mutations are transforming and sensitive to FDA-approved ERBB targeted therapies, including trastuzumab, ado-trastuzumab emtansine, lapatinib, and pertuzumab (PMID:24799465). False +ENST00000267101 NM_001982.3 2065 ERBB3 True ERBB3, a receptor tyrosine kinase, is altered by mutation or amplification in various cancer types. ERBB3 (also HER3) is a transmembrane receptor that is a member of the ERBB family of receptor tyrosine kinases, including EGFR, ERBB2, and ERBB4 (PMID: 19536107, 11252954, 19208461). ERBB3 is unique in that it has limited kinase activity, approximately 1000 fold less than its family member, EGFR (PMID: 8389462, 8058764, 20351256). Thereby, ERBB3 cannot form homodimers (PMID: 15225657) and must heterodimerize with other ERBB family members to initiate downstream signaling (PMID: 8632008). Heterodimerization of ERBB3 with its preferred heterodimer partner, ERBB2, results in activation of several signaling pathways, including the MAPK, PI3K/AKT/mTOR, SRC, and STAT pathways (PMID: 7515147, 8026468, 8264617). Preclinical models of ERBB2-amplified cancers demonstrate that ERBB2-amplified cells exquisitely rely on ERBB3 to drive proliferation and survival (PMID: 12853564, 24651011, 19536107). Moreover, ERBB3 feedback upregulation, localization changes, and ligand overexpression contribute to resistance to ERBB or PI3K/AKT/mTOR inhibitors (PMID: 24520092, 24651011, 19536107). Overexpression of ERBB3 has been correlated with tumor progression and poor prognosis in some human cancers (PMID: 20179223, 20816829). Somatic activating mutations in ERBB3 are found in gastric, bladder, uterine and colorectal cancers, among others (PMID: 23680147). While that are no FDA-approved inhibitors for ERBB3-mutated cancers, preclinical and clinical trials are underway to determine if ERBB targeting compounds alone or in combination with other inhibitors targeting the MAPK pathway are efficacious. False +ENST00000342788 NM_005235.2 2066 ERBB4 True ERBB4, a receptor tyrosine kinase, is altered at low to moderate frequencies in various cancer types, most frequently in melanoma and lung cancer. ERBB4 (also HER4) is a transmembrane receptor that is a member of the ERBB family of receptor tyrosine kinases, including EGFR, ERBB2, and ERBB3 (PMID: 14504474, 9208852, 22427524, 25492965). Binding of ERBB4 by its ligands, including neuregulins (NRG1-4), betacellulin (BTC), HB-EGF or epiregulin (EPR), activates the receptor and initiates downstream signaling pathways including the canonical MAPK and PI3K/AKT/mTOR signaling cascades. ERBB4 forms active kinase dimers with other ERBB isoforms, including the preferential binding partner ERRB2 (PMID: 9130710, 10220407,19208461, 11252954). Somatic activating mutations in ERBB4 have been identified in melanoma (PMID: 22817889, 22842228, 24755198), lung adenocarcinoma (PMID: 18948947), gastric (PMID: 25079317, 25583476), and colorectal cancers (PMID: 22895193); however, the role of ERBB4 in cancer is not well established. Evidence in breast cancer cell lines suggests that ERBB4 is not required for mediating tumorigenesis in ERBB2-positive breast cancer but rather for mediating resistance to ERBB2 inhibitors (PMID: 25590338). Conversely, a subset of literature points to a growth-suppressive role for ERBB4 in breast cancer (PMID: 17120616, 24791013, 16832345, 20603612). The prognostic value of ERBB4 expression in cancer is still debatable, as reports have documented both better and worse outcomes in these tumors; however, this may be due to the lack of discrimination between ERBB4 variants (PMID: 25492965, 18454307). False +ENST00000360905 NM_178040 23085 ERC1 True ERC1, a scaffold protein, is altered by chromosomal rearrangement in various cancers. ERC1, a member of the RIM-binding protein family, encodes for a scaffold protein that functions in regulating the motility and migration of cells by promoting focal adhesion turnover (PMID: 24982445, 27659488). ERC1 associates with the scaffold proteins PPFIA1, also known as liprin-alpha-1, and LL5β to form plasma membrane-associated platforms (PMAPs) on the cellular membrane to support protrusion, cellular motility and invasion (PMID: 37437062). ERC1 is a regulatory subunit of the IKK complex and promotes NF-κB expression by recruiting IκBα to the complex (PMID: 15218148). Overexpression of ERC1 in A549 and HEK293T cells activates NF-kB and other proinflammatory genes as well as increases cellular migration, suggesting that ERC1 functions predominantly as an oncogene (PMID: 37252973). Fusions involving ERC1 have been identified in various types of cancer, including pancreatic cancer and lung adenocarcinoma (PMID: 34733735, 35712652). False +ENST00000300853 NM_001983 2067 ERCC1 False ERCC1, an endonuclease involved in DNA repair, is infrequently altered in cancer. Germline mutations of ERCC1 are associated with Fanconi anemia, Cockayne syndrome and xeroderma pigmentosum, and predispose to certain cancers. ERCC1 encodes for a DNA endonuclease protein which functions primarily in nucleotide excision repair and interstrand crosslink repair of DNA (PMID: 8811092). ERCC1 interacts with endonuclease ERCC4 to form the ERCC1-XPF DNA repair complex (PMID: 23623389). The ERCC1-XPF nuclease is essential for the DNA nucleotide excision repair pathway (PMID: 10320375). Hereditary mutations in ERCC1 have been identified in skin-photosensitive and DNA repair deficient disorders including xeroderma pigmentosum, Cocakyane syndrome and Fanconi Anemia (PMID: 23623389). Somatic ERCC1 mutations are rare in cancer, however ERCC1 polymorphisms have been identified to predispose to certain cancers (PMID: 29544698, 26022132, 29752341). ERCC1 polymorphisms are associated with increased chemosensitivity due to deficiencies in DNA repair pathways (PMID: 34148553, 37141338, 28032496). True +ENST00000391945 NM_000400.3 2068 ERCC2 False 3A ERCC2, a DNA helicase involved in the nucleotide excision repair (NER) pathway, is frequently altered in bladder cancer. Germline mutations of ERCC2 are associated with xeroderma pigmentosum, trichothiodystrophy and Cockayne syndrome, and predispose to certain cancers. ERCC2 is a DNA helicase that is a member of the RAD3/XPD family of protein helicases. ERCC2 is a regulator of the nucleotide excision repair (NER) pathway; NER is used by cells to repair bulky DNA lesions that are caused by environmental mutagens, UV irradiation and certain chemotherapeutic agents, such as cisplatin (reviewed in PMID: 24086042). ERCC2 functions as an ATP-dependent 5' to 3' helicase that unwinds damaged DNA, enabling other NER factors to access the DNA for subsequent repair (PMID: 9351836). Germline mutations of ERCC2 lead to trichothiodystrophy, xeroderma pigmentosum and combined xeroderma pigmentosum and Cockayne syndrome (reviewed in PMID: 19809470). Genetic polymorphisms of ERCC2 are associated with an increased risk of certain cancers, including lung (PMID: 20651612), colorectal cancer, esophageal squamous cell carcinoma (PMID: 16707649) and urothelial cell carcinoma (PMID: 24347488). Somatic ERCC2 mutations occur in approximately 12% of muscle-invasive bladder cancer and have been associated with response to cisplatin-based chemotherapy and checkpoint inhibition (PMID: 24476821, 25096233, 29489427). True +ENST00000285398 NM_000122.1 2071 ERCC3 False ERCC3, a tumor suppressor and helicase involved in DNA repair, is infrequently altered in cancer. Germline mutations of ERCC3 are associated with Cockayne's syndrome, xeroderma pigmentosum and trichothiodystrophy, and may predispose to breast cancer. ERCC3 is an ATP-dependent DNA helicase which is an essential component of the transcription factor II H(TFIIH) complex. ERCC3 functions to unwind the DNA double helix which is required as part of the nucleotide-excision repair (NER) pathway (PMID: 21571596, 8465201, 8107888, 21571596). The TFIIH transcriptional complex also requires activity of ERCC3 for initiation of transcription (PMID: 8152490, 7613092, 8166891). Hereditary ERCC3 mutations are found in individuals with Cockayne's syndrome and trichothiodystrophy (PMID: 4811796, 8408834, 8304337,16947863, 9012405, 23562818). Mutations in ERCC3, likely impairing transcriptional function, have been identified in patients with xeroderma pigmentosum B, a condition resulting in sensitivity to sunlight and increased skin-cancer risk (PMID: 10064601). Loss-of-function ERCC3 truncating mutations have been associated with breast cancer risk, likely due to defects in DNA repair pathways (PMID: 24508195, 27655433). True +ENST00000311895 NM_005236.2 2072 ERCC4 False ERCC4, a tumor suppressor and endonuclease involved in DNA repair, is infrequently altered in cancer. Germline mutations of ERCC4 are associated with Fanconi anemia, Cockayne syndrome and xeroderma pigmentosum, and predispose to certain cancers. ERCC4 (also known as XPF) is a DNA endonuclease protein that is active when in a complex in ERCC1 (PMID: 22101340, 9525876). The ERCC4-ERCC1 complex is required to cut at the junction between double stranded and single stranded DNA and has important functions in nucleotide excision repair, DNA double-strand break repair, and DNA interstrand crosslinks repair (PMID: 22101340, 9525876). Hereditary mutations in ERCC4 have been identified in skin-photosensitive and DNA repair deficient disorders including xeroderma pigmentosum, Cocakyane synrome, XFE progeroid syndrome and Fanconi Anemia (PMID: 23623386, 23623389). Somatic ERCC4 mutations are rare in cancer, however, loss-of-function germline ERCC4 mutations can cause a predisposition for cancer (PMID: 22941649, 24465539). ERCC4-mutant cell are sensitive to DNA damaging reagents due to deficiencies in DNA repair pathways (PMID: 26074087). True +ENST00000652225 NM_000123.4 2073 ERCC5 False ERCC5 is a tumor suppressor and an endonuclease involved in DNA repair. Germline mutations of ERCC5 are associated with xeroderma pigmentosum and Cockayne's syndrome, which predispose to certain cancers. ERCC5 (also known as XPG) is a DNA endonuclease that is involved in the nucleotide-excision repair (NER) pathway (PMID: 8652557, 8206890, 8090225, 17466625). Hereditary variants in ERCC5 have been implicated in several disorders with defective DNA repair including xeroderma pigmentosum, Cocayne's syndrome, cerebrooculofacioskeletal syndrome, and arthrogryposis (PMID: 24700531, 8317483, 2478446). Somatic ERCC5 mutations have not yet been determined to be driver mutations in cancer although aberrant expression has been detected in breast and ovarian cancer (PMID: 18565881, 19289372). ERCC5-mutant cells may be increasingly sensitive to DNA damaging agents due to defects in DNA repair pathways (PMID: 7799936). True +ENST00000222329 NM_006494.2 2077 ERF False ERF, a transcriptional repressor, is altered by mutation at low frequencies in various cancers. ERF is a transcriptional repressor that is a member of the ETS-family of transcription factors (PMID: 21548782). ERF acts as a repressor of ETS2, another member of the ETS family, and its repression leads to EGF-induced cell migration (PMID: 22198386). ERF is a target of the MAP-kinase pathway, and it negatively correlates with expression of oncogenic c-MYC (PMID: 17699159, 17525531). ERF is mutated at low frequencies in various cancers (cBioPortal, MSKCC, Nov 2016). True +ENST00000288319 NM_182918.3 2078 ERG True ERG, a transcription factor, is recurrently altered by chromosomal rearrangement in prostate cancer. ERG (ETS-related gene) is an ETS (E26 transformation-specific) family transcription factor that is important in gene regulation. In normal physiology, ERG is primarily expressed in hematopoietic cells where it is required for normal hematopoiesis (PMID: 18500345) and endothelial cells where it regulates angiogenesis and vascular stability (PMID: 25584796). ERG fusions are the most common alterations of the ERG gene and are found in several cancers, including prostate cancer (PMID: 16254181) and Ewing’s sarcoma (PMID: 8162068). In prostate cancer, approximately 50% of all cases harbor a fusion between ERG and a highly expressed gene (e.g., TMPRSS2) that leads to aberrant overexpression of ERG (PMID: 16254181). In these cases, ERG acts to modify the chromatin landscape of prostate cancer cells, allowing for increased androgen receptor (AR) binding and priming prostate cancer initiation in response to PTEN loss (PMID: 23817021, 28783165). False +ENST00000377482 NM_018948.3 54206 ERRFI1 False ERRFI1, a scaffold protein involved in negative regulation of ERBB receptors, is recurrently altered by mutation and deletion in various cancer types. ERRFI1 (also Mig6) is a scaffold protein involved in ERBB-mediated signaling (PMID: 17940511). ERRFI1 negatively regulates the EGF receptor family and HGF/SF-Met signaling (PMID: 11003669, 26280531, 11843178, 18046415, 15556944, 21576352, 12833145, 16247031). CDC42 binding to ERRFI1 mediates the inhibitory activity on EGF receptor family members (PMID: 10749885, 17599051, 12833145). ERRFI1 regulates many cellular processes including cell signaling, development, tissue homeostasis, and stress response (PMID: 16087873, 19683494, 16782890, 22975324, 22912762, 19710174, 12384522). Murine loss-of-function studies have demonstrated that ERRFI1 is a regulator of keratinocyte development and proliferation (PMID: 17987665). In addition, ERRFI1 loss promotes cancer progression in mouse models, suggesting that ERRFI1 functions as a tumor suppressor (PMID: 16648858, 16819504, 25735773, 29191600). Deletion and downregulation of ERRFI1 have been implicated in various cancer types, including hepatocellular carcinoma, non-small cell lung cancer, and glioblastoma, among others, and is an indicator of poor patient outcome (PMID: 20044804, 21113414, 19439667, 20351267, 10862041, 25753424, 10987304, 15900585, 9287966). The reduction of ERRFI1 expression has also been associated with resistance to trastuzumab, an antibody targeting ERBB2 (PMID: 15856022, 14871811, 22255596). Somatic loss-of-function mutations are also found in patients with various cancer types and these alterations are predicted to activate downstream signaling pathways (PMID: 17940511, 16819504). True +ENST00000305188 NM_001017420.2 157570 ESCO2 False ESCO2, an enzyme required for sister chromatid pairing, is infrequently altered in a diverse range of cancers. ESCO2 is an enzyme that establishes sister chromatid cohesion during the cell cycle (PMID: 15958495). Cohesion between sister chromatids is initiated during DNA replication and must be maintained throughout mitosis or meiosis to ensure proper chromosome-spindle attachments (PMID: 26903600). ESCO2 functions as an acetyltransferase during S phase that acetylates the cohesin component SMC3 and allows for appropriate cohesion distribution (PMID: 18501190). The enzymatic activity of ESCO2 is required for accurate pairing of sister chromatids during cell division and DNA repair (PMID: 22614755). Loss of ESCO2 in cell lines results in premature sister chromatid separation and apoptosis (PMID: 22614755). In addition, ESCO2 forms complexes with several chromatin modifying enzymes, functioning as a transcriptional co-repressor and is bound at pericentric heterochromatin (PMID: 22101327,18501190, 26305936). Germline mutations in ESCO2 have been identified in patients with Roberts syndrome, a disorder characterized by limb and facial abnormalities (PMID: 1582173); however, somatic ESCO2 mutations are infrequent in human cancers. True +ENST00000206249 NM_001122740.1 2099 ESR1 True 1 ESR1 (estrogen receptor alpha) is a transcription factor that is frequently mutated in hormone-resistant metastatic breast cancers. ESR1 is a nuclear receptor that encodes the estrogen receptor alpha (ERα) protein. ERα plays a major role in sexual reproductive development and maintenance, specifically in the female reproductive organs (PMID: 10368776). Binding of the hormone estrogen, the ERα ligand, induces conformational changes to ERα, which allows the receptor to dissociate from HSP90 and dimerize with itself or ERβ. The dimer then translocates to the nucleus where it binds to promoters and enhancers of target genes either directly, via Estrogen Responsive Elements (ERE) in the DNA, or via other transcription factor complexes such as FOS/JUN/SP-1 (PMID: 11162939, 10681512). Once bound, the estrogen receptor recruits co-regulators that modulate the transcription of ESR1 target genes, resulting in changes in proliferation, migration and differentiation (PMID: 21779010). Lack of ERα delays the development of WNT1- and ERBB2 mutant-induced mouse mammary tumors (PMID: 10213494, 12019156) and reduces the occurrence of estrogen and carcinogen-induced mouse mammary tumors (PMID: 20181624, 11156389), indicating the involvement of ERα in tumorigenesis. While mutations in ESR1 are generally very rare in primary cancers (<5%), a number of mutations occurring in the ligand-binding domain (LBD) of the receptor were identified in ~12-25% of hormone-resistant metastatic breast cancer patients (PMID: 24398047, 24185512, 24185510, 24217577). The most recurrent mutations, Y537S and D538G, result in a constitutively active receptor, which is shown to confer acquired resistance to estrogen deprivation therapies. False +ENST00000272342 NM_019002.3 54465 ETAA1 False ETAA1, a replication stress response protein, is infrequently mutated in human cancers. ETAA1 (also ETAA16) is a replication stress protein that promotes fork progression (PMID: 27601467, 27723717, 27723720). In response to replication stress, ETAA1 binds RPA (Replication Protein Complex A), a complex that associates with single-stranded DNA at stalled replication forks and recruits repair proteins to resolve the forks (PMID: 27601467, 27723720, 27818175). The activity of ETAA1 stimulates ATR, a protein kinase involved in DNA sensing (PMID: 27601467), via a distinct arm independent from TOPBP1-mediated repair (PMID: 27723717, 30139873). Specifically, ETAA1 associates with two distinct replication complexes including ATR/ATRIP and BLM/TOP3α/RMI1/RMI2 (PMID: 27723720). Loss of ETAA1 results in genome instability, altered DNA replication and sensitivity to replication stress (PMID: 27723717, 27723720). In addition, reduced ETAA1 expression in murine models results in a diminished T-cell response, suggesting that ETAA1 may have a role in immune cell regulation (PMID: 28607084). ETAA1 is also predicted to function as a surface antigen in Ewing sarcoma (PMID: 16003559). Variants associated with ETAA1 are predictive of susceptibility to pancreatic and colon cancer (PMID: 26098869, 29844832). True +ENST00000671733 NM_018638.4 55500 ETNK1 False ETNK1, a kinase involved in phospholipid biosynthesis, is recurrently altered by mutation in BCR-ABL negative CML and CMML. ETNK1 is a kinase that catalyzes the first step in the phosphatidylethanolamine (PE) biosynthesis pathway (PMID: 13366993). ETNK1 phosphorylates ethanolamine to form phosphoethanolamine, an intermediate which is then processed to PE, a membrane phospholipid (PMID: 13366993, 25343957). PE has a variety of cellular roles including maintaining membrane protein topology, defining membrane architecture, anchoring PE-binding proteins to the membrane as well as regulation of cytokinesis and mitochondrial respiration (PMID: 19703652, 11294902). Somatic ETNK1 mutations are found in BCR-ABL negative chronic myeloid leukemia (CML) and chronic myelomonocytic leukemia (CMML) (PMID: 25343957, 25615281). False +ENST00000319397 NM_005238 2113 ETS1 True ETS1, a transcription factor, is infrequently altered in cancer. ETS1, a member of the ETS family of transcription factors, encodes for a transcription factor that functions in the regulation of various lymphoid cell processes, including survival, differentiation and proliferation, through transcriptional regulation of chemokines and cytokines (PMID: 10698492, 11909962, 32350509, 27069114). Alternative spliced transcript variants of ETS1 have been identified and can result in the p42 isoform, a gain-of-function protein that lacks the autoinhibitory sequences, or the p27 isoform, a dominant negative protein that lacks transactivation activity (PMID: 19377509, 8003962). The oncogenic function of ETS1 is likely tissue-specific. Overexpression of ETS1 in breast cancer cell lines and models induces cellular proliferation, invasion and migration, suggesting that ETS1 can function as an oncogene in this context (PMID: 24706481, 21444677, 22971289). ETS1 amplification has been identified in various types of cancer, including ovarian cancer and prostate cancer (PMID: 11297247, 23064684). Conversely, knockout of ETS1 in other breast cancer cell studies induces cellular proliferation and aberrant lymphoid cell development, suggesting that ETS1 can function as a tumor suppressor gene in this context (PMID: 32477936). Ectopic expression of wildtype ETS1 and the p42 isoform in colorectal and epithelial cancer cell lines induces apoptosis and has been suggested as a potential therapeutic treatment (PMID: 9266972, 7753825). Preclinical studies with breast cancer cell lines overexpressing ETS1 have demonstrated conferral of multidrug resistance (PMID: 20392592). True +ENST00000405192 NM_001163147.1 2115 ETV1 True ETV1, a transcription factor, is altered by chromosomal rearrangement or overexpression in various cancer types. The ETV1 (ETS Translocation Variant 1) gene, belongs to the ETS (E26 transformation-specific) family of transcription factors. The downstream transcriptional targets of ETV1 are diverse and tissue specific. ETV1 is a downstream transcriptional mediator of the MAP kinase pathway and it is tightly regulated by the MAP kinase through transcription, protein stability, and phosphorylation (PMID: 12213813, 19251651, 20927104). The endogenous expression of ETV1 is restricted to several tissues, including specific neurons of the central and peripheral nervous systems (PMID: 16289830, 21746923, 10850491) and the interstitial cells of Cajal (“pacemaker” cells of the gastrointestinal tract) (PMID: 20927104). ETV1 is aberrantly activated in several cancers through distinct mechanisms: In Ewing sarcoma, ETV1 is fused with the EWS protein to generate the chimeric EWS-ETV1 protein. In prostate cancer, ETV1 is aberrantly over-expressed through translocation resulting in either fusion transcript or full-length transcript. In melanoma, ETV1 is aberrantly over-expressed through genetic amplification of its chromosomal locus. In gastrointestinal stromal tumors (GISTs), ETV1 is endogenously highly expressed and required to maintain lineage specification and survival (PMID: 7700648, 17671502, 20160028, 20927104). False +ENST00000319349 NM_001079675.2 2118 ETV4 True ETV4, a transcription factor, is frequently altered by chromosomal rearrangement in prostate cancer and Ewing's sarcoma. ETV4 (also PEA3 and E1AF) is a transcription factor that belongs to the ETS family of transcription factors. The family consists of a highly conserved group of genes that play important roles in cellular proliferation, differentiation, migration, invasion and angiogenesis (PMID: 21548782). ETV4 in particular plays an important role in development, such as in organogenesis of the kidney, mammary gland, and limb buds (PMID: 9285689, 12871699, 19386269). ETV4 is overexpressed in various types of solid cancers, including the esophagus (PMID: 21143918), colon (PMID: 15695237), breast (PMID: 21404275,15387369), ovarian (PMID:12684413), non-small lung (PMID: 11519038) and gastric (PMID: 14604892), where it promotes metastatic progression and correlates with reduced survival. In prostate cancers (~1% of the cases) ETV4 overexpression is associated with translocation of ETV4 to the promoter of a gene highly expressed in prostate (TMPRSS2, KLK2, DDX5, and CANT1) (PMID: 18794152, 16585160, 18451133). Finally, fusions of ETV4 with Ewing's sarcoma (EWSR1) gene have been reported in three cases of Ewing sarcoma (ES) (PMID: 8834175, 8605035, 22429598). The defining feature of this tumor type is chromosomal translocation involving the EWSR1 gene and one of five ETS genes. False +ENST00000306376 NM_004454.2 2119 ETV5 True ETV5, a transcription factor, is rarely altered by chromosomal rearrangement in prostate cancer. ETV5 is an ETS family transcription factor belonging to the PEA3 subfamily involved in multiple cellular processes. PEA3 family members are activated by pathways such as the MAPK and PKA pathway to induce the transcription of gene programs through phosphorylation (PMID: 8895521, 8808707). ETV4 and ETV5 are involved in the proliferation of undifferentiated embryonic stem cells and subsequent induction of differentiation cascades, potentially through changes in Oct3/4 expression (PMID: 26224636). Additionally, ETV5 has been shown to be expressed during embryonic development, especially at sites undergoing branching morphogenesis (PMID: 12871699, 19898483, 19386268). In the testis, ETV5 is exclusively expressed in the Sertoli cells and is required for spermatogonial stem cell self-renewal (PMID: 16107850). False +ENST00000396373 NM_001987.4 2120 ETV6 False ETV6, a transcription factor, is frequently altered by chromosomal rearrangement in hematologic malignancies. ETV6 is a transcription factor that is a member of the ETS protein family. The ETS family is one of the largest families of transcription factors. ETS domains typically bind to a GGAA/T DNA sequence, but can also be involved in protein-protein interactions (PMID: 11175367). ETV6 is essential for hematopoietic stem cells (PMID: 17980166) and may initiate the regulatory cascade leading to their production (PMID: 20412772). Translocations involving band 12p13 around ETV6 are one of the most commonly observed alterations in hematological malignancies (PMID: 22578774). ETV6 has a large number of fusion partners and typically contributes to tumorigenesis by modifying the activity or function of the partner gene or a proto-oncogene close to a translocation site (PMID: 22578774). Somatic mutations occur at a relatively low frequency in solid tumors (cBioPortal, MSKCC, Mar. 2016). Germline ETV6 mutations contribute to hematologic malignancies including ALL (PMID: 25581430, 26573422). ETV6-NTRK3 fusion has been shown to be sensitive to crizotinib (PMID: 25207766). True +ENST00000397938 NM_005243.3 2130 EWSR1 True EWSR1, a multi-functional protein that binds DNA and RNA, is altered by chromosomal rearrangement in various cancer types, most frequently in Ewing Sarcoma. EWSR1 is one of three members of the highly conserved heterogeneous nuclear ribonucleoprotein particle (hnRNP) protein family, FET (PMID: 25494299, 22081015). The EWSR1 protein can bind to DNA or RNA and is known to play a role in transcription via binding to RNA Pol II, RNA processing and metabolism, and DNA damage repair (PMID: 24320889, 25494299). The N-terminal domain of EWSR1 can fuse to the C-terminal domain of a number of transcription factors and give rise to several fusion proteins that have been implicated in Ewing Sarcoma, primitive neuroectodermal tumor, desmoplastic small round cell tumor, myxoid liposarcoma, extraskeletal myxoid chondrosarcoma, and clear cell sarcoma (PMID: 16784984, 25364450, 17691072, 17525681, 17227118, 24320889). False +ENST00000378204 NM_000127 2131 EXT1 False EXT1, a transmembrane glycosyltransferase, is infrequently altered in cancers. EXT1 (Exostoses-1) is an endoplasmic reticulum-resident type II transmembrane glycosyltransferase which is required for the polymerization of heparan sulfate (HS)(PMID: 9756849). HS polymerization is necessary for the formation of fibronectin fibrils and the subsequent formation of the insoluble cell-matrix (PMID: 34890641). The reduction of EXT1, therefore, leads to reduced fibril assembly and global changes in cellular homeostasis, including increased cell size, ER structure and changes to membrane glycome and lipid compositions, which impact the metabolism of the cell (PMID: 33962942). Mutations in EXT1 are associated with hereditary multiple exostoses (HME), an autosomal dominant bone disorder characterized by the formation of osteochondromas and an increased risk for chondro- and osteosarcoma (PMID: 7550340). While somatic mutations of EXT1 are rare in sporadic neoplasms, EXT1 expression can be reduced by the hypermethylation of the CpG island promoter, which has been found as a method of EXT1 loss in cell lines from patients with acute promyelocytic leukemia, acute lymphoblastic leukemia, and non-melanoma skin cancer (PMID: 15385438). True +ENST00000428826 NM_001991.3 2145 EZH1 True EZH1, an epigenetic modifier, is altered by mutation or amplification in various tumors. EZH1 is the catalytic component of the Polycomb repressive complex 2 (PRC2) which methylates histone H3 at lysine 27 (H3K27), resulting in chromatin compaction and target gene repression. Compared to its homolog, EZH2, EZH1-containing PRC2 complexes show weaker methylation activity, target fewer genes, and are more abundant in non-proliferative adult organs (PMID: 19026781). EZH1 plays a role in maintaining embryonic stem cell pluripotency (PMID: 19026780). EZH1 is not commonly altered in cancer, but recurrent mutations in EZH1 are often the second hit in autonomous thyroid adenomas (PMID: 27500488). Dual EZH1/2 inhibitors are being tested preclinically in several cancers (PMID: 24183969, 25395428). False +ENST00000320356 NM_004456.4 2146 EZH2 True 1 EZH2, an epigenetic modifier, is altered by mutation and/or overexpression in solid tumors and hematologic malignancies. EZH2 is the catalytic component of the Polycomb repressive complex 2 (PRC2) which is responsible for transcriptional repression by catalyzing di- and tri-methylation of Histone H3 lysine 27 (H3K27). EZH2 requires other members of the PRC2 complex for full methyltransferase activity, including SUZ12 and EED (PMID: 15225548, 15916951), and PRC2 function is important in repression of developmental regulators such as the HOX genes, and X-inactivation (PMID: 16618801, 12649488). Additionally, non-coding RNA's can guide EZH2 to genomic targets for gene repression (PMID: 17604720, 22659877). EZH2 overexpression is found in many malignancies including lymphoma, bladder cancer, melanoma, prostate cancer, lung cancer, and breast cancer, and is associated with advanced stage and poor prognosis (PMID: 11389032, 16361539, 12374981, 14500907, 16330673, 24097870). Furthermore, gain-of-function mutations in EZH2 occur frequently in follicular lymphoma and diffuse large B-cell lymphomas (PMID: 20081860, 21190999). EZH2 can also act as a tumor suppressor in certain cancer types, and recurrent inactivating mutations are observed in myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN) (PMID: 20601953). Given its importance in multiple cancer types, EZH2 inhibition has shown promise in pre-clinical studies and is a current effort in multiple clinical trials, either through direct inhibition of EZH2 enzymatic activity or through disruption in PRC2 stability (PMID: 26845405). True +ENST00000342995 NM_203407.3 340602 EZHIP True EZHIP, a polycomb binding protein, is recurrently altered by rearrangement and mutation in endometrial stromal sarcomas and posterior fossa ependymomas, respectively. EZHIP is a protein encoded from a single exon on the X chromosome (PMID: 23959973, 27699219). The function of EZHIP is not well-established, however, biochemical studies indicate that EZHIP interacts with Polycomb Repressive Complex 2 (PRC2) (PMID: 21248841). The PRC2 complex catalyzes the tri-methylation of histone H3 at lysine 27 (H3K27me3), a mark important for mediating repression of gene expression (PMID: 21248841). Loss of in neuronal cells results in reduced H3K27me3 and decreased cell growth (PMID: 29909548). In addition, EZHIP is most highly expressed in normal oocytes (PMID: 23959973) and may function as a cancer testis antigen (CTA) to mediate immune recognition in lung adenocarcinoma (PMID: 27699219). Recurrent chromosomal rearrangements involving EZHIP and MBTD1, a Polycomb protein with uncharacterized function, are found in patients with low grade endometrial stromal sarcomas (PMID: 23959973). Gain-of-function mutations are also found in posterior fossa ependymoma, resulting in increased H3K27me3 (PMID: 29275929). False +ENST00000389301 NM_000135.2 2175 FANCA False 1 FANCA is a tumor suppressor and DNA repair protein. Germline mutations of FANCA are associated with the cancer predisposition syndrome Fanconi Anemia. While FANCA is subject to wide variety of mutational types, it has been suggested that there is little prognostic value in the different types as evidenced by no clinical differences in the onset of hematologic disease in patients with a lack of FANCA expression and those which a mutated form of the protein (PMID: 21273304). Cells from Fanconi Anemia (FA) patients and the myeloid leukemia cell line (UoC-M1) show hypersensitivity to DNA cross-linking agents such as diepoxybutane (DEB) and mitomycin C (MMC) when grown and treated with these compounds; diagnostic testing using DEB forms the basis of a gold standard test for FA (PMID: 8374893, PMID: 12637330). True +ENST00000289081 NM_000136.2 2176 FANCC False FANCC, a tumor suppressor and DNA repair protein, is infrequently altered in cancer. Germline mutations of FANCC are associated with the cancer predisposition syndrome Fanconi Anemia. FANCC is a DNA repair protein that is a member of the Fanconi anemia (FA) complementation group (PMID: 21605559). The FA core complex, which includes FANCC and 7 other FA proteins, assemble at sites of damaged chromatin and coordinate the DNA repair response (PMID: 27145721). By scaffolding with BRCA1/2 proteins, the FA core complex facilitates homologous combination via repair of interstrand DNA crosslinks (PMID: 21605559, 16687415). The FA pathway is activated in response to cellular stress, which interrupts replication and transcription (PMID: 23114602). Monoubiquitination of FANCD2 by the core FA complex is required to mediate DNA repair (PMID: 17352736). FANCC directly interacts with transcriptional regulators, such as the co-repressor C-terminal binding protein 1 (Ctbp1) and β-catenin, to modulate gene expression and signaling (PMID: 23303816, 24469828). In addition, FANCC activity is important in several cellular functions including redox regulation, proliferation, genomic stability and apoptosis (PMID: 15327776). Germline mutations in FANCC are found in patients with FA, an inherited bone marrow failure syndrome associated with deficiencies in hematopoietic stem cells, developmental defects, and cancer predisposition (PMID: 24469828). Heterozygous loss-of-function mutations have been associated with hereditary breast and ovarian cancers (PMID: 23779253, 31467304). Furthermore, inactivating mutations in FANCC have been observed in leukemia, oral, breast, and pancreatic cancers, among others (PMID: 16998502, 27165003). FANCC loss and the resulting deficiency in HRR may confer sensitivity to DNA interstrand crosslinking agents (PMID: 20509860). True +ENST00000675286 NM_001018115.1 2177 FANCD2 False FANCD2, a tumor suppressor and DNA repair protein, is infrequently altered in cancer. Germline mutations of FANCD2 are associated with the cancer predisposition syndrome Fanconi Anemia. FANCD2 is a DNA repair protein that is a member of the Fanconi anemia complementation group (PMID: 27145721, 29376519). The Fanconi anemia proteins assemble at sites of damaged chromatin and coordinate the DNA repair response (PMID: 27145721). FANCD2 functions predominantly as a heterodimer in collaboration with FANCI; this complex recruits effector molecules to regions of damaged DNA (PMID: 27405460, 17412408). The FANCD2-FANCI heterodimer is activated via ubiquitination and phosphorylation by components of the Fanconi anemia core complex, including the kinases ATR, ATM, and CHK1 and the E3 ligases FANCL and FANCT (PMID: 29376519). Following DNA repair completion, monoubiquitination of FANCD2-FANCI is reversed by a deubiquitinase complex, resulting in the removal of FANCD2-FANCI from chromatin (PMID: 15694335). FANCD2 has been implicated in various cellular functions including maintenance of cell cycle progression, genomic stability, mitotic apparatus assembly and spindle integrity (PMID: 23934222, 29376519). Loss of FANCD2 expression in murine models results in hematopoietic defects and hypersensitivity to radiation (PMID: 20826722, 16135554). Germline FANCD2 mutations are found in individuals with Fanconi anemia, a condition associated with congenital defects, bone marrow failure, and increased risk of cancer (PMID: 23653579). FANCD2 alterations are found in childhood T-ALL and may be predictive of chemotherapy toxicity (PMID: 17096012, 22829014). FANCD2 overexpression is found in BRCA1- and BRCA2-deficient breast tumors, as well as metastatic melanoma, glioblastomas, and colorectal cancer (PMID: 17891185, 20339950, 27264184). True +ENST00000229769 NM_021922 2178 FANCE False FANCE, a DNA repair protein, is infrequently altered in cancer. FANCE, a member of the Fanconi anemia complementation group, encodes for a DNA repair protein that functions in the Fanconi anemia pathway (PMID: 12093742, 12239156). The Fanconi anemia pathway is a network of proteins and subcomplexes that collectively function in DNA repair and safeguard genomic stability through the activation of the Fanconi anemia core complex (PMID: 12515506). The Fanconi anemia core complex initiates DNA repair through monoubiquitination of FANCD2 and FANCI proteins, which results in DNA interstrand crosslink repair (PMID: 31666700, 32167469). The Fanconi anemia proteins assemble at sites of damaged chromatin to form the Fanconi anemia core complex (PMID: 27145721, 31666700, 24910428). FANCE interacts with FANCC to promote FANCD2 monoubiquitination, activating the subsequent downstream events of the Fanconi anemia pathway (PMID: 12239156). FANCE-null cells demonstrate chromosomal breakage and aberrations, suggesting that FANCE functions predominantly as a tumor suppressor gene (PMID: 24451376, 37779877). Inactivating mutations of FANCE have been identified in esophageal cancer and head and neck carcinoma (PMID: 21279724, 28678401). True +ENST00000327470 NM_022725 2188 FANCF False FANCF, a DNA repair protein, is altered by hypermethylation in cancer. FANCF, a member of the Fanconi anemia complementation group, encodes for a DNA repair protein that functions in the Fanconi anemia pathway (PMID: 15262960, 10615118). The Fanconi anemia pathway is a network of proteins and subcomplexes that collectively function in DNA repair and safeguard genomic stability through the activation of the Fanconi anemia core complex (PMID: 12515506). The Fanconi anemia core complex initiates DNA repair through monoubiquitination of FANCD2 and FANCI proteins, which results in DNA interstrand crosslink repair (PMID: 31666700, 32167469). The Fanconi anemia proteins assemble at sites of damaged chromatin to form the Fanconi anemia core complex (PMID: 27145721, 31666700, 24910428). FANCF functions as an adaptor protein in the assembly of the Fanconi anemia core complex and interacts with the FANCC/FANCE and FANCA/FANCG subcomplexes (PMID: 15262960, 36652992). Inactivation of FANCF in ovarian epithelial cancer cell lines and models induces chromosomal instability, suggesting that FANCF functions predominantly as a tumor suppressor gene (PMID: 12692539, 16418574). Hypermethylation of FANCF has been identified in ovarian cancer and breast cancer (PMID: 16418574, 18414472, 17932744, 34289901). True +ENST00000378643 NM_004629 2189 FANCG False FANCG, a DNA repair protein, is infrequently altered in cancer. Germline mutations of FANCG are associated with the cancer predisposition syndrome Fanconi anemia. FANCG, a member of the Fanconi anemia complementation group, encodes for a DNA repair protein that functions in the Fanconi anemia pathway (PMID: 12861027, 11050007). The Fanconi anemia pathway is a network of proteins and subcomplexes that collectively function in DNA repair and safeguard genomic stability through the activation of the Fanconi anemia core complex (PMID: 12515506). The Fanconi anemia core complex initiates DNA repair through monoubiquitination of FANCD2 and FANCI proteins, which results in DNA interstrand crosslink repair (PMID: 31666700, 32167469). The Fanconi anemia proteins assemble at sites of damaged chromatin to form the Fanconi anemia core complex (PMID: 27145721, 31666700, 24910428). FANCG functions as a scaffold to facilitate the formation of the Fanconi anemia core complex and the D1-D2-G-X3 with BRCA2, FANCD2 and XRCC3 (PMID: 18212739). Knockout of FANCG in human adenocarcinoma cell lines impairs DNA repair pathways and results in chromosome breakage, suggesting that FANCG functions predominantly as a tumor suppressor gene (PMID: 16762635). Germline FANCG mutations are found in individuals with Fanconi anemia, a condition associated with congenital defects, bone marrow failure, and increased risk of cancer (PMID: 23653579). True +ENST00000310775 NM_001113378.2 55215 FANCI False FANCI, a DNA repair protein in the Fanconi Anemia complementation group, is infrequently altered in various cancers. FANCI is a DNA repair protein that is a member of the Fanconi anemia complementation group (PMID: 34256011). FANCI forms a heterodimer with FANCD2, which recruits effector molecules to regions of damaged DNA (PMID: 17460694, 27405460, 17412408). The FANCD2-FANCI heterodimer is activated via ubiquitination and phosphorylation by components of the Fanconi anemia core complex, including the kinases ATR, ATM and CHK1, and the E3 ligases FANCL and FANCT (PMID: 29376519). Following DNA repair completion, monoubiquitination of FANCD2-FANCI is reversed by USP1-UAF1, resulting in the removal of FANCD2-FANCI from chromatin (PMID: 15694335). In the event that DNA repair is unsuccessful, FANCI initiates apoptosis via PIDD1, and thus a reduction in FANCI levels correlates with a reduction in apoptosis (PMID: 34256011, 27097374). FANCI also negatively regulates AKT in response to DNA damage (PMID: 27097374). The roles of FANCI in DNA repair and apoptosis suggest it likely functions as a tumor suppressor, however, there is a lack of experimental evidence to support this designation (PMID: 27097374). On the contrary, cancer cells exploit FANCI to survive the DNA damage caused by chemotherapy, which has been demonstrated in prostate and ovarian cancer cells (PMID: 38023254, 35362384). Additionally, FANCI knockout in mouse models results in hypersensitivity to DNA crosslinking agents, and in vitro knockdown experiments have suggested an oncogenic role for FANCI in cutaneous melanoma, non-small cell lung cancer, ovarian cancer and prostate cancer cells (PMID: 31219578, 38077326, 35703356, 35362384, 38023254). False +ENST00000233741 NM_018062.3 55120 FANCL False 1 FANCL, an E3 ubiquitin ligase involved in DNA repair, is infrequently altered in cancer. Germline mutations of FANCL are associated with the cancer predisposition syndrome Fanconi Anemia. FANCL is an E3 ubiquitin ligase belonging to the Fanconi Anemia (FA) group of proteins. These proteins coordinate homologous recombination repair (HRR) of DNA damage, specifically interstrand DNA crosslinks, by localizing to the site of damage using the BRCA1/2 proteins as a scaffold (PMID: 21605559). Essential for this DNA repair is monoubiquitinated, activated FANCD2 (PMID: 17352736). Monoubiquitination of FANCD2 relies on a nuclear complex of several FA proteins, including FANCL, FANCA, FANCB, FANCC, FANCE, FANCF, FANCG and FANCM; FANCL is the ubiquitin ligase required for FANCD2 monoubiquitination and its resulting HRR activity (PMID: 26149689, 31666700, 27986371, 20154706). Loss of FANCL in the germline can result in Fanconi Anemia, a cancer-predisposing syndrome characterized by hematological abnormalities, bone marrow failure, limb deformities, skin hyperpigmentation and susceptibility to hematologic and solid malignancies, such as acute myeloid leukemia (PMID: 24773018, 25754594). Hematological abnormalities in FA patients may be due in part to the role of FANCL in regulating β-catenin (PMID: 22653977). FANCL is mutated somatically in various cancers including head and neck carcinoma, among others (PMID: 28678401). FANCL loss and the resulting deficiency in HRR may confer sensitivity to PARP inhibitors, such as olaparib, which is FDA-approved for patients with HRR-deficient prostate cancer (PMID: 32343890). True +ENST00000267430 NM_020937 57697 FANCM False FANCM, a DNA repair protein, is infrequently altered in cancer. FANCM (FA complementation group M) encodes for a DNA translocase with DNA-dependent ATPase activity (PMID: 30714416, 20117061, 31663812). FANCM is involved in homologous recombination and repair of interstrand DNA cross-links (ICLs) (PMID: 30714416, 20117061). FANCM participates in the proper functioning of the Fanconi anemia pathway, which helps to suppress the formation of tumors (PMID: 31663812). FANCM also regulates the Bloom’s complex, a complex of proteins in which germline mutations can lead to the cancer predisposition disorder Bloom’s Syndrome (PMID: 31663812). Loss of function of the FANCM gene has not been associated with Fanconi anemia, but rather with infertility and cancer predisposition (PMID: 30714416). The gene is also essential for the viability of alternative lengthening of telomeres (ALT) cancers (PMID: 31663812). FANCM mutations have been identified in patients with breast and ovarian cancers (PMID: 30714416, 36707629). True +ENST00000652046 NM_000043.6 355 FAS False FAS, a death receptor that initiates apoptosis, is recurrently altered by mutation or downregulation in a diverse range of human cancers. FAS (also FAS1, CD95, APO-1) is a death receptor that mediates apoptosis (PMID: 20505730). FAS binds the cognate ligand CD95L, a protein predominantly expressed on T and NK cells, resulting in the death of the associated cell expressing the FAS receptor (PMID: 22042271). The FAS-CD95L interaction results in the formation of a death-inducing signaling complex that includes FADD, caspase 8, and caspase 10 (PMID: 12393594). Proteolytic processing of caspases then triggers a cascade that initiates apoptosis (PMID: 28445729, 28445729). FAS can also activate other downstream signaling cascades, including activation of the NF-KB and JNK pathways (PMID: 8647190). Loss of FAS expression in several murine models of cancer, including ovarian and liver, results in reduced apoptosis and enhanced tumor growth (PMID: 20505730). Germline mutations in FAS are associated with an autoimmune lymphoproliferative syndrome, a disorder associated with chronic lymphadenopathy and an increased risk of lymphoma development (PMID: 7540117, 11418480). Cell surface levels of FAS are frequently downregulated in cancer, allowing cells to evade programmed cell death (PMID: 15907590). Somatic FAS mutations are also found in a variety of tumor types including multiple myeloma, lymphomas, T cell leukemias, and several solid tumor types (PMID: 9373236, 9787134, 10190897, 11059754, 22042271). Mutations are frequently heterozygous and are predicted to be loss-of-function, allowing tumors to evade cell death via apoptosis (PMID: 22042271). True +ENST00000441802 NM_005245.3 2195 FAT1 False FAT1, a tumor suppressor and transmembrane protein, is inactivated by mutation or deletion in various cancer types. FAT1 is a transmembrane protein and member of the cadherin superfamily that is involved in planar cell polarity. FAT1 is involved in the promotion of actin-mediated cell migration as well as inhibition of YAP1-mediated cell proliferation. FAT1 is a potent suppressor of cancer cell growth, owing to its ability to bind β-catenin and abrogate its nuclear localization and transcription of its targets. Alterations in FAT1 decrease its interaction with β-catenin, thus promoting WNT signaling and tumorigenesis. Although most FAT1 alterations in cancer are loss-of-function events (cBioPortal, MSKCC, May 2015), studies suggest that it may be both tumor suppressive or oncogenic in a context-dependent manner (PMID: 8586420, 23076869,19439659, 16682528, 23354438). True +ENST00000403359 NM_001190274.1 80204 FBXO11 False FBXO11, a component of the SCF ubiquitin ligase complex, is recurrently altered by mutation in lymphomas. FBXO11 is an F-box protein that is a subunit of the ubiquitin ligase SCF complex (SKP1-cullin-F-box). FBXO11 is an essential component of the SCF complex which ubiquitinates substrate proteins and targets them for degradation via the proteasome (PMID: 22113614). FBXO11 directly binds SKP1 in the SCF complex and mediates substrate specific recognition (PMID: 16633365). BCL6 is a well-characterized target of SCF-mediated degradation and disruption of this complex results in BCL6 protein stabilization and transformation (PMID: 22113614). Loss of FBXO11 expression in murine models results in an expansion of germinal center B cells due to an overexpression of BCL6 (PMID: 27166359). FBXO11 also mediates the stability of other proteins, including SNAIL, a factor involved in the epithelial-to-mesenchymal transition (PMID: 25203322). Alterations in FBXO11 have been identified in patients with neurological disorders (PMID: 29796876, 30057029). Somatic FBXO11 deletions and loss-of-function mutations are found in diffuse large B cell lymphomas (DLBCL), leading to stabilization of the BCL6 oncogene (PMID: 22113614). True +ENST00000608872 NM_012164 26190 FBXW2 False FBXW2, the substrate binding unit of an E3 ubiquitin ligase complex, is infrequently altered in cancer. FBXW2 is the substrate binding unit of the E3 ubiquitin ligase complex known as SCF (Skp1-Cul1-F-box protein) (PMID: 30918250). FBXW2 is an F-box protein containing WD-40 repeats that is responsible for substrate recognition, substrate binding and substrate specificity for the SCF complex (PMID: 30918250). The binding of SCF to its target proteins results in ubiquitination and subsequent degradation of the target protein (PMID: 30918250). Thus, FBXW2 plays a pivotal role in post-translational protein regulation in the cell. FBXW2 is responsible for the ubiquitination and degradation of proto-oncogenic substrates such as CTNNB1 (PMID: 30918250, 31211237), SKP2 (PMID: 31211237, 28090088), NF-κB p65 (PMID: 34465889) and EGFR (PMID: 35499593), which are instrumental in oncogenic processes in cancers such as non-small cell lung cancer, breast cancer and prostate cancer (PMID: 30918250, 31211237, 28090088, 34465889, 35499593). However, FBXW2 also downregulates inhibitory proteins of the SOX2 transcription factor and therefore plays a role in promoting cell stemness (PMID: 31548378), suggesting FBXW2 may have both oncogenic and tumor-suppressive roles. False +ENST00000281708 NM_033632.3 55294 FBXW7 False 3A FBXW7, a tumor suppressor involved in protein degradation, is inactivated by mutation in various cancer types, most frequently in endometrial and colorectal cancers. The FBXW7 gene encodes an F-box protein subunit involved in substrate recognition by an SCF (Skp1-Cul1-F-box protein)-type ubiquitin ligase complex. Upon substrate identification, this complex modifies the substrate such that it is targeted for protein degradation. Substrates of FBXW7 include the proteins c-MYC, mTOR (PMID: 18787170), NOTCH1, cyclin-E, and JUN, which are instrumental in the regulation of cell division, differentiation and growth, and which are often inappropriately activated in cancer. As most FBXW7 substrates are proto-oncogenes that are processed for degradation by the SCF complex, FBXW7 functions as a tumor suppressor. Inactivation of FBXW7 by mutation or copy number loss results in aberrant accumulation of oncoproteins, which subsequently contributes to malignant transformation (PMID: 18094723, 27399335). Alternate splicing of FBXW7 results in three distinct protein isoforms (α, β, γ) each with differential localization (PMID: 22673505). Mutations in FBXW7 can negatively affect isoform-specific functions, dimerization of subunits, protein localization, SCF assembly or substrate recognition. Most mutations in FBXW7 are point mutations that disrupt substrate binding, while <10% are small deletions or insertions (PMID: 24853181, 17909001). True +ENST00000328850 NM_002005 2242 FES True FES, a cytoplasmic tyrosine kinase, is infrequently altered in cancer. FES encodes for a cytoplasmic tyrosine kinase that functions in the maintenance of cellular transformation (PMID: 15003822). FES is located downstream of cell surface receptors FCER1 and KIT, regulating functions such as cellular differentiation, cell attachment and mast cell signaling (PMID: 11509660, 8999909, 22589410). Mast cell development is controlled by FES through regulation of cross-talk between KIT and β1 integrins to promote cytoskeletal reorganization and cell motility (PMID: 19892014). Knockdown of FES in various cancer cell lines inhibits cell proliferation, migration and invasion, suggesting that FES functions primarily as an oncogene (PMID: 19082481, 28952025). FES overexpression has been identified in various cancer types, including acute myeloid leukemia and breast cancer (PMID: 1984516, 1159660). Inhibition of FES is suggested to induce radiosensitization in cancer (PMID: 31573955). False +ENST00000295727 NM_017521.2 54738 FEV False FEV, an ETS family transcription factor, is infrequently mutated by chromosomal rearrangement in Ewing's Sarcoma. FEV is a transcription factor belonging to the ETS protein family. In normal cells, FEV expression is restricted to a small number of tissues and is thought to act as a transcriptional repressor, as it lacks the N-terminal transcription activation domain found in other ETS family members (PMID: 9121764). However, FEV has also been shown to co-localize with serotonin-producing and cholinergic neurons and be involved in the transcriptional activation of genes in that context. Specific genes involved in neurotransmission, differentiation, and maintenance of neuronal cell types, such as the serotonin transporter and nicotinic acetylcholine receptor, among others, are activated through enhancers containing FEV binding motifs (PMID: 9468386, 10575032). Fusions of FEV with EWSR1, another ETS protein family member, are found as rare chromosomal rearrangements in Ewing Sarcoma (PMID:10976720, 23329308, 9121764). False +ENST00000337706 NM_000800 2246 FGF1 True FGF1, a fibroblast growth factor, is infrequently altered in cancer. FGF1, a member of the FGF family, encodes for a fibroblast growth factor which functions in regulating various cellular processes including proliferation and differentiation (PMID: 1697263, 3523756, 9505167). FGF1 activates cell signaling pathways to regulate cellular proliferation, differentiation and survival through interaction with FGFR1 and integrins (PMID: 18441324, 20422052). In the presence of heparin, FGF1 promotes FGFR1 dimerization and activation through autophosphorylation (PMID: 18411303, 19574212). Knockout of FGF1 in various cancer cell lines and models represses cellular proliferation, suggesting that FGF1 functions predominantly as an oncogene (PMID: 34552869, 36952626, 32615540, 22990650). Amplification of FGF1 has been identified in ovarian cancer and colorectal cancer (PMID: 17538174, 34552869). False +ENST00000264664 NM_004465 2255 FGF10 True FGF10, a fibroblast growth factor, is infrequently altered in cancer. FGF10, a member of the FGF family, encodes for a fibroblast growth factor which functions primarily in mesenchymal-epithelial signaling to promote organ development, tissue repair and cellular differentiation (PMID: 12455635, 11748146, 19498056). FGF10 signals in a paracrine manner through activating FGFR2 and FGFR1 (PMID: 24011590, 16597617). FGF10 expression in various cancer cell lines and models induces cellular proliferation, migration and invasion, suggesting that FGF10 functions predominantly as an oncogene (PMID: 18594526, 25057305). Amplification of FGF10 has been identified in various types of cancer, including gastric cancer, small cell lung cancer and pancreatic cancer (PMID: 26268776, 29748005, 26909576). Preclinical studies have demonstrated FGF10 sensitivity to N-myristoyltransferase inhibitors and inactivation of the FGF10-FGFR2 signaling axis in prostate cancer cell lines (PMID: 14724220, 29038344, 29444487). False +ENST00000376143 NM_004115 2259 FGF14 False FGF14, a fibroblast growth factor, is infrequently altered in cancer. FGF14, a member of the FGF family, encodes for a fibroblast growth factor which functions primarily in the central nervous system to regulate cellular processes, such as neurogenesis, synaptic transmission and plasticity (PMID: 12123606). FGF14 mutations and haploinsufficiency have been associated with increased risk of cognitive disorders, like schizophrenia, due to dysregulation of the central nervous system (PMID: 27163207, 36516086, 17236779). Overexpression of FGF14 in various cancer cell lines and models suppresses cellular proliferation and tumor growth, suggesting that FGF14 functions predominantly as a tumor suppressor gene (PMID: 32707902, 31949485). Downregulation of FGF14 has been identified in lung adenocarcinoma and colorectal cancer (PMID: 32707902, 31949485). True +ENST00000294312 NM_005117.2 9965 FGF19 True FGF19, a fibroblast growth factor, is altered by amplification in various cancer types. The human fibroblast growth factor (FGF) family comprises 22 structurally related polypeptides that play crucial roles in neuronal functions, development, and metabolism. FGFs are classified as intracrine, paracrine, and endocrine FGFs based on their action mechanisms (PMID: 25772309). FGF19 is an endocrine FGF which require α-Klotho or β-Klotho as a cofactor for FGFRs. FGF19 activates FGFR4 with β-Klotho and exhibits metabolic and proliferative activities (PMID: 20018895, 26483756). FGF19 acts as a biomarker for Renal failure, coronary artery disease, intestinal failure-associated liver disease, diabetes, Crohn’s disease, and prostate cancer (PMID: 20013647, 24179013, 23940810, 25595885, 25664662, 23981126, 25518063, 25360305, 25854696). False +ENST00000644866 NM_001361665.2 2247 FGF2 True FGF2, a fibroblast growth factor, is infrequently altered in cancer. FGF2, a member of the FGF family, encodes for a fibroblast growth factor which functions in regulating various cellular processes including differentiation, migration and survival (PMID: 28302677). FGF2 is a pleiotropic ligand that can signal through all FGFRs, activating various downstream pathways such as MAPK/ERK and PI3K/AKT signaling (PMID: 18318041). FGF2 additionally functions as an integrin ligand to promote angiogenesis and stem cell proliferation (PMID: 28302677). FGF2 exists as several isoforms that are generated via alternative translational initiation and differ in subcellular localization and signaling activity (PMID: 16615083). Overexpression of FGF2 in various cancer cell lines and models induces cellular proliferation and invasion, suggesting that FGF2 functions predominantly as an oncogene (PMID: 12898525, 10411093, 27473203, 28515962). FGF2 amplification has been identified in various cancers, including colorectal cancer, pancreatic cancer and prostate cancer (PMID: 27007053, 14522896). False +ENST00000237837 NM_020638 8074 FGF23 True FGF23, a fibroblast growth factor, is infrequently altered in cancer. FGF23, a member of the FGF family, encodes for a fibroblast growth factor primarily secreted by osteocytes and osteoblasts which functions in various cellular processes, including regulation of phosphate homeostasis and vitamin D metabolism (PMID: 15040831, 11062477). FGF23 interacts with αKlotho and FGFR1c to form the FGFR-Klotho complex to modulate phosphate transport and has been implicated in the pathophysiology of phosphate concentration disorders, such as chronic kidney disease (PMID: 32124925, 25326585, 19515808). Overexpression and exogenous expression of FGF23 in various cancer cell lines and models induces metastatic lesions and increased cellular proliferation, migration and invasion, suggesting that FGF23 functions predominantly as an oncogene (PMID: 36604721, 26019137, 28968431). Amplification of FGF23 has been identified in various types of cancer, including breast cancer, colorectal cancer and multiple myeloma (PMID: 31275898, 24574808, 25944690). False +ENST00000334134 NM_005247.2 2248 FGF3 True FGF3, a fibroblast growth factor, is altered by amplification in various cancer types. The human fibroblast growth factor (FGF) family comprises 22 structurally related polypeptides that play crucial roles in neuronal functions, development, and metabolism. FGFs are classified as intracrine, paracrine, and endocrine FGFs based on their action mechanisms (PMID: 25772309). FGF3 belongs to the FGF7 subfamily which includes FGF3, FGF7, FGF10 and FGF22 (PMID: 26369258). For inner ear, FGF3 has fallen into and out of favor as a potential ear-specific inducer. Excess FGF3 can induce the formation of extra otic vesicles (ear rings), whereas insufficient FGF3 can block their formation in chick (PMID: 10906788, 10769226). FGF3 has been identified as a main target of mouse mammary tumor virus (MMTV) insertional activation in mouse mammary tumors (PMID: 6327073). FGF3 specifically cooperate with WNT1 to induce the development of mouse mammary tumors (PMID: 9205106). Endogenous expression of FGF3 in MCF7 cells increases the tumorigenic potential (PMID: 10845805). False +ENST00000168712 NM_002007.2 2249 FGF4 True FGF4, an oncogenic growth factor, is amplified in a diverse range of cancers, most frequently in breast and head and neck cancers. FGF4 belongs to the human fibroblast growth factor family which was originally identified in NIH3T3 transfection assays using human stomach cancer or Kaposi sarcoma derived genomic DNA (PMID: 9715278). In adult and malignant tissues, FGF4 expression is tightly regulated. FGF4 expression is restricted to undifferentiated human embryonal carcinomas (ECs). During induced differentiation, FGF4 expression is repressed (PMID: 9715278). FGF4 gene amplification has been observed in numerous human carcinomas such as breast carcinomas, squamous cell carcinomas of the head and neck and the oesophagus, epithelial ovarian tumors and bladder cancers (PMID: 10368635, 9816285, 9380415, 1532244, 1361954). FGF4 plays a key role in the growth or maturation states of germ cell tumors which is supported by the finding FGF4 expression occurs in a subset of clinical germ cell tumors, especially in those presenting with advanced state (PMID: 1706218). False +ENST00000312465 NM_004464 2250 FGF5 True FGF5, a fibroblast growth factor, is infrequently altered in cancer. FGF5, a member of the FGF family, encodes for a fibroblastic growth factor which functions in regulating various cellular processes including proliferation, differentiation, migration and survival (PMID: 32848626, 27224250). FGF5 binds to receptors FGFR1 and FGFR2 to induce autophosphorylation and activate downstream signaling cascades (PMID: 8386828). FGF5 is an essential regulator of hair growth and has been implicated in early- to mid-stage pattern hair loss (PMID: 24989505, 28280377). Overexpression of FGF5 in various cancer cell lines and models induces cellular proliferation, tumor growth, decreased apoptosis and increased angiogenesis, suggesting that FGF5 functions predominantly as an oncogene (PMID: 31372048, 29152117, 29743851, 25998163). FGF5 amplification has been identified in various cancers, including renal cell cancer, prostate cancer and breast cancer (PMID: 11454700). False +ENST00000228837 NM_020996 2251 FGF6 True FGF6, a fibroblast growth factor, is infrequently altered in cancer. FGF6, a member of the FGF family, encodes for a fibroblast growth factor which functions in regulating various cellular processes including proliferation and differentiation (PMID: 15672378, 11991742, 36607240). FGF6 has been identified in skeletal muscle tissue to support tissue regeneration and promote myoblast migration and proliferation through interaction with FGFR4 (PMID: 9186055, 12769260). Exogenous expression of FGF6 in various types of cancer cell lines and models induces cellular proliferation and transformation, suggesting that FGF6 functions predominantly as an oncogene (PMID: 1549352, 10945637). FGF6 amplification has been identified in various types of cancer, including prostate cancer and head and neck squamous cell carcinoma (PMID: 25950492, 31123723). False +ENST00000267843 NM_002009 2252 FGF7 True FGF7, a fibroblast growth factor, is infrequently altered in cancer. FGF7, a member of the FGF family, encodes for a fibroblast growth factor that functions in regulating various cellular processes including embryogenesis, tissue repair and cellular growth (PMID: 15690149, 35806092, 8331296). FGF7 was identified as a keratinocyte growth factor due to prominent mitogenic activity in keratinocytes rather than fibroblasts and endothelial cells (PMID: 2915979). FGF7 functions as a ligand for FGFR2 to promote dimerization and activate various signaling pathways such as MAPK/ERK and PI3K/AKT signaling (PMID: 2475908, 24002438). Exogenous expression of FGF7 in gastric cancer cell lines and models induces cellular invasion and migration, suggesting that FGF7 functions predominantly as an oncogene (PMID: 28339036). FGF7 overexpression has been identified in urothelial carcinoma, ovarian cancer and fusion-positive rhabdomyosarcoma (PMID: 25623741, 38491511, 34850536). False +ENST00000344255 NM_033164 2253 FGF8 True FGF8, a fibroblast growth factor, is infrequently altered in cancer. FGF8, a member of the FGF family, encodes for a fibroblast growth factor that functions in regulating various cellular processes including cell division, growth and maturation (PMID: 16049112, 12574514). FGF8 functions as a ligand for FGFR1 to promote neuron formation, survival and migration during brain development (PMID: 35833364, 26634071). During embryogenesis, FGF8 has been identified as a key regulator for controlling the growth and differentiation of progenitor cells and directing limb outgrowth and patterning (PMID: 36205075, 37922914, 11101845). Overexpression of FGF8 in various cancer cell lines and models induces cell proliferation, invasion and migration, suggesting that FGF8 functions predominantly as an oncogene (PMID: 25473897, 18386787, 33649301). Overexpression of FGF8 has been identified in breast cancer, ovarian cancer and prostate cancer (PMID: 11953856, 37762545, 10348350). False +ENST00000382353 NM_002010 2254 FGF9 True FGF9, a fibroblast growth factor, is altered by amplification in colorectal cancer. FGF9, a member of the FGF family, encodes for a fibroblast growth factor that functions in regulating various cellular processes including cell division, growth and maturation (PMID: 8663044, 33529250, 35753346). FGF9 has been identified as a key regulator during embryogenesis for lung and skeletal development (PMID: 21750028, 12919696). FGF9 forms a positive feedback loop with SOX9 to promote prostate formation and regulate mammalian sex determination (PMID: 16700629). Overexpression of FGF9 in various cancer cell lines and models induces cell proliferation, migration and invasion, suggesting that FGF9 functions predominantly as an oncogene (PMID: 24334956, 34438248, 25925261). Amplification of FGF9 has been identified in colorectal cancer, and is suggested to mediate anti-EGFR therapy resistance (PMID: 26916220, 32104224, 24334956). False +ENST00000425967 NM_001174067.1 2260 FGFR1 True 1 FGFR1, a receptor tyrosine kinase, is altered by mutation, chromosomal rearrangement or amplification in various cancer types including lung and breast cancers. FGFR1 is a receptor tyrosine kinase that is a member of the fibroblast growth factor receptor (FGFR) family. Binding of FGF ligands to FGFR1 results in the rapid dimerization and activation of downstream signaling pathways including the PI3K/AKT and MAPK pathways (PMID: 16597617). FGFR1 is widely expressed and is necessary for a variety of cellular functions such as embryonic development, skeletogenesis, mitogenesis and differentiation. Cell-type specific FGFR1 regulation is dependent on tissue distribution and ligand availability (PMID: 16597617). Germline mutations in FGFR1 are associated with congenic disorders that present with physical malformations, mental retardation and neurologic deficits (PMID: 23812909). Amplifying or activating mutations in FGFR1 occur in varying frequency in multiple cancers including those of the lung, breast, prostate, head and neck and esophagus (PMID: 21160078, 20179196, 14614009, 16807070, 12147242). In metastatic renal cell carcinoma, FGF signaling mediates acquired treatment resistance from VEGF-directed therapies (PMID: 24387233). Currently, a number of small molecule inhibitors of the FGFR proteins are in use, with the major difference among them being their specificity to FGFR versus other receptor tyrosine kinases (RTKs) (PMID: PMID: 23696246, 24265351). False +ENST00000358487 NM_000141.4 2263 FGFR2 True 1 FGFR2, a receptor tyrosine kinase, is altered by mutation, chromosomal rearrangement or amplification in various cancer types. FGFR2 is a receptor tyrosine kinase that is a member of the fibroblast growth factor receptor (FGFR) family. Binding of FGF ligands to FGFR2 results in the rapid dimerization and activation of downstream signaling pathways including the PI3K/AKT and MAPK pathways (PMID: 28030802). FGFR2 is expressed in ectoderm-derived and endothelial tissues and FGFR2 signaling contributes to a variety of cellular functions including homeostasis, mitogenesis, proliferation and differentiation (PMID: 20094046). Germline mutations in FGFR2 have been identified in syndromes of craniosynostosis, which are characterized by abnormal bone development (PMID: 29392564). Single nucleotide polymorphisms in FGFR2 are linked to the development of ER-positive breast cancer, although the etiology remains unclear (PMID: 18437204). Somatic mutations, fusions and amplifications of FGFR2 have been identified in several human tumors including endometrial, gastric, and breast cancer as well as ameloblastomas (PMID: 18552176, 18636142, 28430863). Currently, a number of small molecule inhibitors of the FGFR proteins are in use, with the major difference among them being their specificity to FGFR versus other receptor tyrosine kinases (RTKs) (PMID: 23696246, 24265351). False +ENST00000440486 NM_000142.4 2261 FGFR3 True 1 FGFR3, a receptor tyrosine kinase, is altered by mutation, chromosomal rearrangement or amplification in various cancers, most frequently in bladder cancer. FGFR3 is a receptor tyrosine kinase that is a member of the fibroblast growth factor receptor (FGFR) family. Binding of FGF ligands to FGFR3 results in the rapid dimerization and activation of downstream signaling pathways including the PI3K/AKT and MAPK pathways (PMID: 28030802). FGFR3 is most highly expressed in neuronal and sensory cell types and FGFR3 signaling contributes to a variety of cellular functions including proliferation, differentiation, cell migration and apoptosis (PMID: 7542215, 20094046). Alternative splicing events in the FGFR3 gene generate two isoforms, FGFR3b and FGFR3c, which have unique tissue expression patterns and ligand-binding specificity (PMID: 8663044, 7512569). Germline mutations in FGFR3 have been identified in syndromes of craniosynostosis, which are characterized by abnormal bone development, in addition to skin and hair follicle disorders (PMID: 10541159, 17568799). Somatic activating mutations in FGFR3 have been identified in up to 70% of bladder cancers and in a low percentage of other solid tumor types (PMID: 11395371, 12743143, 16338952). In addition, a specific FGFR3 translocation is observed in approximately 15% of patients with multiple myeloma, resulting in constitutive expression of FGFR3 (PMID: 17107900). Currently, a number of small molecule inhibitors of the FGFR proteins are in use, with the major difference among them being their specificity to FGFR versus other receptor tyrosine kinases (RTKs) (PMID: PMID: 23696246, 24265351). False +ENST00000292408 NM_213647.1 2264 FGFR4 True FGFR4, a receptor tyrosine kinase, is altered by mutation, chromosomal rearrangement or amplification at low frequencies in various cancer types. FGFR4 is a receptor tyrosine kinase that is a member of the fibroblast growth factor receptor (FGFR) family. Binding of FGF ligands to FGFR4 results in the rapid dimerization and activation of downstream signaling pathways including the PI3K/AKT and MAPK pathways (PMID: 28030802, 10918587). FGFR4 is most highly expressed in liver and lung tissues and FGFR4 signaling contributes to a variety of cellular functions including proliferation, differentiation, and migration (PMID: 10918587). Germline mutations in FGFR4 have been identified in syndromes of craniosynostosis, which are characterized by abnormal bone development (PMID: 21395503). Somatic amplifications and activating mutations are found in rhabdomyosarcomas (PMID: 19809159) and rarely in other solid tumor types. In addition, overexpression of FGFR4 is associated with prostate, colon and liver cancer progression (PMID: 15655558, 23696849, 26498355). Currently, a number of small molecule inhibitors of the FGFR proteins are in use, with the major difference among them being their specificity to FGFR versus other receptor tyrosine kinases (RTKs) (PMID: PMID: 23696246, 24265351). False +ENST00000366560 NM_000143.3 2271 FH False FH is a tumor suppressor and an enzyme that converts fumurate to malate. Germline mutations of FH are associated with hereditary leiomyomatosis and renal cell cancer. FH (fumarate hydratase, also known as fumarase) is an enzyme that converts fumarate to malate as part of the tricarboxylic acid (TCA) cycle. FH exists in a mitochondrial and a cytosolic form, the former of which carries out FH's canonical role in the TCA cycle and the latter of which is likely involved in amino acid metabolism (PMID: 23643539, 14708972). The mitochondrial form of FH is determined by a C-terminal signal sequence (PMID: 18577574). Heterozygous germline mutations of FH cause hereditary leiomyomatosis and renal cell cancer (HLRCC), an autosomal dominant syndrome characterized by multiple cutaneous piloleiomyomas, uterine leiomyomas and papillary type 2 renal cancer (PMID: 20618355, 11865300, 15937070, 12772087, 16155190). Individuals with this disease are at risk for developing cutaneous and uterine leiomyomas, a form kidney cancer (PMID: 19470762). In HLRCC, tumor formation occurs following the inactivation of the wildtype allele, and therefore FH is classified as a tumor suppressor (PMID: 16155190, 20618355). Somatic FH mutations are sporadically found in other cancer types. The mechanism underlying FH-deficient disease is attributed to reduced or ablated FH enzymatic activity (PMID: 12761039, 14708972). True +ENST00000492590 NM_002012 2272 FHIT False FHIT, a nucleoside triphosphatase, is infrequently altered in cancer. FHIT (Fragile Histidine Triad Diadenosine Triphosphatase) is a member of the histidine triad (HIT) nucleotide-binding superfamily and encodes for the protein P1-P3-bis(5'-adenosyl) triphosphate hydrolase involved in purine metabolism (PMID: 11562178, 19086848, 24370550). FHIT may also play a role in regulating the production of reactive oxygen species and genomic damage as it interacts with and stabilizes the mitochondrial flavoprotein ferredoxin reductase (FDXR) (PMID: 19086848). This gene is located on the FRA3B site of chromosome 3, where carcinogen-induced damage can cause gene loss leading to alterations in the DNA damage response and genomic instability (PMID: 11562178, 19086848, 24370550). The most common alterations in FHIT are deletions, DNA hypermethylation, abnormal transcripts, and reduced expression (PMID: 11562178, 24370550), and loss of FHIT has been documented in various cancers including lung, esophageal, cervical, and breast cancers (PMID: 19086848, 11562178, 30941950, 9823304). FHIT plays a role in cell proliferation and apoptosis as overexpression of FHIT in osteosarcoma cells results in inhibition of proliferation and increased apoptosis (PMID: 30655842). True +ENST00000285071 NM_144997.5 201163 FLCN False FLCN is a tumor suppressor and GTPase activating protein. Germline mutations of FLCN are associated with Birt-Hogg-Dubé syndrome and predispose to renal cell carcinomas. FLCN is a GTPase activating protein (GAP) for RagC/D GTPase proteins involved in amino acid sensing and signaling to mTORC1 (PMID:24095279). Varying cellular processes have been implicated with its function including regulation of oxidative metabolism at the mitochondria, mitochondrial biogenesis, and autophagy (PMID:23150719, 24762438, 25126726). Mutations can activate the mTOR pathway and AKT signaling (PMID:19850877, 24908670). FLCN mutations are found in Birt-Hogg-Dubé syndrome which is characterized by fibrofolliculomas, pneumothorax, and renal cell carcinomas (PMID: 22146830,15956655). Mutations have also been identified in gastric cancer (PMID:16870330). True +ENST00000527786 NM_002017.4 2313 FLI1 True 4 FLI1, a transcription factor of the ETS protein family, is frequently altered by chromosomal rearrangement in Ewing's Sarcoma. FLI1, an ETS family transcription factor, is expressed primarily in hematopoietic cells, where it regulates the expression of genes involved in lineage commitment and development (PMID: 11715049, 10891501). Specifically, FLI1 modulates the response of erythroid cells to erythropoietin (Epo), a major cytokine and regulator of erythropoiesis. FLI1 inhibits Epo-induced differentiation of primary erythroblasts by binding and transcriptionally repressing the retinoblastoma gene (Rb), previously shown to be required for the development of mature erythrocytes from progenitor cells, and instead promotes proliferation of these cells (PMID: 10330185, 24320889). FLI1 is most commonly altered in Ewing sarcoma, where the EWSR1-FLI1 gene fusion is the most common chromosomal alteration leading to aberrant FLI1 expression, transcriptional activity and cell transformation in this tumor type (PMID: 8246959, 7517940, 25453903, 10197607). False +ENST00000282397 NM_002019.4 2321 FLT1 True FLT1, a receptor tyrosine kinase involved in cell survival and tumor angiogenesis, is infrequently altered in cancer. FLT1 (also VEGFRA) is a cell surface receptor that is a member of the vascular endothelial growth factor (VEGF) pathway. Binding of the VEGF ligand, VEGFA, to FLT1 activates pathway signaling, which in turn regulates angiogenesis, cell survival, migration and invasion (PMID: 20127948). In addition, the VEGFA-FLT1 complex has been shown to activate mitogen-activated protein kinase (MAPK) and PI3K/AKT signaling, and thus aberrant activation promotes tumor survival (PMID: 16116481, 20127948). FLT1 has also been shown to rescue tumor cells from hypoxia-induced stress (PMID: 16103078) and to regulate inflammatory response genes in macrophages associated with metastases (PMID: 26261265). Somatic mutations in FLT1 have been identified in a variety of tumor types, however, the impact of these alterations are not well-studied (PMID: 19718025, CBioPortal, MSKCC, March 2018). FLT1 overexpression and activation have been associated with increased transformation and invasion in colorectal, pancreatic, and breast cancer models (PMID: 14521839, 16397214, 16671089). A monoclonal antibody targeting FLT1, icrucumab, is currently being tested in clinical trials (PMID: 23903897). False +ENST00000241453 NM_004119.2 2322 FLT3 True 1 FLT3, a receptor tyrosine kinase, is recurrently altered in acute myeloid leukemia and other hematologic malignancies. FLT3 is a transmembrane receptor tyrosine kinase that predominantly functions in the regulation of hematopoiesis (PMID: 12032772). FLT3 is activated following dimerization and autophosphorylation upon binding to its ligand, FLT3L. Activation of FLT3 results in downstream signaling via several pathways including the MAPK, PI3K/AKT and STAT3/5 pathways, which have key roles in hematopoietic proliferation, differentiation and survival (PMID: 23631653, 12951584). Wildtype FLT3 is important for the growth and differentiation of hematopoietic stem cells and is commonly expressed on immature myeloid and lymphoid cells (PMID: 12951584). FLT3 alterations occur in acute myeloid leukemia (AML), most commonly presenting as FLT3 internal tandem duplications (FLT3-ITD) in about 25% of AMLs or point mutations in the tyrosine kinase domain in about 7% of AMLs (PMID: 24319184). FLT3-ITD expression in murine models is not sufficient to cause leukemogenesis, however, additional oncogenic alterations cooperate with overactivation of FLT3 to cause malignancy (PMID: 25873173). FLT3 small molecule kinase inhibitors have been developed and are currently being tested in clinical trials, both alone and in combination with other epigenetic inhibitors (PMID: 24682858, 28193779). False +ENST00000261937 NM_182925.4 2324 FLT4 True FLT4, a receptor tyrosine kinase, is infrequently altered by mutation in a variety of cancer types. FLT4 (also VEGFR3) is a cell surface receptor that is a member of the vascular endothelial growth factor (VEGF) pathway. Binding of the VEGF ligands, VEGF-C or VEGF-D, to FLT4 activates pathway signaling, which in turn mediates cell proliferation, survival, invasion, and resistance to chemotherapy in leukemia (PMID: 11877295, 16530705). In addition, FLT4 is a critical regulator of lymphangiogenesis and is necessary for the maintenance of the lymphatic endothelium (PMID: 10762646). Germline mutations in FLT4 have been identified in hereditary Nonne-Milroy disease, an autosomal dominant form of primary lymphedema type IA (PMID: 11292664). Aberrant FLT4 expression has been observed in several tumor types including lung adenocarcinoma (PMID: 12875690) and colorectal adenocarcinoma (PMID: 12168824), among others, and has been shown to be hypermethylated in clear cell renal cell carcinomas (PMID: 28754676). However, somatic mutations in FLT4 are not common in human cancers. False +ENST00000256999 NM_004476 2346 FOLH1 True FOLH1, a glutamate carboxypeptidase, is infrequently altered in cancer. FOLH1, also known as PSMA, encodes for a type II transmembrane glycoprotein that is part of the M28 peptidase family (PMID: 29025989). FOLH1 functions as a glutamate carboxypeptidase and catalyzes hydrolytic cleavage of glutamates from peptides and small molecules (PMID: 15837926). The enzymatic activity of FOLH1 has been utilized for the design of FOLH1-selective substrate drugs, such as methotrexate, in which the inactive glutamate form of the drug is cleaved and activated only in tissue expressing FOLH1 (PMID: 15837926, 33499427, 33782486). Overexpression of FOLH1 in various cancer cell lines induces cell proliferation and invasion, suggesting that FOLH1 functions predominantly as an oncogene (PMID: 33748101, 24571890). FOLH1 amplification has been identified in various cancers, including prostate cancer, hepatocellular carcinoma and colorectal cancer (PMID: 10397265, 31289613, 19716160). False +ENST00000312293 NM_000802 2348 FOLR1 True FOLR1, a folate transport protein, is altered by amplification in various cancer types. FOLR1, also known as folate receptor α (FRα), is a folate transport protein anchored in the cell membrane that is crucial for one-carbon folate metabolism, a process that provides precursor molecules for nucleic acid synthesis, methylation and DNA repair (PMID: 27641100, 23822983, 27248175). In addition to its role in one-carbon folate metabolism, FOLR1 also interacts with the JAK–STAT3 and ERK1/2 pathways as a signaling molecule (PMID: 35094917). FOLR1 is normally expressed in low levels in select types of epithelial cells (PMID: 25564455). Overexpression of FOLR1 increases folate uptake from the extracellular environment, which in turn provides a growth advantage to cells that facilitates rapid proliferation (PMID: 36426547, 25816016). However, even when FOLR1 is overexpressed, extracellular folate is primarily imported by another type of folate transport system called the reduced folate carrier, indicating that FOLR1 overexpression doesn’t significantly raise intracellular folate levels (PMID: 37711615). Therefore, FOLR1 overexpression may drive tumor growth by other mechanisms, such as activation of the JAK–STAT3 and ERK1/2 pathways (PMID: 35094917, 28782518). FOLR1 overexpression is associated with a less favorable prognosis in patients with rectal cancer and cervical cancer, suggesting it may play a role as an oncogene (PMID: 36426547, 36245230). FOLR1 is overexpressed in various cancers including ovarian, uterine, brain, breast, endometrial, and lung cancers (PMID: 36426547, 36245230, 15745749). Mirvetuximab soravtansine-gynx, an antibody-drug conjugate targeting FOLR1, is FDA-approved for the treatment of FRα-positive, platinum-resistant epithelial ovarian, fallopian tube or primary peritoneal adult cancer patients treated with up to three prior therapies (PMID: 37711615, 38055253). False +ENST00000250448 NM_004496.3 3169 FOXA1 True FOXA1, a transcription factor, is recurrently altered in prostate and breast cancers. FOXA1 is a member of the Forkhead domain containing (FKHD) family of transcription factors (PMID: 19274050). FOXA1 binds to genomic DNA via the N-terminus of the protein and interacts with histone molecules via the C-terminal transactivating domain. Binding of FOXA1 to core histones H3/H4 facilitates the “pioneering activity” of FOXA1 by opening regions of condensed chromatin (PMID: 16909212); this allows for the recruitment of other transcription factors, including the androgen receptor (AR) and estrogen receptor (ER) (PMID: 21934649). FOXA1 is normally expressed in a number of tissue types, including lung, liver, pancreas, colon, bladder, prostate and breast (PMID: 22115363). Expression of FOXA1 is required for normal prostate development and maturation, prostate specific gene expression and cellular differentiation through its direct interaction with AR and modulation of AR signaling (PMID: 15987773, 21934649, 22649425, 18358809). Luminal-specific deletion of FOXA1 in the mouse prostate results in high rates of epithelial cell proliferation and increased expression of basal cell markers (PMID: 24840332), indicating that FOXA1 may play a role in promoting and maintaining epithelial cell differentiation. FOXA1 is also required for normal mammary ductal morphogenesis and expression of ERα (PMID: 20501593). FOXA1 has emerged as one of the most frequent recurrently mutated genes in hormone-dependent cancers including primary and metastatic castration-resistant prostate cancer (CRPC) and breast cancer (PMID: 25470049, 23000897,22495314). FOXA1 is also frequently mutated in urothelial bladder carcinoma and amplified in a number of other tumor types (PMID: 24476821). Somatic FOXA1 mutations predominantly map to the DNA-binding domain, suggesting that they function as loss-of-function alterations (PMID: 25470049, 23000897, 22495314). True +ENST00000262426 NM_001451.2 2294 FOXF1 True FOXF1, a transcription factor, is infrequently altered by mutation in various cancer types. FOXF1 is a transcription factor that is a member of the forkhead protein family (PMID: 29162563). FOXF1 functions as a master regulator of gene expression and cellular identity in several tissues, including in the developing lung (PMID: 28797033, 28878348, 30153454, 26293303). In addition, FOXF1 has been implicated in a variety of cellular activities including ciliogenesis, cellular proliferation, extracellular matrix remodeling, and metastasis (PMID: 30950350, 28623323). Sporadic and familial mutations in FOXF1 have been implicated in alveolar capillary dysplasia with misaligned pulmonary veins (ACDMPV), a congenital disease that results in respiratory failure (PMID: 31199666, 31074124, 30380203,27071622, 23505205). These FOXF1 alterations are loss-of-function and lead to loss of STAT3-FOXF1 protein interactions and reduced chromatin binding (PMID: 31199666). FOXF1 activity has been found to be both increased and decreased in a variety of cancers, suggesting that FOXF1 may function as a tumor suppressor or oncogene depending on the cellular context (PMID: 27165781, 30253191, 30189360, 28623323, 27042124). In Gastrointestinal stromal tumors (GIST), FOXF1 regulates the expression of two genes, KIT and ETV1, by recruiting them to relevant target genes (PMID: 29162563). Loss of FOXF1 results in reduced GIST cellular proliferation and loss of KIT and ETV1 targeting to enhancers in GIST cells (PMID: 29162563). True +ENST00000648323 NM_023067.3 668 FOXL2 True FOXL2, a transcription factor, is recurrently mutated in adult granulosa cell tumors. FOXL2 is a member of the Forkhead domain containing (FKHD) family of transcription factors (PMID: 15492844). FOXL2 contains a DNA binding domain allowing the protein to bind DNA and subsequently regulate gene expression and mediate the recruitment of other transcription factors (PMID: 15492844). Expression of FOXL2 is the highest in ovarian granulosa cells and is essential for granulosa cell differentiation and ovarian development; FOXL2 is also expressed in the pituitary gland and periocular region (PMID: 24817949). Through interaction with other transcription factors and tumor suppressors, FOXL2 regulates several cell processes, including apoptosis, cell cycle progression and cell adhesion (PMID: 19747961). In addition, FOXL2 has a role in the suppression of SOX9 expression during testes formation (PMID: 28193729). As a potential tumor suppressor, FOXL2 has been shown to inhibit cervical squamous cancer cell proliferation and invasion, while promoting apoptosis (PMID: 24817949). Reduced expression of FOXL2 has also been noted in a majority of juvenile ovarian granulosa cell tumors and somatic FOXL2 alterations have been associated with adult granulosa cell tumors. (PMID: 23372819, 23029457, 24342437). True +ENST00000299162 NM_213596 121643 FOXN4 True FOXN4, a transcription factor, is recurrently altered by amplification in lung adenocarcinoma. FOXN4, a member of the forkhead box family of transcription factors, encodes for a transcription factor that functions in regulating neural and non-neural tissue development by upregulating angiogenic growth factor expression (PMID: 15464224, 21438071, 15363391). FOXN4 modulates NOTCH signaling through interaction with transcription factor ASCL1 to mediate BMP/TGFβ signaling (PMID: 24257627). FOXN4 is considered a candidate prognostic biomarker for lung adenocarcinoma (PMID: 33447073). Overexpression of FOXN4 in lung adenocarcinoma cell lines induces downregulation of EGFR expression, a commonly observed phenotype in transformed small-cell lung cancer (PMID: 34155000). FOXN4 upregulation has been observed in lung adenocarcinoma cell lines following treatment with osimertinib (PMID: 34155000). False +ENST00000379561 NM_002015.3 2308 FOXO1 False FOXO1, a transcription factor, is recurrently altered by mutation in hematologic malignancies and by deletion in prostate cancer. FOXO1 is a member of the Forkhead box O (FoxO) transcription factor superfamily. FOXO transcription factors can regulate cell fate by modulating the expression of genes involved in a variety of cellular processes including: apoptosis, cell cycle, DNA repair, oxidative stress and longevity, and control of muscle growth, as well as cell differentiation and glucose metabolism (PMID: 15137936, 15860415, 16288288, 17646672). FOXO1 plays an important role in the regulation of adipogenesis and differentiation of preadipocytes by binding to the promoter of PPARG, a key mediator of adipogenesis initiation (PMID: 12530968). In addition, FOXO1 is critical for regulating gluconeogenesis via insulin signaling (PMID: 10702299) and for maintaining pluripotency in human embryonic stem cells (PMID: 24116102). FOXO1 activity is repressed after phosphorylation by AKT, leading to exclusion of FOXO1 from the nucleus and, in some contexts, apoptosis (PMID: 17646672). CDK2-mediated phosphorylation of FOXO1 is also important for the regulation of cell cycle progression (PMID:17038621). Chromosomal FOXO1 translocations have been identified in alveolar rhabdomyosarcoma, a skeletal-muscle tumor that is prevalent in children (PMID: 17646672, 8275086). Loss-of-function FOXO1 mutations have been identified in diffuse large B cell lymphomas (DLBCLs) and FOXO1 is frequently inactivated in prostate cancers (PMID: 28986382). True +ENST00000343882 NM_001455 2309 FOXO3 False FOXO3, a transcription factor, is infrequently altered in cancer. FOXO3, a member of the class ‘O’ subfamily of the forkhead family of proteins, encodes for a DNA-binding transcriptional activator that functions in regulating cellular processes such as autophagy and apoptosis (PMID: 10102273, 16751106). FOXO transcription factors can regulate cell fate by modulating the expression of genes involved in a variety of cellular processes including apoptosis, cell cycle progression, DNA repair, oxidative stress and longevity, and control of muscle growth, as well as cell differentiation and glucose metabolism (PMID: 15137936, 15860415, 16288288, 17646672). FOXO3 functions at the G2/M-phase in the cell cycle progression as an activator of the DNA-damage repair response through interaction with growth arrest protein GADD45A (PMID: 11964479). The cellular proliferative signaling pathways controlled by FOXO3 are negatively regulated by various signaling pathways, including PI3K and ERK, in response to external stimuli (PMID: 18601916, 18204439). Overexpression of FOXO3 in breast cancer models and endothelial progenitor cells suppresses cellular proliferation, suggesting that FOXO3 functions predominantly as a tumor suppressor (PMID: 18312651, 15084260, 25093499). Downregulation of FOXO3 has been identified in various types of cancer, including glioma and ovarian cancer (PMID: 19911116, 19160093). Preclinical studies of colorectal cancer cell lines suggest that upregulated FOXO3 expression confers resistance to cetuximab (PMID: 27825133, 27685445). False +ENST00000318789 NM_001244814.1 27086 FOXP1 True FOXP1, a transcription factor, is infrequently altered by translocation in lymphomas. FOXP1 is a DNA binding protein that is a member of the P subfamily of forkhead box transcription factors and primarily functions as a transcriptional repressor (PMID: 10702024, 23792361, 23792361). FOXP1 regulates cell-type specific gene expression programs by binding to regulatory units and recruiting histone deacetylases and other cofactors (PMID: 22124370, 20185820). FOXP1 is required for thymocyte development, the generation of naïve T cells, and the development of lung and esophageal tissue (PMID: 19965654, 17428829). FOXP1 loss has been observed in a range of cancer types, including tumors of the kidney, liver, breast, and endometrium (PMID: 23792361, 16258506, 21210727, 15161711, 21901488, 22904134, 11751404). FOXP1 has also been found to be overexpressed in diffuse large B-cell lymphomas and hepatocellular carcinoma, demonstrating that the impact of FOXP1 alterations is context specific (PMID: 19706818, 15709173, 22422806). FOXP1 is part of a translocation observed in the MALT subtype of lymphomas (PMID: 15703784, 20950788, 24214399, 18487996). True +ENST00000397997 NM_001042555 10818 FRS2 True FRS2, an adaptor protein, is altered by amplification in various cancers. FRS2 encodes for a signal transducing adaptor protein, which functions in linking activated receptor tyrosine kinases to downstream signaling pathways (PMID: 10629055). FRS2 has been identified to link FGFR and EGFR signaling with the MAPK signaling cascade (PMID: 12974390, 10629055). Phosphorylation of FRS2 is regulated by receptor tyrosine kinases and allows for activation of various signaling pathways, including ERK, PI3K and protein ubiquitination pathways (PMID: 23782834). Overexpression of FRS2 in various cancer cell lines and models induces anchorage-independent cellular proliferation, tumor growth and angiogenesis, suggesting that FRS2 functions predominantly as an oncogene (PMID: 25368431, 30755618, 26096936, 23393200). Amplification of FRS2 has been identified in various cancers, including ovarian cancer, bladder cancer and osteosarcoma (PMID: 25368431, 30755618, 30001240). False +ENST00000295633 NM_007085 11167 FSTL1 True FSTL1, a secreted glycoprotein, is infrequently altered in cancer. FSTL1, a member of the follistatin protein family, encodes for a secreted glycoprotein that functions in various cellular and physiological processes such as angiogenesis, organogenesis, cellular differentiation and immune cell response (PMID: 22265692, 17129766). FSTL1 binds directly to BMP4 and TLR4 and regulates the TLR4/NFkB/BMP signaling axis to modulate immune response, cellular survival and differentiation (PMID: 26365350, 21482757, 28883005). The oncogenic role of FSTL1 is likely tissue type specific. Overexpression of FSTL1 in glioma and gastric cancer cell lines induces increased cellular proliferation, migration and invasion, suggesting that FSTL1 predominantly functions as an oncogene in these tissues (PMID: 29212066, 33791149). Amplification of FSTL1 has been identified in various different cancer types, including glioblastoma, esophageal squamous cell carcinoma and prostate cancer (PMID: 18483363, 28883005, 27976415). Conversely, ectopic expression of FSTL1 in ovarian cancer and nasopharyngeal carcinoma cell lines suppresses cellular proliferation, migration and invasion (PMID: 18796737, 26918942). Downregulation of FSTL1 has also been identified in various different cancer types including clear cell renal cell carcinoma and lung cancer (PMID: 18546293, 21718795, 31653686). Upregulated FSTL1 expression is suggested to confer enhanced chemoresistance in breast cancer and esophageal squamous cell carcinoma (PMID: 30336071, 28883005). False +ENST00000370768 NM_003902.3 8880 FUBP1 False FUBP1, a tumor suppressor and single-stranded DNA binding protein, is recurrently inactivated by mutation or deletion in glioma. The protein FUBP1, binds single-stranded DNA, including regulatory DNA elements upstream of genes. Among the motifs it binds is the far upstream element (FUSE), which is located upstream of the MYC oncogene (PMID: 22926519). Regulation of MYC by FUBP1 is complex; while overexpression of FUBP1 can activate transcription of the MYC gene, it has also been reported that inactivating mutations of FUBP1 activate MYC expression (PMID: 20420426). FUBP1 is also known to bind RNA (PMID: 23818605), such as in order to regulate the splicing of MDM2, an important negative regulator of the tumor suppressor TP53 (PMID: 24798327). FUBP1 was reported to be mutated at relatively low frequency (<8%) across a variety of cancers (cBioPortal, Nov 3, 2015). It is most frequently mutated in gliomas, which also show frequent deletion of 1p, where the FUBP1 gene is located (PMID: 22869205, 21817013). True +ENST00000268171 NM_001289823.1 5045 FURIN True FURIN, a protease involved in precursor protein cleavage, is infrequently altered in a diverse range of cancers. FURIN is a proprotein convertase that cleaves precursor proteins after translation (PMID: 12360192). FURIN functions as a serine endonuclease that cleaves proteins at basic amino acid sequences in order to convert a preprocessed protein to an activated state (PMID: 12360192). Many FURIN substrates have been identified including precursors for TGF-β, NOTCH1, hormones, metalloproteinases, and cytokines, among others (PMID: 16627761, 12360192, 28821477). In addition, FURIN is required for the proteolytic processing of viral glycoproteins including the proteins that compose the HIV and influenza viral envelopes (PMID: 10707087, 10087614). FURIN is localized to the Golgi and is ubiquitously expressed, but its upregulation during T cell activation plays a key role in STAT transcription factor signaling and peripheral tolerance (PMID: 18701887, 16627761). Because FURIN regulates the processing of a variety of proteins, FURIN is implicated in many cellular functions including signaling, cell proliferation and metastasis (PMID: 18064302). Somatic mutations in FURIN are rare; however, overexpression of FURIN has been identified in several tumor types, including head and neck cancers (PMID: 28369813). Increased expression of FURIN has been associated with metastasis in various tumor types and several FURIN inhibitors are currently in preclinical testing (PMID: 18064302, 28369813). False +ENST00000254108 NM_004960 2521 FUS True FUS, a DNA- and RNA-binding protein, is altered by chromosomal rearrangement in cancer. FUS, also known as TLS, is a DNA- and RNA-binding protein that is a part of the FET/TET heterogeneous nuclear ribonucleoprotein particle protein family (PMID: 22081015). FUS binds to both RNA and DNA through its N-terminus to regulate various cellular processes including cell proliferation, DNA repair, transcription regulation, RNA splicing and RNA transport (PMID: 25494299,19783543, 19674978). Selective knockdown of FUS in cancer cell lines results in impaired cellular proliferation and increased mitotic arrest, suggesting that FUS predominantly functions as an oncogene (PMID: 25501833). Overexpression and chromosomal rearrangements of FUS have been identified in various cancers, including non-small cell lung cancer, Ewing's sarcoma and acute myeloid leukemia (PMID: 30008867, 12907633, 8187069). False +ENST00000368678 NM_153047.3 2534 FYN True FYN, a receptor tyrosine kinase, is altered by mutation in a variety of cancer types including hematologic malignancies and cholangiocarcinomas. FYN is a membrane-associated tyrosine kinase that regulates cellular processes including cytoskeletal remodeling, cell adhesion, integrin signaling, proliferation, immune response and axon guidance (PMID: 10228160, 7617039, 12372285, 20658524, 15781574). FYN-mediated oncogenic signaling has been implicated in tumor progression by mediating cell proliferation, invasion, and metastasis (PMID: 26624980, 21480388). FYN activity is associated with the activation of oncogenic signaling in tumor cells including the EGFR pathway in glioblastomas and the FLT3 pathway in leukemias (PMID:19690143, 26848862, 24882577,19567819). Activating FYN mutations have been identified in peripheral T-cell lymphomas and cholangiocarcinomas, suggesting that FYN acts as an oncogene (PMID: 24413734, 26437031, 25526346). Kinase inhibitors targeting FYN are in development (PMID: 26493492, 24976598, 21813412). False +ENST00000395095 NM_001136198 51343 FZR1 True FZR1, an adaptor protein involved in cell cycle progression, is infrequently altered in cancer. FZR1, also known as CDH1, encodes an adaptor protein for the E3 ubiquitin ligase anaphase promoting complex/cyclosome (APC/C) (PMID: 18598214). The APC/C functions in cell cycle regulation through promoting mitotic exit, maintaining G1 phase and allowing entry into the S phase (PMID: 7787245). FZR1 activates APC/C through recognition of the KEN box consensus motif, allowing binding during the late meiotic phase until G1/S transition (PMID: 25349192). Functional studies using human-derived cell lines demonstrated FZR1 plays a regulatory role in DNA repair through the downregulation of CtIP, a DNA end resection factor protein, in late G2/S phase of the cell cycle (PMID: 25349192). The tumor suppressive role of FZR1 has been demonstrated through in vitro functional assays in human-derived cell lines as measured by FZR1 negatively regulating BRAF oncogenic function through proteolysis and dimerization disruption (PMID: 28174173). Loss of function FZR1 mutations have been identified in colorectal cancer, melanoma and glioma (PMID: 18535175, 28174173, 18662541). Conversely, human-derived xenograft models of colorectal cancer demonstrated an oncogenic role for FZR1 as measured by oncogenic phosphatase PRL-3-mediated aberrant activation of FZR1, promoting tumor growth (PMID: 30498084). In vitro studies with knocked down FZR1 in multiple myeloma cell lines also demonstrated tumor growth arrest (PMID: 27655696). Amplification of FZR1 has been identified in B-cell acute lymphoblastic leukemia and multiple myeloma (PMID: 28143883, 27655696). Rearrangement of FZR1 has been identified in breast cancer and lung adenocarcinoma (PMID: 25500544). True +ENST00000262994 NM_002039.3 2549 GAB1 True GAB1, a signaling adaptor molecule, is altered by mutation in various cancer types including breast cancer. GAB1 is an adaptor protein that is a member of the IRS1-like docking protein family (PMID: 19737390). GAB1 functions as a signaling effector molecule that localizes to the plasma membrane via interactions with the phospholipid PIP3, resulting in phosphorylation-dependent activity in response to growth factor or cytokine stimulation (PMID: 25460044). The association of GAB1 with adaptor molecules (such as GRB2) and with receptor tyrosine kinases (such as MET and EGFR) is required for the activation of downstream signaling cascades (PMID: 9356464, 9444958, 9658397). In addition, GAB1 mediates the activity and recruitment of intracellular kinases such as PI3K and the MAPK pathway (PMID: 9632795). Sophisticated positive and negative feedback mechanisms control the binding of GAB1 to signaling complexes, which can lead to alternate downstream signaling pathway activation (PMID: 18025104). The activity of GAB1 is important for a variety of cellular functions including the regulation of proliferation, migration, and survival (PMID: 19737390). Rare somatic mutations in GAB1 are found in breast cancers, resulting in increased cytokine-independent oncogenic signaling (PMID: 22751113, 16959974). Overexpression of GAB1 has been identified in several cancer types and aberrant GAB1 activity is associated with resistance mechanisms in BRAF-mutant melanomas due to altered feedback regulation of MET signaling (PMID: 28147313, 17463250, 17312329). False +ENST00000361507 NM_080491.2 9846 GAB2 True GAB2, a signaling adaptor molecule, is altered by amplification and overexpression in various cancer types. GAB2 is an adaptor protein that is a member of the IRS1-like docking protein family (PMID: 19737390). GAB2 functions as a signaling effector molecule that localizes to the plasma membrane via interactions with membrane phospholipids and signaling receptor kinases, resulting in phosphorylation-dependent activity in response to growth factor or cytokine stimulation (PMID: 16369543). The association of GAB2 with adaptor molecules (such as GAB1 and GRB2) and with receptor tyrosine kinases (such as ERBB2 and EGFR) is required for the activation of downstream signaling cascades (PMID: 9356464, 9444958, 9658397). In addition, GAB2 mediates the activity and recruitment of intracellular kinases such as PI3K and the MAPK pathway (PMID: 9632795, 23401857). Sophisticated positive and negative feedback mechanisms control the binding of GAB2 to signaling complexes, which can lead to alternate downstream signaling pathway activation (PMID: 28096188). The activity of GAB2 is important for a variety of cellular functions including the regulation of proliferation, apoptosis, migration and survival (PMID: 19737390). Expression of GAB2 in murine models has been associated with the proliferation of breast cancer cells and promotion of metastasis (PMID: 17310989, 16369543). Amplification and overexpression of GAB2 have been identified in several cancer types, including ovarian and breast cancers, among others (PMID: 18314909, 19509136, 19881546, 23362323, 24385586). False +ENST00000274545 NM_000811 2559 GABRA6 True GABRA6, a subunit of the GABA-A receptor, is infrequently altered in cancer. GABRA6 encodes for a subunit of the GABA-A receptors, which function as ligand-gated chloride channels for the inhibitory neurotransmitter GABA (PMID: 8904987, 10195814). The GABA-A receptors are pentamers that are formed through interaction between 19 possible subunits from distinct subunit classes (PMID: 15258161). GABRA6 is selectively expressed in granule neurons and expression is regulated by NFI binding to the GABRA6 promoter (PMID: 2167378, 15466411). GABAergic signaling, the main inhibitory neurotransmitter system signaling in the central nervous system involving the GABA-A receptor, has been identified to regulate tumor immunity and promote tumorigenesis outside of the central nervous system in various cancer models, suggesting that GABRA6 may function predominantly as an oncogene as a subunit of the GABA-A receptor (PMID: 28524180, 24657659, 32964961). False +ENST00000376670 NM_002049.3 2623 GATA1 False GATA1, a transcription factor involved in red blood cell and platelet development, is altered in several hematologic malignancies including transient leukemia and acute megakaryoblastic leukemia. GATA1 is a transcription factor that functions as a master regulator of hematopoietic differentiation (PMID: 1987478). GATA1 activates the expression of many important genes involved in erythroid and megakaryocyte development (PMID:7568185, 7823932), including the beta-globin gene and erythropoietin receptor (PMID:1924329, 1660143). Appropriate expression of GATA1 in hematopoietic progenitor cells is critical for the maturation of red blood cells, megakaryocytes, mast cells and eosinophils (PMID: 15659348). Loss of GATA1 expression in murine models suppresses the production of red blood cells (PMID: 8901585), highlighting the importance of GATA1 expression in erythroid development. Germline mutations in GATA1 are associated with anemia, thrombocytopenia and porphyria (PMID: 10700180, 11675338, 16783379, 17148589). Inherited GATA1 mutations have been implicated in Diamond Blackfan anemia due to the reduced translation of GATA1 protein (PMID: 24952648). GATA1 mutations observed in Down Syndrome patients are associated with acute megakaryocytic leukemia development and transient myeloid disorders (PMID: 12172547, 12747884). Reduced expression of GATA1 corresponds with the development of hematopoietic malignancies due to inadequate production of erythroid cell types (PMID: 12149188). Recurrent GATA1 rearrangements are found in patients with acute basophilic leukemia (PMID: 21474671). False +ENST00000341105 NM_032638.4 2624 GATA2 True GATA2 is a transcription factor involved in red blood cell and platelet development. Germline mutations of GATA2 are associated with Emberger and MonoMAC syndromes and predispose to leukemias. GATA2 encodes for a DNA-binding transcription factor that functions as a master regulator of hematopoiesis through activation of genes involved in hematopoietic differentiation, including those involved in stem cell maintenance and cell specification (PMID:8078582, 12433372, 25578878, 20887958). In addition, GATA2 has been implicated in the regulation of angiogenesis and lymphangiogenesis (PMID:23892628). Appropriate expression of GATA2 is required in hematopoietic stem and progenitor cells to initiate hematopoietic lineage specification (PMID: 28179280). GATA2 regulates the activation of GATA1, a process termed the “GATA switch”, which then ultimately results in the repression of GATA2 (PMID: 12857954). Germline GATA2 mutations are associated with familial myelodysplastic syndrome, acute myeloid leukemia (AML) and Emberger syndrome, a heritable lymphedema disorder associated with a predisposition to AML (PMID: 21892162, 21892158). Inherited GATA2 mutations are also found in patients with MonoMAC syndrome, an immunodeficiency disorder leading to vulnerability to select infectious agents (PMID: 21670465). The oncogenic function of GATA2 may be tissue-specific. Overexpression of GATA2 in prostate cancer cell lines and models induces cellular invasion and metastasis, suggesting that GATA2 functions predominantly as an oncogene in this tissue-specific context (PMID: 37550764, 24448395). Conversely, GATA2 deficiency in murine models induces suppression of definitive hematopoiesis and cellular proliferation, suggesting that GATA2 functions predominantly as a tumor suppressor gene in this tissue-specific context (PMID: 8078582, 34496012). Somatic GATA2 mutations are found in leukemias and myelodysplastic syndromes and often co-occur with CEBPA mutations (PMID: 23634996, 22649106, 23521373,18250304). GATA2-EV1 translocations have been identified in patients with inversion 3 leukemias (PMID:24703711). In solid tumors, GATA2 expression has been linked with regulation of Ras signaling and metastasis (PMID: 22541434, 25670080, 24448395, 25707769). True +ENST00000346208 NM_002051.2 2625 GATA3 True GATA3, a transcription factor, is altered by mutation or amplification in various cancers, most frequently in breast cancer. GATA3 is a DNA binding protein that controls the development of diverse tissues by activating or repressing transcription of genes important in cell proliferation and differentiation (PMID: 21779441, 19798694). GATA3 regulation has cell-type specific effects on gene expression and is expressed in both hematopoietic and non-hematopoietic tissues (PMID: 12923059, 17129787, 19112489). Haploinsufficiency of GATA3 results in the autosomal dominant HDR (hypoparathyroidism, deafness, and renaldysplasia) syndrome, also known as Barakat syndrome (PMID: 10935639). GATA3 expression is essential in the development of normal mammary epithelium in mice and humans and plays a key role in the pathogenesis of luminal breast cancer (reviewed in PMID: 21779441, 19798694). Gain-of-function and loss-of-function GATA3 mutations have been identified in breast cancer, suggesting that in different contexts GATA3 may function as either an oncogene or tumor suppressor (PMID: 27588951). True +ENST00000335135 NM_002052 2626 GATA4 False GATA4, a transcription factor, is altered by silencing in colorectal cancer and lung cancer. GATA4 encodes for a DNA-binding transcription factor which primarily functions in regulation of embryogenesis and cardiogenesis (PMID: 9367431, 30530745, 27984724). GATA4 co-operates with TBX5 to promote cardiomyocyte gene expression and downregulate endothelial gene expression (PMID: 27984724). The expression of GATA4 is suggested to denote that an epithelial cell is fully differentiated (PMID: 21779441). Downregulation of GATA4 in various types of cancer cell lines and models induces tumor growth, colony formation and cellular proliferation, suggesting that GATA4 functions predominantly as a tumor suppressor gene (PMID: 35017504, 30971692, 31903133, 30142155). Hypermethylation of GATA4 has been identified in colorectal cancer and lung cancer (PMID: 19509152, 15585625). True +ENST00000269216 NM_005257 2627 GATA6 True GATA6, a transcription factor, is infrequently altered in cancer. GATA6 encodes for a DNA-binding transcription factor that functions in the development of diverse tissues through transcriptional activation or repression of genes involved in cellular proliferation and differentiation (PMID: 22824924, 22750565, 27756709, 22733991). GATA6 functions in early and later embryogenesis and ​​organogenesis as a regulator for gut, lung and heart development (PMID: 20581743, 18405344, 11959831). Overexpression of GATA6 in various cancer cell lines and models induces epithelial-mesenchymal transition, cellular proliferation and cell cycle progression, suggesting that GATA6 functions predominantly as an oncogene (PMID: 33060563, 26505174, 30194255). GATA6 amplification has been identified in various types of cancer, including esophageal adenocarcinoma, pancreatic cancer and cholangiocarcinoma (PMID: 33300112, 27325420, 33060563). False +ENST00000381254 NM_001130009.3 348654 GEN1 False GEN1, a homologous recombination repair endonuclease, is infrequently altered in cancer. GEN1, an endonuclease of the Rad2/XPG nuclease family, is a homologous recombination (HR) repair protein that helps maintain genomic stability during DNA replication (PMID: 30590761, 20634321, 19020614). During anaphase, GEN1 accesses chromatin and eliminates intermediates that block proper chromatin segregation including monomeric 5’ flaps, replication fork structures and Holliday junctions (PMID: 21962513, 25209024, 20634321, 19020614). GEN1 has functional redundancies with Holliday junction resolution complexes SLX1-SLX4-MUS81-EME1 and the BTR complex, both of which contain a tumor suppressor protein (PMID: 24831703, 21399624). Silencing SLX-4-MUS81 and GEN1 in vitro results in gross chromosomal abnormalities, while single depletions of SLX1, SLX4, MUS81 or GEN1 alone does not result in these chromosomal abnormalities (PMID: 24831703, 24076221). Although there is a lack of functional evidence demonstrating the biological and oncogenic function of GEN1, rare germline GEN1 mutations have been linked to cases of bilateral breast cancer, familial childhood acute lymphoblastic leukemia and multiple primary malignancies involving lung cancer (PMID: 23104382, 26201965, 38349998). False +ENST00000228682 NM_005269.2 2735 GLI1 True GLI1, a transcription factor, is altered by mutation, amplification or overexpression in various cancer types. GLI1 is a zinc-finger transcription factor that plays an important role in normal neural development and function via regulation of the Sonic hedgehog (Shh) signaling pathway (PMID: 9634234,9584120). The GLI1 transcription factor binds DNA directly to activate Shh target genes in response to pathway activation and can function as both a transcription activator and transcription repressor depending on the signaling context (PMID: 10375510). In the absence of Shh ligand, GLI1 is cleaved by proteases to produce a truncated protein lacking C-terminal amino acids necessary for transcription activation (PMID: 9215627). Following Shh ligand exposure, GLI1 is no longer cleaved and can activate transcription of Shh target genes. GLI1 is an oncogene and is typically mutated or overexpressed in glioblastomas, where it can cause aberrant activation of the Shh-Gli signaling pathway (PMID: 12044012). False +ENST00000078429 NM_002067.2 2767 GNA11 True GNA11, a G protein subunit, is recurrently mutated in uveal melanoma. GNA11 is an alpha subunit of heterotrimeric guanine nucleotide-binding proteins (G-proteins) (PMID: 23640210, 28223438). G proteins, composed of α, β, and γ subunits, are intracellular signaling proteins that initiate signaling cascades following activation by membrane-spanning G-protein coupled receptors (GPCRs) (PMID: 23640210). Following activation by a GPCR, GDP-bound GNA11 (a Gαq protein) exchanges GDP for GTP and activates downstream signaling via binding to phospholipase C β (PLCB4), (PMID: 27089179, 28223438). PLCB4 activates PIP2 cleavage, resulting in activation of the second messenger proteins diacylglycerol (DAG) and inositol triphosphate (IP3) to prompt calcium release (PMID: 27089179). GNA11-mediated signaling promotes the activation of a variety of downstream pathways, including PKC, MAPK, and PI3K signaling, which mediate several cellular processes such as proliferation and differentiation (PMID: 27089179, 23177739). GNA11 alterations inhibit the GTPase hydrolysis activity of the protein, thereby causing GNA11 to remain bound to GTP in a constitutively activated state (PMID: 24077403, 21083380). Somatic mutations in GNA11 are found in patients with uveal melanoma, and more rarely, cutaneous melanoma (PMID: 24077403, 21083380). Alterations in GNA11 are mutually exclusive with the G-protein GNAQ in uveal melanoma (PMID: 24713608). Therapeutic strategies targeting the activation of MAPK signaling pathways may be efficacious in patients with GNA11 mutations (PMID: 29206651, 22733540) due to amplification of the GPCR-independent signaling (PMID: 29738114, 28223438). False +ENST00000275364 NM_007353.2 2768 GNA12 True GNA12, a guanine nucleotide exchange protein, is infrequently altered across various cancer types. GNA12 is a guanine nucleotide binding protein that functions as a subunit of heterotrimeric G protein complexes (PMID: 18814923). Heterotrimeric G proteins consist of an alpha subunit, such as GNA12 or GNA13, which bind and hydrolyze GTP to GDP, in concert with beta and gamma subunits (PMID: 18814923). When bound to GDP, the GNA12 alpha subunit, along with the beta and gamma subunits, form an inhibitory complex; subsequently, activated G protein-coupled receptor binding can initiate a conformation change in GNA12, resulting in the exchange of GDP for GTP and release of the beta/gamma subunits (PMID: 19226283). GTP-bound GNA12 now functions as an activated effector molecule mediating downstream signaling (PMID: 18814923, 19226283). GNA12 activates the small GTPase RhoA and RhoGEFs, which in turn mediate multiple signaling pathways that regulate migration, adhesion, apoptosis, and cellular proliferation (PMID: 26989201, 18814923). GNA12 binds several proteins including HSP90 (PMID: 24435554). Somatic GNA12 mutations are rare in human cancers; however, overexpression of activated GNA12 in preclinical models results in cellular transformation (PMID: 16247467). False +ENST00000439174 NM_006572.5 10672 GNA13 True GNA13, a guanine nucleotide exchange protein, is recurrently altered by mutation in lymphomas. GNA13 is a guanine nucleotide binding protein that functions as a subunit of heterotrimeric G protein complexes (PMID: 18814923). Heterotrimeric G proteins consist of an alpha subunit, such as GNA13 or GNA12, which bind and hydrolyze GTP to GDP, in concert with beta and gamma subunits (PMID: 18814923). When bound to GDP, the GNA13 alpha subunit, along with the beta and gamma subunits, form an inhibitory complex; however, activated G protein-coupled receptor binding initiates a conformation change in GNA13, resulting in the exchange of GDP for GTP and release of the beta/gamma subunits (PMID: 19226283). GTP-bound GNA13 now functions as an activated effector molecule mediating downstream signaling (PMID: 18814923, 19226283). GNA13 activates the small GTPase RhoA and RhoGEFs, which in turn mediate multiple signaling pathways that regulate migration, adhesion, apoptosis, and cellular proliferation (PMID: 26989201, 18814923). Loss of GNA13 expression in mice results in germinal center defects and B-cell dissemination in the blood (PMID: 25274307). Somatic GNA13 mutations are found in patients with diffuse large B-cell lymphoma (DLBCL), Burkitt’s and Hodgkin lymphoma (PMID: 22343534, 26616858, 29650799). These alterations generally occur as nonsense or frameshift loss-of-function mutations and suggest that GNA13 functions predominantly as a tumor suppressor gene in this context (PMID: 23143597, 31586074, 33423045). GNA13 overexpression has also been implicated in cell proliferation and transformation in several types of solid tumors, including ovarian cancer (PMID: 26804165, 29255247, 8002992). True +ENST00000286548 NM_002072.3 2776 GNAQ True GNAQ, a G protein subunit, is recurrently mutated in uveal melanoma. GNAQ is an alpha subunit of heterotrimeric guanine nucleotide-binding proteins (G-proteins) (PMID: 23640210, 28223438). G proteins, composed of α, β, and γ subunits, are intracellular signaling proteins that initiate signaling cascades following activation by membrane-spanning G-protein coupled receptors (GPCRs) (PMID: 23640210). Following activation by a GPCR, GDP-bound GNAQ (a Gαq protein) exchanges GDP for GTP and activates downstream signaling via binding to phospholipase C β (PLCB4), (PMID: 27089179, 28223438). PLCB4 activates PIP2 cleavage, resulting in activation of the second messenger proteins diacylglycerol (DAG) and inositol triphosphate (IP3) to prompt calcium release (PMID: 27089179). GNAQ-mediated signaling promotes the activation of a variety of downstream pathways, including PKC, MAPK, and PI3K signaling, which mediate several cellular processes such as proliferation and differentiation (PMID: 27089179, 23177739). GNAQ alterations inhibit the GTPase hydrolysis activity of the protein, thereby causing GNAQ to remain bound to GTP in a constitutively activated state (PMID: 24077403, 21083380). Somatic mutations in GNAQ are found in patients with uveal melanoma, and more rarely, cutaneous melanoma (PMID: 19078957, 18719078, 23640210). Alterations in GNAQ are mutually exclusive with the G-protein GNA11 in uveal melanoma (PMID: 24713608). Therapeutic strategies targeting the activation of MAPK signaling pathways may be efficacious in patients with GNAQ mutations (PMID: 29206651, 22733540) due to the amplification of the GPCR-independent signaling (PMID: 29738114, 28223438). False +ENST00000371085 NM_000516.4 2778 GNAS True GNAS, an intracellular signaling protein, is mutated in various cancers. The GNAS gene encodes the stimulatory G-alpha subunit of the heterotrimeric guanine nucleotide-binding protein (G-protein) membrane complex. Activation of G-protein signaling by an agonist-stimulated G-coupled protein receptor (GPCR) activates signal transduction cascades, which regulate cellular growth and development (PMID: 23640210). Activating mutations in GNAS that have been linked to the endocrine hyperplasia of McCune-Albright syndrome have also been found in growth-hormone-secreting pituitary tumors. Point mutations in the GNAS gene, many of which involve the residues R201 and Q227, can lead to constitutive signaling activity, resulting in cellular proliferation and oncogenesis (PMID: 23640210). Tumor types that have been found to harbor GNAS mutations include colon, parathyroid, and ovarian cancers, hepatocellular carcinoma, and pancreatic intraductal papillary mucinous neoplasms (precursors of pancreatic adenocarcinoma) (PMID: 23640210). False +ENST00000378609 NM_001282539.1 2782 GNB1 True GNB1, a guanine nucleotide binding protein, is recurrently altered by mutation in myelodysplastic syndromes and acute myeloid leukemia. GNB1 (also MRD42) is a guanine nucleotide binding protein that functions as a subunit of heterotrimeric G protein complexes. Heterotrimeric G proteins consist of an alpha subunit, which binds and hydrolyzes GTP to GDP, in concert with the closely bound beta and gamma subunits (PMID: 18814923). When bound to GDP, the alpha and beta-gamma subunits form an inhibitory complex; subsequently, binding by an activated G protein-coupled receptor (GPCR) can initiate dissociation of the alpha subunit from the beta-gamma complex, resulting in the exchange of GDP for GTP (PMID: 19226283). GNB1 remains bound to a gamma subunit and functions as an activated effector molecule mediating downstream signaling, including activation of the PI3K/AKT, MAPK, and PLCβ pathways (PMID: 18814923, 19226283). Germline alterations in GNB1 are associated with a neurological disorder that presents as a developmental delay with seizures (PMID: 27108799). Somatic GNB1 mutations are found in myelodysplastic syndromes and acute myeloid leukemia (PMID: 25485910). GNB1 alterations impact the G protein alpha and beta-gamma binding surface, resulting in activation of signaling downstream of G proteins and resistance to targeted kinase inhibitors (PMID: 25485910). False +ENST00000370818 NM_004484 2719 GPC3 True GPC3, a cell-surface glypican, is frequently overexpressed in hepatocellular carcinoma. GPC3, a member of the glypican-related integral membrane proteoglycan family, encodes for a cell surface proteoglycan that functions primarily in the negative regulation of cell proliferation during development (PMID: 14610063, 18477453). Glypicans play a role in developmental morphogenesis through the regulation of the Wnt and Hedgehog cell signaling pathways (PMID: 30963603, 35142364). GPC3 inhibits Hedgehog cell signaling by competing with PTC1, the Hedgehog cell signaling receptor, and binding with SHH, the Hedgehog cell signaling protein, to trigger internalization and lysosomal degradation of the GPC3-SHH complex (PMID: 23665349, 22467855). Germline mutations of GPC3 are associated with Simpson-Golabi-Behmel syndrome, an X-linked multiple congenital anomalies and overgrowth syndrome, resulting in an increased predisposition to Wilms tumor, hepatoblastoma and neuroblastoma (PMID: 23530909, 29637653). Knockdown of GPC3 in hepatocellular carcinoma cell lines reduces cellular proliferation and downregulates YAP, suggesting that GPC3 functions predominantly as an oncogene (PMID: 23471984, 25758784). Overexpression of GPC3 is frequently identified in hepatocellular carcinoma, and its expression is associated with poor prognosis (PMID: 33384879, 12824919, 36165051). False +ENST00000380728 NM_004489.4 2874 GPS2 False GPS2, a transcriptional cofactor involved in MAPK signaling, is altered by mutation and translocation in a variety of cancer types including medulloblastoma and glioblastoma. GPS2 (also known as AMF1) is a transcriptional cofactor in the G protein-mitogen-activated protein kinase (MAPK) signaling cascade. GPS2 interacts with transcription factors, nuclear receptors and histone acetyltransferases, thereby regulating transcriptional repression and activation (PMID: 11931768, 11486030, 17895379, 19481530, 24953653, 18218630, 10846067). GPS2 is ubiquitously expressed and localizes to both the nucleus, where it acts as a modulator of transcription, and the cytoplasm, where it modulates proinflammatory TNFα signaling and JNK activity (PMID: 22424771, 19858209, 11486030, 16122992, 20159957). Somatic loss-of-function mutations in GPS2 are found in medulloblastoma and are associated with poor prognosis, suggesting that GPS2 functions as a tumor suppressor (PMID: 22820256, 25030029). Translocations have also been observed in glioblastoma multiforme and undifferentiated spindle cell sarcoma (PMID: 23917401, 25139254). True +ENST00000309156 NM_001030002 2886 GRB7 True GRB7, an adaptor protein, is frequently upregulated in various cancer types. GRB7 encodes an adaptor protein that is a member of a SH2 domain-containing adaptor protein family (PMID: 10893408). GRB7 interacts with multiple receptor kinases including EGFR and ephrin receptors, and is involved in multiple cellular processes including kidney development, angiogenic activity, proliferation, anti-apoptosis, gene expression regulation, and T-cell activation (PMID: 33162827, 32737994, 19473962). Through its interaction with focal adhesion kinase (FAK), GRB7 is also involved in the integrin signaling pathway and cell migration (PMID: 19473962). GRB7 function is regulated by the MAPK/ERK pathway, which has been demonstrated in studies of thyroid cancer and ovarian cancer, among others (PMID: 19473962, 32577949, 29290818) GRB7 has been shown to promote cell cycle G1/S transition and AKT activation in bladder cancer (PMID: 33162827). Knockout of GRB7 in various cancer cell lines and models reduces proliferation and migration and promotes apoptosis, suggesting that GRB7 functions predominantly as an oncogene (PMID: 29190909, 29290818, 28275791). High expression of GRB7 has been observed in various cancer types including bladder cancer, colorectal cancer and thyroid cancer (PMID: 33162827, 34718347, 32577949, 29290818). False +ENST00000300177 NM_013372.6 26585 GREM1 True GREM1 includes a BMP antagonist that binds to BMP ligands. It is over-expressed in various tumor types, and a duplication in the upstream region is associated with colon cancer predisposition. GREM1 encodes for gremlin 1, a DAN (differential screening selected gene abberative in neuroblastoma) family bone morphogenic protein (BMP) antagonist (PMID: 24810382). It is a secreted protein that binds to BMP ligands to prevent BMP receptor activation (PMID:25378054). It regulates kidney formation, skeletal development, and the osteochondroreticular stem cell, responsible for making osteoblasts, chondrocytes, and reticular marrow stromal cells (PMID: 17522159, 21303853, 25594183, 15201225). It is expressed in various tumor cells and in glioma cells acts to maintain stem cell potential (PMID: 24788093, 23826422, 17003113). A duplication including the upstream region of the GREM1 gene is associated with hereditary mixed polyposis syndrome and an increased risk of developing colon cancer (PMID: 21128281, 22561515, 26493165, 29804199, 30584801, 30862463). These duplications cause a dramatic increase in GREM1 expression, ectopic expression of GREM1 in the colonic epithelium and acquisition of stem cell capacity in more mature progenitor cells (PMID: 22561515, 25419707, 26493165). False +ENST00000330684 NM_001134407.1 2903 GRIN2A False GRIN2A, a subunit of the NMDA glutamate receptor, is recurrently altered by mutation in various cancer types, most frequently in melanoma. GRIN2A, also known as GluN2A or NR2A, is a regulatory subunit of the glutamate-gated N-methyl-d-aspartate receptor (NMDAR), which plays an important role in cell death, survival, and migration in cancer cells (PMID: 23540692). NMDARs are best known for their roles in the brain, and high expression is found in neurons in the brain and the spinal cord where they play an important role in controlling cation flow through the receptor (PMID: 7512349). Normal NMDAR activity can promote cell survival in neurons through the PI3K and ERK signaling pathways (PMID: 11902114). Studies have shown a high prevalence of somatic mutations in GRIN2A in malignant melanoma (PMID: 21499247, 22197930), although the mechanism or function of these mutations is still unknown. True +ENST00000361669 NM_000840 2913 GRM3 False GRM3, a G-protein coupled receptor, is infrequently altered in cancer. GRM3 encodes for metabotropic glutamate receptor 3, which belongs to group II metabotropic glutamate receptors (PMID: 27130562). Group II receptors are linked to the inhibition of the cyclic AMP cascade ( PMID:27431857). The G-protein coupled receptor modulates synaptic glutamate and is involved in synaptic plasticity and brain function (PMID: 27130562). Mutations in GRM3 have been associated with psychiatric disorders including schizophrenia and bipolar disorder (PMID: 15310849, 27130562, 27431857). Alterations in GRM3 have been associated with neurological conditions rather than cancer. However, increased GRM3 expression has been observed in patients with glioblastoma and activating mutations in GRM3 have been identified in melanoma cells (PMID: 34290229, 21946352). False +ENST00000316626 NM_002093.3 2932 GSK3B True GSK3B, an intracellular kinase, is overexpressed in various cancer types including ovarian, colon and liver cancers. GSK3B is a multifunctional serine /threonine kinase that is a member of the glycogen synthase kinase protein family. The protein kinase functions as an important regulator of cellular signaling pathways involved in metabolism, cell cycle and proliferation (PMID: 24931005). Unlike most protein kinases, GSK3β is constitutively active in resting cells and undergoes a rapid and transient inhibition in response to a number of external signals. GSK3β activity is regulated by site-specific phosphorylation. Several kinases are capable of regulating the protein kinase including p70 S6 kinase, extracellular signal-regulated kinases (ERKs), p90Rsk, protein kinases A, B and C, and MEK1/2 (PMID: 12615961, 11527574, 16935409, 11394906, 15020233). Dysregulated GSK3B has been implicated in the development of a number of human diseases such as diabetes, cardiovascular disease, neurodegenerative diseases and bipolar disorder (PMID: 12615961, 11527574, 16935409). Overexpression of the protein kinase has also been implicated in tumorigenesis and cancer progression including ovarian, colon, liver and pancreatic carcinomas (PMID: 16556076, 17912008, 11883528, 16556076, 16342409, 18606491). Several GSK3β inhibitors have been studied in preclinical trials, for example pharmacological inhibitors suppress proliferation of the ovarian cancer cells in vitro and prevents the formation of tumors in nude mice generated by the inoculation of human ovarian cancer cells (PMID: 16788573). False +ENST00000573035 NM_032999.3 2969 GTF2I True GTF2I, a transcription factor, is recurrently altered by mutation in thymic tumors and lymphomas. GTF2I (also TFII-I) is a general transcription factor that regulates the transcription of several signaling proteins (PMID: 22037610, 22037610). GTF2I mediates the expression of various genes important in cell cycle control, stress response, and genomic stability, including FOS, BRCA, and STAT proteins, among other others, in association with a variety of transcriptional complexes (PMID: 28657656, 24922507, 24231951, 21407215). GTF2I has also been implicated in heavy chain immunoglobulin transcription in immune cells and plays an important role in T-cell receptor signaling (PMID: 21549311, 11313464, 19701889). In addition, GTF2I can directly bind CTCF, a regulator of epigenetic state, to drive transcriptional initiation at target genes (PMID: 25646466). Germline deletions in GTF2I are found in patients with Williams-Beuren syndrome, a multisystem developmental disorder (PMID: 10198167). Somatic GTF2I mutations have been identified in epithelial thymic tumors and follicular T cell-derived lymphomas (PMID: 24974848, 27369867). GTF2I mutations occur predominantly as missense mutations and are predicted to disrupt protein degradation of GTF2I, leading to increased protein expression (PMID: 24974848). These alterations tend to occur in more indolent thymic tumor subtypes and are associated with a better prognosis (PMID: 28676218). False +ENST00000343677 NM_005319.3 3006 H1-2 False H1-2, a histone variant, is infrequently altered by mutation in various cancer types. H1-2 is a histone H1 variant. H1 histone proteins bind to linker DNA between nucleosomes and influences higher order chromatin structure. The histone H1 family comprises eleven members, each one transcribed by its own gene. A number of studies have shown that H1 levels are altered in cancer and variant-specific changes can be observed in different tumor types. Although H1 variants share significant homology in their globular DNA-binding domain, they are more divergent in their C- and N-terminal tails, and evidence suggests that they may have distinct functions in the nucleus. The so-called “main” H1 variants, which include H1-1, H1-2, H1-3, H1-4, H1-5, H1-6, are mainly transcribed in S-phase and therefore expressed at high levels only in dividing cells (PMID: 18208346, 26474902, 26386351). H1-2 mutations have been identified in follicular lymphoma and impair H1-2 binding to DNA, likely impacting chromatin structure and gene expression (PMID: 24362818). False +ENST00000244534 NM_005320.2 3007 H1-3 False H1-3, a histone H1 linker protein, is infrequently altered by mutation in a diverse range of cancers. H1-3 is a histone H1 linker protein that encodes the non-canonical H1.3 histone variant (PMID: 9031620). Histone variants, such as H1.3, have sequences that differ from the canonical histone protein and appear to be interchangeable with the major protein form (PMID: 9031620). Histone proteins are an essential component of the nucleosome which consists of DNA wrapped around eight histone protein molecules (two sets of each H2A, H2B, H3 and H4 histones), and therefore allow for the effective packaging of DNA in the nucleus (PMID: 11498575). In addition to the core histone molecules, H1 linker histones mediate the stabilization of histone molecules and higher order chromatin state (PMID: 9031620). H1-3 expression is replication-dependent and H1-3 is most highly expressed in the thymus, lung, and spleen (PMID: 28794128). H1-3 is detected on chromatin throughout the cell cycle (PMID: 20104577), is depleted at active promoters and regulatory units (PMID: 21852237), suppresses RAD51/RAD54-mediated homologous pairing (PMID: 26757249) and directly mediates chromatin compaction (PMID: 19794910). H1-3 is also a member of an HDAC3 containing complex that mediates the repression of the retinoic acid receptor and the thyroid hormone receptor (PMID: 26663086). Somatic mutations in H1-3 are rare; however, overexpression of H1-3 has been associated with repression of the oncogenic factor H19 in ovarian cancer cells, suggesting it functions as a tumor suppressor (PMID: 28687618, 25205099). True +ENST00000304218 NM_005321.2 3008 H1-4 True H1-4, a histone H1 linker protein, is infrequently altered by mutation in a diverse range of cancers. H1-4 is a histone H1 linker that encodes the non-canonical H1.4 histone variant (PMID: 28794128). Histone variants, such as H1.4, have sequences that differ from the canonical histone protein and appear to be interchangeable with the major protein form (PMID: 9031620). Histone proteins, essential components of the nucleosome, consists of DNA wrapped around eight histone protein molecules (two sets of each H2A, H2B, H3 and H4 histones), and therefore allow for the effective packaging of DNA in the nucleus (PMID: 11498575). In addition to the core histone molecules, H1 linker histones mediate the stabilization of histone molecules and higher order chromatin state (PMID: 9031620). H1-4 expression is replication-dependent and is ubiquitously expressed in a variety of cell types (PMID: 28794128). Expression of H1-4 is gender-specific and is enriched on the paternal inactive chromosome (PMID: 18927631). H1-4 mediates the binding of the repressive protein HP1α and is depleted from active regulatory regions of the chromatin (PMID: 30007360, 23746450). Loss of HISTH1E in breast cancer cells results in growth suppression, suggesting a role in cell survival (PMID: 18927631). Somatic mutations in H1-4 are rare; however, mutations in HISTH1E have been identified in diffuse large B lymphoma (leg type) (PMID: 28479318). False +ENST00000331442 NM_005322.2 3009 H1-5 False H1-5, an H1 histone linker protein, is infrequently altered by mutation in various human cancers. H1-5 is a histone H1 linker protein that encodes the non-canonical H1.5 histone variant (PMID: 9031620). Histone variants, such as H1.5, have sequences that differ from the canonical histone protein and appear to be interchangeable with the major protein form (PMID: 9031620). Histone proteins are an essential component of the nucleosome, which consists of DNA wrapped around eight histone protein molecules (two sets of each H2A, H2B, H3 and H4 histones), and therefore allow for the effective packaging of DNA in the nucleus (PMID:11498575). In addition to the core histone molecules, H1 linker histones mediate the stabilization of histone molecules and higher order chromatin state (PMID: 9031620). H1-5 expression is replication-dependent and H1-5 is most highly expressed in the thymus and spleen (PMID: 28794128). H1-5 binds chromatin in the embryonic germ layers and binding is progressively lost during epigenetic reprogramming (PMID: 28794128, 28794128). In differentiated cells, H1-5 regulates chromatin structure near genes that encode membrane or membrane-associated proteins (PMID: 22956909). H1-5 has been implicated in the repression of gene expression and a regulator of SIRT1 deacetylase activity (PMID: 22956909). Depletion of H1-5 results in loss of SIRT1 binding, loss of H3K9me2, increased chromatin accessibility and decreased cellular growth (PMID: 22956909). H1-5 has also been shown to bind FOXP3 in T regulatory cells at relevant target genes (PMID: 21654845). Rare somatic mutations in H1-5 have been identified in colon cancer and are predicted to maintain a more undifferentiated chromatin state (PMID: 16959974). Downregulation of H1-5 expression has been associated with various tumor types (PMID: 22956909). True +ENST00000359193 NM_021064.5 8969 H2AC11 False H2AC11, a canonical histone H2A protein, is infrequently mutated by amplification and mutation in a diverse range of cancers. H2AC11 is a canonical histone H2A gene that encodes a protein that functions in the core histone complex. H2AC11 is one of five abundantly expressed H2A genes that encode the H2A.1 histone molecule (PMID: 23956221). Histone proteins, essential components of the nucleosome, consist of DNA wrapped around eight histone protein molecules (two sets of each H2A, H2B, H3 and H4 histones), and therefore allow for the effective packaging of DNA in the nucleus (PMID: 11498575). H2AC11 is expressed in a variety of cell types; however, the function has not yet been well characterized in biochemical studies. Somatic mutations in H2AC11 are rare; however, amplifications have been identified in some tumor types (cbioportal, accessed August 2018). False +ENST00000613174 NM_003511.3 8332 H2AC16 False H2AC16, a canonical histone H2A protein, is infrequently mutated by amplification and mutation in a diverse range of cancers. H2AC16 is a canonical histone H2A gene that encodes a protein that functions in the core histone complex. H2AC16 is one of five abundantly expressed H2A genes that encode the H2A.1 histone molecule (PMID: 23956221). Histone proteins, essential components of the nucleosome, consist of DNA wrapped around eight histone protein molecules (two sets of each H2A, H2B, H3 and H4 histones), and therefore allow for the effective packaging of DNA in the nucleus (PMID: 11498575). H2AC16 is expressed in a variety of cell types; however, the function has not yet been well characterized in biochemical studies. Somatic mutations in H2AC16 in human cancers are rare; however, amplifications have been identified in some tumor types (cbioportal, accessed August 2018). False +ENST00000359611 NM_003514 8336 H2AC17 True H2AC17, a canonical histone H2A protein, is infrequently mutated by amplification and mutation in a diverse range of cancers. H2AC17 is a canonical histone H2A gene that encodes a protein that functions in the core histone complex. H2AC17 is one of five abundantly expressed H2A genes that encode the H2A.1 histone molecule (PMID: 23956221). Histone proteins, essential components of the nucleosome, consist of DNA wrapped around eight histone protein molecules (two sets of each H2A, H2B, H3 and H4 histones), and therefore allow for the effective packaging of DNA in the nucleus (PMID: 11498575). H2AC17 is expressed in a variety of cell types; however, the function has not yet been well characterized in biochemical studies. In addition, H2AC17 was found to be overexpressed in cervical patient samples (PMID: 29184082). Somatic mutations in H2AC17 in human cancers are rare; however, amplifications have been identified in some tumor types (cbioportal, accessed August 2018). False +ENST00000314088 NM_003512.3 8334 H2AC6 False H2AC6, an H2A histone variant, is infrequently altered by mutation in a diverse range of cancers. H2AC6 is an H2A histone variant (H2A 2C) that functions as a protein in the core histone complex. Histone variants, such as H2AC6, have sequences that differ from the canonical histone protein and appear to be interchangeable with the major protein form (PMID: 9031620). Histone proteins, essential components of the nucleosome, consist of DNA wrapped around eight histone protein molecules (two sets of each H2A, H2B, H3 and H4 histones), and therefore allow for the effective packaging of DNA in the nucleus (PMID: 11498575). H2AC6 expression is replication-dependent and is expressed in a variety of cell types, including during mesenchymal stem cell differentiation (PMID: 23956221, 23717473). Loss of H2AC6 in cell lines results in reduced proliferation and transformation (PMID: 23956221), suggesting that H2AC6 functions as an oncogene. Somatic mutations in H2AC6 in human cancers are relatively rare, however, increased expression of H2AC6 has been identified in chronic lymphocytic leukemia samples (PMID: 19253275). Missense mutations have also been identified in follicular lymphoma and uterine and ovarian carcinosarcomas (PMID: 28064239, 27791010). False +ENST00000339812 NM_021058.3 8970 H2BC11 False H2BC11, a canonical histone H2B protein, is infrequently mutated by amplification and mutation in a diverse range of cancers. H2BC11 is a canonical histone H2B gene that encodes a protein that functions in the core histone complex. H2BC11 is one of fifteen abundantly expressed H2B genes that encode the H2B.1 histone molecule (PMID: 16319397). Histone proteins, essential components of the nucleosome, consist of DNA wrapped around eight histone protein molecules (two sets of each H2A, H2B, H3 and H4 histones), and therefore allow for the effective packaging of DNA in the nucleus (PMID: 11498575). H2BC11 is expressed in a variety of cell types and is replication-dependent; however, the function has not yet been well-characterized in biochemical studies. Due to the ubiquitous expression of H2BC11, murine H2BC11 reporter models are utilized in preclinical studies (PMID: 22690876). In addition, H2BC11 was found to be overexpressed in cervical cancer patient samples (PMID: 29184082). Somatic mutations in H2BC11 are rare in human cancers; however, missense mutations have been identified in follicular lymphoma and uterine and ovarian carcinosarcomas (PMID: 28064239, 27791010). False +ENST00000356950 NM_080593.2 85236 H2BC12 False H2BC12, a canonical histone H2B protein, is infrequently mutated by amplification and mutation in a diverse range of cancers. H2BC12 is a canonical histone H2B gene that encodes a protein that functions in the core histone complex. H2BC12 is one of fifteen abundantly expressed H2B genes that encode the H2B.1 histone molecule (PMID: 16319397). Histone proteins, essential components of the nucleosome, consist of DNA wrapped around eight histone protein molecules (two sets of each H2A, H2B, H3 and H4 histones), and therefore allow for the effective packaging of DNA in the nucleus (PMID: 11498575). H2BC12 is expressed in a variety of cell types and is replication-dependent; however, the function has not yet been well characterized in biochemical studies. In addition, H2BC12 was found to be upregulated after BET inhibitor treatment and in invasive ductal carcinomas (PMID: 27388964, 26732727). Somatic mutations in H2BC12 are rare in human cancers; however, H2BC12 was identified as a candidate cancer gene in diffuse large B cell lymphoma (DLBCL) and follicular lymphoma in large-scale sequencing studies (PMID: 29713087, 28064239). False +ENST00000616182 NM_003527.4 8348 H2BC17 False H2BC17, a canonical histone H2B protein, is infrequently mutated by amplification and mutation in a diverse range of cancers. H2BC17 is a canonical histone H2B gene that encodes a protein that functions in the core histone complex. H2BC17 is one of fifteen abundantly expressed H2B genes that encode the H2B.1 histone molecule (PMID: 16319397). Histone proteins, essential components of the nucleosome, consist of DNA wrapped around eight histone protein molecules (two sets of each H2A, H2B, H3 and H4 histones), and therefore allow for the effective packaging of DNA in the nucleus (PMID: 11498575). H2BC17 is expressed in a variety of cell types and replication-dependent; however, the function has not yet been well characterized in biochemical studies. Somatic mutations in H2BC17 are rare in human cancers; however, missense mutations have been identified in follicular lymphoma (PMID: 28064239). False +ENST00000314332 NM_003518.3 8347 H2BC4 False H2BC4, a canonical histone H2B protein, is infrequently mutated by amplification and mutation in a diverse range of cancers. H2BC4 is a canonical histone H2B gene that encodes a protein that functions in the core histone complex. H2BC4 is one of fifteen abundantly expressed H2B genes that encode the H2B.1 histone molecule (PMID: 16319397). Histone proteins, essential components of the nucleosome, consist of DNA wrapped around eight histone protein molecules (two sets of each H2A, H2B, H3 and H4 histones), and therefore allow for the effective packaging of DNA in the nucleus (PMID: 11498575). H2BC4 is expressed in a variety of cell types and is replication-dependent; however, the function has not yet been well characterized in biochemical studies. In addition, H2BC4 is expressed during terminal differentiation as evidenced in liver cells (PMID: 27402160). Somatic mutations in H2BC4 are rare in human cancers; however, amplifications have been identified in some tumor types (cbioportal, accessed August 2018). False +ENST00000289316 NM_021063.3 3017 H2BC5 False The H2BC5 gene encodes a histone H2B variant. The H2BC5 gene encodes histone H2B type 1D. Histone proteins are an essential component of the nucleosome which consists of DNA wrapped around eight histone protein cores (two sets of each H2A, H2B, H3 and H4 histones), and therefore allow for the effective packaging of DNA in the nucleus (PMID:11498575). Ubiquitination of histone H2B at specific lysine residues leads to transcriptional activation and is a prerequisite for the placement of the activating mark H3K4me3 (PMID: 14563679, 12077605). False +ENST00000541790 NM_003518.3 8339 H2BC8 False H2BC8, a canonical histone H2B protein, is infrequently mutated by amplification and mutation in a diverse range of cancers. H2BC8 is a canonical histone H2B gene that encodes a protein that functions in the core histone complex. H2BC8 is one of fifteen abundantly expressed H2B genes that encode the H2B.1 histone molecule (PMID: 16319397). Histone proteins, essential components of the nucleosome, consist of DNA wrapped around eight histone protein molecules (two sets of each H2A, H2B, H3 and H4 histones), and therefore allow for the effective packaging of DNA in the nucleus (PMID: 11498575). HIST1H2BC is expressed in a variety of cell types and is replication-dependent; however, the function has not yet been well characterized in biochemical studies. In addition, H2BC8 was identified as a significant prostate cancer biomarker in urine analyses (PMID: 26856686). Somatic mutations in H2BC8 are rare in human cancers; however, missense mutations have been identified in follicular lymphoma and uterine and ovarian carcinosarcomas (PMID: 28064239, 27791010). False +ENST00000366815 NM_002107.4 3020 H3-3A True H3-3A, a histone variant, is recurrently altered by mutation in various pediatric cancers including pediatric glioblastoma. H3-3A is a histone variant that encodes histone H3.3 and is found at actively transcribed genes, transcription factor binding sites and telomeres (PMID: 20211137). Chromatin is the physiological template of human genetic information and is built out of nucleosomes, which are octamers assembled from histones proteins H2A, H2B, H3 and H4 (PMID: 11498575). The exact functions of histone 3.3 are not yet fully understood. Mutations of H3-3A leading to amino acid substitutions at its histone tail are common in pediatric glioblastoma (GBM) and pediatric diffuse pontine glioma and were also reported in chondroblastoma and giant cell tumors (PMID: 22286061, 22286216, 24162739, 24285547, 26399631). Glioblastoma tumors with H3-3A mutations show a different DNA methylation profile when compared to other GBM tumors and H3-3A mutations seem mutually exclusive with IDH1 mutations in GBM (PMID: 23079654). The exact mechanism by which these mutations lead to tumorigenesis are unknown, however, it has been proposed that H3.3 mutations lead to increased expression of oncogenic MYCN (PMID: 23539269). False +ENST00000254810 NM_005324.3 3021 H3-3B False H3-3B, a histone variant, is recurrently altered by mutation in chondroblastomas. H3-3B is one of the “replacement” histone H3.3 variants, which, in contrast to the H3.1 and H3.2 variants, is expressed throughout the cell cycle and is incorporated into chromatin independently of DNA synthesis (PMID: 7199388, 9188772, 14718166,16258499). This feature, which is unique to the H3.3 histone, is attributable to the presence of three unique amino acids, which favor the ability of H3.3 to destabilize nucleosomes in transcriptionally active regions (PMID: 19633671,15776021). Studies in H3-3B knockout mice have shown that H3.3 plays a significant role in the regulation of chromatin, which is important for genome integrity and cell cycle progression (PMID: 23570311). Somatic mutations in H3-3B are seen in approximately 95% of chondroblastomas, with the most common alteration being K36M, which is expected to inhibit methylation at that site (PMID: 26457357, 24162739). In addition, a novel variant in the 3' UTR of the H3-3B gene has been identified in ovarian cancer (PMID:15870878). False +ENST00000366696 NM_003493.2 8290 H3-4 False H3-4, a histone variant, is infrequently altered by mutation in various cancer types. H3-4 is a replication coupled histone variant of unknown physiologic and pathological functions that encodes H3.1t, (PMID: 21481529, 26527279, 25539924). Histone molecules allow for the effective packaging of DNA in the nucleus and are built out of nucleosomes assembled from histone proteins H2A, H2B, H3 and H4(PMID: 11498575). False +ENST00000340398 NM_001013699.2 440093 H3-5 False H3-5, a histone variant, is infrequently altered by mutation in various cancer types. H3-5 is the histone variant H3.5, which is expressed in the human testes (PMID: 21274551). Histone molecules allow for the effective packaging of DNA in the nucleus and are built out of nucleosomes assembled from histone proteins H2A, H2B, H3 and H4 (PMID: 11498575). Histone variants, such as H3.5, are highly conserved compared to the canonical histone protein differing by only a few amino acids. H3-5 is highly expressed in the testes and binds near transcription start sites, implicating H3-5 in transcriptional activation (PMID: 26779285). Somatic H3-5 mutations have not been functionally validated. False +ENST00000613854 NM_003529.2 8350 H3C1 False The H3C1 gene encodes H3.1, an H3 histone variant. The H3C1 gene encodes histone H3.1, a replication dependent histone H3 variant (PMID: 21481529,26527279, 25539924). Histone proteins are an essential component of the nucleosome which consists of DNA wrapped around eight histone protein cores (two sets of each H2A, H2B, H3 and H4 histones), and therefore allow for the effective packaging of DNA in the nucleus (PMID:11498575). Histone variants, such as H3.1 and H3.2 have sequences that differ from the canonical histone protein by only a few amino acids and appear to be interchangeable with the major protein form (PMID: 25561719). False +ENST00000369163 NM_003536.2 8357 H3C10 False H3C10, a histone variant, is infrequently altered by mutation in various cancer types. The H3C10 gene encodes histone H3.1, a replication dependent Histone H3 variant (PMID: 21481529,26527279, 25539924). Histone proteins are an essential component of the nucleosome which consists of DNA wrapped around eight histone protein cores (two sets of each H2A, H2B, H3 and H4 histones), and therefore allow for the effective packaging of DNA in the nucleus (PMID:11498575). Histone variants, such as H3.1 and H3.2 have sequences that differ from the canonical histone protein by only a few amino acids and appear to be interchangeable with the major protein form (PMID: 25561719). False +ENST00000616365 NM_003533.2 8354 H3C11 False H3C11, a histone variant, is infrequently altered by mutation in various cancer types. H3C11 is a replication-dependent histone variant that encodes H3.1 (PMID: 21481529,26527279, 25539924). Histone molecules allow for the effective packaging of DNA in the nucleus and are built out of nucleosomes assembled from histone proteins H2A, H2B, H3 and H4(PMID: 11498575). Histone variants, such as H3.1, have highly conserved sequences compared to the canonical histone protein differing by only a few amino acids. H3C11 K36M mutations have been identified in head and neck cancer; these alterations disrupt methylation/acetylation at that residue with implications for gene expression (PMID: 25484917). False +ENST00000359303 NM_003535.2 8356 H3C12 False H3C12, a histone variant, is infrequently altered by mutation in various cancer types. H3C12 is a replication-dependent histone H3 variant that encodes H3.1 (PMID: 21481529,26527279, 25539924). Histone proteins are an essential component of the nucleosome which consists of DNA wrapped around eight histone protein cores (two sets of each H2A, H2B, H3 and H4 histones), and therefore allow for the effective packaging of DNA in the nucleus (PMID:11498575). Histone variants, such as H3.1 and H3.2 have sequences that differ from the canonical histone protein by only a few amino acids and appear to be interchangeable with the major protein form (PMID: 25561719). False +ENST00000331491 NM_001123375.2 653604 H3C13 False H3C13, a histone variant, is infrequently altered by mutation in various cancer types. H3C13 is a replication-dependent histone H3 variant that encodes H3.2 (PMID: 21481529,26527279, 25539924). Histone proteins are an essential component of the nucleosome which consists of DNA wrapped around eight histone protein cores (two sets of each H2A, H2B, H3 and H4 histones), and therefore allow for the effective packaging of DNA in the nucleus (PMID:11498575). Histone variants, such as H3.1 and H3.2 have sequences that differ from the canonical histone protein by only a few amino acids and appear to be interchangeable with the major protein form (PMID: 25561719). False +ENST00000369158 NM_021059.2 126961 H3C14 False H3C14, a histone variant, is infrequently altered by mutation in various cancer types. H3C14 is a replication-dependent histone H3 variant gene that encodes histone H3.2 (PMID: 21481529,26527279, 25539924). Histone proteins are an essential component of the nucleosome which consists of DNA wrapped around eight histone protein cores (two sets of each H2A, H2B, H3 and H4 histones), and therefore allow for the effective packaging of DNA in the nucleus (PMID:11498575). Histone variants, such as H3.1 and H3.2 have sequences that differ from the canonical histone protein by only a few amino acids and appear to be interchangeable with the major protein form (PMID: 25561719). False +ENST00000403683 NM_001005464.2 333932 H3C15 False H3C15, a histone variant, is infrequently altered by mutation in various cancer types. H3C15 is a replication-dependent histone H3 variant that encodes H3.2 (PMID: 21481529, 26527279, 25539924). Histone proteins are an essential component of the nucleosome which consists of DNA wrapped around eight histone protein cores (two sets of each H2A, H2B, H3 and H4 histones), and therefore allow for the effective packaging of DNA in the nucleus (PMID:11498575). Histone variants, such as H3.1 and H3.2 have sequences that differ from the canonical histone protein by only a few amino acids and appear to be interchangeable with the major protein form (PMID: 25561719). False +ENST00000621411 NM_003537.3 8358 H3C2 False The H3C2 gene encodes H3.1, an H3 histone variant. The H3C2 gene encodes histone H3.1, a replication dependent histone H3 variant (PMID: 21481529,26527279, 25539924). Histone proteins are an essential component of the nucleosome which consists of DNA wrapped around eight histone protein cores (two sets of each H2A, H2B, H3 and H4 histones), and therefore allow for the effective packaging of DNA in the nucleus (PMID:11498575). Histone variants, such as H3.1 and H3.2 have sequences that differ from the canonical histone protein by only a few amino acids and appear to be interchangeable with the major protein form (PMID: 25561719). H3C2 K27M mutations have been found in pediatric diffuse pontine glioma; these alterations disrupt a methylation site that is important for compacting chromatin and transcriptional repression. False +ENST00000612966 NM_003531.2 8352 H3C3 False H3C3, a histone variant, is infrequently altered by mutation in various cancer types. H3C3 is a histone variant gene that encodes the replication-dependent histone H3.1 (PMID: 21481529,26527279, 25539924). Histone proteins are an essential component of the nucleosome which consists of DNA wrapped around eight histone protein cores (two sets of each H2A, H2B, H3 and H4 histones), and therefore allow for the effective packaging of DNA in the nucleus (PMID:11498575). Histone variants, such as H3.1 and H3.2 have sequences that differ from the canonical histone protein by only a few amino acids and appear to be interchangeable with the major protein form (PMID: 25561719). False +ENST00000356476 NM_003530.4 8351 H3C4 False H3C4, a histone variant, is infrequently altered by mutation in various cancer types. H3C4 is a replication-dependent histone H3 variant that encodes histone H3.1 (PMID: 21481529,26527279, 25539924). Histone proteins are an essential component of the nucleosome which consists of DNA wrapped around eight histone protein cores (two sets of each H2A, H2B, H3 and H4 histones), and therefore allow for the effective packaging of DNA in the nucleus (PMID:11498575). Histone variants, such as H3.1 and H3.2 have sequences that differ from the canonical histone protein by only a few amino acids and appear to be interchangeable with the major protein form (PMID: 25561719). False +ENST00000634733 NM_003532.2 8353 H3C6 False H3C6, a histone variant, is infrequently altered by mutation in various cancer types. H3C6 is a replication-dependent histone H3 variant that encodes histone H3.1 (PMID: 21481529,26527279, 25539924). Histone proteins are an essential component of the nucleosome which consists of DNA wrapped around eight histone protein cores (two sets of each H2A, H2B, H3 and H4 histones), and therefore allow for the effective packaging of DNA in the nucleus (PMID:11498575). Histone variants, such as H3.1 and H3.2 have sequences that differ from the canonical histone protein by only a few amino acids and appear to be interchangeable with the major protein form (PMID: 25561719). False +ENST00000618052 NM_021018.2 8968 H3C7 False H3C7, a histone variant, is infrequently altered by mutation in various cancer types. The H3C7 gene encodes histone H3.1, a replication dependent histone H3 variant (PMID: 21481529, 26527279, 25539924). Histone proteins are an essential component of the nucleosome which consists of DNA wrapped around eight histone protein cores (two sets of each H2A, H2B, H3 and H4 histones), and therefore allow for the effective packaging of DNA in the nucleus (PMID:11498575). Histone variants, such as H3.1 and H3.2 have sequences that differ from the canonical histone protein by only a few amino acids and appear to be interchangeable with the major protein form (PMID: 25561719). False +ENST00000614378 NM_003534.2 8355 H3C8 False H3C8, a histone variant, is infrequently altered by mutation in various cancer types. The H3C8 is a replication-dependent histone H3 variant that encodes H3.1 (PMID: 21481529,26527279, 25539924). Histone proteins are an essential component of the nucleosome which consists of DNA wrapped around eight histone protein cores (two sets of each H2A, H2B, H3 and H4 histones), and therefore allow for the effective packaging of DNA in the nucleus (PMID:11498575). Histone variants, such as H3.1 and H3.2 have sequences that differ from the canonical histone protein by only a few amino acids and appear to be interchangeable with the major protein form (PMID: 25561719). False +ENST00000369387 440926 H3P6 False H3P6, a histone variant pseudogene, is infrequently altered by amplification in various cancer types. H3P6 is a pseudogene of H3P6 with unknown function. Chromatin is the physiological template of human genetic information and is built out of nucleosomes, which are octamers assembled from histones proteins H2A, H2B, H3 and H4 (PMID: 11498575). H3P6 is altered by amplification in several cancer types (cBioportal, August 2019). False +ENST00000244537 NM_003540 8361 H4C6 False H4C6, a canonical histone H4 protein, is infrequently altered in cancer. H4C6, also known as HIST1H4F, is a canonical histone H4 gene that encodes a protein that functions as a nucleosome subunit of chromatin (PMID: 12408966, 7412879). H4C6 is one of fourteen expressed H4 genes that encode for the histone H4 (PMID: 35202563). Histone proteins, essential components of the nucleosome, consist of DNA wrapped around eight histone protein molecules (two sets of each H2A, H2B, H3 and H4 histones), and therefore allow for the effective packaging of DNA in the nucleus (PMID: 11498575). H4C6 is expressed in a variety of cell types; however, the function has not yet been well characterized in biochemical studies. Hypermethylation of H4C6 has been identified in various different cancer types, including lung cancer, bladder cancer and hepatocellular carcinoma, and has been suggested to be a universal-cancer-only methylation marker (PMID: 31575549, 36898511, 21625442). False +ENST00000373548 NM_004964.2 3065 HDAC1 True HDAC1, a histone deacetylase, is infrequently altered by mutation in liposarcoma. HDAC1 is a histone deacetylase that is termed a Class I HDAC, in a family with HDAC2, HDAC3, and HDAC8 (PMID: 27599530). Histone deacetylases remove the acetyl group from relevant lysine amino acids on either histone or non-histone cellular substrates, altering epigenetic state and gene transcription (PMID: 24691964). HDAC1 activity regulates several key cellular functions including apoptosis, cell cycle, DNA damage response, and metastasis (PMID: 22147512, 27599530). In addition, HDAC1 deacetylates tumor suppressors and oncogenes, including TP53, HIF-1α, MLL and NK-kB (PMID: 11931769, 12829790), impacting their activity. Knockdown of HDAC1 expression in preclinical models results in an anti-proliferative effect, leading to an induction in p21 and p27 and repression of several cyclins and cyclin-dependent kinases (PMID: 22496786). Somatic HDAC1 mutations are found in patients with liposarcoma (PMID: 22328974); however, alterations tend to be rare in human cancers. Increased expression of HDAC1 is associated with poor outcomes in several tumor types including gastric and ovarian cancers, among others (PMID: 25482492). A variety of HDAC inhibitors are FDA-approved for the treatment of several cancers including vorinostat (cutaneous T cell lymphoma), romidepsin (cutaneous T cell lymphoma), panobinostat (multiple myeloma), and belinostat (peripheral T cell lymphoma). These HDAC inhibitors and others are currently in preclinical and clinical testing for efficacy in additional indications (PMID: 27599530). False +ENST00000519065 NM_001527.3 3066 HDAC2 True HDAC2, a histone deacetylase, is infrequently altered in cancer. HDAC2 encodes for a histone deacetylase that functions in the deacetylation of lysine residues on the N-terminal part of core histones H2A, H2B, H3 and H4 (PMID: 28497810). HDAC2 is a component of multiple corepressor complexes and functions in transcriptional repression of various genes involved in physiological cellular processes (PMID: 12724404, 12493763, 10888872). Overexpression of HDAC2 in various cancer cell lines and models induces cellular proliferation, dysregulation of G1/S cell cycle progression and decreased apoptosis, suggesting that HDAC2 functions predominantly as an oncogene (PMID: 34365463, 23175521, 22492270). Amplification of HDAC2 has been identified in various types of cancer, including breast cancer, pancreatic cancer and colon cancer (PMID: 28560068, 34903606, 24948597). A variety of pan-HDAC inhibitors are FDA-approved for the treatment of several cancers including vorinostat (cutaneous T cell lymphoma), panobinostat (multiple myeloma) and belinostat (peripheral T cell lymphoma) (PMID: 27599530). False +ENST00000345617 NM_006037.3 9759 HDAC4 True HDAC4, a histone deacetylase, is infrequently altered by deletion and mutation in a diverse range of cancers. HDAC4 is a histone deacetylase that is termed a Class IIa HDAC, in a family with HDAC5, HDAC7, and HDAC9 (PMID: 27599530). Histone deacetylases remove the acetyl group from relevant lysine amino acids on either histone or non-histone cellular substrates, altering epigenetic state and gene transcription (PMID: 24691964). HDAC4 activity regulates several key cellular functions including cell cycle, DNA damage response and angiogenesis (PMID: 12668657, 19071119). Expression of 53BP1, a DNA damage protein, co-localizes with HDAC4 and regulates the DNA damage-induced G2 checkpoint (PMID: 12668657). Additionally, HDAC4 transcriptionally activates HIF-1α (PMID: 19071119). Somatic HDAC4 mutations are rare in human cancers; however, HDAC4 is predicted to function as an oncogene or tumor suppressor in different cellular contexts. Deletions in HDAC4 are found in patients with melanoma (PMID: 21571862) while overexpression of HDAC4 is associated with gastric and acute lymphocytic leukemia (PMID: 25091122, 23948281). A variety of pan-HDAC inhibitors are FDA-approved for the treatment of several cancers including vorinostat (cutaneous T cell lymphoma), panobinostat (multiple myeloma), and belinostat (peripheral T cell lymphoma). These HDAC inhibitors and others are currently in preclinical and clinical testing for efficacy in additional indications (PMID: 27599530). True +ENST00000427332 XM_011538481.1 51564 HDAC7 True HDAC7, a histone deacetylase, is infrequently altered by mutation in a diverse range of human cancers. HDAC7 is a histone deacetylase that is termed a Class IIa HDAC, in a family with HDAC4, HDAC5, and HDAC9 (PMID: 27599530). Histone deacetylases remove the acetyl group from relevant lysine amino acids either on histone or non-histone cellular substrates, altering epigenetic state and gene transcription (PMID: 24691964). HDAC7 activity regulates several key cellular functions including downstream signaling, B cell lineage commitment, stem cell maintenance and angiogenesis (PMID: 12668657, 19071119, 27810920, 27694895, 26853466). HDAC7 controls thymic effector transcription in natural killer T cells (PMID: 29664401), transcriptionally activates HIF-1α (PMID: 15280364), and acetylates key signaling molecules including STAT3 (PMID: 29126425). Somatic HDAC7 mutations are rare in human cancers; however, overexpression of HDAC7 has been identified in a variety of tumor types including pancreatic, childhood acute lymphocytic leukemia (ALL) and chronic lymphocytic leukemia (PMID: 20636436, 18506539, 23108383). A variety of pan-HDAC inhibitors are FDA-approved for the treatment of several cancers including vorinostat (cutaneous T cell lymphoma), panobinostat (multiple myeloma), and belinostat (peripheral T cell lymphoma). These HDAC inhibitors and others are currently in preclinical and clinical testing for efficacy in additional indications (PMID: 27599530). False +ENST00000357618 NM_000410 3077 HFE True HFE, a transmembrane protein, is altered by mutation in various cancers. Germline HFE mutations are associated with hemochromatosis and predispose to various cancers. HFE encodes a transmembrane protein that functions primarily in regulating iron uptake and competing with transferrin for binding to transferrin receptor 1 (TRF1) (PMID: 18316026, 15056661). HFE regulates iron homeostasis in liver and intestinal cells through binding to TRF1 to modulate production of hepcidin, a peptide hormone which mediates systemic iron changes (PMID: 15467009, 12429850, 12547226, 18316026). HFE mutations have been implicated in dysregulated iron absorption disorders, such as type 1 hemochromatosis and porphyria (PMID: 15280838, 37163822). Knockdown of HFE in head and neck squamous cell carcinoma models repressed cellular proliferation and tumor growth, suggesting that HFE functions predominantly as an oncogene in this context (PMID: 23991213). Germline mutations of HFE have been implicated in increased susceptibility to various cancers, including breast cancer, hepatocellular carcinoma and colorectal cancer (PMID: 26893171, 20099304). False +ENST00000222390 NM_000601.4 3082 HGF True HGF encodes the natural ligand of the tyrosine kinase MET. Aberrant HGF expression with increased MET signaling has been described in various tumor types and results in increased cell survival, motility and metastasis. HGF (hepatocyte growth factor/scatter factor) is a multidomain protein that directly binds to the tyrosine kinase MET, which leads to its dimerization and activation (PMID: 3319692, 2531289). HGF is primarily expressed as pro-HGF and needs proteolytic activation to form HGF (PMID: 22270953, 1826653). MET activation leads to tyrosine phosphorylation and downstream activation of various effector proteins such as PLC, GAB1, GRB2 and SRC. HGF/MET signaling is physiolgically required for liver and skin regeneration as well as Epithelial-to-mesenchymal-transition (EMT) in embryogenesis. In cancer, HGF/MET signaling is involved in stemness, metastasis and angiogenesis (PMID: 22270953). Downstream effectors in the context of cancer involve the WNT-beta-catenin pathway, PI3K-AKT as well as TGFbeta signalling. A number of small molecule and antibody based MET receptor inhibitors have been developed and are tested in clinical trials with variable results. False +ENST00000337138 NM_001530.3 3091 HIF1A True HIF1A, an oxygen-regulated transcription factor, is infrequently mutated in human cancers. HIF1A is a transcription factor subunit that mediates gene expression in hypoxic conditions (PMID: 13130303). HIF-1, a transcriptional activator that is stabilized in the absence of oxygen, is composed of HIF1A, an oxygen-regulated subunit, and HIF1B, a ubiquitously expressed subunit (PMID: 20965423). In normoxic conditions, the E3 ligase VHL ubiquitinates and targets HIF1A to the proteasome for degradation via binding coordinated by hydroxylation (PMID: 13130303). Normal oxygen levels also preclude the binding of the transcriptional activators p300 and CBP to HIF1A, inhibiting HIF1A-dependent transcriptional activation (PMID: 24421387). In hypoxic conditions, VHL can no longer bind HIF1A due to loss of hydroxylation, resulting in protein stabilization of HIF1A (PMID: 13130303). HIF1A regulates an extensive network of transcriptional activity during hypoxia including regulation of genes involved in cell proliferation, cell survival, apoptosis, metabolism, angiogenesis, and cell adhesion, among others (PMID: 13130303, 28741521, 26955619). Vascular endothelial growth factor (VEGF), a gene involved in angiogenesis, is the most well-established HIF1A transcriptional target; most other transcriptional changes are context dependent. Somatic mutations in HIF1A are rare in human cancers; however, overexpression of HIF1A is found in many tumor types. Intratumoral hypoxia is common in malignant tumors, and increased HIF1A expression has been identified in tumors that have mutations in relevant hypoxia-related genes such as VHL (PMID: 26955619, 24446253). False +ENST00000263208 NM_003325 7290 HIRA False HIRA, a histone chaperone protein, is infrequently altered in cancer. HIRA encodes for a histone chaperone that functions in nucleosome assembly with the H3.3 histone variant (PMID: 16251970). HIRA colocalizes with other histone-binding proteins such as UBN1, CABIN1 and ASF1a to form the HIRA chaperone complex and deposit histone H3.3 at its binding sites (PMID: 23602572). HIRA functions in the repression of histone gene transcription during the cell cycle to trigger a block of DNA synthesis (PMID: 12370293). Deficiency in HIRA in various types of cancer cell types and models induces cellular proliferation and invasion, suggesting that HIRA functions predominantly as a tumor suppressor gene (PMID: 36269833, 11238922, 25512559). Downregulation of HIRA has been identified in hereditary leiomyomatosis and renal cell carcinoma (PMID: 36269833). True +ENST00000376809 NM_001242758.1 3105 HLA-A False HLA-A, an MHC class I component involved in the presentation of antigens to the immune system, is infrequently altered in cancer. HLA-A is a heavy chain subunit of the major histocompatibility class I (MHC I) complex. A critical component of the immune system is the presentation of foreign antigens on the cell surface by the MHC molecules (PMID: 10974135). Tumor cells are vulnerable to such an immune response due to the presentation of tumor-specific antigens, such as mutated oncoproteins, on the cell surface (PMID: 24782321, 24244023, 23157435). Several types of tumors are known to evade such an immunological response by crippling the levels of MHC I-presenting antigens on the tumor cell surface (PMID: 24782321, 24244023, 23157435, 11665717). The HLA-A genes encode for the heavy chain subunit of the MHC (PMID: 22434516). A reduction in HLA-A levels is seen in many tumors, which may be due to factors like genomic alteration, transcriptional regulation, protein transportation, and oncogene regulation (PMID: 24244023, 11665717). Genomic alterations are observed only rarely; chromosomal loss resulting in loss of the HLA locus is observed in 13.8% of colon tumors, 17.6% of laryngeal tumors, 15.3% of melanoma tumors and 17.2% of epithelial squamous cell carcinomas (PMID: 9057360). In HCT116 colorectal cancer cells HLA-A1 and HLA-A2 are down regulated by DNA methylation and by the action of the MEK pathway (PMID: 19569244). Similarly, gastric and esophageal cancers also display HLA-A downregulation via action of RAS, MYC and the HER2 oncogene, as well as the MAP kinase signal transduction pathway (PMID: 24244023, 20715101, 20628381). True +ENST00000412585 NM_005514.6 3106 HLA-B False HLA-B, an MHC class I component involved in antigen presentation to the immune system, is infrequently altered in cancer. HLA-B is a heavy chain subunit of the major histocompatibility class I (MHC I) complex. This protein is involved in the presentation of foreign antigens to the immune system. A critical component of the immune system is the presentation of foreign antigens on the cell surface by the MHC molecules (PMID: 10974135, 15719024). Immune recognition leads to the stimulation of a signaling cascade that results in apoptosis of MHC-presenting target cells (PMID: 15719024). Tumor cells are vulnerable to such an immune response due to the presentation of tumor-specific antigens such as mutated oncoproteins on the cell surface (PMID: 24782321, 24244023, 23157435). HLA-B is anchored in the membrane of most cells, and it has a highly polymorphic region that facilitates a wide binding specificity for a variety of antigens that need to be presented to cytotoxic immune T cells (PMID: 25493333). Germline polymorphisms and haplotypes in HLA-B have been linked with various autoimmune syndromes and hypersensitivity to certain medications (PMID: 22188278, 25877443). True +ENST00000376228 NM_002117.5 3107 HLA-C False HLA-C, an MHC class I component involved in antigen presentation to the immune system, is infrequently altered in cancer. HLA-C is a heavy chain subunit of the major histocompatibility class I (MHC I) complex. HLA-C is one of the three MHC I surface receptors that function as a heterodimer in collaboration with β-microglobulin to regulate immune responses (PMID: 15719024). A critical component of the immune system is the presentation of foreign antigens on the cell surface by the MHC molecules (PMID: 10974135, 15719024). Immune recognition leads to the stimulation of a signaling cascade that results in apoptosis of MHC-presenting target cells (PMID: 15719024). Tumor cells are vulnerable to such an immune response due to the presentation of tumor-specific antigens such as mutated oncoproteins on the cell surface (PMID: 24782321, 24244023, 23157435). HLA-C molecules are highly polymorphic and the breadth of these repertoires can predispose to autoimmune diseases such as psoriasis (PMID: 28855257, 16642438). Several types of tumors are known to evade an immunological response by downregulating the levels of MHC I-presenting antigens on the tumor cell surface (PMID: 24782321, 24244023, 23157435, 11665717). A reduction in HLA-C levels in cancer could occur due to many factors including mutation, transcriptional downregulation, epigenetic silencing and protein stability, among others (PMID: 26796069, 26372948, 31564637). HLA-C downregulation may result in reduced efficacy of immunotherapy in patients whose cancers display an evasion of the immune system (PMID: 9057360, 24782321, 23157435, 26796069). True +ENST00000311487 NM_145899 3159 HMGA1 True HMGA1, a chromatin remodeling protein, is altered by amplification in cancer. HMGA1 encodes for the chromatin remodeling protein isoforms HGMA1a and HGMA1b through alternative splicing (PMID: 6297996, 3192537). HMGA1 has three AT-hook DNA binding domains to bind AT-rich regions in the minor groove of the DNA in chromatin, allowing the recruitment of transcription factor and histone modification proteins to remodel chromatin and modulate gene expression (PMID: 8374955). HMGA1 participates in various cellular processes through gene modulation including cell cycle progression, embryologic development, neoplastic transformation, cellular differentiation, apoptosis, cellular metabolism and DNA repair (PMID: 11389094, 8957086, 11134344, 11076660, 12700639, 15924147, 16007157). Overexpression of HMGA1 in cancer cell lines results in increased cell proliferation, tumor growth and metastasis, suggesting that HMGA1 predominantly functions as an oncogene (PMID: 10866296, 22276142). HMGA1 amplification has been identified in various cancer types, including pancreatic cancer, colon cancer, breast cancer and cervical cancer (PMID: 22249617, 34167089, 23545254, 9458084). Chromosomal rearrangements of HMGA1 leading to amplified HMGA1 expression have been identified in various common benign mesenchymal tumors (PMID: 9060829, 9290959, 8946199). False +ENST00000403681 NM_003483 8091 HMGA2 True HMGA2, a chromatin remodeling protein, is altered by amplification in cancer. HMGA2, or HMGI-C, encodes a chromatin remodeling protein that binds to DNA through AT-hook DNA binding domains, allowing recruitment of transcription factor and histone modification proteins to remodel chromatin and modulate gene expression (PMID: 1692833, 3456586). HMGA2 regulates the transcriptional activity of genes, such as cyclin A and ERCC1, through binding to specific AT-rich sites at the gene promoter region (PMID: 14645522, 14627817). HMGA2 expression is upregulated widely in undifferentiated cells during embryogenesis, and eventually expression is downregulated or absent in tissues over the course of fetal development and into adulthood (PMID: 7651535). Overexpression of HMGA2 in cancer cell lines and mice results in tumor growth and metastasis, suggesting that HMGA2 predominantly functions as an oncogene (PMID: 25014774, 10945639). HMGA2 amplification has been identified in various cancer types, including esophageal squamous carcinoma, colorectal cancer and ovarian cancer (PMID: 27027341, 21252160, 17600087). Chromosomal rearrangements of HMGA2 leading to overexpression have been identified in various common benign mesenchymal tumors (PMID: 7670494). False +ENST00000257555 NM_000545.5 6927 HNF1A False HNF1A, a transcription factor, is altered by mutation in various cancer types. Germline mutations of HNF1A are associated with Maturity Onset Diabetes of Young (MODY3) and hepatic adenomas familial (HEPAF), while somatic inactivating mutations are found in a diverse range of cancers. HNF1A is a liver-specific transcription factor that is a member of the hepatocyte nuclear factor protein family. HNF1A, together with other hepatocyte nuclear factors (HNF4A, HNF6) forms tissue-specific regulatory circuits and acts as master regulators of liver and pancreatic islet transcription (PMID:14988562). HNF1A-/- mice showed defects in hepatic function, renal Fanconi syndrome, type II diabetes and hypercholesterolemia (PMID: 11279518). Heterozygous germline mutations in HNF1A cause Maturity Onset Diabetes of Young or MODY3 (PMID: 8945470). Bi-allelic somatic inactivating mutations and deletions in HNF1A are seen in about 40-50% of hepatocellular adenomas (HCAs) (PMID: 12355088). Two HNF1A mutations, W206 (DNA binding domain) and P291 (Trans-activation domain), have been found over represented across different studies (PMID: 16496320, 20393147, 12355088). Among them, W206 is unique to HCA while P291 is common to both HCA and MODY. In rare cases of hepatocellular carcinomas (HCCs), HNF1A mutations were seen in combination with other genetic alterations (PMID: 12355088). True +ENST00000617811 NM_000458 6928 HNF1B False HNF1B, a transcription factor, is infrequently altered in cancer. HNF1B, a member of the homeobox-containing basic helix-turn-helix family, encodes for a DNA-binding transcription factor that forms a homodimer or heterodimer with HNF1A (PMID: 1763325, 7900999). HNF1B regulates various cellular processes, such as cellular differentiation, apoptosis and autophagy, through the repression and activation of target genes (PMID: 28622294, 25715395). Alterations of HNF1B are found in a large percentage of dominant inherited nephropathy (PMID: 33305128, 21775974). The oncogenic function of HNF1B is likely tissue-specific. Ectopic expression of HNF1B in prostate cancer and serous ovarian carcinoma cell lines suppresses cellular proliferation, migration and invasion, suggesting that HNF1B functions predominantly as a tumor suppressor gene in this tissue context (PMID: 31636385, 33174391, 24105991). Downregulation of HNF1B has been identified in renal cancer, colon adenocarcinoma, glioblastoma, kidney chromophobe and lung squamous cell carcinoma (PMID: 15168014, 28807937, 33173410). Conversely, upregulation of HNF1B has been identified in bladder urothelial carcinoma, cholangiocarcinoma, kidney renal papillary cell carcinoma, liver hepatocellular carcinoma, stomach adenocarcinoma, thyroid carcinoma and uterine corpus endometrial carcinoma (PMID: 33173410). False +ENST00000006015 NM_005523 3207 HOXA11 False HOXA11, a homeobox gene transcription factor, is altered by downregulation and hypermethylation in various cancers. HOXA11, a member of the homeobox gene family, encodes for a transcription factor that primarily functions in embryogenesis and myogenesis (PMID: 36815629, 18942146, 11493536). HOXA11 regulates embryonic development events, such as limb outgrowth and the development of the urogenital tract (PMID: 22190701, 23561734). Germline mutations of HOXA11 have been implicated in the development of radioulnar synostosis with amegakaryocytic thrombocytopenia (PMID: 11101832, 16765069). The oncogenic function of HOXA11 is likely tissue specific. Ectopic expression of HOXA11 in various cancer cell lines and models suppresses cellular proliferation, migration and invasion, suggesting that HOXA11 functions predominantly as a tumor suppressor gene in these contexts (PMID: 28423531, 24259349, 33515421). Downregulation and hypermethylation of HOXA11 has been identified in non-small cell lung cancer, endometrial cancer and glioblastoma (PMID: 24259349, 33515421, 27456940). Conversely, overexpression of HOXA11 in gastric cancer cell lines and models induces cellular proliferation, migration and invasive metastasis, suggesting that HOXA11 may function predominantly as an oncogene in this context (PMID: 37539033). Preclinical studies have suggested downregulation of HOXA11 is associated with poor patient prognosis and confers chemoresistance in the context of glioblastoma (PMID: 27456940). True +ENST00000290295 NM_006361.5 10481 HOXB13 True HOXB13, a transcription factor, is altered by mutation in various cancer types. Germline mutations of HOXB13 predispose to certain cancers, including prostate cancer. HOXB13 is a member of the homeobox (HOX) gene family, which is a group of clustered transcription factors that are evolutionarily conserved and crucial for embryonic development along the anterior-posterior axis (PMID: 1346368). In addition to regulating body axis patterning in embryos, HOXB13 has roles in the regulation of cellular differentiation, proliferation, and cell cycle activity (PMID: 28798948). HOXB13 mediates gene expression in a cell-type specific manner due to variation in interactions with adaptor molecules. HOXB13 has been implicated in prostate cell identity, and mice lacking HOXB13 have prostate defects (PMID: 12668621). HOXB13 functions through the androgen receptor (AR) in both normal adult tissue and prostate cancer by regulating the chromatin state around the AR gene, and can have both growth-enhancing or growth-suppressing effects depending on context (PMID: 15604291, 19917249). Germline HOXB13 mutations have been found in familial prostate cancer and are predictive of prostate cancer risk (PMID: 22236224), while somatic HOXB13 mutations have been identified in several other cancer types (PMID: 28798948). Though HOXB13 is overexpressed during malignant progression of prostate and breast cancer (PMID: 20018680), it is downregulated in colorectal and renal cell cancer models, suggesting that it has context-specific effects in human tumors (PMID: 15928669, 16278676, 15193263, 17453342, 23832664). True +ENST00000451590 NM_005343.2 3265 HRAS True 3A HRAS, a GTPase, is altered in a diverse range of cancers including head and neck squamous cell carcinoma, thyroid, and bladder cancer. HRAS (Harvey Ras) is a membrane-associated GTPase. It plays an important role as an upstream mediator of several pro-proliferative and anti-apoptotic signal transduction pathways, including the mitogen activated protein kinase (MAPK) and PI3 kinase (PI3K) pathways. HRAS, NRAS and KRAS comprise the Ras proto-oncogene family, and all three have a similar structure and function. Transforming, gain-of-function mutations of RAS oncogenes tend to disrupt GTPase activity and promote cell proliferation and angiogenesis (PMID: 12778136). Overexpression of oncogenic HRAS also triggers growth factor-independent cell cycle progression and upregulation of proteins implicated in tumor growth (e.g., matrix metalloproteinases 2 and 9). HRAS mutations are found most commonly in cancers of the thyroid, salivary glands, bladder urinary tract, cervix and prostate (PMID: 21993244, 22589270). Patients with Costello syndrome, a hereditary disorder with germline alterations in HRAS, can develop various malignancies at a young age, including neuroblastoma, rhabdomyosarcoma and transitional cell carcinoma of the bladder (PMID: 22261753, 16170316). RAS mutations (including HRAS) have been found in a significant proportion of RET negative medullary thyroid cancer (PMID: 21325462, 23240926, 22865907, 23264394). And while multikinase inhibitors that include HRAS among its targets are FDA-approved for the treatment of medullary thyroid cancer, the FDA-approval is not based on the HRAS mutant status, therefore not explicitly meeting the OncoKB Level 1 criteria. False +ENST00000199936 NM_002153 3294 HSD17B2 False HSD17B2, a 17β-hydroxysteroid dehydrogenase, is infrequently altered in cancer. HSD17B2 encodes the 17β-hydroxysteroid dehydrogenase enzyme which functions in the catalyzation of estradiol to estrone, testosterone to androstenedione and androstenediol to dehydroepiandrosterone (DHEA) (PMID: 17538076, 19130396). The anti-estrogenic and anti-androgenic function of HSD17B2 maintains cell cycle homeostasis through negative regulation of hormone-induced proliferation and differentiation in endometrial tissue (PMID: 18270252). Overexpression of HSD17B2 in prostate cancer cell lines suppresses cell proliferation and xenograft growth, suggesting that HSD17B2 functions primarily as a tumor suppressor gene (PMID: 30228209). Downregulation of HSD17B2 has been identified in prostate cancer and breast cancer (PMID: 30228209, 18372405). True +ENST00000369413 NM_000862 3283 HSD3B1 True HSD3B1, a 3β-hydroxysteroid dehydrogenase, is altered by mutation and amplification in castration-resistant prostate cancer. HSD3B1 encodes for a 3β-hydroxysteroid dehydrogenase which functions in the formation of steroid hormones through the oxidation and isomerization of hydroxysteroid precursors (PMID: 1944309). HSD3B1 is essential to the androgen biosynthesis pathway to catalyze the rate-limiting step of adrenal precursor steroids (PMID: 20534728). Knockdown of HSD3B1 in breast cancer models suppresses tumor growth and cellular proliferation and migration, suggesting that HSD3B1 functions predominantly as an oncogene (PMID: 28744792). Amplification and mutations of HSD3B1 have been identified in castration-resistant prostate cancer and breast cancer (PMID: 34747051, 28744792). The HSD3B1(1245C) allele upregulates dihydrotestosterone synthesis and is associated with prostate cancer resistance to androgen-deprivation therapy and poor prognosis (PMID: 27575027). False +ENST00000216281 NM_005348 3320 HSP90AA1 True HSP90AA1, a heat shock protein, is infrequently altered in cancer. HSP90AA1, a member of the HSP90 family of heat shock proteins, encodes for a molecular chaperone which functions in maintaining cellular homeostasis and cell cycle control through ATPase activity (PMID: 11812147, 11274138). HSP90AA1 recruits ATP and co-chaperones to substrate proteins, referred to as client proteins, and facilitates assembly, folding and degradation (PMID: 34380015). The numerous client proteins of HSP90AA1 typically include steroid hormone receptors and protein kinases, such as PIM1, AKT and HIF1A (PMID: 10544245, 3900074, 30536958). Knockdown of HSP90AA1 in various cancer cell lines and models suppresses cellular proliferation and induces apoptosis, suggesting that HSP90AA1 functions predominantly as an oncogene (PMID: 35095481, 30153855). Upregulation of HSP90AA1 has been identified in various cancers, including colorectal cancer, breast cancer and hepatocellular carcinoma (PMID: 31687275, 34109171, 30521791). HSP90AA1 has been identified to confer multi-drug resistance in various cancer cell lines through inhibition of apoptosis and promotion of autophagy via the AKT and JNK pathways (PMID: 30153855, 33738259). False +ENST00000421577 NM_001098521 10553 HTATIP2 False HTATIP2, a nuclear transport inhibiting oxidoreductase, is altered by deletion in cancer. HTATIP2, also known as TIP30 or CC3, encodes an oxidoreductase that functions in nuclear transport inhibition through importin binding and transcription regulation (PMID: 15728189). HTATIP2 functions in the stimulation of TAT-mediated transcription, upregulating apoptosis and tumor suppression through transcription promotion of apoptosis-related genes Bad and Siva and tumor suppressor gene NM23-H2 (PMID: 10698937). TAT-mediated transcription enhancement occurs through HTATIP2 phosphorylating the C-terminal domain of the largest RNA polymerase II subunit in a TAT-dependent manner (PMID: 10698937). Overexpression of HTATIP2 in cancer cell lines results in reduced cell proliferation, reduced tumor metastasis and increased apoptosis, suggesting that HTATIP2 predominantly functions as a tumor suppressor (PMID: 30249892, 25617528, 25544767). Loss of HTATIP2 has been identified in various cancer types, including glioma, lung adenocarcinoma and hepatocellular carcinoma (PMID: 25617528, 32545251,19010857). Epigenetic silencing of HTATIP2 through hypermethylation is a mechanism identified in various cancer cells that results in HTATIP2 downregulation and is associated with poor patient prognosis (PMID: 25617528, 19010857). True +ENST00000407780 NM_015259.4 23308 ICOSLG True ICOSLG, an immune costimulatory ligand, is altered by mutation in primary immunodeficiencies. ICOSLG is a T-cell co-stimulator ligand which is constitutively expressed on B-cells and inducible on monocytes and dendritic cells. Co-stimulator ligands like ICOSLG are typically required for activation of T-cells, cytokine production, and antigen recognition by the T-cell receptor. ICOSLG binds to the co-stimulatory receptor, ICOS, which shares similar structural and functional similarities to CD28. ICOSLG expression on plasmacytoid dendritic cells has been associated with disease progression (PMID: 23026134) and may serve as a potential biomarker of trastuzumab resistance in breast cancer (PMID: 25449779). Germline mutations of ICOSLG and its promoter region are associated with common variable immunodeficiency and Alopecia areata (PMID: 23196741, 15963052). False +ENST00000376112 NM_002165 3397 ID1 True ID1, a DNA-binding inhibitor protein, is infrequently altered in cancer. ID1 encodes for a DNA-binding inhibitor protein that interacts with the basic helix-loop-helix family of transcription factors to regulate their activity (PMID: 2156629). As ID1 has no DNA binding activity of its own, interactions with the helix-loop-helix family of transcription factors result in the inhibition of DNA binding and transcriptional activity through the formation of nonfunctional heterodimeric complexes (PMID: 2156629). ID1 has been implicated in the promotion of cell proliferation, cell differentiation and cell cycle proliferation through the inactivation of tumor suppressor genes (PMID: 25924227). Overexpression of ID1 in various cancer cell lines and mouse models has demonstrated increased metastatic ability and cellular proliferation, suggesting that ID1 functions primarily as an oncogene (PMID: 32705157, 24160469, 25938540). ID1 amplification has been identified in various cancers, including pancreatic cancer, gastric cancer and glioblastoma (PMID: 31582374, 22245935, 31292163). False +ENST00000374561 NM_002167.4 3399 ID3 False ID3 encodes a helix-loop-helix protein involved in transcription. Mutations and overexpression of ID3 are found in a variety of cancers. ID3 (Inhibitor for DNA binding 3) is a protein that binds basic helix-loop-helix (HLH) transcription factors and inhibits their activity. ID3 proteins form heterodimers with tissue-specific HLH proteins, such as E proteins, that disrupt their binding to DNA (PMID: 2000388, 2156629, 16034366). ID3 can regulate cell differentiation, cell proliferation, cell invasiveness and angiogenesis (PMID: 8197168, 11840325, 11840326, 10197587, 11058077, 9528806, 16034366). Loss of ID3 expression in mice results in defects in B-cell proliferation and the development of lymphomas (PMID: 10454544). Loss-of-function mutations in ID3 are common in Burkitt's lymphoma and result in disruption of ID3 transcriptional activity (PMID: 23143595). ID3 is also overexpressed in various tumors, with both growth-enhancing and growth-suppressing effects (PMID: 26135667, 26384138, 10537105, 11689883, 11085505) suggesting that ID3 appears to have context-dependent oncogenic and tumor suppressor functions in cancer. True +ENST00000345146 NM_005896.2 3417 IDH1 True 1 IDH1, a cell metabolism enzyme, is recurrently mutated in various cancer types including acute myeloid leukemia and gliomas. The IDH1 (isocitrate dehydrogenase 1) protein is an enzyme that catalyzes the oxidative decarboxylation of isocitrate to α-ketoglutarate (α-KG), a crucial step in the tricarboxylic acid (TCA) cycle. IDH1 utilizes NADP(+) as an electron acceptor and it is predominantly expressed in the cytosol and peroxisomes, playing a role in the cytoplasmic production of NADPH. Cancer-associated mutations in the catalytic site of IDH1 confer a gain-of-function of neomorphic enzymatic activity, allowing the mutant enzyme to convert α-KG to the “oncometabolite” D-2-hydroxyglutarate (2-HG) (PMID: 20171147). 2-HG promotes tumor development by inhibiting a variety of enzymes that require α-KG as a substrate, including enzymes involved in DNA demethylation, histone demethylation, adaptation to hypoxia and collagen maturation. IDH1 mutations have been identified in glioma, cholangiocarcinoma and acute myeloid leukemia (AML) among others (PMID: 19657110, 23630074) and may contribute to the progression of myeloproliferative neoplasms to bone marrow failure or AML (PMID: 29355841). False +ENST00000330062 NM_002168.2 3418 IDH2 True 1 IDH2, a cell metabolism enzyme, is recurrently mutated in various cancer types including acute myeloid leukemia, glioblastoma, and cholangiocarcinoma. The IDH2 (isocitrate dehydrogenase 2) protein is an enzyme that catalyzes the oxidative decarboxylation of isocitrate to α-ketoglutarate (α-KG) in the tricarboxylic acid (TCA) cycle. IDH2 utilizes NADP(+) as an electron acceptor and it is expressed in the mitochondria, where it plays a role in cell metabolism and energy production via TCA cycle. Cancer-associated mutations in the catalytic site of IDH2 confer a gain-of-function of neomorphic enzymatic activity allowing the mutant enzyme to convert α-KG to the “oncometabolite” D-2-hydroxyglutarate (2-HG) (PMID: 20171147). 2-HG promotes tumor development by inhibiting a variety of enzymes that require α-KG as a substrate, including enzymes involved in DNA demethylation, histone demethylation, adaptation to hypoxia and collagen maturation (PMID: 23630074). IDH2 mutations have been identified in hematologic malignancies, particularly in acute myeloid leukemia (AML), as well as in solid tumors such as gliomas and cholangiocarcinomas, and may contribute to the progression of myeloproliferative neoplasms to bone marrow failure or AML (PMID: 29355841).. False +ENST00000270139 NM_000629 3454 IFNAR1 False IFNAR1, a subunit of the interferon receptor, is infrequently altered in cancer. IFNAR1 encodes the protein interferon alpha and beta receptor subunit 1, which, along with the IFNAR2 subunit, composes the type I interferon receptor (IFNAR) (PMID:33552080, 24362405). Binding of type I interferons to the receptor activates the JAK/STAT signaling pathway resulting in transcriptional activation or repression of interferon-regulated genes. IFNAR1 and IFNAR2 form a heterodimer complex and are associated with tyrosine kinase 2 (Tyk2) and JAK1, respectively, which are required for STAT recruitment to the receptor complex. STAT proteins are phosphorylated by the JAKs, which promote their translocation to the nucleus to regulate gene expression (PMID: 24362405, 22410872, 33552080, 32378445, 30555157). IFNAR is widely expressed in lymphocytes, natural killer cells and myeloid-derived suppressor cells (PMID: 36063748). The protein encoded by INFAR1 also functions as an antiviral factor (PMID: 24362405, 30555157). Inhibition of IFNAR1 signaling in natural killer cells has been demonstrated to promote virus clearance (PMID: 33771858). Elevated levels of IFNAR1 have been associated with poor prognosis in breast and head and neck squamous cell carcinoma, while in colorectal cancer elevated levels are positively associated with T-cell infiltration and better response to chemotherapy (PMID: 36063748, 30555157, 32378445). Overexpression of IFNAR1 in mammary adenocarcinoma cells results in elevated PD-L1 expression, suggesting pro-tumorigenic effects in this context (PMID: 32378445). False +ENST00000367739 NM_000416.2 3459 IFNGR1 False IFNGR1, a subunit of the interferon-γ receptor, is altered by deletion in metastatic melanomas that are resistant to immunotherapy. IFNGR1 is a high-affinity subunit of the interferon-γ (IFN-γ) receptor, which is required by macrophages for killing intracellular pathogens such as mycobacteria. After binding to interferon-γ, two IFNGR1 molecules form a heterodimeric complex with two IFNGR2 molecules, which initiates interferon signaling. IFNGR1 binds JAK1, and stimulation of the interferon response results in downstream activation of the JAK-STAT signaling pathway (PMID: 22410872). Three cases of malignancy have been reported in patients with complete IFNGR1 deficiency: human herpesvirus-8 associated Kaposi sarcoma (PMID:15069403), Epstein Barr Virus (EBV) related B-cell lymphoma (PMID: 23800860) and pineal germinoma, an intracranial tumor (PMID: 25216720). Mutations in IFNGR1 can result in enhanced susceptibility to mycobacterial infections, and low expression of IFNGR1 leads to a functional blockade of IFN-γ signaling (PMID:15589309). Somatic mutations in IFNGR1 have not yet been identified in human cancers, however, IFNGR1 expression is reduced in some breast cancers (PMID:22182699) and downregulated in a subset of metastatic prostate cancers (PMID:24953652). In addition, IFNGR1 deletions have been identified in patients with metastatic melanoma that are non-responders to anti-CTLA4 immunotherapies (PMID: 27667683). True +ENST00000307046 NM_001111285.1 3479 IGF1 True IGF1, an insulin growth factor, is infrequently altered by mutation in various cancer types. IGF1 is an insulin-like growth factor that signals through the IGF1 receptor (IGF1R) and the insulin receptor (IR). The main function of IGF1 is to stimulate growth in a wide array of tissues. IGF1 is broadly expressed however the liver produces the majority of circulating IGF1 in response to GH secreted by the pituitary. Circulating IGF1 is bound to IGF-binding proteins (IGFBPs), e.g. IGFBP3, and only the free IGF1 is biologically active. In epidemiologic studies, high circulating levels of IGF1 and low levels of IGFBP3 have been associated with breast, prostate, colon, lung, and genitourinary cancers (PMID: 9593409, 9365156, 9438850, 10203281, 9923856). Genetic variation in the 3-prime region of the IGF1 gene may contribute to increased circulating IGF1 levels (PubMed: 17911177). Tissues can regulate levels of IGF1R and IGFBPs to modify IGF1 signaling and alterations in this local control may result in cancer (PMID: 23569026). False +ENST00000650285 NM_000875.3 3480 IGF1R True IGF1R, an insulin growth factor receptor, is altered by mutation in various cancer types. IGF1R is an insulin-like growth factor receptor (PMID: 19029956), a tyrosine kinase which activates downstream pathways involved in growth and cell survival. IGF1R binds several ligands, including high affinity ligands (insulin-like growth factor I (IGF1)) and low-affinity ligands (insulin, insulin-like growth factor II (IGF2)) (PMID: 12360255, 19029956, 22337149). Binding to ligands activates two oncogenic pathways, the PI3-kinase/AKT pathway and the RAS-MAPK pathway (PMID: 25984556). Missense mutations of IGF1R are observed across the entire gene body, and several of these mutations have been linked to changes in the basal activity of IGF1R (PMID: 22778948). IGF1R is over-expressed in several cancers, and its over-expression in cell lines can induce transformation (PMID: 9196021). IGF1R is frequently mutated/amplified across a variety of cancer types (frequency ~8%) (cBioPortal, Nov 2015, PMID: 25984556). Binding of ligand to IGF1R has been reported to mediate both resistance and sensitivity to both targeted and cytotoxic therapy across a number of cancer types (PMID: 25984556, 22337149). Various therapeutics have been developed to target IGF1R, either as monoclonal antibodies against IGF1R or IGF1R ligands, or as inhibitors of the kinase activity of IGF1R, but these therapeutics have shown limited success in large clinical trials (PMID: 23601239, 24338270 ). False +ENST00000434045 NM_001127598.1 3481 IGF2 True IGF2, an insulin growth factor, is frequently altered by overexpression in various cancer types, including Wilms tumors. Loss of imprinting of IGF2 is associated with Beckwith-Wiedemann syndrome and predisposes to several pediatric cancers. IGF2 is an insulin growth factor which binds to receptor tyrosine kinases to activate downstream mitogenic signaling pathways (PMID: 24080445, 25704323). IGF2 binds to one of several receptor tyrosine kinases, including IGF1R and IR-A, to initiate a cascade that activates mitogenic and metabolic signaling via the PI3K-AKT and MAPK pathways (PMID: 24080445). In most adult tissues IGF2 is imprinted, and thus its expression is restricted to the paternal allele only (PMID: 12637750). Aberrant IGF2 expression, in many cases due to loss of imprinting, is implicated in the development of several tumor types (e.g. breast, ovarian, and Wilms tumors) (PMID: 17686827, 24080445), as well as the progression of tumors to more aggressive disease (e.g. breast cancer, chronic myeloid leukemia) (PMID: 20089431, 9558368, 24080445). Loss-of-imprinting of IGF2 is causative for Beckwith-Wiedemann syndrome, which confers an increased risk of developing childhood tumors such as Wilms’ tumor and hepatoblastoma (PMID: 8968759, 12668598, 23620526). Overexpression of IGF2 is also a critical event in non-islet cell tumor hypoglycemia (PMID: 24616774, 24080445). False +ENST00000581977 NM_014002.3 9641 IKBKE True IKBKE, an intracellular kinase, is altered by mutation and overexpression in various cancer types. Inhibitor of Kappa Light Polypeptide Gene Enhancer in B-Cell, Kinase Epsilon (IKBKE) is a serine/threonine kinase that has important functions in the regulation of inflammatory responses to infection as well as cancer (PMID: 23333767, 19160540). It is activated in cells that are infected with virus and as a result associates with DDX3X and phophorylates its target protein such as interferon regulatory factors (IRF3, IRF7) (PMID: 23333767, 19160540). As a result of their phosphorylation IRFs translocate to the nucleus and activate transcription of pro-inflammatory and anti-viral genes such as IFNB. IKBKE also phosphorylates inhibitors of NF-kappa-B leading to their degredation and further enhancing pro-inflammatory responses (PMID: 23333767, 19160540). It is overexpressed in >30% of primary breast cancer and amplifications affecting IKBKE locus have been observed (PMID: 23333767, 21042276, 17574021). IKBKE has been shown to exhibit oncogenic functions through the phosphorylation of CYLD at serine 418 and TRAF2 at serine 11(PMID: 19481526, 23007157). Additionally IKBKE also phosphorylates NF-kappa-B and AKT1 leading to higher NF-kappa-B activity (PMID: 21908616, 21464307). IKBKE has also been implicated in several other tumor entities (PMID:22942254, 19497997, 20001340, 21271611, 22266464). Recently, IKBKE inhibitors have been developed and are currently tested pre-clinically (PMID: 22305584, 23099093, 19426678). False +ENST00000331340 NM_006060.6 10320 IKZF1 False IKZF1 encodes a transcription factor involved in lymphocyte development. Loss-of-function alterations of IKZF1 are frequently found in B-cell acute lymphocytic leukemia. The IKZF1 gene encodes the Ikaros family zinc finger 1 transcription factor (IKZF1). IKZF1 functions in hematopoietic stem cells to induce lymphoid specification and differentiation (PMID: 19345118, 16518393). As a transcription factor, IKZF1 alters chromatin and regulates gene expression by recruiting histone deacetylases and chromatin remodeling ATPases to target genes (PMID: 10204490). IKZF1 is the target of lenalidomide-induced degradation in multiple myeloma and its degradation is a key component of the drug's activity in myeloma (PMID: 24292625). IKZF1 mutations and deletions are most commonly found in B-cell acute lymphocytic leukemia (B-ALL) and may be a mechanism of leukemic transformation in Philadelphia chromosome-positive (BCR-ABL) B-ALLs (PMID: 17344859, 18408710). Mutation of IKZF1 is associated with poor prognosis in B-ALL (PMID: 19129520). It is also deleted more rarely in other leukemias such as acute myeloid leukemia (PMID: 26069293, 25331116, 24072100). False +ENST00000346872 NM_012481.4 22806 IKZF3 True IKZF3, a hematopoietic-specific transcription factor, is altered by mutation and deletion in hematopoietic malignancies. IKZF3 (also Aiolos) is a transcription factor that functions as a member of the Ikaros protein family (PMID: 9560339). Ikaros family transcription factors are required for normal development of the lymphoid system (PMID: 9560339). IKZF1, IKZF2, and IKZF3 form homo- and heterodimers to increase their affinity to bind DNA and to activate hematopoietic-specific transcription (PMID: 9560339). Specifically, IKZF3 is more highly expressed in committed lymphoid progenitor cells and mediates differentiation into pre-T and pre-B cell precursors and subsequent maturation (PMID: 9155026, 9806640). In addition, IKZF3 interacts with histone modifying complexes, such as the NURD complexes, and mediates their activity during lymphocyte maturation (PMID: 10204490, 10357820). Anti-apoptosis genes, such as BCL-2 and BCL-XL, are regulated by IKZF3, leading to control of lymphocyte survival (PMID: 11714801, 10369681). Expression of IKZF3 is upregulated in chronic lymphocytic leukemias (CLL) (PMID: 19016725, 18184862) and missense hotspot mutations, predicted to stabilize the IKZF3 protein, have been identified in CLL (PMID: 28584254, 23415222). However, deletions in IKZF3 have been identified in acute lymphoblastic leukemia and other hematopoietic malignancies, suggesting IKZF3 may function as both an oncogene and tumor suppressor (PMID: 17344859, 24212482, 24072100). Lenalidomide, a drug with efficacy in multiple myeloma and B cell malignancies, specifically targets IKZF3 and IKZF1 for proteasome-mediated degradation, which contributes to the cytotoxicity of the drug (PMID: 24292625, 24292623). True +ENST00000423557 NM_000572.2 3586 IL10 False IL10, an anti-inflammatory cytokine, is not commonly mutated in cancer. IL-10 is a cytokine that inhibits the secretion of several pro-inflammatory cytokines by regulatory T cells, activated macrophages, and other immune cells (PMID: 11244051). IL-10 expression is tightly regulated by specific transcription factors based on immune cell type, which prevents excessive immune responses and autoimmune disease (PMID: 20154735). In macrophages and dendritic cells, IL-10 is involved in the regulation of the JAK-STAT signaling pathway and can block NF-κB activity (PMID: 14678266). IL-10 deficient mice develop inflammatory diseases with excessive immune responses after pathogen challenge (PMID: 24566625). Conversely, high IL-10 expression in mice has also been shown to promote an anti-tumor immune response (PMID: 18613832). IL-10 mutations have been identified in early-onset immune disorders such as inflammatory bowel disease (PMID: 25373860). Higher IL-10 levels are associated with more aggressive disease and increased macrophage recruitment following chemotherapy in pre-clinical models of breast cancer (PMID: 25559954) and blockade of IL-10 receptors can improve chemotherapy responses in mice (PMID: 25446896). False +ENST00000296870 NM_000588.3 3562 IL3 True IL3, a cytokine involved in immune regulation, is altered by chromosomal rearrangement in acute lymphoblastic leukemia. IL3 is an interleukin that is a member of the beta common (βc) cytokine family, which also includes IL5 and GM-CSF (PMID: 29374162, 23046136, 23535386). IL3 is highly expressed in activated T lymphocytes and is important in mediating the immune responses of mast cells, dendritic cells, and basophils (PMID: 23046136). The main receptor partner of IL3 is IL3R, a heterodimeric cell-surface receptor, which binds IL3 via the cytokine-specific α-subunit to recruit the shared βc subunit (PMID: 29374162). Initiation of IL3-IL3R signaling results in the activation of downstream effector pathways, including the JAK-STAT pathway which mediates STAT-dependent transcription of immune target genes (PMID: 18692472). IL3 signaling regulates various aspects of immune regulation including differentiation, inflammation, proliferation, and survival (PMID: 3087441, 18178860, 23535386). Increased IL3 expression in hematopoietic studies results in leukemic self-renewal and survival, suggesting that IL3 functions predominantly as an oncogene (PMID: 2439154, 10536003). Overexpression of IL3 has also been implicated in autoimmune diseases, resulting in hyper-responsiveness to IL3 stimulation (PMID: 18341658, 6430708, 28031576, 9446636, 26131743). Rearrangements involving IL3 are found in patients with B-precursor acute lymphoblastic leukemias, typically leading to increased IL3 expression and eosinophilic proliferation (PMID: 29424254, 3546615, 30207070). False +ENST00000336909 NM_002184.3 3572 IL6ST True IL6ST, a transmembrane signal transducer, is infrequently altered in cancer. IL6ST encodes gp130, a membrane glycoprotein that serves as the signal transducer for IL-6 family cytokines (PMID: 2261637). IL-6 cytokines bind to IL-6R, which leads to gp130 homodimerization and formation of a hexameric receptor complex with IL-6/IL-6R (PMID: 2261637, 19915009). gp130 then activates the JAK/STAT pathway through the effector STAT3 to regulate diverse cellular processes, including immune responses, development and hematopoiesis (PMID: 10661409, 8632998, 15650055). gp130 also mediates proliferation and cell migration independent of STAT3 by activating YAP, Notch and ERK1/2 signaling pathways (PMID: 25731159, 17256754). The activity of gp130 is negatively regulated by the inhibitor SOCS3 (PMID: 12754506). In-frame deletions in the binding site of gp130 result in the constitutive activation of the signal transducer and subsequent upregulation of its targets, including STAT3, YAP and Notch (PMID: 19020503). Mice engineered to express mutant gp130 exhibit increased STAT3 activation and rapid gastric tumorigenesis compared to wildtype (PMID: 18431520, 14699500). IL6ST is altered, mostly by in-frame deletions and missense mutations in the IL-6/IL-6R binding site, in inflammatory hepatocellular tumors (PMID: 19020503, 24501689). False +ENST00000303115 NM_002185.3 3575 IL7R True IL7R, a subunit of the interleukin 7 receptor, is altered in various hematologic malignancies including pediatric acute lymphoblastic leukemia. IL7R is a component of the interleukin 7 (IL7) receptor that heterodimerizes with the common interleukin 2 receptor gamma chain. IL7R signals through the JAK-STAT pathway (PMID:15067053). IL7 regulates T, B, and NK cell development (PMID:17013389, 25729925, 23242416, 22267219, 21167753). In addition, IL7R signaling regulates VDJ and T-cell receptr (TCR) rearragements (PMID:12594950, 9858510). IL7R mutations leading to loss of function result in severe combined immunodeficiency syndrome (SCID) (PMID:9843216, 24759676). Activating mutations in IL7R result in an oncogene that signals independently of cytokine binding (PMID:21892159). Activating IL7R mutations are most commonly found in pediatric acute lymphoblastic leukemia (PMID: 25207766, 22237106, 21536738). False +ENST00000375774 NM_005537 3621 ING1 False ING1, a nuclear protein, is infrequently altered in cancer. ING1, inhibitor of growth family member 1, is a member of the ING family, which consists of five protein-coding genes (ING1 to ING5) and a pseudogene (INGX) (PMID: 34685579). ING1 encodes a nuclear protein and component of the p53 signaling pathway that interacts with the tumor suppressor protein p53 (PMID: 24008732, 12015309, 11461112, 21286670). ING1 inhibits cellular proliferation via the regulation of pathways involved with apoptosis, cellular senescence, DNA repair, cell migration and invasion (PMID: 34685579, 34493070, 11461112). ING1 modulates transcription through chromatin remodeling via physical association with both histone acetyltransferases (HATs) and histone deacetylases (HDACs); this function is linked to its anti-proliferative and pro-apoptotic effects (PMID: 34493070, 12015309). While mutations in the ING1 gene are rare, reduced levels of ING1 protein have been found in breast and prostate cancers, supporting its role as a tumor suppressor gene (PMID: 24008732, 12015309, 24962136, 34685579). Overexpression of ING1 induces cell cycle arrest and apoptosis in breast and lung cancer cell lines and inhibits tumor metastasis in experimental mouse models (PMID: 24962136, 21286670). True +ENST00000243786 NM_002191.3 3623 INHA False INHA, a regulator of gonadal hormone secretion, is altered by mutation in various cancer types. INHA (Inhibin alpha) is a member of the TGF-beta superfamily of proteins and is the alpha subunit of inhibin A and B protein complexes, which have been implicated in the regulation of cell proliferation, apoptosis, and hormone secretion. In particular, INHA negatively regulates follicle stimulating hormone (FSH) secretion from the pituitary gland (PMID: 3696240, 19602521) and mutations in the gene can lead to male infertility and ovarian failure (PMID: 25617520, 19752047). INHA deletion in mouse models leads to gonadal stromal tumors (PMID: 1448148 ), and polymorphisms in INHA are associated with an increased risk of testicular germ cell tumors (PMID: 18413775), both of which are consistent with its role in the regulation of hormone secretion. True +ENST00000242208 NM_002192.2 3624 INHBA True INHBA, a regulator of gonadal hormone secretion, is altered by mutation in various cancer types. INHBA (inhibin beta A) is a ligand that participates in the formation of activin and inhibin protein complexes that have opposing functions in the gonads and pituitary glands. INHBA can homo- or heterodimerize to regulate follicle stimulating hormone (FSH) synthesis (PMID: 27328872). INHBA interacts with transforming growth factor-β (TGF-β) transmembrane receptors and activates downstream TGF-β signaling (PMID: 25560921). Activin complexes have been associated with regulation of cell differentiation in the ovary, placenta, prostate, and testis (PMID: 9464268, 9207855). Rare somatic mutations in INHBA have been reported (PMID: 18948947) and overexpression of activin has been identified in several cancer types (PMID: 11511564, 9360551, 9714055, 9570994,9543140, 17143484, 9543140, 11994376, 19240652, 19308293). However, there are reports of an anti-tumorigenic effect of the activin signal in many cancers, wherein activin induces growth inhibition and apoptosis mainly through Smad-dependent pathways (PMID: 10869285, 15753386, 16140969, 19493612,22761777), suggesting that INHBA may have context-specific effects on tumor progression. True +ENST00000074304 NM_001134224.1 3631 INPP4A False INPP4A, a lipid phosphatase involved in PI3K signaling, is altered in various cancer types including mesothelioma and asbestos-exposed lung adenocarcinoma. INPP4A is a lipid inositol polyphosphate 4-phosphatase that has a role in negatively regulating the PI3K/AKT signaling pathway. The primary function of INPP4A is to selectively hydrolyze the position 4 phosphate group on the inositol ring, converting PI(3,4)P2 to PI(3)P (PMID: 24069021). INPP4A is predominantly expressed in the brain and maintains the integrity of the brain by regulating excitotoxic neuronal death (PMID 20463662). INPP4A has been implicated in the suppression of cell proliferation and tumor growth in mice via downregulation of the PI3K/AKT pathway (PMID: 21127264, 19325558). Recent studies have shown co-mutations with BAP1 and INPP4A in patients with mesothelioma and asbestos-exposed lung adenocarcinoma (PMID 26463840). False +ENST00000262992 NM_001101669.1 8821 INPP4B False INPP4B, a lipid phosphatase involved in PI3K signaling, is altered by mutation in various cancer types. INPP4B is a lipid inositol polyphosphate 4-phosphatase that has a role in negatively regulating the PI3K/AKT signaling pathway. The primary function of INPP4B is to selectively hydrolyze the position 4 phosphate group on the inositol ring, converting PI(3,4)P2 to PI(3)P (PMID: 24069021). INPP4B has been implicated in the suppression of cell proliferation, cell motility and tumor growth in mice via control of the PI3K/AKT pathway (PMID: 21127264, 19325558, 24069021). INPP4B loss of heterozygosity has been identified in breast and ovarian cancer patients, suggesting that INPP4B functions as a tumor suppressor (PMID: 19647222, 21127264). Loss-of-function studies in breast cancer cell line and murine models demonstrate that reduced expression of INPP4B results in enhanced AKT expression, cell invasiveness, and tumor progression (PMID: 19647222). Loss of INPP4B expression is observed in breast, ovarian, and prostate cancers, and correlates with lower overall survival (PMID 19647222). True +ENST00000298229 NM_001567.3 3636 INPPL1 False INPPL1, a lipid phosphatase involved in PI3K signaling, is altered by amplification in various cancer types including breast cancer. INPPL1 is a phosphatidylinositol phosphatase, an enzyme that catalyzes the conversion of phosphatidylinositol-trisphosphate (PIP3) to its diphosphate counterpart (PIP2), thus negatively regulating PI3K pathway signaling (PMID: 10761925). INPPL1 also plays a role in insulin signaling, EGFR turnover and actin cytoskeleton dynamics (PMID: 9660833, 11349134, 11739414). INPPL1 promotes cell proliferation in vitro, and its overexpression correlates with invasive features in breast cancer (PMID: 19065064, 19082482) and other cancers. INPPL1 is mainly altered by amplification, particularly in breast tumors, but also in esophagus and head and neck cancers (cBioPortal, MSKCC, Nov 2016). True +ENST00000302850 NM_000208.2 3643 INSR True INSR, a receptor tyrosine kinase involved in insulin signaling, is altered by chromosomal rearrangement in colorectal cancers. Germline mutations of INSR are associated with Donohue syndrome. INSR is the insulin receptor, a receptor tyrosine kinase that is a key mediator of insulin in the regulation of glucose metabolism (PMID: 2859121, 22337149). Insulin, IGF-I and IGF-II are the natural ligands of INSR and their binding to INSR leads to receptor auto-phosphorylation as well as phosphorylation of INSR targets (IRS1-4, SHC, GAB1, CBL) (PMID: 19274663). As a result of INSR signaling cells upregulate glucose uptake and proliferation and angiogenesis is increased (PMID: 25864925). High INSR pathway activation has oncogenic functions in several tumor entities (PMID: 25821562, 25694511, 26406954). High INSR activity driven by IGF2 is a mechanism of chemoresistance in GATA2 high prostate cancer (PMID: 25670080). NSR activity seems required for the transformation by ETV6-NTRK3 in secretory breast cancer cells (PMID: 21148487). The INSR pathway seems required for the growth of hormone-dependent breast cancer and targeted inhibition of INSR with small molecules has been shown to synergize with hormonal agents in estrogen-dependent breast cancer (PMID: 22042792, 21908557). False +ENST00000311234 NM_012141 26512 INTS6 False INTS6, a DEAD box subunit of the integrator complex involved in snRNA processing, is infrequently altered by deletion in cancer. INTS6, also known as DICE1 and DDX26, encodes a DEAD box protein subunit of the integrator complex that functions in small nuclear RNA processing (PMID: 19906297). The C-terminus of RNA polymerase II interacts with the integrator complex to mediate the interaction between the complex and promoter of the small nuclear RNA, allowing for transcription and 3′ end processing of the transcripts (PMID: 20457598). INTS6 has been associated with the Wnt signaling pathway, showcasing tumor suppressive activity through the upregulation of Wnt genes in prostate cancer cell lines re-expressing INTS6 (PMID: 19906297). INTS6 is located on the tumor suppressor locus of chromosome 13q14, physically close to both BRCA2 and RB1 (PMID: 10467397). Loss of INTS6 has been identified in various cancer types, including non-small cell lung carcinoma, prostate cancer and esophageal squamous cell carcinoma (PMID: 10467397, 19906297, 12527901). Significant downregulation of INTS6 expression occurs in prostate cancer cell lines due to hypermethylation of the INTS6 promoter region (PMID: 16007164). Ectopic expression of INTS6 in non-small cell lung carcinoma and prostate cancer cell lines suppresses tumor growth and anchorage-independent growth (PMID: 15254679). True +ENST00000268182 NM_003870 8826 IQGAP1 True IQGAP1, a scaffold protein, is infrequently altered in cancer. IQGAP1, a member of the IQGAP family, encodes for a scaffold protein that functions in regulating various cellular processes including actin cytoskeleton organization, cellular adhesion and cell cycle proliferation (PMID: 8670801, 11584017, 19454477). IQGAP1 mediates the EGFR pathway and the Ras-MAPK pathway through direct binding with its multiple protein interaction domains (PMID: 21349850, 23603816). Overexpression of IQGAP1 in various cancer cell lines and models induces increased cellular proliferation, motility and adhesion, suggesting that IQGAP1 functions predominantly as an oncogene (PMID: 15695121, 18281532, 33526450, 31597661). IQGAP1 amplification has been identified in various types of cancer, including head and neck squamous cell carcinoma and hepatocellular carcinoma (PMID: 29846864, 20530982). False +ENST00000245414 NM_002198.2 3659 IRF1 False IRF1, a transcription factor, is infrequently altered by deletion and mutation in hematopoietic malignancies. IRF1 is a transcription factor that is a member of the interferon regulatory protein family (IRF) (PMID: 29599126). IRF1 functions as both a transcriptional activator and repressor of various target genes including the cytokine interferon beta, among others (PMID: 3409321). IRF1 regulates the expression of genes involved in multiple cellular functions including DNA damage, apoptosis, inflammatory response, and adaptive immunity (PMID: 19129219, 15548708, 29599126). IRF1 expression is activated by IFN-γ, resulting in activation of Toll-like receptor signaling via MYD88 (PMID: 24092468, 17457343). In addition, IRF1 activates TP53, a tumor suppressor protein, via the recruitment of p300 and co-regulates the expression of cell cycle genes including p21 and Cyclin D1 (PMID: 8752276, 17409403, 9659924). IRF1 and IRF2 have direct and indirect roles in the repression of each other, with IRF1 predominantly mediating tumor suppression (PMID: 2475256). IRF1 mutations have been identified in clonally expanded CD8+ cells (PMID: 28635960) from patients with rheumatoid arthritis, highlighting the role of IRF1 in inflammation. Somatic mutations in IRF1 are rare; however, deletions of IRF1 have been identified in pediatric B-cell precursor acute lymphoblastic leukemia (PMID: 27090575). The IRF1 gene is also located on a chromosomal region (5q) frequently deleted in leukemias and myelodysplastic syndromes. Exon skipping events leading to loss of IRF1 expression have also been identified in hematopoietic malignancies (PMID: 8438156, 12358902). Reduced expression of IRF1 has been associated with a variety of cancer types including hematopoietic, breast, and melanoma, among others (PMID: 15548708, 10493631), suggesting that IRF1 predominantly functions as a tumor suppressor. True +ENST00000393593 NM_002199 3660 IRF2 False IRF2, a transcription factor, is infrequently altered by deletion in various cancers. IRF2, a member of the interferon regulatory protein family (IRF), encodes for a transcription factor which functions as both a transcriptional activator and repressor of various target genes (PMID: 23243601, 12799427, 7566094). IRF2 regulates the expression of genes involved in immune cell activation, survival, differentiation and signaling (PMID: 36544762, 36370712). IRF2 is constitutively expressed in various immune cells and its expression is upregulated in response to type 1 and type 2 interferons (PMID: 2475256). IRF1 and IRF2 have direct and indirect roles in the repression of each other (PMID: 2475256). Downregulation of IRF2 in various types of cancer cell lines and models induces immune evasion, impaired TP53 function and increased cellular proliferation, suggesting that IRF2 functions predominantly as a tumor suppressor gene (PMID: 31471524, 23264911, 35115027). IRF2 deletion has been identified in various types of cancer, including breast cancer, lung cancer and prostate cancer (PMID: 31471524). True +ENST00000380956 NM_002460.3 3662 IRF4 True IRF4, a transcription factor, is altered by mutation and chromosomal rearrangement in various hematologic malignancies. The IRF4 gene encodes for interferon regulatory factor 4, a transcription factor involved in regulating cytokine responses and lymphocyte development (PMID:18303999, 8999800). It can homo- or heterodimerize with other transcription factors to bind DNA (PMID:12453417). IRF4 is important for immune response and in NFkB signaling as a downstream mediator (PMID: 10601358,17785208). It regulates the development and survival of B- and T-cells (PMID:15249594, 24591370, 24356538). Its activity is also involved in melanocyte pigmentation (PMID:24267888). Expression of IRF4 (also known as MUM1) is used to classify diffuse large B-cell lymphoma subtypes (PMID:12393466). Translocations involving IRF4 and the IgH locus have been identified in multiple myeloma and with additional gene loci in lymphomas (PMID: 9326949, 18987657, 15510210). IRF4 polymorphisms have also been linked to chronic lymphocytic leukemia (CLL) susceptibility and mutations are found in T-cell leukemia and lymphomas (PMID: 18758461, 26437031). False +ENST00000268638 NM_002163.2 3394 IRF8 False IRF8, a transcription factor, is altered by mutation in a variety of hematopoietic malignancies. IRF8 (also ICSBP) is a transcription factor that is a member of the interferon regulatory protein family (IRF) (PMID: 29599126). IRF8 is predominantly expressed in hematopoietic stem, progenitor and terminally differentiated cells including myeloid, NK and dendritic cells (PMID: 28650480). IRF8 functions as a transcriptional activator and repressor that is required to mediate immune cell differentiation and execution of cell-type-specific gene expression programs (PMID: 25024380). IRF8 also regulates the expression of genes involved in several cellular functions including adaptive immunity, cell cycle regulation and apoptosis (PMID: 27338637, 29858012). Loss of IRF8 in murine models results in a hematopoietic malignancy, in part due to STAT5 repression of IRF8 tumor suppressive activity (PMID: 24753251). Homozygous biallelic IRF8 mutations have been identified in NK deficiency syndromes and IRF8 missense mutations have been identified in dendritic cell deficiency syndromes (PMID: 27893462, 21524210), suggesting IRF8 is required for functional NK and dendritic cell development. Somatic hotspot mutations in the IRF8 DNA binding domain have been identified in pediatric-type follicular lymphoma (PMID: 28533310) and in diffuse large B cell lymphoma (PMID: 23292937). In addition, IRF8 downregulation is found in hematopoietic malignancies due to epigenetic and signaling dysregulation (PMID: 21475251, 24753251). True +ENST00000305123 NM_005544.2 3667 IRS1 True IRS1, a signaling molecule involved in insulin signaling, is altered by mutation in various cancer types. Insulin receptor substrate 1 (IRS1) is one of the key mediator of Insulin receptor (INSR) signalling in cells (PMID: 1648180, 19029956). Upon activation of INSR, IRS1 is phosphorylated and activated leading to the activation of the PI3-Kinase and MAPK pathway (PMID: 1648180, 11292874, 21597332). IRS1 has oncogenic functions in multiple tumor entities such as breast cancer and high IRS1 expression is associated with adverse prognosis (PMID: 17030631, 22337149). IRS-1 associates with BCL-2 and increases its anti-apoptotic functions (PMID: 10679027). IRS-1 interacts with GRB2 leading to JAK activation (PMID: 8491186, 8536716, 9492017). ETV6-NTRK3 induced cell transformation requires high levels of IRS-1 phosphorylation (PMID: 12173038). Phosphorylation of IRS1 S307 seems to abrogate its ability to mediate insulin receptor signalling (PMID: 11606564). Drugs that specifically target the insulin receptor pathway and IRS1 activity have been developed and clinically investigated (PMID: 19581933, 20807783). False +ENST00000375856 NM_003749.2 8660 IRS2 True IRS2, a signaling molecule involved in insulin signaling, is altered by amplification and mutation in various cancer types. Insulin receptor substrate 2 (IRS2) is one of the mediators of Insulin receptor (INSR) signalling in cells (PMID: 1648180, 19029956). Upon activation of INSR, IRS2 is phosphorylated and activated leading to the activation of the AKT and MAPK pathway (PMID: 1648180, 11292874, 21597332, 24810113). Dysregulation or IRS2 leads to obesity and diabetes and IRS2 deficiency impairs brain growth (PMID: 15467829, 12904469). IRS1 has oncogenic functions in multiple tumor entities such as squamous cell carcinoma and high IRS1 expression is associated with adverse prognosis (PMID: 24810113, 17030631, 22337149). Nedd4-induced ubiquitination or IRS2 enhances IGF signalling and its mitotic activity (PMID: 25879670). IRS2 amplifications have been observed in colorectal cancer which result in increased susceptibility to anti-EGFR therapy (PMID: 26416732). False +ENST00000272117 NM_002221 3707 ITPKB True ITPKB, an inositol phosphate kinase, is infrequently altered in cancer. ITPKB, a member of the inositol trisphosphate-kinase family encodes for an inositol phosphate kinase that functions in regulating inositol phosphate metabolism in cellular signaling through phosphorylation of inositol polyphosphates (PMID: 24401760, 22981169). ITPKB is one of three isoforms in the inositol triphosphate-kinase family that share the conserved C-terminal catalytic domain but differ in regulation mechanisms (PMID: 24401760). ITPKB regulates calcium homeostasis by inhibiting calcium transport from the endoplasmic reticulum to the mitochondria (PMID: 12747803, 33443159). Knockdown of ITPKB in various patient-derived xenograft models represses cisplatin-resistant tumor growth mediated through NOX4 and sensitizes cancer cells to cisplatin, suggesting that ITPKB functions predominantly as an oncogene (PMID: 31081803). Upregulation of ITPKB has been identified in head and neck squamous cell carcinoma, lung cancer and ovarian cancer (PMID: 31081803). False +ENST00000342505 NM_002227.2 3716 JAK1 True JAK1, an intracellular kinase, is frequently altered in hematologic malignancies and gynecological cancers. The JAK1 gene encodes Janus kinase 1 (JAK1), a ubiquitously expressed member of the JAK family of protein tyrosine kinases (PMID: 25057888, 9096349). JAK1 forms a complex with cytokine receptors to initiate cytokine-mediated signaling. Upon cytokine activation, JAK1 forms oligodimers which phosphorylate tyrosine residues within the cytoplasmic region of the cytokine receptors, leading to recruitment and activation of downstream targets such as STAT1-6 (PMID: 25057888). The STAT proteins then translocate to the nucleus and act as transcription factors, mediating several cellular functions including proliferation, differentiation and antigen presentation (PMID: 23406773). Several activating mutations in JAK1 have been detected in acute lymphoblastic leukemia and other hematological malignancies, and inhibitors of the JAK/STAT pathway have been suggested as a potential therapy in those cases (PMID: 23340138). However, truncating mutations leading to loss-of-function of JAK1 have been frequently reported in gynecologic tumors and other cancers with microsatellite instability (PMID: 24154688, 29121062). Loss of JAK1 function is suggested to mediate immune escape in these tumors through impaired tumor antigen presentation and abolished JAK1-mediated interferon response (PMID: 24154688, 12576323, 29121062). True +ENST00000381652 NM_004972.3 3717 JAK2 True 2 JAK2, an intracellular kinase, is frequently altered by mutation or chromosomal rearrangement in hematologic malignancies. JAK2 is a non-receptor tyrosine kinase that regulates cytokine signaling and requires a cognate receptor to respond to extracellular cytokine signaling (PMID: 25057888, 1848670). Activated JAK2 signaling is necessary for the normal production of blood cells such as erythrocytes and thrombocytes (PMID: 9590173). Activation of JAK2 leads to the recruitment and phosphorylation of downstream effectors, such as STAT3/5 and MAPK, enabling the translocation of these signaling molecules to the nucleus to activate transcription (PMID: 25057888). Gain-of-function mutations in JAK2 have been identified in patients with myeloproliferative disorders, including 95% of polycythemia vera and 50% of essential thrombocytopenia and myelofibrosis malignancies (PMID: 1583762, 23009934, 25629741), suggesting that JAK2 functions predominantly as an oncogene. JAK2 fusions and activating mutations have also been identified in various leukemias and lymphomas (PMID: 9360930, 18270328). The most commonly identified mutation is JAK2 V617F, an alteration that activates kinase activity by impairing the autoinhibitory domain of the kinase, leading to constitutive activation of the JAK/STAT signaling pathway (PMID: 17721432). Murine models engineered to express the JAK2 V617F mutation develop a myeloproliferative disorder (PMID: 28640953). While JAK2 mutations are rare in solid tumors, activation of the JAK2/STAT pathway has been found to be oncogenic in many tumor types (PMID: 26151455). The JAK2 kinase inhibitor ruxolitinib has been FDA-approved for the treatment of patients with high-risk myelofibrosis and polycythemia vera (PMID: 20843246). However, resistance to JAK2 inhibition has been found to occur via the formation of drug-resistant JAK1/JAK2 heterodimers (PMID: 22820254). Additional JAK2 inhibitors are currently being tested in preclinical and clinical trials to improve drug efficacy and reduce off-target effects (PMID: 28673391). False +ENST00000458235 NM_000215.3 3718 JAK3 True JAK3, a non-receptor tyrosine kinase, is recurrently altered by mutation in hematologic malignancies. JAK3 encodes for Janus Kinase 3, a non-receptor tyrosine kinase. JAK3 activation results in activation of the STAT family of proteins (PMID:8986719) and can also signal through the MAPK and AKT pathways (PMID:22120524). JAK3 regulates response to cytokines, chemokines, and metabolism (PMID:8022486, 24498424, 25493954, 26451047). JAK3 signaling plays a crucial role in T-cell development, including regulation of T-cell apoptosis (PMID:11134353). Clinically JAK3 signaling can mediate autoimmune disease and graft rejection (PMID:14593182, 26230873). JAK3 mutations are seen in acute leukemias (PMID:22237106, 16843266), myeloid and lymphoid leukemia subtypes (PMID:23832011, 24446122), and lymphomas (PMID:24837469, 23689514). JAK3 mutations are also found in solid tumors but at lower incidence (PMID:18559588, 26096009, 24821835, 21868263). Loss of function mutations in JAK3 can lead to severe combined immunodeficiency (SCID) (PMID:10075926). False +ENST00000341776 NM_004973.3 3720 JARID2 True JARID2, an epigenetic complex cofactor, is infrequently altered by mutation and deletion in a diverse range of cancers. JARID2 is a transcription factor that mediates the recruitment of epigenetic complexes to chromatin. JARID2 associates with the Polycomb repressive complex 2 (PRC2), which is responsible for transcriptional repression of target genes by catalyzing the placement of the repressive di- and tri-methyl Histone H3 lysine 27 (H3K27) marks on chromatin (PMID: 20123894, 29932905, 29348366, 25620564). In addition, JARID2 binds other histone modifications in order to regulate crosstalk between PRC2 and PRC1 (Polycomb Repressive Complex 1) (PMID: 27892467). PRC2 function is important in the repression of developmental regulators such as the HOX genes and X-inactivation (PMID: 16618801, 12649488). JARID2 activity is also essential in several contexts including skeletal muscle and cardiac tissue development (PMID: 29891551, 30119689). Increased JARID2 expression has been associated with proliferation, migration, and invasion in ovarian, hepatocellular, and bladder cancer cells, among others (PMID: 28765957, 28445934, 27259236, 22431509). Deletions and missense mutations are found in hematopoietic malignancies and non-small cell lung cancer (PMID: 22190018, 23047306, 22053108, 30423295). True +ENST00000371222 NM_002228.3 3725 JUN True JUN, a transcription factor, is altered by amplification and overexpression in various cancer types. JUN (also c-Jun) is a transcription factor that dimerizes with the Activator protein 1 (AP-1) transcription factor complex. The AP-1 complex regulates a plethora of cellular process including differentiation, proliferation, and apoptosis through transcriptional control of several downstream target genes, including p53, cyclin D1 and EGFR (PMID: 12791272, 10072388, 10790372). In its turn, c-Jun is regulated by phosphorylation, mediated in particular by the JNK, p38 and WNT signaling pathways for directing cell proliferation, differentiation, survival and migration processes (PMID: 10080190, 16007074, 20231272). AP-1 is a potent transforming factor in multiple experimental models, although anti-oncogenic effects have also been described in specific contexts (PMID: 11988758, 14668816). Although a direct oncogenic role for AP-1 has not been described in human tumors, mechanisms for a putative role have been explored in for example breast cancer cell lines and models of liposarcoma, a tumor type in which c-Jun amplification has been observed (PMID: 17637753, 17418412). False +ENST00000265713 NM_006766.4 7994 KAT6A False KAT6A, a histone acetyltransferase, is recurrently altered by translocation in acute myeloid leukemia. KAT6A (also MYST3 or MOZ) is a histone acetyltransferase that is a member of MYST family of proteins (PMID: 16626284, 18754862, 17694081). KAT6A functions as a transcriptional coactivator that has intrinsic histone acetyltransferase activity, with the ability to acetylate several histone residues (PMID: 11313971). In addition, KAT6A forms complexes with transcriptional regulators to coordinate gene expression, including the hematopoietic proteins AML1, PU.1, and RUNX, among others (PMID: 11742995, 16702405, 11965546, 12771199). The activity of KAT6A has been implicated in the formation of additional transcriptional complexes with ING proteins that regulate a variety of cellular processes including differentiation, DNA damage, chromatin state and cellular proliferation (PMID: 17694081). Loss of KAT6A expression in murine models results in defects in the hematopoietic stem and progenitor compartments, consistent with a role of KAT6A in hematopoietic gene regulation (PMID: 16651658, 12676584). Dominant germline mutations in KAT6A are found in individuals with intellectual disabilities (PMID: 25728777). Recurrent translocations involving KAT6A are found in patients with acute myeloid leukemia (PMID: 9447825, 8782817, 9558366). KAT6A rearrangements promote leukemic transformation due to aberrant targeting of epigenetic complexes to chromatin, suggesting that KAT6A functions as an oncogene (PMID: 12676584). False +ENST00000259021 NM_007067 11143 KAT7 True KAT7, the catalytic subunit of the HBO1 complex, is infrequently altered in cancer. KAT7 encodes for the catalytic subunit of the histone acetyltransferase HBO1 multimeric complex (PMID: 21753189). The HBO1 complex mediates acetylation of histone H3K14ac, regulating various processes such as transcriptional activation and immune response (PMID: 24065767, 26620551). The multimeric complex also functions in acetylation of other histones, including H4K5ac, H4K8ac and H4K12ac, to regulate DNA replication initiation and inhibit NF-kB signaling (PMID: 16997280, 19187766, 20129055). Overexpression of KAT7 in cancer cell lines induces cell growth, migration and invasion, suggesting that KAT7 functions primarily as an oncogene (PMID: 35868058, 34039960, 19372580). KAT7 amplification and point mutations have been identified in various cancers, including breast cancer and gastric cancer (PMID: 35868058, 36724120). False +ENST00000395288 NM_016506.5 55709 KBTBD4 False KBTBD4, a predicted E3 ligase adaptor protein, is recurrently altered by mutation in medulloblastoma. KBTBD4 is a protein that is a predicted E3 ligase adaptor protein with Kelch-BTB-BACK domains (PMID: 28726821). KBTBD4 has not yet been functionally characterized, however, it is a member of a family of cullin-RING ubiquitin ligase adaptor proteins (PMID: 28726821). Adaptor molecules mediate the specificity of E3 ligase proteins, which ubiquitinate and target proteins for degradation via the proteasome (PMID: 23349464). In-frame insertions in KBTBD4, typically in the Kelch domain, have been found recurrently in patients with Group 3 or Group 4 subtypes of medulloblastoma (PMID: 28726821) and as the sole alteration in several pineal parenchymal tumors of intermediate differentiation (PPTID)(PMID: 30877433). These insertions are predicted by structural studies to occur in the substrate-binding interface of the protein (PMID: 28726821, 23349464). However, this recurrence may be limited to certain populations, as follow-up studies have demonstrated that KBTBD4 insertions were absent in a cohort of medulloblastomas from Brazilian centers (PMID: 31403685). Additional studies are required to determine the role of KBTBD4 mutations in cancer. False +ENST00000399788 NM_001042603.1 5927 KDM5A True KDM5A, a histone methyltransferase, is altered by chromosomal rearrangement and amplification in various cancer types. KDM5A (also known as JARID1A) is a histone demethylase for histone 3 lysine 4 (H3K4) (PMID:17320161). KDM5A's plant homeodomain (PHD) recognizes unmethylated H3K4 to locate the enzyme to specific chromatin regions (PMID: 25686748). Through chromatin modification and transcriptional silencing, KDM5A regulates cellular differentiation and cooperates with the retinoblastoma protein (pRB) in controlling cell cycle progression (PMID:18722178, 15949438, 23093672, 23112189). It also affects cellular metabolism and circadian rhythms (PMID: 26314709, 21960634). In cancer KDM5A promotes tumor progression by targeting cell cycle and angiogenesis genes and enhancing treatment resistance (PMID:23722541, 24716659, 26566863, 20371346). It is amplified in breast and head and neck cancers (PMID:22937203, 24425785). It is translocated in leukemia with the NUP98 gene and alters HOX gene expression (PMID:16419055, 19430464). False +ENST00000375401 NM_004187.3 8242 KDM5C False KDM5C, a tumor suppressor and histone demethylase, is altered in various cancers, most frequently in renal cell carcinoma and endometrial cancer. The KDM5C gene encodes a member of an ARID protein family that acts as an epigenetic regulator by removing di-tri-methyl groups from lysine 4 of histone H3 (H3K4) on transcriptional targets (PMID: 21575681, 24583395, 20054297, 22249190). KDM5C is ubiquitously expressed in almost all human tissues, including white blood cells, with the highest levels of expression found in the brain and skeletal muscle (PMID: 23356856). Loss of KDM5C exerts an essential role in mammalian DNA replication. Moreover, KDM5C silencing induces aberrant H3K4me3 levels at active origins, thus halting DNA replication and ultimately S phase progression (PMID: 25712104). Mutation of the KDM5C gene was first described as causing X-linked intellectual disability (XLID) in 2005 (PMID: 15586325), and has been linked to some forms of cancer (PMID: 21544224, 20181063, 20133580). The prevalence of KDM5C mutations in patients with XLID is estimated to be ~3% (PMID: 23356856), and somatic mutations in this gene have been identified in 4-9% of clear cell renal cell carcinoma (ccRCC) (PMID: 20054297, 24166983, 22138691). Knockdown of KDM5C in von Hippel-Lindau (VHL) -/- ccRCC cells significantly enhanced tumor growth in a xenograft model, suggesting that KDM5C functions as a tumor suppressor in this cancer model (PMID: 21725364, 25111482). Through siRNA screen, KDM5C was identified as a mediator of the human papillomavirus (HPV) E2 tumor suppressor protein in cervical cancer (PMID: 20133580). True +ENST00000317961 NM_004653 8284 KDM5D True KDM5D, a histone lysine demethylase, is altered by reduced expression in various cancers. KDM5D, part of the KDM5 family, is located on the Y chromosome and encodes a male-specific histone demethylase that targets trimethylated H3K4 (PMID: 34127738, 30864186, 35805040, 26747897). KDM5D plays a role in transcriptional regulation, as the demethylation of H3K4 is suggested to repress gene transcription (PMID: 30864186, 26747897). KDM5D is associated with male organ rejection in female recipients due to a short peptide derived from the protein that is a minor histocompatibility antigen (PMID: 35805040). Down-regulation of KDM5D has been observed in various cancer types including lung, prostate, gastric, colorectal and renal cancer, and is in part due to deletions on the Y chromosome; this supports its role as a tumor suppressor (PMID: 34127738, 26747897). In both in vitro and in vivo models of prostate and gastric cancer, knock-down of KDM5D promoted cellular invasion and increased expression of epithelial-mesenchymal transition (EMT) regulators such as N-cadherin, slug and vimentin (PMID: 30864186, 26747897). Overexpression of KDM5D inhibited proliferation and increased apoptosis in colorectal cancer cells and reduced the growth rate of tumors in mice (PMID: 34688635). However, KDM5D was found up-regulated in KRAS-mutant colorectal cancer in male patients and was associated with increased metastases, suggesting KDM5D may function as an oncogene in this tumor-specific context through the repression of genes involved in cell adhesion and immune recognition (PMID:37344599). True +ENST00000377967 NM_021140.2 7403 KDM6A False 4 KDM6A, a histone demethylase, is altered in various cancer types, most frequently in bladder cancer. KDM6A (lysine-specific demethylase 6A) encodes a chromatin-modifying enzyme that mediates transcriptional co-activation by functioning as a di- and tri-methylated histone H3 lysine 27 (H3K27) demethylase. KDM6A is part of the larger ASC-2 complex (ASCOM) that also contains lysine-specific methyltransferase 2D (KMT2D) and lysine-specific methyltransferase 2C (KMT2C). KDM6A is located on Xp11.2, but it escapes X inactivation, resulting in bi-allelic expression in females (PMID: 9499428). Association of KDM6A with KMT2D and KMT2C couples H3K27 demethylation to H3K4 methylation (PMID: 17761849). Germline deletions and point mutations in KDM6A cause Kabuki syndrome, which is characterized by typical facial features, skeletal anomalies, dermatoglyphic abnormalities, mild-to-moderate intellectual disability and postnatal short stature (PMID: 22197486, 22840376, 22901312, 23076834). Early sequencing efforts led to the discovery of inactivating KDM6A mutations in a number of human malignancies including multiple myeloma and esophageal squamous cell carcinoma (PMID: 19330029). Later studies found KDM6A mutations in clear cell renal cell carcinoma (PMID: 21248752), medulloblastoma (PMID: 22722829, 22832583), adenoid cystic carcinoma (PMID: 23685749), urothelial bladder cancer (PMID: 24476821, 21822268, 25092538, 25225064), aristolochic acid-associated upper tract urothelial carcinoma (PMID: 23926199), T-cell acute lymphoblastic leukemia (PMID: 25320243), and pancreatic cancer (PMID: 25719666). In prostate cancer, KDM6A mutations are seen in progression to lethal castration-resistant disease (PMID: 22722839). Loss of KDM6A may confer sensitivity to EZH2 inhibitors (PMID: 28228601). True +ENST00000263923 NM_002253.2 3791 KDR True KDR, a receptor tyrosine kinase, is altered by mutation or amplification in various cancers, most frequently in skin cancers. KDR (kinase domain receptor), also known as VEGFR2 or Flk-1, is a tyrosine kinase receptor for vascular endothelial growth factor (VEGF) and plays a key role in angiogenesis. In hypoxic conditions, hypoxia-inducible factor 1 (HIF1) protein stabilization leads to upregulation of KDR and VEGF (PMID: 23172303). Binding of VEGF to KDR results in stimulation of angiogenesis via receptor dimerization and autophosphorylation, activation of phospholipase C (PLC-gamma) and downstream signaling via protein kinase C (PKC) and RAF/MEK/ERK (PMID: 10327068, 12778165). Mutations of KDR are rare in tumors, and alterations of KDR activity typically occur via KDR amplification and subsequent overexpression. Most therapies blocking KDR signaling target the angiogenesis pathway in general, such as bevacizumab, an antibody that targets VEGF-A (PMID: 15136787). False +ENST00000171111 NM_203500.1 9817 KEAP1 False KEAP1, a tumor suppressor and adaptor protein, is recurrently mutated in lung cancer. KEAP1 encodes a substrate adaptor protein for the E3 ubiquitin ligase complex. This complex is formed by the proteins CUL3 and RBX1 and targets NRF2 for ubiquitination and subsequent proteasomal degradation (PMID:15572695). NRF2 (encoded by the gene NFE2L2) is a master transcriptional regulator of the cellular antioxidant response (PMID: 24142871, 21251164). Activation of NRF2 can provide a fitness advantage for cells by upregulating pathways for handling xenobiotic stress and detoxification (PMID: 21251164). The BTB domain of KEAP1 binds CUL3, and the Kelch-repeat domain binds NRF2 via KEAP1 homodimerization (PMID:21251164). The IVR region contains critical cysteine residues whose thiol side chains are modified in response to oxidative stress. Modification of cysteine residues in the IVR disrupts binding of KEAP1 to NRF2 and CUL3, resulting in the release of NRF2 for transcriptional activation of target genes (PMID:12193649, PMID:14585973). Mutations in KEAP1 tend to occur throughout the body of the gene (cBioPortal, MSKCC, Apr. 2015), and are commonly thought to disrupt KEAP1-dependent regulation of NRF2. This disruption activates NRF2-dependent pathways, including those regulated in the oxidative stress response (PMID: 24142871). True +ENST00000355265 NM_000420 3792 KEL True KEL, a transmembrane glycoprotein, is altered by amplification in various cancers. KEL encodes for a type II transmembrane zinc-dependent endopeptidase glycoprotein expressed solely in erythroid cells and tissues, which functions in the human blood group Kell antigen system (PMID: 7949106, 10438732, 7849312). KEL is highly polymorphic and at least 25 different antigens are encoded, which define the Kel blood group system (PMID: 8542022). KEL functions as a proteolytic enzyme and cleaves large EDN3 to yield bioactive EDN3 to maintain vascular homeostasis (PMID: 10438732, 7849312). Overexpression of KEL in acute erythroleukemia models induces cellular proliferation, migration and invasion, suggesting that KEL functions predominantly as an oncogene (PMID: 35140839). Amplification of KEL has been identified in acute erythroleukemia (PMID: 35140839). False +ENST00000288135 NM_000222.2 3815 KIT True 1 R2 KIT, a receptor tyrosine kinase, is recurrently mutated in gastrointestinal stromal tumors. The proto-oncogene KIT encodes a type 3 transmembrane receptor tyrosine kinase. The receptor is activated through dimerization and autophosphorylation upon binding by its ligand, stem cell factor (SCF) also known as mast cell growth factor (MGF) (PMID: 9438854). KIT activation results in increased intracellular signaling through several pathways including PI3K, MAPK and STAT, ultimately leading to cell proliferation and survival (PMID: 17546049, 11896121, 22089421). For patients with wildtype gastrointestinal stromal tumors (GIST; no KIT or PDGFRA mutations), NCCN recommends testing for germline succinate dehydrogenase (SDH) mutations. About 10-15% of GISTs are wildtype; thus, the absence of a mutation does not exclude the diagnosis of GIST. In patients without KIT mutations, a subset of those with advanced GISTs benefit from imatinib (0-45% of patients) (NCCN Soft Tissue Sarcoma v.2.2017). Activating KIT mutations occur in 80 - 90% of GISTs and are distributed over multiple exons with different frequencies (exons 11 (66.1%), exon 9 (13%), exon 13 (1.2%), and exon 17 (0.6%)) (PMID:15365079, 17268243, 11719439). There are at least eight small molecule tyrosine kinase inhibitors (TKIs) targeting KIT that have been approved by the US Food and Drug Administration with the efficacy of each TKI strongly depending on the location of the activating KIT mutation (PMID: 2427414, 18955458,19164557). R2 False +ENST00000248071 NM_016270.2 10365 KLF2 False KLF2, a transcription factor that regulates the activity of NF-κB, is recurrently altered by mutation in splenic marginal zone lymphoma. KLF2 is a transcription factor that is a member of the Kruppel protein family (PMID: 25428260). KLF2 expression is important for maintenance of quiescence in a variety of cell types, including in non-cycling B-cells and naïve T-cells (PMID: 17681603, 18246069, 16455954, 16455954). Transcriptional activity of KLF2 mediates the suppression of gene expression programs required for B- and T-cell activation (PMID: 17681603, 18246069). In addition, KLF2 represses the transcriptional activity of NF-κB in response to stimulation from a variety of signaling pathway including Toll-like receptor (TLR) and B cell receptor (BCR) signaling, among others (PMID: 25428260). Loss of KLF2 in murine models leads to expanded marginal zone B-cells, likely due to altered differentiation and homing of B cells (PMID: 20691614, 21187409). Somatic inactivating mutations in KLF2 are found in splenic marginal zone lymphoma (PMID: 25428260, 25283840), suggesting that KLF2 functions as a tumor suppressor. Loss-of-function variants in KLF2 result in unrestricted activation of NF-κB, leading to constitutive activation of various B-cell related signaling pathways (PMID: 25428260). True +ENST00000261438 NM_016531.5 51274 KLF3 False KLF3, a transcription factor, is altered by mutation in various cancer types. KLF3 is a transcription factor that is a member of the Kruppel protein family (PMID: 21360637). KLF3 modulates epithelial homeostasis by controlling the activation of epidermal differentiation gene programs (PMID: 32659720). In addition, KLF3 functions as a transcriptional repressor in adipocyte, erythroid and chondrocyte differentiation (PMID: 32385917, 32523103, 30619490, 30324848, 29775748, 23918807). Binding of KLF3 to target genes is important for various cellular activities including differentiation, proliferation, fat accumulation, angiogenesis and inflammation (PMID: 31486564, 32213596, 27226561, 31196982). KLF3 cooperates with other transcriptional and chromatin regulators, such as CBP, CtBP2, and C/EBPα, to activate gene expression (PMID: 32659720, 30619490, 25659434, 10756197). KLF family member-mediated gene regulation is complex due to the competition for binding sites across the genome at enhancers and promoters (PMID: 28541545). In various cell types, altered KLF3 activity mediates gene expression via interactions with long non-coding RNAs and micro RNAs (PMID: 31462890). KLF3 expression is downregulated in several cancer types, including lung and colon cancer, and is indicative of poor patient prognosis (PMID: 32213596, 28423541, 21470678). Somatic mutations are infrequent in human cancers and require functional validation (PMID: 21360637). True +ENST00000374672 NM_004235.4 9314 KLF4 True KLF4, a transcription factor, is altered by mutation in various cancer types including meningiomas. KLF4 is a transcription factor that regulates the development of multiple organs and tissues including the skin, cerebellum, and colon (PMID: 10431239, 12015290, 18604447, 26226504). Overexpression of KLF4 with OCT3/4, SOX2, and c-MYC is able to induce pluripotent stem cells from adult tissues (PMID: 16904174). It is also involved in terminal differentiation of monocytes and the T-cell immune response (PMID: 18390749, 25992862). In certain cancers, KLF4 functions to regulate the differentiation of tumor cells and may have a potential tumor suppressor role (PMID: 25181544, 26113043, 26338995, 26880805, 21224073, 22284679, 26934576). Thus, induction of KLF4 expression is being studied for therapeutic advantage (PMID: 26268924). True +ENST00000377687 NM_001730.4 688 KLF5 True KLF5, a transcription factor, is altered by amplification and mutation in various cancer types. KLF5 (Kruppel-like factor 5) is a zinc-finger-containing transcription factor whose expression is highest in rapidly dividing cells, such as in the crypt epithelium of the intestinal tract or the basal layer of the dermis, and results in the induction of genes regulated by cyclin D1 (PMID: 15077182, 10767086). KLF5 binds to GC-rich regions of DNA and has antagonizing effects on gene expression compared to KLF4, another KLF family member involved in stemness and regulation of cellular differentiation (PMID: 16904174). KLF5 is important in regulating the integrity of intestinal stem cells and has been implicated as a stemness reprogramming factor (PMID: 24626089, 23112162). In tumor models, KLF5 mediates RAS-driven oncogenesis (PMID: 18054006, 15077182) and while amplification of KLF5 is implicated in gastric cancer, it is also thought to regulate breast cancer invasiveness (PMID: 26189798, 26419610). False +ENST00000341319 NM_130446 89857 KLHL6 True KLHL6, an E3 ligase, is infrequently altered in cancer. KLHL6 (kelch like family member 6) encodes a BTB (Broad-Complex, Tramtrack and Bric a brac)-Kelch protein that is selectively expressed in lymphoid tissue and involved in B-cell antigen receptor signaling and germinal center B-cell maturation (PMID: 29695787, 16166635, 30646831). The protein functions as an E3 ligase through assembly with CULLIN3 to form a functional CULLIN-RING ubiquitin ligase (PMID: 29695787, 28807996, 30646831). Mutations in the KLHL6 gene may cause dissociation of CULLIN3 from KLHL6 resulting in loss of E3 ligase catalytic activity (PMID: 30646831, 29695787). KLHL6 gene mutations have been identified in patients with B-cell malignancies including diffuse large B-cell lymphoma (DLBCL), chronic lymphocytic leukemia and multiple myeloma (PMID: 29695787, 29044464, 21642962, 27959900). In vitro and in vivo studies demonstrate that loss of KLHL6 favors DLBCL growth and survival (PMID: 29695787, 30646831). However, KLHL6 has been found to be up-regulated in gastric cancer and is associated with a less favorable prognosis in this tumor type. Consistent with its role as an oncogene in gastric cancer, down-regulation of KLHL6 in human gastric carcinoma cells results in reduced colony formation, proliferation and viability, and suppressed tumor growth in mice (PMID: 29044464). True +ENST00000534358 NM_001197104.1 4297 KMT2A False 1 KMT2A, a histone methyltransferase, is altered by mutation or deletion in various solid tumors, and by chromosomal rearrangement in various hematologic malignancies. KMT2A (also MLL1) is a histone methyltransferase that functions as an epigenetic modulator that methylates lysine residue 4 on the tail of histone H3 (H3K4). Methylation of H3K4 leads to increased genome accessibility, recruitment of transcriptional complexes, and activation of gene expression (PMID: 25998713). KMT2A is crucial for embryogenesis and normal hematopoiesis by stimulating expression of several important developmental genes including the homeobox (Hox) genes (PMID: 24213472). Chromosomal translocations involving KMT2A that result in gain-of-function fusion proteins have been identified in pediatric and adult acute myeloid leukemia (AML) and acute lymphoid leukemia (ALL) and are overrepresented in therapy-related AML. Though KMT2A has a diverse group of fusion partners in leukemia, the most common KMT2A recombination partners include AF4, AF9, and ENL, which are proteins that interact with transcriptional elongation machinery (PMID: 28701730). KMT2A fusion proteins disrupt the normal activity of hematopoietic stem cells and the normal chromatin state, leading to activation of oncogenic signaling pathways (PMID: 16862118). In addition, loss-of-function mutations in KMT2A have been identified in solid tumors including bladder, stomach and endometrial cancers (PMID: 21822268, 23636398). DOT1L inhibitors, which are currently being tested in clinical trials, have been shown to have activity against KMT2A-rearranged leukemias (PMID: 21741597, 21741596). True +ENST00000420124 NM_014727.3 9757 KMT2B False KMT2B, a histone methyltransferase, is mutated at low frequencies in various cancer types. KMT2B (also MLL4) is a histone methyltransferase that functions as an epigenetic modulator that methylates lysine residue 4 on the tail of histone H3 (H3K4). Methylation of H3K4 leads to increased genome accessibility, recruitment of transcriptional complexes, and activation of gene expression (PMID: 25998713). KMT2B methylates H3K4 at enhancer regions, leading to increased expression of target genes and changes in chromatin looping structures (PMID: 25998713, 28759003, 24368734). KMT2B plays a role in regulating cell cycle progression and cell viability and induces transcription of leukemic genes (PMID: 22713656). True +ENST00000262189 NM_170606.2 58508 KMT2C False KMT2C, a tumor suppressor and histone methyltransferase, is altered in various solid and hematologic malignancies. KMT2C (also MLL3) is a histone methyltransferase that functions as an epigenetic modulator that methylates lysine residue 4 on the tail of histone H3 (H3K4). Methylation of H3K4 leads to increased genome accessibility, recruitment of transcriptional complexes, and activation of gene expression (PMID: 25998713). KMT2C specifically binds histones at enhancer regions, leading to increased expression of a wide range of target genes and regulation of enhancer RNA synthesis (PMID: 24081332, 23166019, 28483418, 27926873). KMT2C is ubiquitously expressed and its function is crucial for normal embryonal development and cell proliferation (PMID: 11718452, 17021013). Genetic deletion of the region containing KMT2C is the most common chromosomal abnormality in acute myeloid leukemia (PMID: 25794446, 11891048, 22234698, 25030029), and KMT2C is mutated in various types of cancer (PMID: 25537518, 25303977, 25151357, 28801450). True +ENST00000301067 NM_003482.3 8085 KMT2D False KMT2D, a tumor suppressor and histone methyltransferase, is one of the most frequently mutated genes in cancer. KMT2D (also MLL2) is a histone methyltransferase that functions as an epigenetic modulator that methylates lysine residue 4 on the tail of histone H3 (H3K4). Methylation of H3K4 leads to increased genome accessibility, recruitment of transcriptional complexes, and activation of gene expression (PMID: 25998713). Deletion of KMT2D in human cells leads to genomic instability due to transcriptional stress (PMID: 26883360). In murine models, loss of KMT2D results in accelerated B cell malignancy, impaired B cell differentiation, and defects in class switching (PMID: 26366710). KMT2D activity is critical for the survival and proliferation of KMT2A-rearranged leukemias (PMID: 28609655). Though KMT2D is not as commonly mutated as KMT2A in human cancers, KMT2D is one of the most recurrently mutated genes in follicular and diffuse large B cell lymphoma (PMID: 24476821, 21804550, 21796119, 24476821). True +ENST00000402868 NM_020382.7 387893 KMT5A False KMT5A, a methyltransferase and transcriptional repressor, is mutated or amplified at low frequencies in various cancers. KMT5A encodes the lysine methyltransferase SETD8, which specifically methylates lysine 20 of histone H4 (H4K20me1), a histone mark implicated in DNA replication and DNA repair. KMT5A is typically bound to euchromatin regions and the placement of the H4K20me1 mark is thought to have a role in transcriptional repression (PMID: 12086618, 16517599). KMT5A is also required for proper chromosome segregation during mitosis and subsequent cellular proliferation (PMID: 15200950). Additionally, KMT5A has other methylation targets independent of histones including PCNA, Numb and p53, where methylation has roles in promoting the epithelial-mesenchymal transition, regulating cell proliferation, and suppression of p53-dependent transcriptional programs (PMID: 26717907, 23706821, 22556262, 17707234). KMT5A mutations are rare in human cancers. False +ENST00000249776 NM_033286.3 90417 KNSTRN False KNSTRN, a component of the mitotic spindle, is mutated in cutaneous squamous cell carcinoma. KNSTRN encodes a protein involved in chromosome segregation during mitosis (PMID: 19667759, 22110139). KNSTRN, as part of the SKAP complex, maintains the mitotic spindle architecture and coordinates the dynamics of microtubules during cell division (PMID: 23035123). KNSTRN promotes cell migration in vitro and in vivo by directing the microtubule dynamics in response to signaling by small GTPases (PMID: 26242911). KNSTRN mutations are rare events in cancers, but they are frequent in cutaneous squamous cell carcinoma (cBioPortal, MSKCC, Nov 2016) (PMID: 25194279, 25303977). False +ENST00000311936 NM_004985.3 3845 KRAS True 1 R1 KRAS, a GTPase which functions as an upstream regulator of the MAPK pathway, is frequently mutated in various cancer types including lung, colorectal and pancreatic cancers. KRAS is a member of the RAS family of small GTPases, which catalyze the hydrolysis of GTP to GDP. Under physiologic conditions, these RAS proteins cycle between an active (GTP-bound) and an inactive (GDP-bound) state, to activate the MAPK and PI3K oncogenic pathway signaling downstream of Receptor Tyrosine Kinases (RTKs) (PMID: 22189424). The function of RAS enzymes is regulated by guanine nucleotide exchange factors (GEFs), such as SOS, which enable the exchange of GDP to GTP, as well as by GTPase activating proteins, such as NF1, which increase the ability of RAS to hydrolyze GTP. Once activated, RAS mediates the regulation of cellular proliferation and other cellular functions through the activation of distinct intracellular signaling pathways, including the RAF/MEK/ERK and PI3K/AKT/mTOR pathways. Transforming mutations in KRAS are frequently found in pancreatic, colon, endometrial, ovarian and biliary cancers; almost all of these mutations result in constitutive activation of KRAS, thereby promoting cell proliferation (PMID: 21993244, 24651010). KRAS mutations occur primarily in three major hotspots, G12, G13 and Q61, the first two of which occur in the GTP-ase domain and the latter interferes with the ability of NF1 to bind and regulate KRAS (PMID: 22589270, 21993244, 24651010). Other less well-characterized mutations such as A146T/V/P and L19F have also been characterized and found to be activating albeit at lower frequencies (PMID: 20147967, 20432530, 20570890). Germline KRAS mutations are responsible for both Noonan syndrome (NS) and cardio-facio-cutaneous (CFC) syndrome (PMID: 16474405, 16474404, 19467855, 17056636) that are associated with hyperactivated MAPK pathway, distinctive clinical characteristics and a predisposition to cancer (PMID: 19467855, 17704260). R1 False +ENST00000339824 NM_173598.6 283455 KSR2 True KSR2, a MAPK scaffolding protein, is infrequently altered in various cancer types. KSR2 is a scaffolding protein that is a member of the kinase suppressor Ras (KSR) family (PMID: 19560418). The KSR protein family has been implicated in the activation of MAPK signaling cascades via direct protein interactions and substrate localization (PMID: 19560418, 26891695). Proteomic analyses show that KSR2 interacts with several components of the MAPK signaling pathway including BRAF, MEK and ERK, as well as other proteins involved in cellular localization, including C-TAK1, 14-3-3 and PP2A1 (PMID: 19560418, 21441910). KSR2 specifically bridges the signaling molecules RAF and MEK to mediate RAF-mediated MEK phosphorylation (PMID: 11850406, 19560418, 29433126). In addition, KSR2 interacts with the phosphatase calcineurin to regulate calcium-mediated MAPK signaling (PMID: 19560418). KSR2 activity is also important for AMPK signaling and for glucose update and fatty acid oxidation (PMID: 19883615). KSR2 plays a role in negative feedback of the MAPK pathway, possibly by allosterically binding RAF (PMID: 19560418, 29433126). KSR2 is an important regulator of body fat as determined in a murine screen (PMID: 18719666). Loss of KSR2 in mice results in increased adiposity, reduced energy expenditure and insulin resistance, a phenotype consistent with human obesity (PMID: 19883615, 21127480). Germline mutations in KSR2 are associated with obesity and linked to hyperphagia, insulin resistance and impaired fatty oxidation in individuals (PMID: 24209692, 29273807). Somatic mutations in KSR2 are rare in human cancers; however, overexpression of KSR2 has been found in several cancer types including breast cancer (PMID: 21403620). Overexpression of KSR2 in preclinical studies is also associated with increased anchorage-independent growth and proliferation (PMID: 22801368). Small molecule inhibitors of KSR have shown preclinical efficacy and synergy with MEK inhibition, likely due to inhibition of negative feedback signaling (PMID: 27556948, 28333549). False +ENST00000316157 NM_015155.2 23185 LARP4B False LARP4B, an RNA binding protein, is altered by deletion and mutation in various cancer types. LARP4B is an RNA binding protein that is a member of the LARP family (PMID: 26501340). LARP4B binds to messenger ribonucleoprotein (mRNP) components, such as RACK1 and poly(A) binding protein (PABP), at 3’ poly(A) regions of mRNA (PMID: 12388589, 32517187, 26644407). These LARP4B-containing mRNP complexes mediate translation by serving as a bridge between protein regulators and ribosomes (PMID: 20573744). Because LARP4B has varied roles in mRNA stability and protein translation, LARP4B is important in many cellular processes including proliferation and growth control (PMID: 26001795, 32517187, 29462618). Somatic mutations in LARP4B are found in hypermutated stomach adenocarcinomas and are predicted to promote nonsense-mediated decay, resulting in loss of protein expression (PMID: 28649990). Additional studies have demonstrated that LARP4B may function as a tumor suppressor in glioma and prostate cancer (PMID: 26933087, 25534202, 31173237). However, LARP4B also has cancer-promoting roles in acute myeloid leukemia and liver cancer, suggesting that LARP4B has context-specific roles in cancer progression (PMID: 31772683, 31173237). False +ENST00000253339 NM_004690.3 9113 LATS1 False LATS1, an intracellular kinase involved in Hippo signaling, is recurrently altered by mutation in various cancer types. LATS1 is a serine/threonine protein kinase that is a regulator of the Hippo signal transduction pathway (PMID: 20935475, 27300434), which is involved in several processes of cancer progression and physiologically has important regulatory functions in organ development and regeneration (PMID: 23467301, 24825474, 24336504). Phosphorylation of LATS1 and co-activator MOB1 by upstream kinases MST1/2 results in LATS1 activation. Under physiologic conditions, activated LATS1 phosphorylates the transcriptional co-activators YAP1 and TAZ (PMID: 19878874). Through such regulation, LATS1 controls the nuclear localization of YAP1/TAZ, thereby regulating expression of genes involved in various cellular functions including proliferation and apoptosis (PMID: 20951342, 18158288). LATS1 is thought to function as a tumor suppressor via the negative regulation of cellular survival pathways mediated by YAP1/TAZ (PMID: 18158288). Somatic loss-of-function alterations in the LATS1 gene are found in several human cancers including malignant mesothelioma (PMID: 25902174, 26928227). In addition, the promoter region of the LATS1 gene is frequently hypermethylated in multiple types of human cancers (PMID: 15746036, 17049657, 23885148). True +ENST00000382592 NM_014572.2 26524 LATS2 False LATS2, an intracellular kinase involved in Hippo signaling, is recurrently altered by mutation in various cancer types. LATS2 is a serine/threonine protein kinase that is a regulator of the Hippo signal transduction pathway (PMID: 20935475, 27300434), which is involved in several processes of cancer progression and physiologically has important regulatory functions in organ development and regeneration (PMID: 23467301, 24825474, 24336504). Phosphorylation of LATS2 and co-activator MOB1 by upstream kinases MST1/2 results in LATS2 activation. Under physiologic conditions, activated LATS2 phosphorylates the transcriptional co-activators YAP1 and TAZ (PMID: 19878874). Through such regulation, LATS2 controls the nuclear localization of YAP1/TAZ, thereby regulating expression of genes involved in various cellular functions, including proliferation and apoptosis (PMID: 20951342, 18158288). LATS2 is thought to function as a tumor suppressor via the negative regulation of cellular survival pathways mediated by YAP1/TAZ (PMID: 18158288). Somatic loss-of-function mutations and deletions in the LATS2 gene are found in several human cancers including malignant mesothelioma (PMID: 26928227, 21245096). LATS2 mutations have been identified to co-occur with NF2 alterations, leading to Hippo pathway dysregulation (PMID: 28003305). True +ENST00000336890 NM_001042771.2 3932 LCK True LCK, a tyrosine kinase that regulates T-cell receptor signaling, is altered by rearrangement in hematologic malignancies. LCK is a tyrosine kinase that is a member of the SRC family of kinases and is important in the regulation of immune signaling pathways (PMID: 20541955). LCK is expressed predominantly on T-cells and mediates pre-T-cell receptor (TCR) and TCR signaling (PMID: 27469439). TCR signaling requires phosphorylation of immunoreceptor tyrosine-based activation motifs (ITAMs) on the TCR after peptide-MHC molecule binding (PMID: 20541955). LCK stably binds the cytoplasmic tails of T-cell co-receptors, such as CD4 and CD8, and is recruited to the ITAMs on the TCR/CD3 co-receptor complex to facilitate ITAM phosphorylation (PMID: 2455897, 2470098). Phosphorylation of the TCR complex results in the recruitment of ZAP70, a protein kinase, which initiates LAT phosphorylation, where LAT serves as a docking site for downstream signaling cascades (PMID: 29915297). LCK can also interact with a variety of signaling molecules to mediate signaling axes including CD55, CD44 and NOTCH1, among others (PMID: 28838952, 9573028, 14583609). Overexpression of LCK in mice results in thymic tumors, suggesting that LCK can function as an oncogene (PMID: 1708890). Aberrant activation of LCK has been identified in several tumor types and rearrangements of LCK are found in lymphoid tumors (PMID: 3463975, 18316591). In addition, LCK activity has been associated with cancer stemness and metastasis in solid tumors (PMID: 30353164). Small molecule kinase inhibitors that target LCK, such as saracatinib, are currently under preclinical investigation (PMID: 28838952). False +ENST00000265165 NM_016269 51176 LEF1 True LEF1, a T-cell and B-cell enhancer transcription factor, is infrequently altered in cancer. LEF1, a member of the T-cell factor/lymphoid enhancer factor family, encodes for a transcription factor expressed in pre-B and T cells (PMID: 10933391). LEF1 binds to the T-cell receptor-alpha enhancer to drive T-cell antigen receptor-alpha chain expression (PMID: 7958926, 2010090). LEF1 functions as a nuclear effector in the Wnt/β-catenin signaling pathway to regulate cellular proliferation and cellular apoptosis (PMID: 8757136, 18316418). Overexpression of LEF1 in various cancer cell lines and models induces tumorigenesis, cellular proliferation, migration and resistance to chemotherapy, suggesting that LEF1 functions predominantly as an oncogene (PMID: 31296250, 18316418, 34639214). Amplification of LEF1 has been identified in acute lymphoblastic leukemia and chronic lymphocytic leukemia (PMID: 25942645, 26950276, 22184516). False +ENST00000266674 NM_003667 8549 LGR5 True LGR5, a G-protein coupled receptor that regulates Wnt/beta-catenin signaling, is infrequently altered by amplification in cancer. LGR5, also known as GPR5, is a G-protein coupled receptor that regulates the Wnt/beta-catenin signaling pathway through binding to R-spondin (PMID: 21693646, 26086949). LGR5 is a marker for adult stem cells in various organs and tissues, stimulating stem cell proliferation and self-renewal through Wnt signaling (PMID: 22969042). Rearrangement of LGR5 has been identified in glioblastoma multiforme (PMID: 25500544). Amplified LGR5 mutations have been identified in various cancer types including basal cell carcinomas, hepatocellular carcinomas, colorectal tumors and ovarian tumors (PMID: 16575208, 18688030). Aberrant expression of LGR5 in breast cancer cells promotes tumorigenesis through long-term potentiation of the Wnt/beta-catenin signal pathway, leading to cancer cell mobility and tumor formation (PMID: 26086949). Conversely, LGR5 has been identified as a negative regulator of Wnt/beta-catenin signaling in the context of B cells, demonstrated by upregulated nuclear beta-catenin and tumor growth suppression following ablation of LGR5 in B-cell lineage acute lymphoblastic leukemia cells (Abstract: Cosgun et al. Abstract# 4515, AACR 2018. https://aacrjournals.org/cancerres/article/78/13_Supplement/4515/628888/). Loss of LGR5 mutations have been identified in colorectal tumors (PMID: 23349017). Methylation of LGR5 promotes tumorigenesis in colorectal cancer cell lines and primary tumors as measured by decreased Wnt signaling, increased risk of metastasis and tumor recurrence (PMID: 22056143). LGR5 promotes tumor suppressive activity through Wnt signaling and loss of this function through alteration promotes tumorigenicity as measured by increased invasion, anchorage-independent growth and enhanced tumorigenicity in xenograft models (PMID: 22056143, 23349017). False +ENST00000368300 NM_170707 4000 LMNA True LMNA, an intermediate filament protein, is infrequently altered in cancer. LMNA encodes for intermediate filament proteins lamin A and C that provide stability and structure of the nuclear lamina through the assembly of a filamentous meshwork (PMID: 8344919, 2188730). LMNA regulates the structural integrity and matrix stiffness of the nuclear envelope, playing an integral role in nuclear assembly and chromatin organization (PMID: 2344612, 23990565, 15317753). LMNA is recruited to DNA double-strand break sites by DNA repair proteins XRCC4 and IFFO1 to immobilize the broken DNA ends and suppress chromosome translocation (PMID: 31548606). Germline mutations of LMNA are associated with laminopathies, such as Emery-Dreifuss muscular dystrophy (PMID: 10080180, 12075506, 12927431). Overexpression of LMNA in various cancer cell lines and models induces tumorigenesis, migration and invasion, suggesting that LMNA functions predominantly as an oncogene (PMID: 22301279, 34680461, 32896989). Amplification of LMNA has been identified in various cancers, including cervical cancer, prostate cancer and hepatocellular carcinoma (PMID: 32896989). False +ENST00000335790 NM_002315.2 4004 LMO1 True LMO1, a transcriptional regulator of the cell cycle and metastasis, is altered in the germline of some patients predisposed to neuroblastoma. LMO1 (Lim-domain-only 1, also known as TTG1 and Rhombotin 1) is a Lim-domain-only protein that functions to regulate the formation of transcriptional complexes (PMID: 23303138). The Lim-domain-only proteins (LMO1-4) are characterized by two tandemly arrayed protein interacting LIM domains. The LIM domain is similar to a zinc finger domain; however, instead of mediating DNA-interactions it mediates protein-protein interactions (PMID: 10704826). LMO1 was first described to have oncogenic functions in T-lymphoblastic leukemia. It is was found to be located near chromosome 11 translocation breakpoints leading to overexpression in these leukemias (PMID: 2034676, 2115645). LMO1 expression can drive leukemogenesis and form protein complexes with TAL1 and other proteins. LMO1 protein complexes regulate transcription of known oncogenes such as MYB, one mechanism through which LMO1 leads to leukemogenesis (PMID: 22897851, 1508213). LMO1 is also described as an oncogene in neuroblastoma. A subset of neuroblastoma is robustly associated with germline sequence variants close to the LMO1 gene (PMID: 21124317). These sequence variants lead to high LMO1 expression through differential GATA transcription factor binding (PMID: 26560027). It is clear that LMO1 is associated with poor survival and a higher risk of metastasis, but the exact mechanisms of action are not well understood (PMID: 23303138). False +ENST00000395833 NM_001142315.1 4005 LMO2 True LMO2, a transcription factor involved in the regulation of hematopoiesis, is recurrently altered by chromosomal rearrangement in T-lymphoblastic leukemia. LMO2 is a transcription factor that is a member of the LIM-domain only protein family (PMID: 26108219, 20861166). LMO2 is expressed in hematopoietic cells and across many tissues during development; however, LMO2 is silenced in mature lymphoid lineages (PMID: 11248806). LMO2 regulates both primitive and definitive hematopoiesis as well as angiogenesis and maintenance of stemness (PMID: 8033210, 21343360). LMO2 functions as a member of a transcriptional complex containing TAL1, GATA1/2, RUNX1, MYB, and E-proteins, but LMO2 itself does not have any intrinsic DNA binding ability, acting predominantly to mediate protein-protein interactions (PMID: 25466247, 9214632). LMO2 is dependent on the binding of other proteins for stability, and these interactions are context-dependent (PMID: 26598604). LMO2 predominantly functions as a bridging protein to coordinate the binding of transcriptional complexes across GATA and E-box motifs and serves as an LDB1 docking site to activate enhancers at erythroid genes (PMID: 28636938). Increased expression of LMO2 in murine models results in a differentiation block, resulting in an accumulation of immature thymocyte progenitors (PMID: 8605871, 7579400). In combination with TAL1 activation or NOTCH1 mutations, LMO2 expression in thymocytes results in enhanced tumor-initiating properties (PMID: 8605871, 21670468). LMO2 also functions as the driver oncogene in X chromosome-linked severe combined immuno-deficiency syndrome therapy associated leukemias (PMID: 14985489). LMO2 overexpression is common in patients with T-acute lymphoblastic leukemia (T-ALL), due to recurrent deletions or translocations that fall upstream of LMO2, resulting in activation (PMID: 20861166, 26998100, 16873670, 25682596), suggesting that LMO2 functions predominantly as an oncogene. False +ENST00000389484 NM_018557 53353 LRP1B False LRP1B, a low-density lipoprotein receptor, is infrequently altered in cancer. LRP1B, a member of the low-density lipoprotein receptor family, functions in various cellular functions such as signal transduction, DNA damage response, synaptic transmission and cell migration (PMID: 19071120, 15082773). LRP1B interacts with cytosolic adapter and scaffold protein binding partners through canonical receptor-mediated endocytosis or its intracellular domain (PMID: 19071120). The LRP1B intracellular domain is soluble and is released from the extracellular domain through regulated intramembrane proteolysis cleavage (PMID: 17227771). The cleaved LRP1B intracellular domain localizes to the nucleus via nuclear localization signaling and mediates transcriptional activity through interactions with various binding partners (PMID: 17227771). LRP1B-deficient cancer cells demonstrate anchorage-independent growth and the inability to suppress colony formation, suggesting that LRP1B functions predominantly as a tumor suppressor gene (PMID: 17227771, 20095042, 27499094). Loss of LRP1B has been identified in various different cancers, including prostate cancer, ovarian cancer and multiple myeloma (PMID: 31270961, 27939411, 30719154). Epigenetic silencing of LRP1B, for example hypermethylation and histone deacetylation, has also been identified in different cancers, which include thyroid cancer and renal cell cancer (PMID: 27499094, 23521319). Loss of LRP1B is suggested to contribute to resistance to liposomal therapies such as pegylated liposomal doxorubicin, due to dysfunction in endocytic activity affecting drug uptake (PMID: 22896685). True +ENST00000294304 NM_001291902.1 4041 LRP5 True LRP5, a receptor involved in WNT signaling, is altered by mutation in various cancer types. Germline mutations in LRP5 are associated with familial exudative vitreoretinopathy and bone loss disorders. LRP5 is a transmembrane receptor that is a member of the LDL-related protein family (PMID: 28979801, 17143291). LRP5 interacts with the co-receptors LRP6 and Frizzled family members at the plasma membrane following WNT ligand binding, leading to initiation of WNT-mediated downstream signaling (PMID: 24316024, 23258168). WNT signaling is a critical developmental pathway with roles in determining cell fate, tissue identity and polarity (PMID: 28218291). LRP5/6 binding by WNT ligands results in phosphorylation of CK1α and GSK3β, which recruit the signaling molecule DVL to the plasma membrane for polymerization and activation (PMID: 23258168, 19619488). DVL inactivates the β-catenin destruction complex (containing APC, GSK3β and AXIN) due to recruitment of AXIN to the co-receptor complex, allowing β-catenin to accumulate and translocate to the nucleus (PMID: 23258168). In the nucleus, β-catenin associates with the transcription factors LEF and TCF, displacing the repressive TLE proteins and forming transcription factor complexes that promote the expression of β-catenin target genes (PMID: 23258168, 19619488). LRP5 can also interact with antagonists of WNT, like the Dickkopf (DKK) proteins or SOST, to inhibit WNT activation (PMID: 17052975). Germline mutations in LRP5 have been identified in several malignancies including familial exudative vitreoretinopathy (FEVR), which causes progressive vision loss, and diseases related to altered bone mass (PMID: 15024691, 20340138, 28341377). LRP5 mutations have been identified in various cancer types, though the functional role of these alterations has not yet been carefully elucidated (PMID: 31575382, 19158955, 18044981, 16266997, 19619488). However, mutations in LRP5 are predicted to result in deregulation of WNT signaling. True +ENST00000261349 NM_002336.2 4040 LRP6 True LRP6, a receptor involved in WNT signaling, is altered by mutation in various cancer types. Germline mutations in LRP6 are associated with early coronary disease, oligodontia, and bone mass disorders. LRP6 is a transmembrane receptor that is a member of the LDL-related protein family (PMID: 27617575, 17143291). LRP6 interacts with the co-receptors LRP5 and Frizzled family members at the plasma membrane following WNT ligand binding, leading to initiation of WNT-mediated downstream signaling (PMID: 24316024, 23258168). WNT signaling is a critical developmental pathway with roles in determining cell fate, tissue identity and polarity (PMID: 28218291). LRP5/6 binding by WNT ligands results in phosphorylation of CK1α and GSK3β, which recruit the signaling molecule DVL to the plasma membrane for polymerization and activation (PMID: 23258168, 19619488). DVL inactivates the β-catenin destruction complex (containing APC, GSK3β and AXIN) due to recruitment of AXIN to the co-receptor complex, allowing β-catenin to accumulate and translocate to the nucleus (PMID: 23258168). In the nucleus, β-catenin associates with the transcription factors LEF and TCF, displacing the repressive TLE proteins and forming transcription factor complexes that promote the expression of β-catenin target genes (PMID: 23258168, 19619488). LRP6 can also interact with antagonists of WNT, like the Dickkopf (DKK) proteins, to inhibit WNT activation (PMID: 21866564, 31412666, 22000856). LRP5/6 also have roles in the regulation of tissue homeostasis and intestinal epithelial development (PMID: 31412666). Germline mutations in LRP6 are associated with several malignancies including tooth agenesis, bone mass disorders, early coronary disease and neural tube defects (PMID: 26387593, 26963285, 31085352, 24203697, 17332414). LRP6 mutations have been identified in various cancer types; however, the functional role of these alterations have not yet been carefully elucidated (PMID: 25500543, 15064719). However, overexpression of LRP6 is found in a variety of cancer types, including liver, breast and colorectal cancer, suggesting that LRP6 predominantly functions as an oncogene (PMID: 31412666, 20194742). False +ENST00000376117 NM_002341.1 4050 LTB True LTB, a tumor suppressor involved in inflammatory signaling, is recurrently mutated in multiple myeloma. LTB (also TNF-C) is a lymphotoxin or cytokine that is a member of the tumor necrosis factor (TNF) superfamily of ligands (PMID: 8621492). LTB forms a heterotrimeric complex with another TNF family member, LTα (one subunit of LTα; two subunits of LTB), which is termed the lymphotoxin protein complex (PMID: 8621492, 27323847). The lymphotoxin protein complex is found on the surface of activated T-, B- and natural killer cells (PMID: 27323847) and serves as the primary ligand for the lymphotoxin beta receptor, which is found on nonlymphoid cells (PMID: 27323847, 8621492). LTB activity is important for follicular dendritic cell development in germinal centers and is an important chemoattractant relevant for B-cell homing to follicles in the lymph node and spleen (PMID: 10917533, 10049949). Lymphotoxin signaling is necessary for normal lymphoid tissue organogenesis and maintenance (PMID: 9256477) and for regulation of stromal cell expression of chemokines in tissues such as the spleen (PMID: 9892622). LTB induces the expression of cytokines and chemokines that promote a positive feedback loop to recruit immune cells (PMID: 10917533, 27323847). Loss of LTB expression in mice results in reduced follicular dendritic cell development, impaired B-cell memory and abnormal lymphoid tissue development (PMID: 9256477). In addition, LTB is a regulator of NF-KB-mediated inflammatory signaling (PMID: 8798772, 28196873). Inflammatory gene expression signatures in autoimmune patients have been linked to lymphotoxin signaling, such as in rheumatoid arthritis (PMID: 25405351). Somatic mutations in LTB are found in patients with multiple myeloma and are predicted to be loss-of-function (PMID: 24429703, 28550183, 26282654). In addition, LTB overexpression has been linked to cancers that are driven by inflammation, such as hepatocellular carcinomas (PMID: 19800575). True +ENST00000263800 NM_002344 4058 LTK True LTK, a receptor tyrosine kinase, is infrequently altered in cancer. LTK (leukocyte tyrosine kinase) is a receptor tyrosine kinase that localizes to the endoplasmic reticulum and is activated by the FAM10A/B proteins (PMID: 31227593, 25331893, 26630010). LTK is a member of the insulin receptor family and is closely related to ALK, with 79% sequence similarity among the tyrosine kinase domains and sensitivity to ALK inhibitors (PMID: 9223670, 31227593, 22347506, 25331893). LTK is normally expressed in pre-B lymphocytes and neuronal tissues (PMID: 9223670, 31227593). When bound to its ligands, LTK phosphorylates Shc and IRS-1 to activate downstream Ras signaling, thus promoting cell growth and inhibiting apoptosis (PMID: 8910363). Activated LTK also transmits anti-apoptotic signals through the PI3-kinase pathway by phosphorylating c-Cbl (PMID: 9223670). Kinase domain mutations in LTK lead to constitutive phosphorylation of the receptor and activation of downstream signaling targets including Shc, ERK, JAK1 and JAK2 (PMID: 22347506). LTK kinase domain mutants also transform epithelial cells and induce neural outgrowth in vitro (PMID: 22347506). LTK is involved in regulating endoplasmic reticulum (ER) protein export, such that knockdown or pharmacological inhibition of LTK leads to significantly fewer ER exit sites compared to wildtype/untreated cells (PMID: 31227593). While LTK is overexpressed among acute myeloid leukemia samples, alteration of LTK in human cancers is not well-characterized (PMID: 14977821). False +ENST00000519728 NM_002350.3 4067 LYN True LYN, a non-receptor tyrosine kinase, is altered by amplification in various cancers. The LYN gene encodes a non-receptor tyrosine kinase of the Src family (PMID: 9202419). LYN is involved in immune responses, B-cell signaling, signal transduction of growth factors and response to DNA damage, among other functions (PMID: 19290919, 10574931, 11825908, 11435302). LYN is a mediator that can positively or negatively regulate different processes depending on the cellular and physiological context (PMID: 15664155). LYN has been described to promote tumor growth, invasion, epithelial to mesenchymal transition (EMT) and ERK signaling in different cancer contexts (PMID: 20215510, 22490227, 22731636). The LYN gene is typically altered by amplification in various tumors, including prostate, breast and ovarian cancers (cBioPortal, MSKCC, Nov 2016). LYN can be pharmacologically targeted with Src-kinase inhibitors, such as dasatinib (PMID: 20215510, 22490227, 18056483). False +ENST00000646124 NM_006767.3 8216 LZTR1 False LZTR1, a ubiquitin ligase adaptor protein, is recurrently altered by mutation in glioblastoma, Noonan syndrome, and schwannomatosis. LZTR1 is a ubiquitin ligase adaptor protein that is a member of the BTB/POZ family (PMID: 30442762). LZTR1 functions as a scaffolding component of the CUL3 E3-ligase complex that targets substrate proteins to the proteasome for ubiquitin-mediated degradation (PMID: 23917401, 30442762). The oncogene RAS is ubiquitinated by the LZTR1-CUL3 complex which is essential for the normal protein turnover of RAS (PMID: 30442762). In addition, LZTR1 also binds RAF1, a signaling molecule in the MAPK pathway (PMID: 30368668). Loss of LZTR1 expression in hematopoietic cell lines results in enhanced MAPK signaling, reduced RAS ubiquitination, and increased association of RAS at the plasma membrane (PMID: 30442762). Germline mutations in LZTR1 have been identified in patients with Noonan syndrome and schwannomatosis (PMID: 24362817, 25335493, 25795793, 30481304). Somatic loss-of-function variants in LZTR1 are also found in patients with glioblastomas and hepatocellular carcinomas (PMID: 28622513), leading to activation of MAPK signaling due to RAS stabilization (PMID: 30442762). Reduced LZTR1 expression in preclinical studies results in resistance to several tyrosine kinase inhibitors, including imatinib, ponatinib, and rebastinib, due to constitutively active RAS signaling (PMID: 30442762). True +ENST00000235310 NM_001127325.1 10459 MAD2L2 True MAD2L2, an adaptor protein involved in DNA repair, is altered by mutation and overexpression in various cancer types. MAD2L2 (also MAD2B and REV7) is a DNA repair protein that functions as an adaptor protein in several DNA repair-associated complexes (PMID: 25896508, 30154076). MAD2L2 is the non-catalytic subunit of polymerase zeta, which functions as an error-prone DNA polymerase that bypasses DNA lesions during replication (PMID: 19258535, 31410467). The H2AX-53BP1 checkpoint complex recruits MAD2L2 to double strand breaks leading to blockage of homologous recombination (HR) (PMID: 25799992). MAD2L2 then promotes non-homologous end-joining (NHEJ), including at unprotected telomeres, by inhibiting 5’ end resection downstream of 53BP1 and RIF1 (PMID: 25799990, 30046110, 30022168). MAD2L2-mediated NHEJ is important for specific cellular functions such as immunoglobulin class switch recombination (PMID: 25799992). MAD2L2 is also a member of the mitotic assembly checkpoint that prevents activation of the anaphase promoting complex/cyclosome (APC/C) during metaphase (PMID: 25896508). Overexpression of MAD2L2 has been found in several cancer types likely contributing to genomic instability (PMID: 17044027). In addition, MAD2L2-dependent translesion synthesis is predicted to contribute to error-prone repair after chemotherapy and, therefore, small molecule inhibitors targeting polymerase zeta are under development (PMID: 31178121). Loss of MAD2L2 activity has been implicated as a mechanism of PARP inhibitor resistance in BRCA1-deficient patients, due to a switch to HR repair; however, HR restoration may render these cancers radiosensitive (PMID: 25799992, 29789392). True +ENST00000393350 NM_001031804.2 4094 MAF False MAF, a transcription factor, is recurrently altered by rearrangement in multiple myeloma. MAF is a transcription factor that is a member of the AP1 protein family (PMID: 19143053). MAF, along with MAFA and MAFB, are categorized as large MAF proteins that regulate gene expression via transactivation domains (PMID: 19143053). MAF coordinates DNA binding as a homodimer, or a heterodimer in complex with other MAF family members (PMID: 19143053), and recruits co-activators (such as EP300, CREBBP, KAT2B, and TBP) to initiate transcription (PMID: 11943779, 18042454, 15328344). MAF activity regulates a variety of cellular processes including migration, cell cycle, proliferation, differentiation, and cell-cell interactions, among others (PMID: 19143053, 16247450, 14998494). In addition, tightly regulated MAF expression is important for context-specific control of transcriptional programs during development and terminal differentiation (PMID: 17569705). The activity of large MAF proteins is also mediated by competition with small MAF proteins for the same binding site (PMID: 8552399). Loss of MAF in murine models results in altered cytokine expression with implications for immune regulation while increased expression of MAF leads to transformation (PMID: 10403649, 16424013, 16247450). Germline mutations in MAF are found in lens development disorders such as pulverulent cataracts (PMID: 12642301). Overexpression of MAF is common in multiple myelomas and T-cell lymphomas, suggesting that MAF predominantly functions as an oncogene (PMID: 19143053). Rearrangements involving MAF and the immunoglobulin gene are recurrent in multiple myelomas and predicted to be a primary initiating event in the disease (PMID: 9616139, 18070707). False +ENST00000373313 NM_005461.4 9935 MAFB True MAFB, a transcription factor, is recurrently altered by chromosomal rearrangement in multiple myeloma. MAFB is a transcription factor that is a member of the AP1 protein family (PMID: 19143053). MAFB, along with MAF and MAFA, are categorized as large MAF proteins that regulate gene expression via transactivation domains (PMID: 19143053). MAFB coordinates DNA binding as a homodimer or a heterodimer in complex with other MAF family members (PMID: 19143053), and recruits co-activators (such as EP300, CREBBP, KAT2B, and TBP) to initiate transcription (PMID: 11943779, 18042454, 15328344). MAFB activity regulates a variety of cellular processes including migration, cell cycle, proliferation, differentiation, and cell-cell interactions, among others (PMID: 19143053, 16247450, 14998494). In addition, tightly regulated MAFB expression is important for context-specific control of transcriptional programs during development and terminal differentiation (PMID: 17569705, 28025141, 8620536). The activity of large MAFB proteins is also mediated by competition with small MAF proteins for the same binding site (PMID: 8552399). Forced expression of MAFB in murine models results in plasma cell neoplasms (PMID: 16424013). Overexpression of MAFB is common in multiple myelomas and T-cell lymphomas, suggesting that MAFB predominantly functions as an oncogene (PMID: 19143053). Rearrangements involving MAFB and the immunoglobulin gene are recurrent in multiple myelomas and predicted to be a primary initiating event in the disease (PMID: 9616139, 18070707, 24638926). False +ENST00000354212 NM_012301.4 9863 MAGI2 False MAGI2, a membrane-associated guanylate kinase, is altered in various cancers. MAGI2 is a membrane-associated guanylate kinase that functions primarily as a scaffold protein at cell junctions (PMID: 10644767, 22361463). With eight protein-binding domains and three isoforms, α, β, and γ, MAGI2 can organize, assemble and anchor many different proteins, particularly cell signaling proteins, at synaptic junctions (PMID: 29542165, 10644767, 22361463). MAGI2 is also known as the synaptic scaffolding molecule (S-SCAM), atrophin-interacting protein-1 (AIP-1) and activin receptor-interacting protein 1 (ARIP1) (PMID: 22593065, 25637633, 17880912). MAGI2 is highly expressed in the brain where it is implicated in AMPA-type glutamate receptor trafficking and is important for overall synapse formation (PMID: 22361463, 22593065, 17644382, 38045729). The scaffolding protein also plays a key role in the glomerulus of the kidney by stabilizing and organizing nephrin as well as regulating the dynamics of the podocyte cytoskeleton and slit diaphragm (PMID: 25271328). MAGI2 enhances the ability of PTEN to suppress the activity of AKT by stabilizing a multiprotein signaling complex with PTEN that localizes to tight junctions and increases signaling efficiency (PMID: 10760291, 17880912). Suppression of MAGI2 in hepatocellular carcinoma cells causes loss of PTEN stability and induces cell migration and proliferation in vitro (PMID: 17880912). MAGI2 promoter methylation occurs in acute lymphoblastic leukemia, gastric cancer, colorectal cancer, lung cancer and breast cancer, among others (PMID: 33530176, 32730644). In addition to the tumor suppressive behavior of the MAGI2 protein, MAGI2-AS3, the long noncoding RNA antisense transcript of MAGI2, has demonstrated tissue-specific oncogenic and tumor suppressive roles (PMID: 35071487, 31837602). True +ENST00000614891 NM_052886.3 114569 MAL2 False MAL2, a transmembrane protein, is infrequently altered in cancer. MAL2, a member of the MAL proteolipid family, is an essential transmembrane protein for the basolateral-to-apical transcytotic pathway (PMID: 11549320, 14576188). MAL2 traffics vesicles from the subapical compartment to fuse with basal cargo-containing endosomes and then subsequently traffics basal cargo vesicles back to the apical surface (PMID: 12370246, 16445687, 20493814). The transcytotic function of MAL2 is regulated by binding partners INF2 and CDC42 (PMID: 20493814). Overexpression of MAL2 in human colorectal cancer cells inhibits cell proliferation and invasion, suggesting that MAL2 functions primarily as a tumor suppressor gene (PMID: 35847380). Despite functioning as a tumor suppressor gene, upregulation of MAL2 has been identified in various epithelial-derived cancers such as breast cancer, renal cell carcinoma and cholangiocarcinoma (PMID: 28562687, 32990678, 19287191). This is suggested to be due to the amplification of chromosomal region 8q24.12 enhancing expression of both MAL2 and known oncogene MYC (PMID: 32059473). The enhanced MAL2 expression is predicted to be associated with earlier stages of cancer progression and eventually, its expression is repressed during metastases as MYC expression increases (PMID: 32059473). True +ENST00000649217 NM_006785.3 10892 MALT1 False MALT1, a paracaspase, is recurrently altered by chromosomal rearrangement in MALT lymphoma. MALT1 is a mucosal-associated lymphoid tissue lymphoma translocation protein 1, a cysteine paracaspase. MALT1 cleaves multiple substrates including BCL10, RELB, and TNFAIP3, and promotes NFkB signaling (PMID: 21873235,18223652,18264101). It associates with CARMA1 and BCL10 to form a complex (CBM) with scaffold function to recruit proteins important for signaling (PMID:24074955,15125833). MALT1 activity is employed in B-cell and T-cell antigen receptor activation and IL2 production (PMID: 23706741, 14614861, 14576442). Germline mutation can lead to immunodeficiency (PMID: 25627829, 23727036). MALT1 is translocated with partner API2 (BIRC3) in Mucosal-associated B-cell lymphomas (PMID: 10339464). The fusion protein causes dimerization and activation of NFkB (PMID: 11262391). MALT1 can also be amplified or overexpressed by translocation with the IgH chain locus in non-Hodgkins lymphomas (PMID: 12560219). MALT1 activity was found to be critical for the growth of activated B-cell type Diffuse Large B-cell Lymphomas (DLBCL) (PMID: 19897720). Inhibitors of MALT1 proteolytic activity are in development for lymphoma therapy (PMID: 23238016). False +ENST00000307102 NM_002755.3 5604 MAP2K1 True 2 MAP2K1, an intracellular kinase, is mutated at low frequencies in various cancer types including melanoma, colorectal and lung cancers. MAP2K1 (also known as MEK1) is a serine/threonine kinase that functions as an effector protein in the mitogen-activated protein kinase (MAPK) signaling cascade (PMID: 25435214, 17496922). The MAPK signaling pathway is involved in the regulation of diverse cellular processes including proliferation, differentiation, cell adhesion and transcription (PMID: 25435214, 17496922). As a component of a three-tiered MAPK cascade, MEK1 activity is dependent on phosphorylation by upstream RAF kinases. Activated MEK1 in turn phosphorylates ERK1/2 (extracellular-signal-regulated kinases1/2) which then serves as a transcriptional regulator (PMID: 22177953). These signaling events are triggered by growth factors, cytokines, and hormones that activate upstream receptor tyrosine kinases, ultimately leading to altered expression of key regulators of cell growth, differentiation, proliferation and survival (PMID: 9069255, 11242034). Dysregulation of MEK1 signaling is commonly associated with genetic alterations in RAS and RAF (PMID: 12068308, 12509763). Hyperactivation of the MAPK pathway is frequently observed in human cancers, such as melanoma, colorectal and lung cancers; however, oncogenic mutations in MEK1 in primary tumors are infrequent (PMID: 22753777, 25351745). The MEK1/2 inhibitors trametinib and cobimetinib are FDA-approved for the treatment of melanoma in combination with RAF inhibition and preclinical and clinical efforts are ongoing to determine the efficacy of MEK1 inhibition for other indications (PMID: 25435214). Some MEK1 mutations may confer resistance to both MEK and RAF inhibitors and can arise as a resistance mechanism to RAF inhibition (PMID: 19915144, 21383288). False +ENST00000262948 NM_030662.3 5605 MAP2K2 True 2 MAP2K2, an intracellular kinase, is altered by mutation in various cancer types. MAP2K2 (also known as MEK2) is a serine/threonine kinase that functions as an effector protein in the mitogen-activated protein kinase (MAPK) signaling cascade (PMID: 25435214, 17496922). The MAPK signaling pathway is involved in the regulation of diverse cellular processes including proliferation, differentiation, cell adhesion and transcription (PMID: 25435214, 17496922). As a component of a three-tiered MAPK cascade, MEK2 activity is dependent on phosphorylation by upstream RAF kinases. Activated MEK2 in turn phosphorylates ERK1/2 (extracellular-signal-regulated kinases1/2) which then serves as a transcriptional regulator (PMID: 22177953). These signaling events are triggered by growth factors, cytokines, and hormones that activate upstream receptor tyrosine kinases, ultimately leading to altered expression of key regulators of cell growth, differentiation, proliferation and survival (PMID: 9069255, 11242034). Germline missense mutations and deletions in MEK2 are found in patients with cardio-facio-cutaneous syndrome (PMID: 20358587, 18456719, 21178588, 24311457, 23379592). Hyperactivation of the MAPK pathway is frequently observed in human cancers; however, oncogenic mutations in MAP2K2 in primary tumors are infrequent (PMID: 24840079). Because of its major role in signaling as a RAF oncogene effector, several inhibitors of wildtype MEK2 and its close structural and functional homolog, MEK1, have been developed (PMID: 20149254, 24840079). The MEK1/2 inhibitors trametinib and cobimetinib are FDA-approved for the treatment of melanoma in combination with RAF inhibition and preclinical and clinical efforts are ongoing to determine the efficacy of MEK1/2 inhibition for other indications (PMID: 25435214). Mutations in MEK2 have been identified in melanomas insensitive to RAF and MEK inhibition and may mediate resistance to MAPK pathway targeted agents (PMID: 24265153, 24055054, 22197931). False +ENST00000353533 NM_003010.3 6416 MAP2K4 False MAP2K4, a tumor suppressor and intracellular kinase, is altered in various cancer types. MAP2K4 is a dual specificity kinase that directly phosphorylates and activates JNK (c-Jun N-terminal kinase) and p38 MAP kinase (PMID: 7716521). MAP2K4 itself is phosphorylated and activated by one of several upstream MAP kinase kinase kinases (MAPKKK). The activation of JNK and p38 MAP kinase pathways occurs in response to a variety of environmental stressors, such as DNA damage, hypoxia, heat shock, ionizing radiation, as well as inflammatory cytokines and growth factors (PMID: 17496914,19629069). Activation of these signaling pathways leads to altered transcriptional activity of downstream effector molecules such as c-Jun, p53, ELK1, ATF2 and several other transcription factors involved in apoptosis, cell survival, growth and differentiation (PMID: 17496914,19629069). Inactivating mutations in MAP2K4 have been identified in a variety of tumor cell lines and human cancers, suggesting that MAP2K4 functions primarily as a tumor suppressor (PMID: 9331070, 9622070, 17496914, 22522925). Loss of heterozygosity of the 17p chromosomal region, where MAP2K4 is located in close proximity to TP53, is observed at a high frequency in many cancers (PMID: 16721048, 16627982, 19603523). In addition, MAP2K4 has been found to act as a suppressor of metastasis in prostate and ovarian cell lines (PMID: 10554023, 12438272). True +ENST00000399503 NM_005921.1 4214 MAP3K1 False MAP3K1, an intracellular kinase, is altered by mutation or deletion in various cancer types, most frequently in breast and endometrial cancer. The MAP3K1 gene encodes MEKK1, a kinase that signals in the pro-oncogenic MAP-kinase and JNK signaling pathways. MAP3K1 is unique among the MAPK signaling molecules in that it also acts as an E3 ubiquitin ligase for ERK1/2, thus allowing for the regulation of pathway output (PMID: 12049732, 25613373). Activation of MAP-kinase and JNK pathways occurs in response to a variety of stimuli such as environmental stress, inflammatory cytokines, pro-apoptotic signals and growth factors (PMID: 10639576, 9528810, 8621725, 11784851, 9078260). Activated MAP3K1 phosphorylates downstream effector molecules such as MAP2K4/7, MAP2K1/2, IKK alpha/beta and other transcription factors involved in apoptosis, cell survival, growth and differentiation (PMID: 7997270, 7624324, 9008162, 12471242) leading to activation of downstream signaling pathways. Germline mutations in MAP3K1 disrupt normal sex development and cause 46,XY sex development disorder (PMID: 21129722, 24135036). Truncating mutations and deletions in MAP3K1 mutations have been identified in breast cancer, predominantly in the luminal A subtype (PMID: 24386504), suggesting that MAP3K1 functions as a putative tumor suppressor. MAP3K1 may also promote oncogenesis and metastasis in some contexts. Elevated MAP3K1 expression has been found in human melanoma samples (PMID: 24003131) and MAP3K1 plays a pro-metastatic role in some cancers, as demonstrated by experimental studies in breast and pancreatic cancer models (PMID: 19513748, 16568086). True +ENST00000265026 NM_004721.4 9175 MAP3K13 True MAP3K13, a serine/threonine kinase, is infrequently altered in cancer. MAP3K13 is a serine/threonine kinase that is a member of the JNK signaling pathway. MAP3K13 phosphorylates MAPK8 (JNK) and MAP2K7, resulting in activation of the JNK pathway (PMID: 11163770, 8637721), which is a mitogen-activated protein kinase (MAPK) pathway activated in response to proinflammatory cytokines and extracellular stresses (PMID: 11163770) and functions as a regulator of cellular proliferation, apoptosis and morphogenesis (PMID: 9561845). Through the leucine/isoleucine zipper domain, MAP3K13 forms dimers or oligomers with other proteins, such as JNK interacting protein (JIP-1), an interaction that is essential for the activation of MKK7 in the JNK signaling cascade (PMID: 9353328, 11163770, 11726227). In addition, MAP3K13 has been found to interact with PRDX3 and regulates the activation of NF-κB in the cytosol (PMID: 12492477). MAP3K13 mRNA is found primarily in the pancreas, with lower levels of expression in the brain, liver and placenta (PMID: 9353328). Amplification and loss-of-function mutations in MAP3K13 are found in various solid tumors, including breast, lung cancer, and melanoma (PMID: 22722201, 22817889, 28760853). False +ENST00000344686 NM_003954.3 9020 MAP3K14 True MAP3K14, a serine/threonine kinase, is infrequently altered in cancer. MAP3K14 (also NIK) is a serine/threonine kinase which is an important signaling molecule in the noncanonical NF-kB pathway (PMID: 15485626). Following ligand stimulation, the TRAFT2/3 ubiquitin ligase complex releases MAP3K14, which then phosphorylates and activates IKK-α. IKK-α homodimers phosphorylate and activate a precursor protein of the NF-kB complex, p100, triggering its cleavage and ultimately activation of the NF-kB cascade (PMID: 11520989, 11239468, 22435551). Through its role in NF-kB signaling, MAP3K14 influences a wide range of cellular processes, including regulation of B- and T-cells (PMID: 14764671, 16034105, 18799149, 10878354, 10637282), production of inflammatory cytokines and chemokines (PMID: 18997792, 18997794), formation of osteoclasts (PMID: 12939342) and response to viral infection (PMID: 9182687, 20685151, 18550535). Mice lacking MAP3K14 are immunodeficient, with a reduced B-cell population and a lack of lymph nodes (PMID: 11069060, 10878354, 8605936, 25406581), highlighting the importance of MAP3K14 in immune regulation. Overexpression of MAP3K14 has been linked to lethal liver inflammation and fibrosis. In obese mice, high levels of MAP3K14 result in hyperglycemia and glucose intolerance (PMID: 22581287, 25088600). MAP3K14 overexpression caused by amplification or translocation has been observed in various hematological malignancies, including multiple myeloma, splenic marginal zone lymphoma and Hodgkin lymphoma (PMID: 17692804, 17692805, 21881048, 22469134). Although less common, aberrant expression of MAP3K14 has been observed in some solid tumor models, including pancreatic cancer, lung cancer and melanoma (PMID: 19646419, 20338663). False +ENST00000366624 NM_032435 84451 MAP3K21 True MAP3K21, a serine/threonine kinase, is altered by amplification and mutation in various cancers. MAP3K21 encodes for a serine/threonine kinase that functions primarily in the negative regulation of the TLR4 signaling pathway (PMID: 21602844). There are conflicting reports of the role MAP3K21 plays in the JNK, ERK and p38 signaling pathways. MAP3K21 has been identified to mediate both negative and positive regulation of MAPK signaling pathways (PMID: 21602844, 23552557, 28757353, 23319808). Overexpression of MAP3K21 in various cancer cell lines and models induces cellular proliferation, migration and invasion, suggesting that MAP3K21 functions predominantly as an oncogene (PMID: 30552384, 23319808, 34839359). MAP3K21 amplification and mutations have been identified in various cancers, including breast cancer and melanoma (PMID: 30552384, 24849047). False +ENST00000369329 NM_145331 6885 MAP3K7 True MAP3K7, a serine/threonine protein kinase, is infrequently altered in cancer. MAP3K7 encodes for a serine/threonine protein kinase that functions in the MAP kinase signaling pathway to regulate various physiological cellular processes (PMID: 9079627, 8663074). MAP3K7 mediates signal transduction from various cytokines, including TGF-β, TLR and IL-1, to regulate transcription and apoptosis (PMID: 24801688, 10094049, 16845370, 16893890). MAP3K7 functions upstream of the MKK/JNK signal transduction cascade, which in turn activates MAP kinases that control various transcription factors (PMID: 11460167, 8663074). Knockdown of MAP3K7 in various cancer cell lines and models attenuates tumor formation and cellular proliferation, suggesting that MAP3K7 functions predominantly as an oncogene (PMID: 31214512, 28194669, 21834757, 21743023, 32523651). Amplification of MAP3K7 has been identified in various types of cancer, including breast cancer and hepatocellular carcinoma (PMID: 28820959, 35053591). Clinical trials have investigated the efficacy of MAP3K7 inhibitors to trigger cell death in the context of various cancers (PMID: 28820959, 34676048, 32273474). False +ENST00000347699 NM_001242559 9448 MAP4K4 True MAP4K4, a serine/threonine kinase, is infrequently altered in cancer. MAP4K4, a member of the mammalian sterile 20 protein kinase family, is a serine/threonine kinase that regulates activation of the JNK signaling pathway (PMID: 10021364). TNFa upregulates the expression of MAP4K4 through a TNFR1-dependent mechanism (PMID: 17500068). MAP4K4 has been implicated in various physiological processes including embryonic development, inflammation, cell migration, cell proliferation and cell adhesion through activation of the JNK pathway (PMID: 11290295, 19407801, 35941177, 25490267). MAP3K11 (or MLK3) is an activator of the JNK pathway and is a direct downstream target of MAP4K4 phosphorylation (PMID: 34511598, 10232608). Inhibition of MAP4K4 in pancreatic cancer cell lines reduces cancer cell growth and migration, suggesting that MAP4K4 functions predominantly as an oncogene (PMID: 34511598). Overexpression of MAP4K4 has been identified in various cancers, including hepatocellular carcinoma, pancreatic cancer and lung adenocarcinoma (PMID: 27010469, 18981001, 22824148). Alternative splice variants of MAP4K4 that retain the N-terminal kinase domain have been identified in various different human tissues with unknown biological significance (PMID: 12612079). False +ENST00000215832 NM_002745.4 5594 MAPK1 True MAPK1 (ERK2), a serine/threonine kinase, is altered by mutation or amplification in various cancer types including head and neck, cervical and ovarian cancer. MAPK1 (also known as ERK2) is a serine/threonine kinase that functions as an effector protein in the mitogen-activated protein kinase (MAPK) signaling cascade (PMID: 25435214, 17496922). The MAPK signaling pathway is involved in the regulation of diverse cellular processes including proliferation, differentiation, cell adhesion and transcription (PMID: 25435214, 17496922). As a component of a three-tiered MAPK cascade, ERK2 activity is dependent on phosphorylation by upstream MEK1/2 kinases (PMID: 22177953). Activated ERK2 homodimerizes and phosphorylates downstream targets, including transcription factors with central roles in cell proliferation and survival such as RSK (ribosomal S6 kinase), MSK (mitogen- and stress-activated protein kinases) and MYC (PMID: 25320010, 22569528). However, ERK2 targets also include upstream MAPK pathway effectors, highlighting the role ERK2 plays in negative feedback on the MAPK pathway (PMID: 15664191, 8816480). ERK2 targets also include cytoskeletal molecules and nucleoporins (PMID: 25320010, 22569528). These signaling events are triggered by growth factors, cytokines and hormones that activate upstream receptor tyrosine kinases, ultimately leading to altered expression of key regulators of cell growth, differentiation, proliferation and survival (PMID: 9069255, 11242034). ERK2 and its homolog, ERK1 (MAPK3), are essential for cell proliferation; they are ubiquitously and often simultaneously expressed, but evidence suggests they may have some distinct functions in specialized contexts (PMID: 23482492, 21248139, 17496918). ERK2 is infrequently mutated in human cancers; however, a recurrent ERK2 mutation is found in cervical and head and neck cancers and amplification is observed in ovarian cancer (PMID: 25631445, 21720365, 23820584). Inhibitors of ERK1/2 are being explored as complementary and alternative options to RAF and MEK inhibition in cases of resistance or partial response (PMID: 25435214). False +ENST00000263025 NM_002746.2 5595 MAPK3 True MAPK3 (ERK1), a serine/threonine kinase, is infrequently altered in cancer. MAPK3 (also known as ERK1) is a serine/threonine kinase that functions as an effector protein in the mitogen-activated protein kinase (MAPK) signaling cascade (PMID: 25435214, 17496922). The MAPK signaling pathway is involved in the regulation of diverse cellular processes including proliferation, differentiation, cell adhesion and transcription (PMID: 25435214, 17496922). As a component of a three-tiered MAPK cascade, ERK1 activity is dependent on phosphorylation by upstream MEK1/2 kinases (PMID: 22177953). Activated ERK1 homodimerizes and phosphorylates downstream targets, including transcription factors with central roles in cell proliferation and survival such as RSK (ribosomal S6 kinase), MSK ( mitogen- and stress-activated protein kinases) and MYC (PMID: 25320010, 22569528). However, ERK1 targets also include upstream MAPK pathway effectors, highlighting the role ERK1 plays in negative feedback on the MAPK pathway (PMID: 15664191, 8816480). ERK1 targets also include cytoskeletal molecules and nucleoporins (PMID: 25320010, 22569528). These signaling events are triggered by growth factors, cytokines and hormones that activate upstream receptor tyrosine kinases, ultimately leading to altered expression of key regulators of cell growth, differentiation, proliferation and survival (PMID: 9069255, 11242034). ERK1 and its homolog, ERK2 (MAPK1), are essential for cell proliferation; they are ubiquitously and often simultaneously expressed, but evidence suggests they may have some distinct functions in specialized contexts (PMID: 23482492, 21248139, 17496918). ERK1 is infrequently mutated in human cancers; however, inhibitors of ERK1/2 are being explored as complementary and alternative options to RAF and MEK inhibition in cases of resistance or partial response (PMID: 25435214). False +ENST00000265960 NM_001006617.1 79109 MAPKAP1 False MAPKAP1, a component of the mTORC2 complex, is mutated or amplified at low frequencies in various cancers. MAPKAP1 (also SIN1) is a component of the mTORC2 complex, which is involved in cell growth and cytoskeletal organization (PMID: 19339977). MAPKAP1 not only acts as a scaffold protein for mTORC2 complex formation but also as a key factor in mTORC2-mediated phosphorylation of AKT (PMID: 24795562, 16962653, 17043309). Functional experiments have demonstrated that knockdown of MAPKAP1 activity results in reduced invasion and migration (PMID: 27993679). In addition, MAPKAP1 can bind RAS and suppress the mitogen-activated protein kinase (MAPK) signaling pathway (PMID: 17303383). Somatic mutations in MAPKAP1 are infrequent in human cancers; however, MAPKAP1 expression levels are elevated in a subset of patients with breast cancer (PMID: 27780891). False +ENST00000358664 NM_002382.4 4149 MAX False MAX, a transcription factor, is altered by mutation and deletion in various cancer types including small-cell lung cancer. Germline mutations of MAX are associated with hereditary pheochromocytoma. "MAX (Myc-associated factor X) is a transcription factor that is a member of the basic helix-loop-helix leucine zipper (bHLHZ) family (PMID: 8479534, 2006410). MAX functions at the center of a transcription factor network that governs many aspects of cell behavior, inducing cell proliferation, by binding to enhancer-boxes containing the CANNTG sequence (PMID: 16908182, 1557420). MAX lacks a transactivation domain, and thus MAX homodimers act as transcriptional repressors (PMID: 9824157). However, MAX also dimerizes with other bHLHZs such as MYC, MAD or MXL1 (PMID: 12553908). Heterodimers of MYC/MAX can bind and transactivate gene expression and promote cell proliferation and apoptosis. MAX is expressed in different splice-isoforms, each having different functions (PMID: 10229200, 1566084, 8426752). A ""delta MAX"" isoform, truncated at its C-terminus, appears to enhance MYC-driven tumorigenesis, whereas full-length MAX suppresses MYC-driven tumorigenesis (PMID: 1566084). Chromosomal rearrangements involving the MAX gene location at 14q22-q24 are common in several malignancies such as malignant lymphoma, chronic lymphocytic leukemia and uterine leiomyomas (PMID:1594250). Germline loss-of-function mutations in the MAX gene are found in patients with hereditary pheochromocytoma and paragangliomas (PMID: 21685915, 22452945). Other studies, however, were not able to reproduce these findings in a separate cohort (PMID: 23743562). MAX is recurrently inactivated through somatic mutations in small-cell lung cancer (SCLC) (PMID: 24362264)." True +ENST00000249910 NM_003925 8930 MBD4 False MBD4, a DNA glycosylase, is infrequently altered in cancer. MBD4 encodes a DNA glycosylase that functions in the detection and repair of deamination of methyl-cytosines (PMID: 10499592, 30049810). The methyl-CpG domain at the N-terminus of the protein functions in binding methylated DNA and repressing transcription from methylated gene promoters (PMID: 10930409). The mismatch-specific glycosylase domain at the C-terminus of the protein functions in DNA mismatch repair in CpG methylation regions (PMID: 10930409, 10499592). MBD4-deficient mice demonstrate accelerated tumor formation in cancer-predisposing backgrounds and increased CpG mutation burden, suggesting that MBD4 functions primarily as a tumor suppressor gene (PMID: 12130785, 12417741). Loss of MBD4 has been identified in colorectal cancer, acute myeloid leukemia and uveal melanoma (PMID: 17285135, 35460607, 32421892, 30049810). True +ENST00000355673 NM_052897.3 114785 MBD6 False MBD6, a chromatin-associated protein, is infrequently mutated in various cancer types. MBD6 (also KIAA1887) is a chromatin-associated protein that is a member of the methyl-binding domain (MBD) protein family (PMID: 20700456, 12529184). Expression of MDB6 is most predominant in the brain and testes (PMID: 20700456, 16713569). MBD6 localizes to heterochromatin regions of DNA; however, this interaction is independent of DNA methylation (PMID: 20700456). MBD6 interacts with the Polycomb Repressive-Deubiquitinase Complex (PR-DUB), which removes monoubiquitin at lysine 119 on histone H2A, a critical protein complex involved in gene repression (PMID: 20436459, 24634419). The interaction of MBD6 with PR-DUB is mutually exclusive with family member MBD5, suggesting functional redundancies (PMID: 24634419). In addition, MBD6 binds to sites of DNA damage independent of PR-DUB (PMID: 24634419). MBD6 was also found to interact with the RNA binding protein ATXN1 in neuronal cells, and the protein has been implicated in self-renewal and cellular proliferation (PMID: 16713569, 23052207). Germline mutations in MBD6 are found in patients with autism and Wilson’s disease, a metabolic disorder which stems from accumulation of copper in tissues due to defective biliary excretion (PMID: 30230192, 23055267). Somatic mutations in MBD6 are infrequent in human cancers and their function has not yet been characterized. True +ENST00000369026 NM_021960.4 4170 MCL1 True MCL1, an anti-apoptotic protein, is amplified in various cancer types. MCL1 (Myeloid cell leukemia 1) is a member of the BCL2 pro-survival protein family (PMID: 11960321, 18955968, 23478333). The BCL2 family is defined by the presence of BCL2 homology (BH) domains. MCL1, similar to BCL2, confers cell survival through inhibition of apoptosis. Together with BCL2, MCL1 regulates mitochondrial outer membrane permeabilization, release of pro-apoptotic factors such as cytochrome c and activation of caspases (PMID: 21763611, 20683470). Genome-wide studies have identified increased gene copy numbers of MCL1 across many cancer entities (PMID: 20164920). Focal amplifications of MCL1 were found in over 10% of cancers and were even higher in lung and breast cancers (PMID: 20164920). MCL1 expression can drive lymphomagenesis (PMID: 9787159) and is required for lung adenocarcinoma formation (PMID: 21406400), possibly through interaction with AKT (PMID: 31662324). Through inhibition of apoptosis, MCL1 leads to increased survival of cancer cells and resistance to pro-apoptotic stimuli (PMID: 23478333). Therapies targeting MCL1 and other BCL2 family members are being developed and are currently under investigation (PMID: 26045609). False +ENST00000376406 NM_014641.2 9656 MDC1 False MDC1 is a regulator of the cell cycle response to DNA damage. It has tumor suppressor functions in the context of cancer. Mediator of DNA damage check point protein 1 (MDC1) is a key regulator of the cell cycle in response to DNA damage (PMID: 12607005, 14519663). MDC1 binds to sites of DNA double-stranded breaks through its SDT domain, which binds to the MRN complex, and its BRCT domain which binds to phospho-H2AX (PMID: 16377563, 11741547, 16618811, 15201865). The main functions of MDC1 are to regulate the cell cycle check points in S and G2/M phase through Chk1/2 and to regulate TP53 apoptotic response to DNA damage (PMID: 12607005, 11100718, 12607004, 12607003, 16427009). MDC1 binds TP53 through its BRC1 domain which inhibits TP53 transactivation domain (PMID: 17535811, 24194938). Loss of MDC1 results in genomic instability and promotes oncogenesis in a variety of cancer entities (PMID: 17546051). In some cancers, however, oncogenic functions of MDC1 have been observed (PMID: 21853275). False +ENST00000258149 NM_002392.5 4193 MDM2 True 3A MDM2, a ubiquitin ligase and p53 inhibitor, is amplified in a diverse range of cancers including well-differentiated liposarcomas. The MDM2 gene encodes an E3 ubiquitin ligase that negatively regulates the p53 tumor suppressor protein (PMID: 8875929, 1535557, 25550083). The MDM2-p53 interaction blocks the activation domain of p53, inhibiting its transcriptional activity (PMID: 8875929, 25550083, 7686617). Additionally, the MDM2-p53 interaction results in increased proteasomal degradation of the p53 protein (PMID: 8653711, 9153396, 9153395, 9382809). Transcription of the MDM2 gene is directly activated by p53, and levels of both p53 and MDM2 are maintained at low levels in unstressed cells (PMID: 8265599, 8440237, 8319905). Cells may acquire oncogenic potential from p53 loss (50% of tumors) or MDM2 amplification, which cripple the p53 pathway in tumor cells (PMID: 10549356, 23161690, 9671804, 20025780). Recently, numerous studies targeting the interaction between p53 and MDM2 have resulted in the development of therapeutic strategies aimed at normalizing p53 levels in tumor cells (PMID: 14704432, 15715460, 16759082, 15956260, 17126603, 14704432, 15715460, 16759082, 15956260, 17126603). False +ENST00000367182 NM_002393.4 4194 MDM4 True MDM4, a negative regulator of the p53 tumor suppressor, is altered by amplification and overexpression in various cancer types including breast cancer. MDM4 is a negative regulator of the p53 tumor suppressor, the most frequently inactivated gene in human cancer (PMID: 25960041, 22154076). The two major negative regulators of p53, MDM2 and MDM4, function by blocking its N-terminal transactivation domain (PMID: 21730163). In addition, MDM4 stimulates the MDM2-catalysed ubiquitination of p53 which leads to its degradation (PMID: 14507994, 12162806). Similar to MDM2, MDM4 is deregulated in several tumor types such as cutaneous melanoma, primary breast tumors, retinoblastomas (PMID: 17080083), Ewing sarcomas (PMID: 21098696) and gliomas (PMID: 22820643, 15199139, 12640683, 11280734). In the overwhelming majority of cases, cells with deregulated MDM2 or MDM4 retain wild-type p53 (PMID: 23303139). Thus, inhibition of the p53 interaction with MDM2 or MDM4 is an attractive candidate strategy for the treatment of cancer via the reactivation of p53 (PMID: 25621298, 21098696, 20080970, 14704432, 25201201, 23374098, 16905541, 16540668). False +ENST00000468789 NM_001105078.3 2122 MECOM True MECOM, a transcription factor expressed in hematopoietic stem cells, is recurrently altered by chromosomal rearrangement in hematologic malignancies. MECOM (also EVI1) is a transcription factor that is encoded by the MDS1 and EVI1 complex (MECOM) gene locus (PMID: 26729571). MECOM expression is restricted to long and short term hematopoietic stem cells and is transcriptionally silent during hematopoietic differentiation (PMID: 21666053). MECOM functions as a DNA binding protein that regulates the expression of many hematopoietic genes, including SPI1, a master regulator of myelopoiesis (PMID: 30315161). In addition, MECOM activity regulates additional cellular functions including proliferation, apoptosis, and chromatin state (PMID: 28538183). MECOM was identified as an oncogene in retroviral integration assays, which revealed that MECOM could transform murine hematopoietic cells (PMID: 2542863, 2827004). Increased expression of MECOM in hematopoietic assays and murine models leads to ineffective differentiation and skewing towards the expansion of myeloid populations (PMID: 1370341, 8321231). Recurrent MECOM rearrangements are found in patients with myelodysplastic syndromes and acute myeloid leukemia (AML) (PMID: 19016745, 15156182), resulting in increased EVI1 activity. Overexpression of MECOM is also common in myeloid malignancies and breast cancers, suggesting that MECOM functions predominantly as an oncogene (PMID: 18272813, 28209621). EVI1 alterations may require cooperation with other genetic events to drive transformation to acute myeloid leukemia (PMID: 17227832). False +ENST00000374080 NM_005120.2 9968 MED12 True MED12 is a component of CDK8, a subcomplex involved in transcription initiation. MED12 plays a role in the genesis of benign tumors such as uterine leiomyoma and breast fibroadenoma and is altered in a variety of estrogen-dependent tumors. MED12 is a component of the CDK8 subcomplex that is involved in transcription initiation. The MED12 protein is essential for activating CDK8 kinase. The CDK8 subcomplex which includes MED13, CDK8 kinase and cyclin C, modulates mediator-polymerase II interactions thereby regulating transcription initiation and reinitiation rates (RefSeq August 2009). The most commonly seen mutations in MED12 are in exon 2. Mutations in this domain have been described in uterine leiomyomas (PMID: 25108465, 24980722, 23443020, 23738515), breast fibroadenomas (PMID: 25038752), and Phyllodes tumors of the breast (PMID: 25593300). In benign breast tumors, MED12 hotspot mutations are thought to be early events that lead to deregulation of estrogen signaling (PMID: 25593300). MED12 is the most frequently mutated gene in uterine leiomyomas, suggesting it has a major role in the development of these lesions (PMID: 25108465). MED12 somatic exon 2 mutations have also been described in uterine leiomyosarcoma (uLMS) and colorectal cancer (CRC) (PMID: 23132392). The presence of the same MED12 mutations in uLMS as in uterine leiomyomas suggests that a subgroup of the malignant tumors may develop from a leiomyoma precursor. Leucine (L) to Phenylalanine (F) mutations at amino acid 1224 have been described in prostate cancer. These mutations are thought to play a role in tumorigenesis via perturbation of transcriptional programs linked to p53 and androgen signaling (PMID: 22610119). True +ENST00000424583 NM_001145785.1 100271849 MEF2B True MEF2B, a transcriptional activator, is altered by mutation in various hematological malignancies including follicular lymphoma. MEF2B is a transcription factor that has a role in mediating differentiation in heart and skeletal muscle (PMID: 17959722). MEF2B regulates transcriptional programs that facilitate cell migration and epithelial-mesenchymal transition as well as the cancer genes MYC, TGFB1, CARD11, RHOB and NDRG1 (PMID: 26245647). Consistent with a role in epithelial-mesenchymal transition, overexpression of MEF2B in human cell lines results in increased cell migration (PMID: 26506234). MEF2B has been found to be amplified in several cancer types including ovarian serous cystadenocarcinomas, adrenocortical carcinomas and esophageal carcinomas (PMID: 26506234). Recurrent somatic mutations in MEF2B have been identified in diffuse large B-cell lymphoma (DLBCL) (PMID: 21796119, 22343534, 21804550, 23292937), follicular lymphoma (FL) (PMID: 21796119) and mantle cell lymphoma (MCL) (PMID: 24145436). The recurrence of MEF2B mutations at particular residues is consistent with the notion that MEF2B mutations have either gain-of-function or dominant negative effects on MEF2B activity. Mutations in MEF2B in DLBCL lead to increased transcription of BCL6, a proto-oncogene essential for DLBCL germinal center proliferation and decreased association with the co-repressor CABIN1 (PMID: 23974956). However, other data suggest that MEF2B mutations lead to loss of DNA binding and decreased DLBCL cell chemotaxis (PMID: 26245647). False +ENST00000437473 NM_001193350 4208 MEF2C True MEF2C, a transcription factor important for muscle development, is infrequently altered in cancer. MEF2C, a Myocyte Enhancer Factor 2 family transcription factor, is an early expressed gene that is a direct transcriptional target of ETS transcription factors and which binds to the MEF2 element in muscle-specific genes to promote muscle differentiation. In addition to its role in myogenesis, MEF2C expression is critical for the development of the neural system, vascular endothelium, heart and bone (PMID: 15501228, 29340119). MEF2C has been shown to have a role in hematopoietic cell differentiation, particularly germinal center formation in B-cells (PMID: 18955699). Germline haploinsufficiency of MEF2C has been linked to neurodevelopmental disorders associated with cognitive disability and epilepsy, highlighting its importance in neural differentiation (PMID: 23389741). In cancer, MEF2C contributes to oncogenicity by enhancing the invasion and stemness of cancer cells, and may act as a tumor suppressor or oncogene depending on the cancer context (PMID: 16862118, 23435431, 21481790, 25328135, 24043307, 25404735). True +ENST00000348159 NM_005920.3 4209 MEF2D True MEF2D, a transcriptional activator, is altered by rearrangement in acute lymphoblastic leukemia. MEF2D is a transcription factor that is a member of the myocyte-specific enhancer factor 2 (MEF2) protein family (PMID: 29879430). Gene expression programs necessary for muscle, neuronal, and B-cell differentiation, among other cell types, are modulated by MEF2D activity (PMID: 20716948, 26660426). MEF2D predominantly functions as a transcriptional activator and interacts with other co-activators and chromatin-modifying proteins (e.g. MYOD, p300 and PCAF) to regulate context-specific target gene expression (PMID: 20716948, 32512162, 32512162, 31722213). However, MEF transcription factors can also function as transcriptional repressors (PMID: 28419090). MEF2D expression is important for a variety of cellular activities including proliferation, DNA damage response and cell cycle progression (PMID: 29879430, 24672010, 26506234). The activity of MEF2D has also been linked to the regulation of oxidative stress and pro-survival gene programs (PMID: 2512162). Aberrant MEF2D localization and activity have been linked to cancer progression in a variety of cancer types (PMID: 28419090, 29218083, 25814384). In B-cell precursor acute lymphoblastic leukemia (B-ALL), MEF2D translocations occur between recurrent partner proteins including DAZAP1, FOXJ2, SS18 and BCL9 (PMID: 28778863, 30630978) and are associated with poor patient outcome (PMID: 27824051). MEF2D fusion proteins demonstrate oncogenic activity by increasing MEF2D transcriptional activity, HDAC9 expression, and cellular transformation (PMID: 27507882, 27824051). HDAC inhibition may be efficacious in patients with MEF2D translocations (PMID: 27507882). False +ENST00000312049 NM_130799.2 4221 MEN1 False MEN1, a transcriptional repressor, is altered by mutation and deletion in various cancer types including parathyroid and endocrine cancers. Germline mutations of MEN1 are associated with Multiple Endocrine Neoplasia Syndrome and predispose to certain cancers. MEN1 is a putative tumor suppressor gene that localizes to the nucleus (PMID: 19068082). The function of MEN1 is not well-understood as MEN1 does not share sequence homology with any other known proteins (PMID: 19068082). MEN1 interacts with multiple proteins that play critical roles in the regulation of cell proliferation, including JunD, SMAD, and activator of S-phase kinase (PMID:16740708, 9103196, 9215690). In addition, MEN1 binds several histone regulatory proteins and is predicted to be a transcriptional regulator (PMID: 19068082). Germline loss-of-function mutations in MEN1 are associated with MEN1 syndrome, a disease that causes tumors in the pituitary, parathyroid, lung, and enteropancreatic endocrine tissues (PMID: 14992727). Somatic mutations and deletions in MEN1 have been identified in a variety of sporadic endocrine tumors, thyroid tumors, and a subset of pancreatic neuroendocrine tumors (PMID: 9361035, 9241276, 9766672, 21252315). True +ENST00000295408 NM_006343.2 10461 MERTK True MERTK, a transmembrane tyrosine kinase, is infrequently altered in cancer. MERTK encodes for a TYRO3/AXL/MER (TAM) receptor kinase family transmembrane tyrosine kinase that functions in transducing extracellular matrix signals into the cytoplasm through binding several ligands, including Gas6 and ProS1 (PMID: 35636929). MERTK regulates various physiological functions including cellular survival, efferocytosis, cytokine secretion and cellular differentiation (PMID: 19386698, 19301199). Overexpression of MERTK in various cancer cells induces cell motility, chemoresistance, cell growth and tumor growth, suggesting that MERTK functions primarily as an oncogene (PMID: 25074939, 35728303, 36939040). Amplification and point mutations of MERTK have been identified in various cancers, including breast cancer and hepatocellular carcinoma (PMID: 33239426, 35728303). False +ENST00000397752 NM_000245.2 4233 MET True 1 R2 MET, a receptor tyrosine kinase, is recurrently altered by mutation or amplification in various cancer types. The MET (Mesenchymal Epithelial Transition) proto-oncogene is a receptor tyrosine kinase, also called c-MET or hepatocyte growth factor (HGF) receptor. MET is a ubiquitously expressed cell surface receptor that binds to extracellular HGF, leading to the activation of several downstream intracellular pathways. These include the PI3K/AKT and RAS/RAF/MEK pathways, which promote cellular growth and proliferation, motility, migration and angiogenesis (PMID: 25770121, 23867513). Dysregulation of MET via gene amplification, germline or somatic mutations or receptor overexpression has been observed in a variety of epithelial cancers, including breast (PMID: 15455388), prostate cancer (PMID 10454259), non-small cell lung cancer (PMID: 9699182), renal papillary carcinoma (PMID: 24812413), hepatocellular (PMID: 24222167) and gastric carcinomas (PMID: 9759658). R2 False +ENST00000219905 NM_001164273.1 23269 MGA False MGA, a tumor suppressor and transcription factor, is altered by mutation, deletion or chromosomal translocation in a diverse range of cancers. MGA (MAX-gene associated protein) is a dual-specificity transcription factor that regulates the expression of MAX-target genes and T-box family target genes. MAX is a transcription factor that heterodimerizes with other basic helix-loop-helix leucine zipper (bHLHZ) family members, including MYC and MXI1, to regulate the expression of genes involved in cellular proliferation. As part of this network, MGA contains a MYC-like bHLHZip motif and heterodimerize with MAX to bind to MYC-MAX DNA binding sites (PMID: 10601024). MGA contains a second DNA-binding domain, known as the T-domain, that binds to genes containing Brachyury-binding sites. In vitro studies demonstrated that MGA can function as a transcriptional activator or repressor, and transcriptional activation is dependent on MAX (PMID: 10601024). MGA loss of function mutations have been observed in lung cancer, leukemia and lymphoma, and are mutually exclusive with MYC amplifications (PMID: 25079552, 26192917, 23039309, 23047824). True +ENST00000549489 NM_004668.2 8972 MGAM True MGAM, an intestinal glucosidase, is infrequently altered in various cancer types. MGAM (also MGA) is a glucosidase that regulates the digestion of starch to glucose (PMID: 17592362). MGAM and a second glucosidase, sucrose isomaltase (SI), are responsible for the last enzymatic step that results in the release of glucose during starch digestion (PMID: 18036614, 21924903). Starch digestion initially involves breakdown by α-amylases into small malto-oligosaccharides, which then are hydrolyzed by glucosidases (PMID: 22851177, 23838818). The main enzymatic activity of MGAM is to hydrolyze short, linear alpha-1,4-oligosaccharides, resulting in the production of glucose to the lumen (PMID: 20356844, 22058037). Dietary restriction alters chromatin modifications at the MGAM promoter, suggesting that gene expression is regulated by diet (PMID: 22819554). MGAM expression is localized to gastric tissues and is predominantly found anchored to the brush border membrane of the intestinal mucosa (PMID: 3143729, 18036614). Loss of MGAM expression in mice results in the inability to increase intestinal alpha-glucosidic activities in response to a starch-based diet, implicating MGAM in glucose homeostasis (PMID: 19193815). Somatic mutations in MGAM are rare; however, overexpression and amplification of MGAM have been found in several tumor types including gastric and oral cancers, among others (PMID: 17611641, 23405089). In addition, MGAM has been identified as a possible serum biomarker in intestinal cancer (PMID: 23924158) and a proposed drug target for type 2 diabetes (PMID: 22058037). False +ENST00000286523 NM_001043318.2 91748 MIDEAS False MIDEAS, a chromatin-associated protein that mediates histone deaceylation, is recurrently altered by mutation in a variety of cancers. MIDEAS is a chromatin-associated protein that shares sequence homology with the REST co-repressor (PMID: 21258344). MIDEAS was identified in a proteomic study to identify interactions of proteins with histone deacetylase (HDAC) inhibitors (PMID: 21258344). HDAC complexes remove acetyl groups from histone molecules, typically leading to gene repression and compacted chromatin (PMID: 17694093, 26908329). MIDEAS functions in the mitotic deacetylase complex (MiDAC) in association with class I HDACs (HDAC1 and HDAC2) and DNTTIP1, a DNA polymerase involved in the generation of diverse immunoglobulin genes (PMID: 21258344); however, several non-canonical MiDAC complexes have also been elucidated (PMID: 21258344). Biochemical studies have demonstrated that the MiDAC complex has increased HDAC activity in arrested cells (PMID: 21258344). In addition, MIDEAS associates with HDAC1 in mouse embryonic stem cells and controls the expression of neurodevelopmental gene programs via deacetylation of lysine 20 on histone 4 (PMID: 21258344). MIDEAS has been associated with histone acetylation at lysine 27 on histone H3, suggesting a role in active transcription (PMID: 25755260). True +ENST00000394351 NM_000248.4 4286 MITF True MITF, a transcription factor involved in melanocyte differentiation, is altered by amplification and mutation in melanomas. Germline mutations of MITF predispose to various cancer types, including melanoma and renal cell cancers. Microphthalmia associated transcription factor (MITF) is a master regulator of melanocyte lineage (PMID: 14597395, 12789276, 12789278, 10898786). MITF regulates the proliferation and differentiation of neural crest melanocyte progenitor cells (PMID: 16862190). It cooperates with BRAF mutations in the transformation process of melanocytes to malignant melanoma. MITF is amplified in >15% of metastatic melanoma (PMID: 12789286). The proliferative activity seems to be mediated by Ink4a, RB1 and CDK2, and MITF has anti-apoptotic activity mediated by BCL2 (PMID: 12086670,15607961, 15623583, 15716956). True +ENST00000368654 NM_002417 4288 MKI67 True MKI67, a non-histone nuclear protein only expressed in proliferating cells, is rarely altered in cancer. MKI67 (Ki-67) is a non-histone nuclear protein involved in the formation of the perichromosomal layer that helps chromosome organization during mitosis by preventing chromosomal aggregation (PMID: 24867636). Levels of Ki-67 protein are regulated by the cell cycle (PMID: 28283655). Thus, as Ki-67 is only expressed in proliferating cells, it is commonly used as an immunohistochemical marker of cell proliferation in vitro and in tumor samples (PMID: 10837136). While early studies investigated the requirement of Ki-67 for cell proliferation (PMID: 12740923) and ribosomal RNA synthesis (PMID: 17531085) more recent studies have demonstrated that it is not essential for either (PMID: 26823390, 26949251). Ki-67 is rarely overexpressed or mutated in cancer; however, it is critical for tumor formation, tumor growth, regulation of global transcription, promotion of stemness, and metastasis (PMID: 33658388). False +ENST00000231790 NM_000249.3 4292 MLH1 False 1 MLH1, a tumor suppressor involved in DNA mismatch repair, is recurrently altered by deletion and mutation in various cancer types. Germline mutations of MLH1 are associated with Lynch syndrome and predispose to colorectal cancer. The MLH1 gene encodes a DNA mismatch repair protein. MLH1 functions to correct mismatched nucleotides and insertion/deletion loops that are erroneously incorporated into the newly synthesized strand of DNA during replication, using the parental strand of DNA as a template. As part of this pathway, MLH1 heterodimerizes with PMS2 (most commonly), PMS1 or MLH3 to form an endonuclease complex that incises the damaged strand, leading to its local excision (PMID: 10037723, 10542278, 10615123). Mutations in MLH1 lead to an inability to correctly repair mismatches and insertion/deletion loops, which are most frequently associated with microsatellite repeat sequences. Tumors with inactivating MLH1 mutations are likely to exhibit a microsatellite instability-high phenotype (PMID: 9823339, 12454837). Mutations in MLH1 occur in multiple tissue types, but are most common in a specific subset of sporadic colon, gastric and endometrial cancers (PMID: 8484122, 8040889). Germline heterozygous mutations in MLH1 similarly predispose patients to colorectal, endometrial, ovarian, urothelial, and other cancers as part of Lynch syndrome, also known as hereditary non-polyposis colon cancer (HNPCC) (PMID: 8261393, 30627969, 31171120), whereas biallelic mutations cause constitutional mismatch repair deficiency (CMMRD) (PMID: 24737826). Defects in the MMR pathway have been associated with improved response to radiotherapy, chemotherapy and immunotherapy (PMID: 20153885, 26028255), and the FDA has approved the immunotherapy pembrolizumab for all mismatch repair deficient (dMMR) and MSI tumors, irrespective of specific tumor etiology. True +ENST00000355774 NM_001040108 27030 MLH3 False MLH3, a DNA mismatch repair protein, is infrequently altered in cancer. MLH3, a member of MLH family, encodes for a DNA mismatch repair protein that functions in preventing microsatellite instability (MSI) and promoting meiotic crossover (PMID: 10615123, 23316435). MLH3 heterodimerizes with MLH1 to form an endonuclease complex that incises damaged DNA strands leading to local excision (PMID: 34088835, 10615123). Knockdown of MLH3 in various cancer cell lines and models induces MSI, impairs DNA damage response, and increases susceptibility to tumors such as gastrointestinal tumors, suggesting that MLH3 functions predominantly as a tumor suppressor gene (PMID: 16204034). Inactivating mutations of MLH3 have been identified in various types of cancer, including hereditary nonpolyposis colorectal cancer, endometrial cancer and gastric cancer (PMID: 18521850, 16885347, 18551179). True +ENST00000252674 NM_005934.3 4298 MLLT1 False MLLT1, a scaffolding protein involved in transcriptional elongation, is recurrently altered by translocation in hematologic malignancies. MLLT1 (also ENL) is a transcriptional adaptor protein that is a member of the eleven-nineteen leukemia (ENL) family (PMID: 17855633, 20153263, 28241139). MLLT1 associates with the super elongation transcription complex composed of p-TEFb (Positive Transcription Elongation Factor b), a protein complex implicated in the phosphorylation of RNA pol II (PMID: 20153263), and other KMT2A-associated adaptor proteins involved in transactivation (PMID: 17855633). The super elongation complex targets KMT2A, a hematopoietic transcriptional coactivator, to hematopoietic genes to initiate transcription (PMID: 20153263). MLLT1 interacts with a variety of proteins involved in chromatin regulation, such as the histone H3 K79 methyltransferase DOT1L, and other KMT2A-related adaptor proteins (PMID: 17855633, 17957188, 15856011). Activating mutations in MLLT1 have been identified in patients with Wilm's tumor and these alterations impact the binding of MLLT1 to histone tails (PMID: 26635203). MLLT1 is the third most common fusion partner of KMT2A, a commonly rearranged gene in hematopoietic malignancies such as acute myeloid leukemia and acute lymphoblastic leukemia (PMID: 23628958). Mouse and human hematopoietic stem cells engineered to express MLLT1 fusion proteins exhibit altered hematopoietic lineage identity, clonal expansion and transformation in functional assays (PMID: 28572162, 28572162, 17957188, 28068328). MLLT1-rearranged proteins are aberrantly targeted to KMT2A target genes, leading to activation of gene expression programs that promote transformation (PMID: 20153263, 27050521). DOT1L inhibitors or therapeutics targeting transcriptional elongation, such as BRD4 inhibitors, may be efficacious in patients with MLLT1 rearrangements (PMID: 31157223). False +ENST00000307729 NM_001195626.1 8028 MLLT10 True MLLT10, a histone methyltransferase cofactor, is recurrently altered by chromosomal rearrangement in hematologic malignancies. MLLT10 (also AF10) is a histone methyltransferase cofactor that is a member of the MLL family of PHD finger proteins (PMID: 7888665). MLLT10 regulates the methylation of H3K79 on histone H3, a histone mark that is predominantly found within gene bodies (PMID: 21724828). Histone proteins are an essential component of the nucleosome, which consists of DNA wrapped around eight histone protein molecules (two sets of each H2A, H2B, H3 and H4 histones) and histone methylation results in the activation or repression of gene expression in different contexts (PMID: 11498575). Methylation of H3K79 has been implicated in a variety of cellular functions including DNA repair, cellular differentiation, splicing, cell cycle, and regulation of transcription, among others (PMID: 27234562). Binding of MLLT10 to chromatin, in collaboration with the histone methyltransferase DOT1L, mediates the conversion of H3K79me1 to H3K79me2, which serves as a signal for gene expression changes important in several differentiation programs including at the HOXA locus (PMID: 25464900, 21724828). Reduced expression of MLLT10 results in weakened transforming ability in hematopoietic assays, suggesting that MLLT10 functions predominantly as an oncogene (PMID: 25464900). Recurrent fusion proteins containing MLLT10 have been identified in patients with hematopoietic malignancies including acute myeloid leukemia and T-ALL (PMID: 23673860, 28242784, 23673860). MLLT10-rearrangements are predicted to bind chromatin and activate DOT1L H3K79-methyltransferase activity (PMID: 28242784, 15851025). Hematopoietic malignancies with aberrant MLLT10 activity may be sensitive to DOT1L inhibitors, as demonstrated in functional assays (PMID: 25464900). False +ENST00000380338 NM_004529 4300 MLLT3 True MLLT3, a subunit of the super elongation complex, is recurrently altered by rearrangement in cancer. MLLT3, or A9, is a subunit of the super elongation complex, which plays a key role in the regulation of the transcriptional elongation checkpoint of transcription (PMID: 20159561). MLLT3 is a key regulator of the self-renewal of human hematopoietic stem cells through the maintenance of their transcriptional program (PMID: 31776511). In coordination with the histone methyltransferase DOT1L, MLLT3 localizes to active transcription start sites through its YEATS domain (PMID: 31776511). The YEATS domain of MLLT3 recognizes crotonylated histone H3 and links crotonylation to active transcription (PMID: 27105114). Knocked-down expression of MLLT3 in cell lines results in suppressed cell proliferation and JNK signaling (PMID: 31966817). MLLT3 rearrangements that result in truncation and loss of the YEATS domain promote tumorigenesis through aberrant gene transcription (PMID: 31776511). MLLT3 fusion proteins have been identified in a variety of tumor types including osteosarcoma, acute myeloid leukemia and acute lymphoblastic leukemia (PMID: 31966817, 20844554). MLLT3 rearrangements may be sensitive to DOT1L inhibitors, as demonstrated in functional assays (PMID: 25464900). False +ENST00000302326 NM_002430 4330 MN1 True MN1, a transcriptional coregulator, is altered by amplification and chromosomal translocation in acute myeloid leukemia. MN1 encodes for a transcriptional coregulator which primarily functions in mediating activation of nuclear hormone receptors to regulate cellular proliferation and differentiation (PMID: 12569362, 15890672). MN1 synergistically induces transcriptional activity when co-expressed with RAC3 or EP300 in RAR-RXR-mediated transcription or steroid receptor coactivators in vitamin D receptor-mediated transcription (PMID: 12569362, 15890672). Inactivation of MN1 has been identified in meningioma through a balanced translocation (4;22) (PMID: 7731706). Mutations in the C-terminal region of MN1 have been implicated in the neurodevelopmental and craniofacial disorder MN1 C-terminal truncation (MCTT) syndrome (PMID: 31834374). Overexpression of MN1 in acute myeloid leukemia mouse models induces lethal acute myeloid leukemia, suggesting that MN1 functions predominantly as an oncogene (PMID: 17494859, 22905229). Amplification of MN1 and chromosomal translocations have been identified in acute myeloid leukemia, and are associated with poor patient prognosis (PMID: 35483876, 28440611, 28892045, 33974912). Preclinical studies suggest that MN1 overexpression may confer resistance to all-trans retinoic acid (ATRA) treatment and chemotherapy in the context of acute myeloid leukemia (PMID: 17494859, 22905229). False +ENST00000262244 NM_024761.4 79817 MOB3B False MOB3B, a kinase activator likely involved in the Hippo signaling pathway, is recurrently deleted in mantle cell lymphomas. MOB3B (also MOBKL2B) is a kinase activator that shares homology with the MOB family of proteins (PMID: 28792927). While the function of MOB3B is unknown, MOB3B is a paralog of MOB1A/B, components of the Hippo signaling pathway (PMID: 28792927). MOB proteins bind activated Hippo, resulting in the recruitment and activation of the signaling factor LATS (PMID: 30183404). The MOB-LATS complex recruits additional signaling proteins and controls the activity of the downstream transcription factors YAP and TAZ (PMID: 30183404). In addition, MOB proteins have been implicated in the regulation of mitotic checkpoint regulation, cellular proliferation and spindle pole body duplication (PMID: 18328423, 9436989). Deletions in MOB3B are found in patients with mantle cell lymphoma and these alterations are associated with poorer patient outcome (PMID: 20421449, 18984860). In addition, MOB3B overexpression has been implicated in resistance to the tyrosine kinase inhibitors vemurafenib and cetuximab (PMID: 28792927, 29802456), likely due to altered Hippo signaling (PMID: 28792927). True +ENST00000361050 NM_001039396.1 219972 MPEG1 False MPEG1, a pore forming protein involved in innate immunity, is infrequently altered in various cancer types. MPEG1 (also Perforin-2) is a pore forming protein that perforates target cell membranes or bacterial envelopes (PMID: 27857713, 7888681, 23257510). MPEG1 is a membrane protein that is most highly expressed in macrophages and is involved in the host defense against intracellular and extracellular bacteria (PMID: 7888681, 25717326, 28705375). Pore-forming proteins, such as MPEG1, homopolymerize resulting in a hollow hydrophobic cylinder that allows for insertion into the membrane or bacterial cell walls (PMID: 27857713, 20860583). Following the MPEG1-mediated immune attack, pore clusters render bacteria susceptible to secondary attack by antimicrobial effectors including reactive oxygen species, the lysozyme and proteases (PMID: 26402460, 26402460). MPEG1 is a largely unspecific effector in innate immunity and is conserved across multicellular organisms (PMID: 26307549). The unspecific mechanism of MPEG1 allows for the clearance of Gram-negative, Gram-positive, and acid-fast bacteria (PMID: 27857713). Expression of MPEG1 in mouse embryonic fibroblasts results in the ability to clear bacteria from the culture, unlike wildtype cells (PMID: 23257510). Loss of MPEG1 expression in model organisms results in an abnormal immune response and the inability to effectively combat bacterial infection (PMID: 25247677, 28422754, 30249808, 26831467). Mutations in MPEG1 are found in patients with persistent nontuberculous mycobacterial infections and immune cells isolated from these patients are unable to kill bacteria in functional assays (PMID: 28422754). Somatic mutations in MPEG1 are infrequent in human cancers. False +ENST00000372470 NM_005373.2 4352 MPL True MPL, a transmembrane protein receptor, is frequently mutated in myeloproliferative neoplasms including essential thrombocytosis and myelofibrosis. MPL encodes for the myeloproliferative leukemia proto-oncogene, thrombopoietin receptor. The gene was first identified in as the oncogene v-mpl, from the murine myeloproliferative leukemia virus that transformed hematopoietic cells from the bone marrow in mice (PMID: 7836743). The normal receptor protein is critical in growth and regulation of megakaryocytes and platelet production (PMID: 8202154). The gene is a transmembrane protein with an extracellular cytokine binding domain and intracellular cytokine signaling domains. Binding of its ligand, thrombopoietin (TPO), results in receptor dimerization and activation of the JAK family of tyrosine kinases; this leads to activation of the STAT family of transcription factors (PMID: 7796811). The MAPK pathway can also be activated as a result of receptor activation (PMID: 10438715). The most common mutations, W515L and W515K, which activate receptor signaling are found in myeloproliferative neoplasms such as essential thrombocytosis and myelofibrosis (PMID: 16834459). Aberrant expression of MPL has been reported in some solid tumors. In a study of 128 colorectal cancer cases, higher MPL expression was associated with metastasis to liver and lung (PMID:23747337). However, in a study of 118 breast tumors and 29 lung tumors, MPL mRNA was either not detectable or at very low levels (PMID: 22967017). The thromobopoietin receptor can be activated by administration of drug agonists such as eltrombopag and romiplostim. These therapies have been approved for the treatment of idiopathic thrombocytopenic purpura (ITP) (PMID:18046028,7050891). False +ENST00000323929 NM_005591.3 4361 MRE11 False 1 MRE11 is a tumor suppressor involved in DNA repair. Germline mutations of MRE11 are associated with ataxia-telangiectasia-like disorder and predispose to breast and ovarian cancers. MRE11 is a member of the Mre11-Rad50-Nbs (MRN) complex involved in sensing and repairing DNA double strand breaks (PMID:10523656, 11430828). The complex activates the kinases ATM (ataxia telangiectasia mutated) and ATR (ATM- and RAD3-related) to initiate DNA damage responses and is itself phosphorylated by ATM (PMID: 23525106, 23582259, 26512707). MRE11 has DNA nuclease activity important for stimulating repair (PMID:18854157). Activation of the MRN complex enables the G2/M cell cycle checkpoint in response to DNA damage (PMID:14657032). The complex is also important for genomic integrity at telomeres, replication forks, immunoglobulin gene loci during rearrangements, and DNA breaks formed in meiosis (PMID:19667071, 21565612, 16285919, 17291760). Activation of repair mechanisms include non-homologous end joining and homologous recombination repair (PMID:12422221, 24316220). Mutations in MRE11 are associated with an ataxia-telangiectasia-like disorder, resulting in chromosomal instability and sensitivity to ionizing radiation (PMID:10612394). MRE11 is also a familial breast and ovarian cancer susceptibility gene and mutations have also been identified in endometrial, colorectal, and lymphoid cancers (PMID:19383352, 24549055, 24894818, 23755103, 11196167, 11850399, 16959974). MRE11 polymorphisms and mutations affect response to chemotherapy, radiotherapy, and Poly(ADP-ribose) polymerases (PARP) inhibitors (PMID:24623370, 25310185, 24927325, 24215868, 25324139, 24240112). True +ENST00000345732 NM_021950 931 MS4A1 False MS4A1, a B-cell membrane protein, is infrequently altered in cancer. MS4A1, which encodes the B-cell surface marker CD20, is a member of the MS4A (membrane-spanning 4-domains family, subfamily A) family that is comprised of proteins that span the cellular membrane four times (PMID: 25835430, 35091527). MS4A1 functions in B-cell activation, proliferation, and differentiation (PMID: 33352466, 35091527). MS4A1 can associate with a variety of membrane proteins, including major histocompatibility complex (MHC) class I, MHC class II, tetraspanins (CD53, CD81, and CD82), and CD40; however the exact nature of these associations are still unknown (PMID: 25835430, 32482755). MS4A1 is involved in calcium conductance, as it functions as a store-operated calcium (SOC) channel that promotes calcium influx through physical association with the B-cell receptor (BCR) (PMID: 25835430). MS4A1 is required for optimal humoral immunity, as MS4A1 deficiency in both humans and mice results in impaired immune responses (PMID: 25835430, 32482755). In colorectal cancer, MS4A1 is significantly downregulated and CD20 expression is positively correlated with the patient survival rate (PMID: 33352466). In ovarian cancer, CD20-positive T-cells were shown to be elevated in ascites fluid of patients and were associated with a positive prognosis, as these cells mediate antitumor immunity (PMID: 26137418, 34654826). In breast cancer, patients who demonstrated higher MS4A1 expression also had a better prognosis (PMID: 35091527). CD20 expression is a clinically useful biomarker for B-cell targeted monoclonal antibody therapies, including rituximab, ofatumumab and obinutuzumab (PMID: 34654826, 25835430, 32482755). False +ENST00000233146 NM_000251.2 4436 MSH2 False MSH2 is a tumor suppressor involved in DNA mismatch repair. Select mutations of MSH2 are associated with Lynch syndrome and can lead to genomic instability in tumors. The MSH2 (MutS protein homolog 2) protein is a tumor suppressor involved in the mismatch repair process. MSH2 forms heterodimers with other MutS proteins, MSH6 and MSH3, to form the MutS-alpha and MutS-beta mismatch repair (MMR) complexes, respectively (PMID: 8252616, 7973733). Both complexes are involved in the recognition of a mismatched base pair, forming a DNA-MutS complex that signals other components of the MMR machinery to excise the aberrant nucleotide. MSH2 and other MMR genes are most notably implicated in Lynch syndrome, also known as hereditary non-polyposis colon cancer (HNPCC), which predisposes individuals to colorectal, endometrial, ovarian, urothelial, and other cancers (PMID: 428275, 1648437, 30627969, 31171120). Biallelic mutations in MSH2 also result in constitutional mismatch repair deficiency (CMMRD) (PMID: 24737826). Loss of function mutations or epigenetic silencing both in the germline and somatic context lead to an increased mutation rate that drives carcinogenesis as well as microsatellite instability (MSI). MSH2 mutations represent approximately 40% of all HNPCC cases (PMID: 11852992) and are associated with the MSI-high phenotype, along with mutations in MLH1 (PMID: 9823339, 9354436). Although most commonly seen in colon cancer, MSH2 mutations have also been reported in a diverse range of other cancer types and syndromes, including endometrial and uterine cancers, and sebaceous gland tumors (PMID: 19078925,16826164). Tumors with a large number of somatic mutations due to mismatch-repair defects have been predictive of clinical benefit to certain immune checkpoint blockade therapies (PMID:26028255, 25409260). Recently, the FDA approved pembrolizumab (PD-1 blockade) for all mismatch repair deficient and microsatellite unstable (MSI-high) tumors, irrespective of specific tumor etiology. True +ENST00000265081 NM_002439.4 4437 MSH3 False MSH3, a protein that participates in mismatch DNA repair pathway, is frequently lost in colorectal cancers. The MSH3 gene encodes the protein MutS Homolog 3 (MSH3), the human homolog of the bacterial MutS protein, which functions in the mismatch repair (MMR) pathway of DNA repair. MSH3 partners with MSH2 to form the heterodimer MutS-beta, which is important for recognition and repair of mismatched base pairs, forming a DNA-MutS complex that signals other components of the MMR machinery to excise the aberrant nucleotide (PMID: 22179786, 8942985, 9679053). MSH3 deletion or loss-of-function mutations can result in MMR deficiency, leading to an increased mutation rate and increased tumorigenesis in cooperation with loss of MSH6 (PMID: 10706084). Unlike other MMR genes, germline mutations in MSH3 are associated with autosomal recessive familial adenomatous polyposis (PMID: 27476653, 34250384, 35675019, 37402566, 38243056), and there is minimal evidence for an association with Lynch syndrome (PMID: 21128252, 34250384). MSH3 is altered in nearly 50% of MMR-deficient colorectal cancers by somatic frameshift mutations (PMID: 23724141, 18922920, 14871813, 9331106). Tumors with a large number of somatic mutations due to mismatch-repair defects have been predictive of clinical benefit to certain immune checkpoint blockade therapies (PMID: 26028255, 25409260). Recently, the FDA approved pembrolizumab (PD-1 blockade) for all mismatch repair deficient and microsatellite unstable (MSI-high) tumors, irrespective of specific tumor etiology. True +ENST00000234420 NM_000179.2 2956 MSH6 False MSH6 is a tumor suppressor involved in post-replication DNA mismatch repair. Select mutations of MSH6 are associated with Lynch syndrome and can lead to genomic instability via microsatellite instability in tumors. The MSH6 (mutS homolog 6) gene encodes the DNA repair mismatch protein MSH6. MSH6 is a tumor suppressor which heterodimerizes with MSH2 to form MutS-alpha. This complex recognizes single base pair mismatches and dinucleotide insertion-deletion loops, initiating the mismatch repair (MMR) process (PMID: 8816473). MSH6 and other MMR genes are most notably implicated in Lynch syndrome, also known as hereditary non-polyposis colon cancer (HNPCC), which predisposes individuals to colorectal, endometrial, ovarian, urothelial, and other cancers (PMID: 428275, 1648437, 30627969, 31171120). Biallelic mutations in MSH6 also result in constitutional mismatch repair deficiency (CMMRD) (PMID: 24737826). Loss of function mutations or epigenetic silencing both in the germline and somatic context lead to an increased mutation rate that drives carcinogenesis as well as microsatellite instability (MSI). Although most commonly seen in colon cancer, MSH6 mutations have also been reported in a wide range of other cancer types and syndromes, including endometrial and uterine cancers (PMID: 19078925,16106253). Tumors with a large number of somatic mutations due to mismatch-repair defects have been predictive of clinical benefit to certain immune checkpoint blockade therapies (PMID: 26028255, 25409260, 29489427). Recently, the FDA approved pembrolizumab (PD-1 blockade) for all mismatch repair deficient and microsatellite unstable (MSI-high) tumors, irrespective of specific tumor etiology. True +ENST00000257552 NM_002442.3 4440 MSI1 True MSI1, an RNA-binding protein expressed in stem cells of neural and intestinal origin, is overexpressed in various cancer types. MSI1 (Musashi1) is an RNA-binding protein which binds to the consensus RNA sequence GU3-5(G/AG) on specific mRNAs and controls their expression by translational repression (PMID: 22201732). The Musashi family of RNA-binding proteins is known to be important for cell fate determination, neural development and maintenance of stem-cell state, differentiation and tumorigenesis. Musashi1 is selectively expressed in neural progenitor cells, including neural stem cells (PMID: 9790759). Musashi1, in cooperation with Musashi2, activates Notch signaling through translational repression of Numb mRNA, an intracellular Notch signal repressor, and maintains the self-renewing ability of neural stem cells (NSCs) (PMID: 15925591). Musashi1 also activates the WNT pathway and serves to sustain mammary gland stem cell pools (PMID: 18362162). In addition, Musashi1 is a selective marker for intestinal stem or early lineage cells (PMID: 12924647, 15925591). Elevated Musashi1 expression is found in gliomas and glioblastomas and correlates with tumor proliferation (PMID: 11284014, 11896183), however, Musashi1 is infrequently mutated in human cancers. False +ENST00000284073 NM_138962.2 124540 MSI2 True MSI2, an RNA-binding protein expressed in stem cells of neural and hematopoietic origin, is over-expressed in myeloid leukemias. MSI2 (Musashi2) is an RNA-binding protein which binds to the consensus RNA sequences on specific mRNAs and controls their expression in part by translational repression (PMID: 28143872). The Musashi family of RNA-binding proteins is known to be important for cell fate determination, neural development and maintenance of stem-cell state, differentiation and tumorigenesis. Musashi2, like Musashi1, activates Notch signaling through translational repression of Numb mRNA, an intracellular Notch signal repressor, and maintains the self-renewing ability of neural stem cells (NSCs) (PMID: 15925591). In addition, Musashi2 expression is required for self-renewal and pluripotency of embryonic stem cells in early stages of differentiation (PMID: 22496868). Musashi2 is highly expressed in hematopoietic stem cells (HSCs) and is important in the maintenance of the stem cell compartment and proliferation of hematopoietic progenitor cells (PMID: 21613258). Overexpression of Musashi2 in mouse models cooperates with the BCR-ABL1 oncoprotein to drive aggressive leukemia (PMID: 20616797). Musashi2 is overexpressed in human myeloid leukemias and increased expression directly correlates with survival of patients with the disease (PMID: 20616797, 20639863); however, Musashi2 is infrequently mutated in human cancers. False +ENST00000449682 NM_020998.3 4485 MST1 False MST1, an intracellular kinase, is infrequently altered in various cancer types. MST1 (mammalian sterile 20-like kinase 1) is an intracellular kinase and key component of the Hippo signaling pathway. The Hippo signaling cascade is a critical regulator for controlling cell growth, differentiation and organ size control (PMID: 22683405, 22898666). MST1 is proteolyticaly activated by caspases during apoptosis; activation is mediated by apoptotic stimuli and other stress signals. Full activation of MST1 kinase requires autophosphorylation at Thr-183 and caspase-mediated cleavage. Once activated, MST1 phosphorylates Lats1/2 (large tumor suppressor 1/2), which then phosphorylates and inhibits two transcriptional coactivators in the Hippo pathway, YAP and TAZ (PMID:17889654). Phosphorylated YAP and TAZ remain in the cytoplasm and cannot induce the expression of genes that promote cell growth and proliferation (PMID: 17889654). Hence, MST1 negatively regulates YAP and TAZ and acts as a tumor suppressor. Reduced expression of MST1 has been observed in gastric cancer, liver cancer, prostate cancer and soft tissue sarcoma (PMID: 21940329, 17538946, 18381433). True +ENST00000296474 NM_002447.2 4486 MST1R True MST1R, a receptor tyrosine kinase, is altered by overexpression and mutation in various cancer types. MST1R (Macrophage Stimulating 1 Receptor) is a cell surface receptor for macrophage-stimulating protein (MSP). The MST1R protein is one of two members of the MET receptor tyrosine kinase family, along with parent receptor MET. Activation of MST1R triggers downstream signaling cascades, including RAS, PI3-kinase (PI3-K), and mitogen-activated protein kinases (MAPK) to induce cell scattering, migration, survival and invasion (PMID: 12807733,18836480, 25997828). MST1R is expressed in various cell types including macrophages, epithelial and hematopoietic cells. MST1R is overexpressed in pancreatic and epithelial cancers of the breast, colon, lung, and prostate (PMID: 22834780, 17616662, 17311308, 26477314, 15289319), and is involved in tumor progression and metastasis (PMID: 15289319, 10910951, 19956854). MST1R is rarely mutated, but alternative splicing events are common as the gene transcript is increasingly overexpressed. Approximately eight different MST1R isoforms have been described in various epithelial cancer types (PMID: 23792360). In breast cancer, short-form MST1R overexpression specifically activates the PI3K signaling pathway, resulting in increased tumor growth, epithelial to mesenchymal transition and metastasis (PMID: 22207901). In prostate cancer cells, MST1R has been shown to regulate angiogenic chemokine production (PMID: 19838218). Additionally, one study using gastroesophageal carcinoma (GEC) samples reported increased MST1R gene copy number in 35.5% (16/45) of cases and a novel somatic MST1R juxtamembrane mutation (R1018G) in 11% of samples, making MST1R an important prognostic marker in this GEC cohort (PMID: 21543897). False +ENST00000644715 NM_002451.3 4507 MTAP False 3A MTAP, a phosphorylase involved in methionine salvage pathways, is recurrently altered by deletion in various cancer types. MTAP is a methylthioadenosine phosphorylase that is a regulator of polyamine metabolism (PMID: 27068473, 26912360). MTAP metabolizes 2-methylthiosdenosine (MTA), a byproduct of polyamine synthesis, for the salvage of methionine amino acids and adenine nucleotides (PMID: 21301207). Loss of MTAP results in increased sensitivity to purine starvation and has been linked to regulation of stemness, apoptosis, and inflammation (PMID: 31040154, 30854099). The MTAP gene resides within the 9p21 chromosomal region, which is deleted in 15% of all cancers (PMID: 27068473). The 9p21 region includes the tumor suppressors CDKN2A, p16-INK4A, and p19-ARF; MTAP co-deletion with these genes occurs in a majority of 9p21 deletions (PMID: 27068473, 26912360). Deletion of MTAP in cancer cell lines results in the accumulation of MTA, a metabolic inhibitor of the arginine methyltransferase PRMT5, due to reduced MTAP-mediated byproduct cleavage (PMID: 27068473, 26912360). PRMT5 activity and expression of PRMT5 binding partners are downregulated in MTAP-deleted cancer cells, including RIOK1 and WDR77 (PMID: 27068473, 26912360). Functional studies demonstrated that MTAP-deleted cancer cell lines have an increased sensitivity to PRMT5 inhibitors, and PRMT5 inhibitors may be an efficacious therapeutic strategy in 9p21-deleted cancers (PMID: 27068473, 26912360, 31257072). In addition, MAT2A, a methionine adenosyltransferase that produces a byproduct that also inhibits PRMT5, was identified as an additional vulnerability in MTAP-deleted cancers (PMID: 27068473). True +ENST00000394053 NM_006636 10797 MTHFD2 True MTHFD2, a mitochondrial folate metabolism enzyme, is frequently overexpressed in various cancer types. MTHFD2 is a mitochondrial folate metabolism enzyme that functions in one-carbon folate metabolism, a process that provides precursor molecules for nucleic acid synthesis. MTHFD2 also helps regenerate the cofactor NADP(H) through its action as a dehydrogenase (PMID: 38422037, 27641100, 35693982). Under normal conditions, MTHFD2 is active only during early embryogenesis and supports rapid cell proliferation by supplying nucleotides (PMID: 35228749, 33782411). In cancer cells, MTHFD2 expression promotes tumor cell proliferation, migration, and invasion by multiple mechanisms including immune evasion via the upregulation of PD-L1 (PMID: 26461067, 23295955, 33782411). Increased MTHFD2 expression has been observed in many cancer types, and may be indicative of poor prognosis (PMID: 24451681, 30466107, 24870594, 38422037, 30534944). Inhibition of MTHFD2 in various cancer lines and models impairs cell proliferation and increases chemosensitivity in hepatocellular carcinoma cells (PMID: 24451681, 32411609, 38287824). False +ENST00000361445 NM_004958.3 2475 MTOR True 3A MTOR, an intracellular kinase that regulates cell growth and metabolism, is infrequently mutated in various cancer types. The MTOR protein is a serine-threonine kinase that coordinates cell growth, protein synthesis and metabolic signaling (PMID: 22500797, 21157483). MTOR activity is mediated through two distinct multi-protein complexes, mTORC1 and mTORC2 (PMID: 22500797, 21157483) which are composed of common subunits (mTOR, mLST8, DEPTOR) (PMID: 12718876, 19446321) and uniquely defined by specific subunits. mTORC1 is defined by the PRAS40 and RAPTOR subunits (PMID: 12150926, 12150925, 17386266, 17510057), while mTORC2 is defined by RICTOR, mSIN1 and PROTOR1/2 (PMID: 15268862, 15718470, 16919458). The two best characterized downstream targets of mTORC1, S6K and 4EBP1, dictate the rate of protein synthesis, nutrient response and many additional features required for rapid tumor growth (PMID: 15314020). Consequently, inhibition of mTORC1 has been therapeutically exploited across a variety of malignancies. mTORC2 coordinates with PDK1 to phosphorylate and activate AKT. mTORC2 is known to regulate the actin cytoskeleton, cell cycle progression and cellular survival (PMID: 18566586). Missense mutations of the MTOR gene occur in many tumors, notably in approximately 6% of clear cell renal cell carcinoma, 7.5% of lung adenocarcinomas, 5% of endometrial carcinomas and 4% of colon and rectal carcinomas (PMID: 24132290). Furthermore, various mTOR mutations have been characterized that cause increased MTOR pathway activation and increased sensitivity to rapamycin (PMID: 24631838, 24625776). Several case reports in the literature have reported extreme durable responses to rapamycin-analogue (rapalogue) therapies in patients with heavily pre-treated metastatic cancer and activating mTOR mutations (PMID: 24622468, 24625776). Additionally, two rapalogue mTOR inhibitors, everolimus and temsirolimus, are FDA-approved for the treatment of human cancer, and numerous compounds with alternative mechanisms of action are in various stages of development (PMID: 26299952). False +ENST00000372115 NM_001048171.1 4595 MUTYH False MUTYH is a tumor suppressor involved in DNA repair. Germline mutations of MUTYH are associated with MUTYH-associated Polyposis syndrome. MUTYH is a DNA glycosylase that mediates base excision repair. MUTYH can repair DNA lesions in which oxidized guanine is mispaired with adenine due to oxidative damage (PMID: 23507534, 1495996). Repair of these lesions prevents GC to TA transversions (PMID: 17581577). Germline mutations in MUTYH lead to colorectal polyposis and adenomas and are inherited in a recessive fashion (PMID: 12606733, 19506731, 31171120); risks for cancer in heterozygous carriers is controversial (PMID: 21063410, 21171015, 34244858, 38394468). MUTYH alterations result in increased TA transversions in colon cancer patients, suggesting that these are loss-of-function alterations (PMID: 12393807). Somatic allelic loss and rare mutations of MUTYH have been identified in colon cancer, however, these alterations did not lead to increased transversions (PMID:22641385). Further functional studies are required to determine if somatic MUTYH mutations are drivers of human cancer. True +ENST00000367814 NM_005375 4602 MYB True MYB, a transcription factor, is altered by chromosomal rearrangement in cancer. MYB encodes for a transcription factor that functions primarily in fetal hematopoiesis and lymphocyte development (PMID: 10323859, 16169500, 19843942). MYB can function as both a transcriptional repressor and transcriptional activator for genes essential to cellular proliferation, such as RUNX1 and CEBPB, and can either suppress differentiation or promote cellular proliferation (PMID: 21317192). The C-terminal region of MYB contains a negative regulatory domain and mutations or deletion of this region can promote cellular transformation (PMID: 2670562). Ectopic expression of MYB in various types of cancer cell lines and models induces cellular growth and increased cell survival, suggesting that MYB functions predominantly as an oncogene (PMID: 21948968, 11290547). Amplification and rearrangements of MYB have been identified in various types of cancer, such as breast cancer, acute myelogenous leukemia and salivary gland adenoid cystic carcinoma (PMID: 11034064, 3281804, 25963073). False +ENST00000522677 NM_001080416 4603 MYBL1 True MYBL1, a transcription factor involved in male-specific meiosis, is infrequently altered by amplification and translocation in cancer. MYBL1 is a transcription factor that regulates spermatogenesis in the pachynema stage of male-specific meiosis. The conserved N-terminal helix-turn-helix DNA binding domain and the trans-activating domain located at the central portion of the protein allow for binding to specific DNA sequences and subsequent meiotic gene transcription, respectively (PMID: 8058310). The conserved C-terminal negative regulatory domain regulates the expression of MYBL1 (PMID: 33637673). MYBL1 serves as the master regulator of meiotic genes involved in multiple meiotic processes such as DNA double-strand break repair, synapsis, crossing over, pachynema cell cycle progression and postmeiotic transcription (PMID: 21750041). Alterations of MYBL1 have been identified to truncate the C-terminal negative regulatory domain, leading to the activation of MYBL1 (PMID: 33637673). Overexpression of MYBL1 promotes tumorigenesis due to aberrant meiotic gene transcription causing angiogenesis (PMID: 35987690). MYBL1 alterations have been identified in a variety of tumor types including adenoid cystic carcinoma, low-grade glioma and hepatocellular carcinoma (PMID: 26631609, 29410490, 33637673, 32637581, 35987690). False +ENST00000621592 NM_002467.4 4609 MYC True MYC, a transcription factor, is altered by chromosomal rearrangement, amplification and overexpression in a variety of cancer types. "MYC is a transcription factor in the MYC family of proteins (c-MYC, n-MYC and l-MYC) that heterodimerizes with the protein MAX to control the transcription of thousands of genes. MYC promotes tumorigenesis by inducing cell proliferation, inhibiting exit from the cell cycle, stimulating vascularization and enhancing genomic instability (PMID: 22464321,10378696,16934487,19029958). The MYC gene contains several distinct structural domains, including five ""Myc-boxes"", which are highly conserved in MYC family proteins across multiple species (PMID: 19029958). Mutations of known function reside near residue T58, which is a phosphorylation site on MYC critical for ubiquitination and subsequent degradation of the MYC protein (PMID: 10706881, 22464321). Mutations in the MYC gene occur but are less frequent than amplification and translocation." False +ENST00000397332 NM_001033082.2 4610 MYCL True MYCL, a transcription factor, is altered by overexpression and amplification in various cancer types including small cell lung cancer. MYCL is a transcription factor and member of the MYC oncoprotein family (PMID: 3322939). The architecture of the MYCL gene shows substantial homology with the other members of the human MYC gene family (MYC and MYCN) (PMID:10378696). Unlike MYC, which is expressed ubiquitously, MYCL is preferentially expressed in the developing kidney and lung (PMID: 8657155), and appears to be less potent in terms of transformation potential (PMID: 2457153). Reports of cancer-associated genomic alterations of MYCL are predominantly limited to small cell lung carcinomas, where MYCL is found amplified in approximately 5-10% of samples (PMID: 2997622,1327035). Amplification of other MYC family members also occurs in small cell lung cancer, and in some cases these amplifications may co-occur with amplifications of MYCL (PMID:10378696,1327035). False +ENST00000281043 NM_005378.4 4613 MYCN True MYCN, a transcription factor, is altered by amplification and overexpression in a variety of cancer types including in neuroblastoma. MYCN is a MYC-family transcription factor with high homology to the commonly amplified transcription factor c-MYC (encoded by the gene MYC) (PMID: 20399964). MYCN has been shown to function both as a transcriptional activator and repressor, regulating the expression of genes involved in the cell cycle, proliferation, apoptosis, metabolism and regulation of the tumor microenvironment, among other processes (PMID: 16934487, 20399964). The MYCN gene is organized into an N-terminal transcriptional activation domain and a C-terminal basic helix-loop-helix leucine zipper DNA-binding domain. Unlike c-MYC, which is ubiquitously expressed, expression of n-MYC is temporally restricted to embryonic development and spatially restricted to cells of the nervous system, kidney, lung and spleen. Amplification of MYCN is predominantly associated with cancers of neural origin (e.g. neuroblastoma, medulloblastoma, glioblastoma), but has been observed in other solid tumors including prostate, breast and small cell lung cancers (PMID: 24589438, 16934487,15013217). Targeting MYCN directly has been challenging, and therefore therapeutic strategies have focused on targeting MYCN downstream targets, factors involved in MYCN transcriptional activity or MYCN stability (PMID: 24857145, 24086065). False +ENST00000396334 NM_002468.5 4615 MYD88 True MYD88, an adaptor protein, is frequently altered in hematologic malignancies including Waldenström's macroglobulinemia. MYD88 encodes for the signaling adaptor protein Myeloid differentiation primary response 88. It functions to transduce signaling from Toll-like receptors and the Interleukin-1 receptor important for innate immunity (PMID: 16413925, 12467250, 11544529). Signaling through MYD88 activates the NFkB pathway (PMID: 9734363). Patients with MYD88 loss of function mutations are more susceptible to bacterial infections due to immune dysfunction (PMID:18669862). Activating mutations of MYD88, particularly the L265P mutation, are frequently identified in Waldenström's macroglobulinemia patients (PMID: 22931316). The same mutation is also found in lymphomas, including chronic lymphocytic leukemia and the Activated B-cell type Diffuse Large B-cell Lymphomas (DLBCL) (PMID: 21179087, 22150006). False +ENST00000300036 NM_002474 4629 MYH11 False MYH11, a smooth muscle myosin protein, is altered at low frequencies in various cancer types. MYH11 is a smooth muscle myosin protein belonging to the myosin heavy chain family (PMID: 32382337). MYH11 functions as a contractile protein involved in inducing muscle contraction via ATP hydrolysis, but may also be able to regulate gene expression patterns of the cell by binding DNA as a transcription factor (PMID: 34380460). Pathogenic germline alterations in MYH11 predispose to familial thoracic aortic aneurysm and aortic dissection (TAAD), and individuals with these mutations show smooth muscle cell disarray and hyperplasia (PMID: 17666408). Meanwhile, in vitro overexpression of MYH11 inhibits cell migration, proliferation and invasion suggesting it acts as a tumor suppressor (PMID: 34380460). Inversion of chromosome 16 can result in the CBFB-MYH11 fusion, which is found in the M4 type of acute myeloid leukemia with associated eosinophilia (PMID: 23160462). This fusion protein disrupts the CBF complex and results in a block in proper hematopoiesis (PMID: 20007544). True +ENST00000399231 NM_000259 4644 MYO5A True MYO5A, a myosin motor protein, is infrequently altered in various cancer types. MYO5A encodes for myosin Va (5a), a motor protein that is part of the myosin protein superfamily. The myosin protein superfamily consists of actin-based motors that play critical roles in normal cell motility and migration through interaction with actin in the cytoskeleton (PMID: 16904206, 27757761). Myosin proteins are responsible for forming transport vesicles such as insulin granules and melanosomes, cell polarization, and cytokinesis during mitosis and meiosis (PMID: 29898384, 21151132, 28903372, 12382324). MYO5A is involved in cell and organelle motility, spindle formation, nuclear morphogenesis and transport of molecules to the cell membrane such as cell-surface receptors, pigments and RNA (PMID: 23176491, 21151132, 28903372). In cancer cells, MYO5A enhances tumor cell motility and viability enabling tumor progression and migration (PMID: 28903372). Upregulation of MYO5A promotes cell invasion and metastasis in colorectal cancer cells and head and neck squamous cell carcinoma cells, while MYO5A knockout decreases cell migration in lung cancer cells, suggesting MYO5A functions primarily as an oncogene (PMID: 28903372, 38129784). MYO5A is frequently overexpressed in multiple cancers including head and neck squamous cell carcinoma, metastatic colorectal cancer, melanoma, breast, prostate and bladder cancers (PMID: 38129784, 19521958, 23652798). It has also been shown to be overexpressed in metastatic lung, breast, prostate and colon cancer-derived cell lines (PMID: 19521958). False +ENST00000250003 NM_002478.4 4654 MYOD1 False MYOD1, a transcription factor involved in muscle differentiation, is recurrently altered by mutation in rhabdomyosarcoma. MYOD1 is a transcription factor that is a member of the bHLH protein family. MYOD1, together with the closely related regulatory transcription factors MYF5, MRF4 and MYOGENIN, control myogenic differentiation. MYOD1 commits mesoderm cells to a skeletal myoblast lineage, regulates their continued state and can also regulate muscle repair (PMID:16099183). MYOD1 removes cells from the cell cycle by increasing the transcription of p21 and myogenin, which is important for the switch from cellular proliferation to differentiation. Loss of this control can lead to the formation of rhabdomyosarcoma (PMID:16099183, 12783965). MYOD1 is infrequently mutated in embryonal rhabdomyosarcoma (PMID:25295632, 24824843, 24793135, 24272621). True +ENST00000341426 NM_001198993.1 65220 NADK True NADK, a metabolic enzyme involved in the conversion of NAD+ to NADPH, is altered by overexpression and mutation in pancreatic and colon cancers. NADK is a kinase involved in the regulation of several metabolic and biosynthetic pathways (PMID: 27582489, 21526340, 17855339). NADK is localized to the cytoplasm and catalyzes the phosphorylation of nicotinamide adenine dinucleotide (NAD+) to NADP+ (PMID 27582489, 21526340, 17855339). NADK-dependent phosphorylation requires ATP and magnesium cofactors for this conversion (PMID: 21526340, 17855339). NADP+ is then reduced to NADPH by dehydrogenases, such as glucose-6-phosphate dehydrogenase and malic enzymes (PMID: 27582489, 21526340). NADPH is an important cofactor involved in several protein, nucleotide and lipid biosynthesis pathways (PMID: 27582489). Proliferating cancer cells are increasingly dependent on these biosynthetic pathways during growth (PMID: 27582489). In addition, NADPH is necessary for maintenance of the cellular redox state and neutralizes reactive oxygen species (ROS) during cancer cell proliferation (PMID: 22550069, 18020963). Additional roles of NADPH include antioxidant host defense and regulation of glucose-mediated insulin secretion (PMID: 22550069). Somatic gain-of-function mutations in NADK have been identified in patients with pancreatic and colorectal cancer (PMID: 28954733, 26806015). Overexpression of NADK has also been found in patients with various cancers, suggesting that NADK may predominantly function as an oncogene (PMID: 27582489). Suppression of the NADPH pool has been proposed as a therapeutic strategy in cancer patients (PMID: 26219913). False +ENST00000265433 NM_002485.4 4683 NBN False 1 NBN is a tumor suppressor involved in DNA double-strand break repair. Germline mutations of NBN are associated with Nijmegen breakage syndrome and a predisposition to cancer. NBN is a component of the Mre11-Rad50-Nbs (MRN) complex involved in DNA double-strand break sensing and repair (PMID: 9590181). The complex activates the kinases ATM (ataxia telangiectasia mutated) and ATR (ATM- and RAD3-related) to initiate DNA damage response and is itself phosphorylated by ATM (PMID: 23525106, 23582259, 26512707, 10802669). The complex has DNA nuclease activity important for stimulating repair (PMID: 18854157). Activation of the MRN complex enables the G2/M cell cycle checkpoint response to DNA damage (PMID: 14657032). The complex is also important for genomic integrity at telomeres, replication forks, immunoglobulin gene loci during rearrangements and DNA breaks formed in meiosis (PMID: 19667071, 21565612, 16285919, 17291760). Activation of repair mechanisms includes non-homologous end joining and homologous recombination repair (PMID: 12422221, 24316220). Germline NBN mutations are associated with the Nijmegen breakage syndrome, characterized by increased cancer incidence, microcephaly, growth retardation, immunodeficiency and sensitivity to ionizing radiation (PMID: 9590180, 9590181). Mutations have been found in cholangiocarcinoma, liver, prostate cancer, lymphoma, leukemia, medulloblastoma and other cancers (PMID: 24349281, 22864661, 21923652, 18593981,18056440). Mutations and copy number alterations in NBN may lead to susceptibility to radiation and specific inhibitors related to DNA damage including Poly(ADP-ribose) polymerases (PARP) inhibitors (PMID: 22396666, 25324139, 25415046, 24240112). True +ENST00000371998 NM_181659.2 8202 NCOA3 True NCOA3, a nuclear hormone receptor co-activator, is altered by amplification and mutation in various cancer types. NCOA3 (also known as pCIP, SRC3) is a nuclear receptor co-activator involved in the regulation of transcription. It interacts with nuclear hormone receptors to enhance transcription (PMID:23850489, 15383283). NCOA3 has histone acetyltransferase activity and can recruit other histone acetyltransferase enzymes to the complex (PMID:9296499, 9192892). It acts to regulate pluripotency in stem cells, mammary gland development and response to TNF alpha (PMID: 10823921, 23019124, 15383283). It is expressed in various cancer cells and affects processes including cancer metabolism, anti-apoptosis, and cell growth (PMID:24584933, 23388826, 20663904). Its overexpression is associated with poor prognosis in various tumor types including gastric and non-small cell lung cancer (PMID: 25970779, 20064830). The gene has been found to be amplified in breast, ovarian, and colorectal cancer (PMID:9252329, 22371647). Inhibitors of NCOA3 are in development for anti-tumor therapy (PMID:24743578, 24390736). False +ENST00000268712 NM_006311.3 9611 NCOR1 False NCOR1, a transcriptional co-repressor, is altered by chromosomal translocation and mutation in various cancer types. NCOR1 is a nuclear transcriptional co-repressor that represses transcription mainly by recruiting histone deacetylase HDAC3 to DNA promoter regions (PMID: 20084085). Physiologically, NCOR1 is involved in the control of metabolism and inflammation as well as embryonal development (PMID: 20084085). NCOR1 is involved in the regulation of S-phase progression and genomic stability. It does so by maintaining acetylation and methylation patterns during S phase, which are essential for DNA repair and genomic stability (PMID: 21075309). NCOR1 has previously been linked to several kinds of cancers such as leukemia, glioblastoma multiforme, colorectal as well as endometrial carcinoma and prostate cancer (PMID: 17190815, 17630505, 17694085, 17312396, 19414341, 19269830, 12441355, 16373395, 22695118). Some leukemias are caused by translocation events that pair co-repressor-interacting proteins with proteins that are not regulated by NCOR1. This results in aberrant gene repression, which in some cases can be overcome by HDAC inhibitors (PMID: 9462740). NCOR is dramatically increased in glioblastoma multiforme, which correlates with de-differentiated phenotype and progression of the tumors (PMID: 16479164, 16534112). In these cases, preclinical evidence has shown that inhibition of the NCOR1 pathway can be achieved by simultaneous administration of Retinoic Acid and the protein phosphatase 1 (PP1) inhibitors which led to dramatic increase in differentiation and inhibition (PMID: 17312396). True +ENST00000405201 NM_006312.6 9612 NCOR2 False NCOR2, a nuclear hormone transcriptional co-repressor, is altered by mutation in a range of human cancers. NCOR2 (also SMRT) is a nuclear hormone transcriptional co-repressor that is a member of the NCOR protein family (PMID: 20084085). NCOR2 represses transcription mainly by recruiting the histone deacetylase HDAC3 to DNA promoter regions (PMID: 20084085, 11509652). Histone deacetylases predominantly function to add repressive marks to chromatin, resulting in chromatin compaction and reduced gene expression (PMID: 17694085). NCOR2 is homologous to NCOR1 and both corepressors bind similar substrates, namely the HDAC3 complex, which includes TBL1, TBLR1 and GPS2 (PMID: 20084085). In addition, NCOR2 associates with additional DNA binding proteins that regulate actin binding, kinase inhibition, histone binding and scaffolding, p53-dependent DNA damage and ubiquitination (PMID: 20084085). While NCOR1 and NCOR2 have some overlapping functions, non-redundant upstream kinases regulate their activation and differential expression patterns contribute to their context-specificity (PMID: 15491994, 17928865). In addition, NCOR2 preferentially regulates the activity of the retinoic acid receptor (PMID: 11435607). In addition, NCOR2 has been implicated in the regulation of neural stem cell proliferation, lineage commitment, metabolism, and inflammation (PMID: 19066220). Somatic mutations in NCOR2 are rare; however, aberrant NCOR2 activity is predicted to aberrantly regulate histone deacetylation and gene repression in human cancers (PMID: 17694085). In leukemias, NCOR2 mediates the binding of fusion proteins to DNA, such as PML/RARα, to coordinate gene regulation (PMID: 15729358). Additional mutations in NCOR2 binding partners lead to abnormal NCOR2/HDAC3 activity in cancers; however, NCOR2 mutations have not been extensively characterized (PMID: 27733359). False +ENST00000294785 NM_015331.2 23385 NCSTN True NCSTN, an endoprotease, is infrequently altered by mutation and amplification in a diverse range of cancers. NCSTN is a protease that serves as an essential component of the gamma-secretase complex (PMID: 25565961). NCSTN catalyzes the cleavage of membrane proteins, including Notch receptors 1-4, in order to release a processed intracellular NOTCH domain that can then activate gene expression in the nucleus (PMID: 22547652). The NOTCH signaling pathway regulates various aspects of cell differentiation, growth, proliferation, survival, and metabolism (PMID: 27507209). Deletion of NCSTN in the hematopoietic system in murine models results in increased numbers of thymic dendritic cells and T regulatory cells, implicating NCSTN in immune homeostasis (PMID: 22547652). In addition, NCSTN functions as a protease in other contexts, including in the cleavage of APP (amyloid-beta precursor protein) into amyloid-beta peptides, which compose plaques in the brains of Alzheimer’s patients (PMID: 12297508). Germline and somatic NCSTN alterations have been identified in patients with Alzheimer’s disease as well as in dermatological disorders (PMID: 11992262, 12419494, 25211177, 26224166). Somatic mutations in NCSTN are rare in human cancers; however, amplifications in NCSTN may lead to increased NOTCH signaling (PMID: 26109346, cbioportal accessed August 2018). Inhibitors targeting gamma-secretase are currently in clinical trials and may have activity in patients with aberrant NCSTN activity (PMID: 28539479). False +ENST00000357731 NM_173808.2 257194 NEGR1 False NEGR1, a cell adhesion protein, is altered by deletion and mutation in various cancer types. NEGR1 is a cell adhesion protein that is primarily localized to cell membrane rafts, especially in regions of cell-to-cell contact. NEGR1 is extracellularly tethered to the membrane using a specialized lipid moiety termed a GPI-anchor. NEGR1 and other GPI-anchored proteins are highly enriched in lipid raft domains and are involved in a number of important cellular activities including signaling processes and cell adhesion (PMID: 12440695). Genetic alterations of NEGR1 have been implicated in human obesity and dyslexia (PMID: 19079261). NEGR1 is downregulated in several cancers types (PMID: 21624008) and reintroduction of NEGR1 into a human cancer cell line results in reduced cell proliferation (PMID: 21624008, 25057311). These data suggest that NEGR1 functions as a putative tumor suppressor, however, pro-tumorigenic roles have been assigned to NEGR1 in the maintenance of tumorigenic activity in metastatic breast cancer cells (PMID: 24648515). In addition, a study aimed at identifying protein biomarkers in urine for early detection of invasive breast cancer found NEGR1 as a protein that was significantly upregulated in patients with metastatic breast cancer compared to the normal control subjects (PMID: 26544852). False +ENST00000356175 NM_000267.3 4763 NF1 False 1 NF1, a negative regulator of RAS, is inactivated by mutation or deletion in various solid and hematologic malignancies. The NF1 gene encodes a GTPase activating protein (GAP) for the small GTPases HRAS, KRAS and NRAS (PMID: 2121370,1946382). When bound to RAS, the NF1 protein stabilizes the GTPase activity of the RAS proteins, which switches RAS from its active, GTP-bound state to its inactive, GDP-bound state (PMID: 9219684, 9302992). The GAP-related domain (GRD) is the catalytic domain of NF1, which is directly responsible for its GAP activity but only encompasses approximately 10% of the protein. NF1 is congenitally altered in the cancer-predisposing syndrome Neurofibromatosis Type 1 and is somatically altered in many tumor types including breast cancer, melanoma, and glioma (PMID: 2134734, 1946382, 18772890, 23000897, 9639526, 18948947, 22817889). Inactivation of NF1 due to gene deletion, gene mutation, or protein degradation results in elevated levels of active, GTP-bound RAS and activation of downstream pathways such as the MAPK/ERK pathway and the PI3K pathway (PMID: 19573811, 24576830, 8563751, 7542586, 8052307, 12509763). Missense and truncating mutations occur across the entire gene and do not localize to hotspots. Alterations occurring on one allele of NF1 likely lead to haploinsufficiency of the protein (PMID: 7920653,18089636) as many patients with Neurofibromatosis Type 1 have an unaltered second allele despite exhibiting symptoms of the syndrome. Additionally, functional loss of heterozygosity likely occurs on the second NF1 allele, as tumors with NF1 point mutations have lower levels of mRNA than wildtype tumors (cBioPortal, MSKCC, May 2015). True +ENST00000338641 NM_000268.3 4771 NF2 False NF2 is a tumor suppressor involved in the regulation of downstream signaling pathways. Germline mutations of NF2 are associated with Neurofibromatosis Type 2 and predispose to certain cancers. NF2, also known as Merlin, is a membrane-cytoskeleton scaffolding protein that is expressed predominantly in nervous tissues (PMID:25893302). NF2 is important in indirectly linking actin-transmembrane receptors and intracellular effectors to modulate signaling pathways controlling cell proliferation and survival. These include downstream signaling pathways of receptor tyrosine kinases (RTKs), cell adhesion, small GTPases, mTOR, PI3K/Akt and hippo pathways (PMID: 20491622). NF2 is a tumor suppressor. Germline inactivation of NF2 by mutation or deletion results in the autosomal dominant tumor syndrome Neurofibromatosis Type 2, which is associated with the development of benign central nervous system (CNS) tumors such as vestibular schwannomas (PMID: 7911002). NF2 is found to be somatically mutated in other types of cancers. True +ENST00000312156 NM_001136023.2 4778 NFE2 True NFE2, a hematopoietic transcription factor, is infrequently altered by mutation in hematopoietic malignancies. NFE2 is a transcription factor that regulates erythroid and megakaryocytic gene expression (PMID: 11154691, 8469283). The NFE2 transcription factor complex consists of two subunits: p45, a hematopoietic-specific subunit and the smaller Maf protein subunit, which is more ubiquitously expressed (PMID: 11154691). NFE2, in collaboration with the chromatin regulatory protein CBP, binds erythroid and megakaryocytic promoters to regulate gene expression and epigenetic state (PMID: 11154691). In addition, NFE2 co-binds with the transcription factor AP-1 to modulate the expression of the erythroid globin genes (PMID: 12920035). NFE2 expression is regulated by JAK2 in myeloproliferative neoplasms, a malignancy that is dependent on JAK-STAT pathway activity (PMID: 29519804). Overexpression of NFE2 results in leukemic transformation in murine models, likely due to the upregulation of a chronic inflammatory response and subsequent clonal evolution (PMID: 23932394, 22231305). Somatic NFE2 mutations in human cancers are rare; however, NFE2 is overexpressed in myeloproliferative neoplasms and polycythemias (PMID: 16572198, 24297870). In addition, rare truncating gain-of-function mutations have been identified in myeloproliferative neoplasms (PMID: 23589569), suggesting the NFE2 predominantly functions as an oncogene. False +ENST00000397062 NM_006164.4 4780 NFE2L2 True NFE2L2, a transcription factor involved in oxidative stress response, is recurrently altered by mutation in lung cancer. NFE2L2 (Nuclear factor-erythroid 2-related factor 2), also known as NRF2, is a transcription factor that is important in activating antioxidant proteins to protect against certain environmental and oxidative stresses (PMID: 16968214). Under normal cellular conditions, the interaction of NRF2 with KEAP1 retains the protein in the cytoplasm and promotes its proteasomal degradation via ubiquitination (PMID: 9887101). Upon sensing stress signals, KEAP1 undergoes a conformational change, preventing it from interacting with NRF2 and allowing NRF2 to translocate to the nucleus and drive the expression of specific genes (PMID:12359864). NRF2 can have a protective role in cancer formation from certain chemical carcinogens (PMID: 11248092). However, chronic activation of NRF2 can also support the development of chemo- and radio-resistance (PMID: 24142871). Tumor-associated NRF2 activation can result from inactivation of KEAP1 through mutation, loss of heterozygosity or epigenetic silencing (PMID: 19321346). NRF2 activation can also arise directly from mutations in NFE2L2 in the KEAP1-binding domains (PMID: 18757741, 19967722). False +ENST00000216797 NM_020529.2 4792 NFKBIA False NFκBIα, a negative regulator of NF-κB, is altered by mutation and deletion in various cancer types. NFκBIα (NF-κB inhibitor α) is a protein that represses signaling of NF-κB, a family of transcription factors activated by the epidermal growth factor receptor (EGFR) pathway. NFκBIα helps keep NFκB in an inactive state by supporting its interaction with inhibitory molecules in the cell cytoplasm. A range of external stimuli, including pro-inflammatory cytokines, growth factors or stress, can lead to phosphorylation of NFκBIα and subsequently the release and nuclear translocation of NFκB; this results in the transcriptional activation of hundreds of genes that regulate the immune response, protect against apoptosis and signaling pathways critical to the formation of ectodermal tissues. Lack of NFκB is often due to loss-of-function mutations (small insertions, deletions, or missense) in one allele of NFκBIα coupled with deletion or inactivation of the second allele (PMID: 9572494). Constitutive expression of NF-κB signaling results in overexpression of several target genes encoding anti-apoptotic proteins and growth-promoting proteins (PMID: 11313274). Deletion of NFκBIA has demonstrated an effect similar to EGFR amplification in glioblastomas (GBM) and is associated with relatively reduced survival (PMID: 21175304). Further, enrichment of single-nucleotide polymorphisms (SNPs) and mutations in NFκBIA have been observed in Hodgkin’s lymphoma (PMID: 10023670, 19507254), colorectal cancer (PMID: 17354114), melanoma (PMID: 17492467), hepatocellular carcinoma (PMID: 19797428), breast cancer (PMID: 16959974) and multiple myeloma (PMID: 16540234). True +ENST00000262613 NM_004252 9368 NHERF1 True NHERF1, a scaffold protein, is infrequently altered in cancer. NHERF1 (NHERF family PDZ scaffold protein 1) encodes for sodium-hydrogen antiporter 3 regulator 1, also known as ERM Binding Protein 50 (EBP50) or Na+/H+ Exchanger Regulatory Factor 1 (NHERF1) (PMID: 28068322). NHERF1 is expressed abundantly in the plasma membrane of polarized epithelial cells and functions as a scaffold protein by stabilizing macromolecule signaling complexes linking extracellular signals with cytoskeleton machinery. Major signaling pathways that are regulated by NHERF1 include the PI3K/AKT pathway as well as PDGFR, EGFR, and Wnt/ꞵ-catenin signaling (PMID: 33965858, 29846905, 28684865, 28068322). NHERF1 regulates transporters and channels through actin-binding ERM (ezrin-radixin-moesin) proteins (PMID: 28068322). The role of NHERF1 in cancer depends on its cellular location, acting as a tumor suppressor when localized in the cell membrane and as an oncogene when expressed in the cytoplasm or nucleus of cancer cells, where it participates in the epithelial-to-mesenchymal transition process (PMID: 33965858, 29846905, 28684865). NHERF1 expression in the nucleus has been observed in renal, breast, liver, colon, and ovarian cancer cells (PMID: 33965858, 28011475). Cytoplasmic expression of NHERF1 has been observed in head and neck squamous cell carcinoma and melanoma (PMID: 29846905, 25897829). True +ENST00000354822 NM_001079668.2 7080 NKX2-1 True NKX2-1, a transcription factor expressed in lung and thyroid lineages, is altered by mutation, amplification, and rearrangement in lung and thyroid cancers. NKX2-1 is a homeobox-containing transcription factor essential for the development of the lung, thyroid and ventral forebrain (PMID: 16405855). Expression of NKX2-1 is restricted to specific cell types in these lineages and NKX2-1 has a role in the regulation of cell-type specific transcriptional programs. In the lung, NKX2-1 is a critical regulator of the expression of surfactants, which are proteins important for reducing surface tension in the lung and play a critical role in host defense against infection and inflammation (PMID: 15173172). Thyroid precursor cells express NKX2-1 in order to regulate thyroid-specific genes and maintenance of NKX2-1 expression is important in adult tissues for the regulation of thyroid hormones (PMID: 25350068). In thyroid carcinomas, NKX2-1 is primarily expressed in follicular neoplasm and papillary carcinoma but not in anaplastic carcinoma (PMID: 12023581). Germline mutations in NKX2-1 have been identified in families affected by multinodular goiter and papillary thyroid carcinoma (PMID: 19176457). In lung adenocarcinoma, somatic mutations of NKX2-1 are rare but sustained expression of NKX2-1 is frequently associated with gene amplification (PMID: 17925434, 18212743, 17616654, 17982442). Loss of NKX2-1 expression is also associated with favorable prognosis and reduced metastasis in murine models and humans (PMID: 21471965, 23125078), likely due to altered differentiation programs controlled by NKX2-1 (PMID: 23523371). Rearrangements of NKX2-1 with T-cell receptor or immunoglobulin heavy chain loci have also been identified in T-cell acute lymphoblastic leukemia (PMID: 21481790). False +ENST00000380871 NM_006167.3 4824 NKX3-1 False NKX3-1, a transcription factor expressed in prostate lineages, is altered by deletion and mutation including in prostate cancer. NKX3-1 (NK3 homeobox 1, also known as NKX3.1) is a homeobox-contiaing transcription factor and prostate-specific tumor suppressor that is under tight androgenic control (PMID: 11839815, 19886863, 11085535, 9226374). NKX3-1 is expressed at high levels in the prostate where it plays a role in tissue differentiation and homeostasis (PMID: 11839815, 8943214, 10215624), and is proposed to be a marker of prostate-specific stem cells (PMID: 19741607). Loss of heterozygosity of the 8p21 genomic locus, which includes NKX3-1, is associated with tissue dedifferentiation and lost of androgen response in prostate cancer (PMID: 9226374). Loss of NKX3-1 expression is found in prostate tumors of different stages, from benign prostate hyperplasia to castrate-resistant and metastatic prostate cancer (PMID: 11085535, TCGA PRAD paper, no PMID yet). True +ENST00000651671 NM_017617.5 4851 NOTCH1 True NOTCH1, a transmembrane receptor and transcription factor, can function as both an oncogene and tumor suppressor. NOTCH1 is a transmembrane receptor that participates in an evolutionarily conserved cell-to-cell signal transduction pathway (PMID: 24651013). Interaction of the NOTCH1 receptor with ligand molecules on adjacent cells results in the proteolytic cleavage of NOTCH1 by gamma-secretase (PMID: 24651013). The cleaved intracellular NOTCH1 domain can then activate gene expression in the nucleus and regulate various aspects of cell differentiation, growth, proliferation, survival, and metabolism (PMID: 27507209). The specific effects of NOTCH1 signaling vary depending on the cellular context (PMID: 21508972, 24651013). NOTCH family members are frequently mutated in a variety of cancers, and these mutations can be either gain- or loss-of-function mutations (PMID: 21948802). Translocations and activating mutations in NOTCH1 have been identified in T-cell acute lymphoblastic leukemia (T-ALL), chronic lymphocytic leukemia, and adenoid cystic carcinoma (PMID: 15472075, 24170027, 27870570). These NOTCH1 activating mutations either enhance the cleavage of NOTCH1 by gamma-secretase or extend the half-life of intracellular NOTCH1 (PMID: 15472075). NOTCH1 loss-of-function mutations are most common in solid tumors, namely squamous cell carcinomas, and occur as missense, frameshift or nonsense mutations in important NOTCH1 functional domains (PMID: 28154375, 30087145). Inhibitors targeting gamma-secretase are currently in clinical trials and may have activity in patients with activating NOTCH1 mutations (PMID: 28539479). True +ENST00000256646 NM_024408.3 4853 NOTCH2 True NOTCH2 encodes a transmembrane receptor that regulates many aspects of development by affecting cell-fate determination. NOTCH2 is a transmembrane receptor that participates in an evolutionarily conserved cell-to-cell signal transduction pathway (PMID: 24651013). Interaction of the NOTCH2 receptor with ligand molecules on adjacent cells results in the proteolytic cleavage of NOTCH2 by the protease termed gamma-secretase (PMID: 24651013). The cleaved intracellular NOTCH2 domain can then activate gene expression in the nucleus and regulate various aspects of cell differentiation, growth, proliferation, survival and metabolism (PMID: 27507209). The specific effects of NOTCH2 signaling vary depending on the cellular context (PMID: 21508972, 24651013). Truncating mutations in NOTCH2, known to cause Hajdu-Cheney syndrome, interrupt the regulation of the protein degradation process, leading to activation of the NOTCH2 intracellular domain (PMID: 15284851, 21378989). NOTCH family members are frequently mutated in a variety of cancers, and these mutations can be either gain- or loss-of-function mutations (PMID: 21948802). Truncating mutations and focal amplifications of NOTCH2 have been observed in diffuse large B-cell lymphoma (DLBCL) and triple negative breast cancer, leading to stabilization and activation of intracellular NOTCH2 (PMID: 25314575, 19445024, 25564152). NOTCH2 inactivating mutations are most common in solid tumors, namely squamous cell carcinomas, and occur as missense, frameshift or nonsense mutations in important NOTCH2 functional domains (PMID: 28154375). Inhibitors targeting gamma-secretase are currently in clinical trials and may have activity in patients with activating NOTCH2 mutations (PMID: 28539479). True +ENST00000263388 NM_000435.2 4854 NOTCH3 True NOTCH3 encodes a Type I transmembrane protein of the Notch family. Missense and nonsense mutations in NOTCH3 have been identified in various cancers. NOTCH3 is a transmembrane receptor that participates in an evolutionarily conserved cell-to-cell signal transduction pathway (PMID: 24651013, 19165418). Interaction of the NOTCH3 receptor with ligand molecules on adjacent cells results in the proteolytic cleavage of NOTCH3 by gamma-secretase (PMID: 24651013). The cleaved intracellular NOTCH3 domain can then activate gene expression in the nucleus and regulate various aspects of cell differentiation, growth, proliferation, survival, and metabolism (PMID: 27507209). The specific effects of NOTCH3 signaling vary depending on the cellular context (PMID: 21508972, 24651013). NOTCH3 mutations were initially identified in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) (PMID: 26715087). Activating mutations and focal amplifications of NOTCH3 have been identified in T-cell acute lymphoblastic leukemia (T-ALL), and triple negative breast cancer (PMID: 27157619, 25564152). These NOTCH3 activating mutations either enhance the cleavage of NOTCH3 by gamma-secretase or extend the half-life of intracellular NOTCH3 (PMID: 15472075). NOTCH3 inactivating mutations are most common in solid tumors, namely squamous cell carcinomas, and occur as missense, frameshift or nonsense mutations in important NOTCH3 functional domains (PMID: 28154375). Inhibitors targeting gamma-secretase are currently in clinical trials and may have activity in patients with activating NOTCH2 mutations (PMID: 28539479). True +ENST00000375023 NM_004557.3 4855 NOTCH4 True NOTCH4, a transmembrane receptor, can function as both an oncogene and tumor suppressor. NOTCH4 is a transmembrane receptor that participates in an evolutionarily conserved cell-to-cell signal transduction pathway (PMID: 24651013, 19165418). Interaction of the NOTCH4 receptor with ligand molecules on adjacent cells results in the proteolytic cleavage of NOTCH4 by gamma-secretase (PMID: 24651013). The cleaved intracellular NOTCH4 domain can then activate gene expression in the nucleus and regulate various aspects of cell differentiation, growth, proliferation, survival, and metabolism (PMID: 27507209). The specific effects of NOTCH4 signaling vary depending on the cellular context (PMID: 21508972, 24651013). NOTCH4 was first identified as oncogenic following truncation in a retrovirus-induced murine mammary cancer (PMID: 19165418). These NOTCH4 oncoproteins either enhance the cleavage of NOTCH4 by gamma-secretase or extend the half-life of intracellular NOTCH4. Expression of activated NOTCH4 disrupts mammary gland morphogenesis and promotes carcinomas in different cancer types (PMID: 11344305, 8620493, 10797286, 26323259, 25511451). NOTCH4 inactivating mutations have been identified in gliomas and neuroendocrine cancers and occur as missense, frameshift or nonsense mutations in important NOTCH4 functional domains (PMID: 28154375, 26061751, 26960398). Inhibitors targeting gamma-secretase are currently in clinical trials and may have activity in patients with activating NOTCH4 mutations (PMID: 28539479). True +ENST00000296930 NM_002520.6 4869 NPM1 False 3A NPM1, a nucleolar phosphoprotein, is frequently altered in hematologic malignancies. NPM1, also known as nucleophosmin, is a nucleolar phosphoprotein that has diverse cellular functions including regulation of ribosome biogenesis, mRNA processing, chromatin remodeling, apoptosis and DNA damage repair (PMID: 16007073). NPM1 has been implicated in the regulation of several DNA repair processes including homologous recombination, translesion synthesis, and repair of lesions created by UV light (PMID: 27553022). Loss of NPM1 has also been associated with increased genome instability (PMID: 16007073). In addition, NPM1 plays an important role in the regulation of the TP53 tumor suppressor pathway. The TP53-stabilizing protein ARF binds NPM1, sequestering ARF and NPM1 from binding the ubiquitin ligase MDM2 that is responsible for degrading TP53. Disruption of the NPM1-ARF interaction allows NPM1 and ARF to inhibit MDM2-mediated degradation of p53 leading to apoptosis (PMID: 15144954,15684379). Translocations and loss-of-function mutations have been identified in various human lymphomas and leukemias (PMID: 15659725, 8122112, 17488663). Mutations in NPM1 commonly result in a cytoplasmic form, NPM1c, which functions as a dominant negative and excludes NPM1 from the nucleus. NPM1c mutations in acute myeloid leukemia have been associated with a more favorable patient prognosis (PMID: 15659725). Murine models engineered to express NPM1 mutations develop hematopoietic disease and cooperate with other oncogenes to induce leukemias (PMID: 26559910). In solid tumors, NPM1 is commonly overexpressed leading to mislocalization of NPM1 (PMID: 26559910, 21258971,18037965, 26559910). True +ENST00000320623 NM_000903 1728 NQO1 True NQO1, a quinone oxidoreductase, is altered by amplification in various cancers. NQO1, a member of the NAD(P)H dehydrogenase (quinone) family, encodes for a cytoplasmic 2-electron reductase and functions in reducing quinones to hydroquinones (PMID: 22687461). NQO1 has been identified to regulate various cellular processes such as cellular homeostasis and cell cycle progression through redox reactions (PMID: 33298924, 36793872). NQO1 protects against oxidative stress through the generation of antioxidative agents such as α-tocopherol hydroquinone and long-chain CoQ derivatives (PMID: 9271353, 8637908). There is conflicting evidence on the oncogenic effect of NQO1 depending on the tissue context. Overexpression of NQO1 in various cancer cell lines and models induces HIF-1α signaling and tumor growth, suggesting that NQO1 functions predominantly as an oncogene (PMID: 27966538, 24499631). Amplification of NQO1 has been identified in various cancers, including gastric cancer, breast cancer and colon cancer (PMID: 34168410, 27966538, 25885439). Knockdown of NQO1 in prostate cancer cells and models induces increased cellular migration and sensitivity to oxidative stress, suggesting that NQO1 may function as a tumor suppressor gene in this context (PMID: 31909204). False +ENST00000395097 NM_006981.3 8013 NR4A3 True NR4A3, a hormone receptor transcription factor, is rarely altered by chromosomal rearrangement in extraskeletal myxoid chondrosarcoma. NR4A3 (NOR-1) is a member of the steroid-thyroid hormone-retinoid receptor superfamily that acts as a transcriptional activator in a ligand-independent manner (PMID: 16604165). NOR-1 is expressed in a limited number of adult tissues and has been shown to be involved in the cellular response to a variety of stimuli, including TLR-mediated activation of dendritic cells, IFN-γ and LPS-induced activation and proliferation of macrophages, development of dopaminergic neurons, induction of adipocyte differentiation, and cAMP response in vascular smooth muscle cells (PMID:8961274,15964844,16051664,16051663,14962944). Gene expression resulting from the binding of NR4A3 to DNA leads to proliferation, differentiation, or apoptosis, depending on the stimuli and cell type. False +ENST00000369535 NM_002524.4 4893 NRAS True 1 R1 NRAS, a GTPase, is mutated in a diverse range of cancers, most frequently in melanoma and thyroid cancer. The NRAS gene encodes a membrane-associated GTPase that controls intracellular oncogenic MAPK and PI3K signaling pathways. Activating NRAS mutations lock the enzyme in an active state causing increased cellular proliferation via hyperactivating these downstream pathways (PMID: 20194776, 21993244). NRAS mutations are common in thyroid cancer, ovarian cancers, melanoma and hematological cancers (PMID: 21993244, 22589270, 24651010). NRAS is also important during development with germline mutations enhancing stimulus-dependent MAPK activation and accounting for some cases of Noonan syndrome (PMID: 19966803). NRAS mutations and upregulation can also provide resistance to cancer therapies, including epidermal growth factor receptor (EGFR) and BRAF inhibitors (PMID: 22389471, 20619739, 25110411, 24024839). R1 False +ENST00000405005 NM_013964.3 3084 NRG1 True 1 NRG1, a ligand that binds HER3, is recurrently altered by fusions in lung, pancreatic, and other cancers. NRG1 is a cell adhesion protein that is a member of the neuregulin protein family (PMID: 18478032, 25501131). The NRG1 gene encodes six types of proteins with distinct N-terminal domains and at least 31 different isoforms, which all contain an EGF-binding domain (PMID: 18478032, 11042203). NRG1 growth factors are predominantly synthesized as membrane-bound proteins that are cleaved and released into the extracellular space; however, type III NRG1 isoforms have transmembrane and intracellular activities (PMID: 18478032, 9789034). NRG1 functions as a ligand for the HER receptor tyrosine kinases, with specificity for HER3 and HER4 (PMID: 11042203, 17250808). Binding of NRG1 via the EGF-domain initiates HER dimerization, leading to the activation of downstream signaling pathways including the MAPK and PI3K pathways (PMID: 18478032, 25501131). NRG1-mediated signaling regulates a variety of cellular functions including neuronal survival, migration, differentiation, and cellular proliferation, among others (PMID: 12821646, 18478032, 25501131). The expression and processing of the differential NRG1 proteins are highly cell-type specific, leading to the activation of specialized cellular programs (PMID: 27989735, 24237343). Germline NRG1 variants are found in developmental disorders and schizophrenia (PMID: 30180823, 30180823). Overexpression of NRG1 has been implicated in tumor progression in a variety of cancer types including ovarian cancer and gastric cancer, among others (PMID: 20227043, 28573357). NRG1 rearrangements are also found in patients with non-small cell lung cancer and pancreatic cancer, resulting in increased NRG1 expression, suggesting that NRG1 functions as an oncogene (PMID: 25501131, 24469108, 27626312, 29802158). False +ENST00000439151 NM_022455.4 64324 NSD1 True NSD1 encodes a nuclear receptor that can both positively and negatively regulate transcription. Translocations involving NSD1 and the NUP98 gene are highly recurrent in pediatric acute myeloid leukemia. NSD1 is a ligand-regulated nuclear transcription factor that is activated by steroid hormones (PMID: 11733144). NSD1 has a unique role as a bifunctional cofactor that can both positively and negatively regulate transcription (PMID: 12805229, 9628876, 11733144). Additionally, NSD1 recognizes histone lysines and contains histone methyltransferase activity with specificity for H3K36 and H4K20 (PMID: 12805229, 21972110). H3K36 methylation is most commonly associated with activation of gene transcription, but may also affect other processes such as DNA repair or RNA splicing (PMID: 22266761). Germline mutations of NSD1 are associated with Sotos syndrome, characterized by overgrowth, distinctive appearance, and developmental delay (PMID: 11896389). Translocations involving NSD1 and the NUP98 gene are highly prevalent in pediatric acute myeloid leukemia and are associated with a poor prognosis (PMID:11895789, 23630019, PMID: 24951466 ). Loss-of-function NSD1 mutations have also been identified in head and neck squamous cell carcinomas and leukemias (PMID: 25631445, 26438511, 25056374, 22976956). NUP98-NSD1 fusions and NSD1 loss-of-function mutations result in global genomic histone methylation changes leading to altered gene expression (PMID: 17589499, 26690673, 28067913). True +ENST00000382891 NM_001042424.2 7468 NSD2 True NSD2, a histone methyltransferase, is altered by translocation in hematologic malignancies. The NSD2 gene encodes the NSD2 histone lysine methyltransferase. NSD2 specifically methylates the H3K36 residue of histones and promotes an open chromatin state that favors gene transcription (PMID: 22099308, 20974671, 19808676). Activation of NSD2 enhances an oncogenic H3K36me2-dependent transcriptional program that includes genes such as MET, PAK1 and PRKCA, and activates tumorigenesis in in vitro and in vivo cancer models (PMID: 19808676, 24076604, 37463241). NSD2 is mutated in acute lymphoblastic leukemia and Mantle cell lymphoma (PMID: 24076604, 24145436). False +ENST00000317025 NM_023034.1 54904 NSD3 False NSD3, a histone methyltransferase, is altered by amplification in various cancers. The NSD3 gene encodes the NSD3 histone lysine methyltransferase. NSD3 methylates both the H3K4 residue, which constitutes an epigenetic mark for transcriptional activation, and the H3K27 residue, which acts as a repressive mark (PMID: 16682010). Thus, it is controversial whether this gene acts as an oncogene or a tumor suppressor (PMID: 20599755). NSD3 is altered by amplification in a subset of various cancers, including breast and lung tumors (PMID: 20940404, 25942451; cBioPortal, MSKCC, Dec. 2016). False +ENST00000343289 NM_001134373.2 22978 NT5C2 True NT5C2, a 5' nucleotidase, is frequently altered by mutation in relapsed hematopoietic malignancies. NT5C2 (also CN-II) is a 5’ nucleotidase that catalyzes the hydrolysis of nucleotides (PMID: 29990496, 30201983). Activity of NT5C2 is important for the maintenance of nucleotide pools and the export of excess purine nucleotides out of the cell (PMID: 29990496). NT5C2 functions as a dimer of dimers to dephosphorylate purine substrates including inosine monophosphate (IMP), xanthine monophosphate (XMP), and guanosine monophosphate (GMP), resulting in the clearance of purine nucleosides (PMID: 30201983). Nucleotide analog chemotherapies that disrupt DNA synthesis, such as cytarabine and thiopurines, are also targets of dephosphorylation by NT5C2, ultimately leading to their inactivation (PMID: 30201983). High expression of NT5C2 in patients with myelodysplastic syndromes and acute myeloid leukemia correlates with drug resistance and poor outcome (PMID: 16330448, 17350683, 26294725). Activating NT5C2 mutations are found in patients with hematopoietic malignancies, including childhood and adult acute lymphoblastic leukemia (ALL) and B-lymphoblastic leukemia, predominantly after relapse to nucleotide analog chemotherapies (PMID: 29990496, 23377183, 23377281, 25790293, 28253933). Gain-of-function NT5C2 mutations can activate NT5C2 by several distinct mechanisms: locking the enzymatic complex in an activate state, disrupting the NT5C2 off-switch, or loss of the negative regulation at the C-terminal (PMID: 29535428, 29990496). Germline NT5C2 variants have also been linked to relapse in hematopoietic and non-small cell lung cancers (PMID: 30201983, 22173087, 28573946). Expression of activating NT5C2 mutations in murine models results in impaired leukemia growth and tumor-initiating capacity due to the excessive export of purines, suggesting that NT5C2 functions as an oncogene at relapse but not at tumor initiation (PMID: 29342136). In preclinical studies, NT5C2-mutant leukemia cells were sensitive to blocking guanosine synthesis by inhibiting inosine-5'-monophosphate dehydrogenase (IMPDH) (PMID: 29342136). False +ENST00000219066 NM_002528.5 4913 NTHL1 False NTHL1, a DNA damage repair protein, is mutated in the germline of families with hereditary cancer syndromes. The NTHL1 gene encodes a protein involved in the repair of oxidative DNA damage. NTHL1 localizes in the nucleus, where it catalyzes the N-glycosylation of damaged DNA and subsequent cleavage of the resulting modified bond, constituting the first steps towards DNA repair in the base excision repair (BER) pathway (PMID: 10882850, 18166975, 21930793, 9890904, 17923696). Low NTHL1 expression has been associated with a decreased capacity for DNA repair in gastric cancer (PMID: 19414504). However, a dual role for NTHL1 has been described in irradiated cells; it both repairs potentially lethal DNA lesions and generates lethal double-strand breaks at radiation-induced sites (PMID: 16111924). NTHL1 interacts with PCNA and p53 proteins (PMID: 15358233). Germline truncating mutations of NTHL1 have been identified as the causal alteration in families with hereditary colorectal tumors and other neoplasias (PMID: 25938944, 26559593). Paradoxically, NTHL1 is somatically amplified in a subset of breast and pancreatic tumors (cBioPortal, MSKCC, Dec. 2016). True +ENST00000524377 NM_002529.3 4914 NTRK1 True 1 R1 NTRK1, a receptor tyrosine kinase, is altered by gene fusions in various cancer types. The NTRK1 (neurotrophic receptor tyrosine kinase 1) protein is a transmembrane neurotrophic receptor that is found in neural cells and is triggered via the binding of its main ligand, nerve growth factor (NGF). NTRK1 consists of an extracellular ligand-binding domain, a transmembrane domain and an intracellular region harboring the tyrosine kinase domain. Oncogenic activation of NTRK1 leads to autophosphorylation and activation of the MAP-kinase, PI3-kinase and PLC-γ pathways, mediating cell proliferation, survival and differentiation (PMID: 10851172, 12652644). NTRK1 mutations and fusions are found in various cancers. Treatment strategies for NTRK1-altered cells include broad inhibitors of receptor tyrosine kinases as well as more specific inhibitors of the NTRK-family of kinases. R1 False +ENST00000277120 NM_006180.3 4915 NTRK2 True 1 NTRK2, a receptor tyrosine kinase, is altered by mutation or chromosomal rearrangement in a diverse range of cancers. The NTRK2 gene (neurotrophic receptor tyrosine kinase 2) encodes a transmembrane neurotrophic receptor involved in signaling that is important for normal neurologic development (PMID: 8402890, 8145823). NTRK2 consists of an extracellular ligand-binding domain, a transmembrane domain and an intracellular region harboring the tyrosine kinase domain. Normal activation in neural cells occurs upon binding one of its three ligands, the nerve growth factor (NGF), the brain-derived neurotrophic factor (BDNF) or neurotrophin-3 (NT-3), leading to autophosphorylation and activation of downstream signaling pathways controlling and promoting cell proliferation, survival and differentiation via MAPK, PI3K and PLC-γ (PMID: 1649702, 1649703, 10851172). NTRK2 alterations, especially fusions, are found in several human cancers, such as lung cancer, pilocytic astrocytoma, and neuroblastoma (PMID: 25204415, 21242122, 23817572, 8264643, 9049830). False +ENST00000360948 NM_001012338.2 4916 NTRK3 True 1 R1 NTRK3, a receptor tyrosine kinase, is altered by gene fusion in various cancer types. The NTRK3 (neurotrophic receptor tyrosine kinase 3) gene encodes a transmembrane neurotrophic receptor normally activated in neural cells upon binding of its main ligand, the neurotrophin-3 (NT-3). NTRK3 consists of an extracellular ligand-binding domain, a transmembrane domain and an intracellular region harboring the tyrosine kinase domain. Activation of NTRK3 leads to autophosphorylation and subsequent activation of a downstream signaling pathway controlling cell proliferation, survival and differentiation via MAPK, PI3K and PLC-γ (PMID: 10851172). NTRK3 has been found altered, mainly in the form of oncogenic fusions, in several human cancers (PMID: 9462753, 11801301, 10895816, 12450792, 9823307, 25207766, 21401966, 24327398, 24135138, 23583981, 24705251). While NTRK3 is overexpressed in some leukemias (PMID: 23832765) it has been found inactivated and transcriptionally downregulated in breast and colon cancer (PMID: 25520870, 23341610, 23874207) showing that NTRK3 may have dual context-dependent roles as both a tumor suppressor and an oncogene. Treatment strategies for NTRK3-altered cells include broad inhibitors of receptor tyrosine kinases as well as more specific inhibitors of the NTRK-family of kinases. R1 False +ENST00000271452 NM_031423.3 83540 NUF2 True NUF2, a protein involved in mitosis, is altered by amplification in various cancers. The NUF2 gene encodes a protein involved in chromosome segregation during meiosis and mitosis. NUF2 is essential for kinetochore-microtubule interactions and spindle checkpoint activity (PMID: 15358233, 15239953, 15548592, 17535814, 15062103). Silencing of NUF2 inhibits cell proliferation and induces apoptosis in normal and cancer cells (PMID: 12438418, 19878654, 25481014, 25370920, 25374179). The NUF2 gene is amplified in various tumors, including breast, prostate, bladder and liver (cBioPortal, MSKCC, Dec. 2016). NUF2 overexpression has been associated with poor prognosis in colorectal cancers (PMID: 24247253), and RNA interference screens have implicated NUF2 as a therapeutic target in ovarian cancers (PMID: 23056589). False +ENST00000359428 NM_005085 8021 NUP214 True NUP214, a nucleoporin protein, is altered by translocation in leukemia. NUP214 is a nucleoporin found on the cytoplasmic side of the nuclear pore complex (PMID: 8108440). NUP214, a phenylalanine-glycine (FG)-repeat-containing nucleoporin, is responsible for nucleocytoplasmic transport of proteins and mRNA across the nuclear envelope in conjunction with NUP88 and the nuclear export receptor XPO1 (PMID: 7878057, 9488438, 8896451, 16943420). The FG-repeat of NUP214 is a disordered domain that contributes to selective transport while also acting as a selective barrier to specific proteins and RNAs, and mutations that alter this domain affect the movement of molecules between the cytoplasm and the nucleus (PMID: 16769882). Because NUP214 regulates the proteins and mRNA that cross the nuclear envelope, it plays a role in the regulation of cell cycle, mitosis and gene expression (PMID: 30669574, 9488438). NUP214 fusions such as SET-NUP214 and DEK-NUP214, which may arise de novo or due to prior treatment, have been identified in liquid tumors such as AML and ALL (PMID: 30669574) and are associated with disease that is characterized as more aggressive, with poor prognosis, higher risk of relapse, etc. (PMID: 24441146, 16628187, 30669574). False +ENST00000308159 NM_014669.4 9688 NUP93 False NUP93 encodes subunit of the nucleoporin complex that controls the transport of molecules across the nuclear envelope. NUP93 is a subunit of the nuclear pore complex that is essential for the exchange of macromolecules across the nuclear envelope (PMID: 24572986). NUP93 activity promotes and maintains the correct assembly of the nuclear pore complex (PMID: 15229283, 22171326). Functional studies have suggested that NUP93 plays a role in gene regulation by tethering chromatin at superenhancer sites to generate the necessary structural environment for transcriptional repression or activation (PMID: 26341556, 27807035). Expression of NUP93, along with other members of the nucleoporin complex, is increased in cardiac tissue of patients with heart failure and decreased in the thymus of patients with Down syndrome (PMID: 23152829, 21856934). While NUP93 copy number alterations are observed in a variety of solid cancers (cBioPortal, MSKCC, Nov. 2017), NUP93 mutations in human cancers are not common. However, a recent analysis identified the NUP93 E14K mutation as a hotspot mutation with unknown function in multiple cancers (PMID: 26619011). False +ENST00000355260 NM_139132.4 4928 NUP98 True NUP98, a protein involved in the nuclear pore and nuclear-cytoplasmic trafficking, is altered by chromosomal rearrangements in hematologic malignancies. NUP98 is a scaffold component of the nuclear pore complex, a large multi-protein structure embedded in the nuclear membrane that is required for nuclear-cytoplasmic trafficking. Localization studies have shown that NUP98 is located on the nucleoplasmic side of the NPC and facilitates docking of proteins being imported into the nucleus from the cytoplasm (PMID: 7736573). During mitosis, the NPC disassembles along with the nuclear membrane, which is initiated by phosphorylation of proteins in the NPC. Studies have shown that hyperphosphorylation of NUP98 by CDK1 and Neks is an early and required step in the NPC disassembly and is proposed to be a rate-limiting step in the process (PMID: 21335236). NUP98 is fused to a variety of partner genes in hematologic malignancies (PMID: 21948299). False +ENST00000333756 XM_011521429.1 256646 NUTM1 False NUTM1, a gene of unknown function, is recurrently altered by chromosomal rearrangement in NUT midline carcinoma. NUTM1 encodes the nuclear protein in testis (NUT), which is expressed in normal spermatocytes. NUTM1 is a novel gene located on chromosome 15; not much is known about its function, except that the protein harbors an acidic binding domain for the acetyltransferase p300 (PMID: 20676058). Most of the current knowledge on NUTM1 is focused on alterations involved in cancer (PMID: 17934517). More specifically, chromosomal translocations involving NUT and BRD proteins—in particular BRD4, but also BRD3—are found in NUT midline carcinoma (NMC), a rare, aggressive, and lethal genetically defined epithelial cancer syndrome, characterized by the insurgence of carcinomas in various tissues along the upper midline of the body, that mainly affects young individuals (PMID: 17934517, 26551281, 24655834,12543779, 25675182). Approximately 75% of NMC cases feature BRD4-NUT translocation, where the fusion oncogene is expressed under the BRD4 promoter and consists of the first half of the BRD4 protein (which contains all of the functional domain of BRD4) and all of the coding region of NUT. Translocation leading to the fusion protein BRD3-NUT is less common. A novel translocation that results in the fusion protein NSD3-NUT has been observed in NMC of the lung (PMID: 25466466). In a small number of cases involving NUT rearrangements, called NUT variants, the partner of the translocation is unknown. These NUT variants are associated with longer survival, compared with BRD4-NUT carcinomas (PMID: 15483023). NUT rearrangements are found in 18% of cases of undifferentiated carcinoma of the upper aerodigestive tract (PMID: 18391746). Missense mutations and copy number alterations, although rare, are found in some solid cancers (cBioPortal, MSKCC, Nov. 2015). False +ENST00000491143 NM_004852 9480 ONECUT2 True ONECUT2, a transcription factor, is recurrently altered by amplification in lung adenocarcinoma. ONECUT2, a member of the ONECUT transcription factor family, encodes for a transcription factor that functions in the regulation of various cellular functions such as development, proliferation and differentiation (PMID: 20354101, 16950765, 16103213). ONECUT2 has a redundant role in the regulation of cellular development with ONECUT1 (PMID: 25228773). Overexpression of ONECUT2 in various types of cancer cell lines and models induces cellular proliferation, invasion, tumor growth and metastasis, suggesting that ONECUT2 functions predominantly as an oncogene (PMID: 31882655, 14656735, 29737581). Amplification of ONECUT2 has been identified in various cancers, including prostate cancer, hepatocellular carcinoma and small cell lung cancer (PMID: 25788493, 26547929, 34155000). Upregulation of ONECUT2 has been observed in lung adenocarcinoma cell lines following treatment with osimertinib (PMID: 34155000). False + -2 Other Biomarkers False 1 False +ENST00000381297 NM_178129.4 286530 P2RY8 False P2RY8, a member of the G-protein coupled receptor family, is altered by mutation or fusion in lymphomas. P2RY8 is an orphan receptor that is a member of the G-protein coupled receptor family (GPCRs). GPCRs signal by association with heterotrimeric G proteins at the plasma membrane and function as exchange factors leading to G-protein activation (PMID: 30262890). P2RY8 signals via the G-protein GNA13 and the downstream effector ARHGEF1, leading to activation of signaling pathways (PMID: 26573295). P2RY8 is highly expressed in germinal center B cells; functional studies in murine B cells demonstrate that P2RY8 suppresses B cell growth and mediates B cell positioning in the germinal center in a GNA13-dependent manner (PMID: 25274307, 26573295). In addition, P2RY8 is required to promote the clustering of activated B cells within follicles in collaboration with follicular dendritic cells (PMID: 26573295). P2RY8 fusions are found in patients with B-progenitor acute lymphoblastic leukemia (ALL) and ALL-associated Down Syndrome (PMID: 19838194). P2RY8 predominantly fuses with CRLF2, and P2RY8-CRLF2 rearrangements are associated with relapse and poor prognosis in ALL (PMID: 20139093, 22484421). In addition, loss-of-function P2RY8 mutations have been identified in diffuse large B cell lymphomas (DBLCL) and follicular lymphomas; however, the function of these mutations have yet to be determined (PMID: 22343534, 27959929). True +ENST00000356341 NM_002576.4 5058 PAK1 True PAK1 encodes a serine/threonine kinase involved in cytoskeletal remodeling and cellular motility, adhesion and survival. Amplifications and overexpression of PAK1 are found in a variety of cancers. PAK1 is serine/threonine protein kinase that in physiologic states is expressed in a wide variety of tissue types and plays important roles in cytoskeletal remodeling, cell motility, adhesion and survival (PMID: 21653999). PAK1 is overexpressed in several cancer types, through amplification of the PAK1 gene on chromosome 11q13, a feature most commonly described in estrogen receptor (ER) positive breast carcinomas (PMID: 9533029) or through other mechanisms. PAK1 plays several roles in oncogenesis, including increasing cancer proliferation through activation of MAPK signaling (PMID: 7592806), mediation of the oncogenic transformation caused by ErbB2 overexpression (PMID: 23576562), activation of the Wnt pathway (PMID: 21822311), inhibition of apoptosis through activation of BAD (PMID: 15849194, 10611223) and promotion of cancer cell metastasis through direct action on the cytoskeleton (PMID: 21196207). False +ENST00000353224 NM_177990.2 57144 PAK5 True PAK5, a serine/threonine kinase, is altered by mutation in various cancer types, including melanoma and lung cancers. PAK5 (also PAK7) is a serine/threonine kinase and member of the PAK family of proteins, which function as downstream effectors of Rho GTPases (PMID: 24869804). PAK5 is predominantly expressed in neuronal cell types and functions as a target of the Rho GTPases Cdc42 and RAC (PMID: 11756552, 12860998). Cdc42 cycles between a GDP-bound inactive state and a GTP-bound active state, in which PAK5 binds activated Cdc42 to initiate downstream signaling pathways (PMID: 24869804). PAK5 mediates a variety of cellular functions including regulation of MAPK and JNK signaling, as well as cell motility and survival (PMID: 12032833, 11756552, 18199048), apoptosis via phosphorylation of the pro-apoptotic protein BAD (PMID: 12897128, 20567954), and cytoskeletal stability (PMID: 16014608, 20564219). In neuronal cell types, PAK5 is predominantly localized in the mitochondria (PMID: 12897128) and expression of PAK5 leads to the induction of neurite formation via downstream activity of Cdc42 and Rac (PMID: 11756552, 15322108). Loss of PAK5 expression in mice results in defects in memory and learning and variants in PAK5 have been associated with the risk of psychosis in humans (PMID: 24474471). PAK5 overexpression has been identified in a variety of human tumor types including lung cancer, gastric cancer and melanoma, among others (PMID: 19415746, 16845324, 20564219, 23685956, 23106939, 25052921, 26116538). Expression of PAK5 in preclinical studies has been associated with increased invasion and migration and cellular protection from apoptosis (PMID: 25726523, 19415746, 20567954). Somatic variants in PAK5 are rare in human cancers; however, mutations in PAK5 have been identified in melanoma and lung cancer and are predicted to result in gain-of-function activity (PMID: 29875996, 23836671, 17344846). False +ENST00000261584 NM_024675.3 79728 PALB2 False 1 PALB2 is a component of the Fanconi anemia complementation (FANCC) group involved in DNA double-strand break repair. Germline mutations of PALB2 are associated with Fanconi anemia and predispose to breast cancer. PALB2 (Partner and localizer of BRCA2, also known as FANCN) encodes a DNA-repair factor and BRCA2 binding protein (PMID: 16793542). PALB2 acts as a scaffold protein in the homologous recombination (HR) pathway for the repair of double-stranded DNA breaks, likely mediating recruitment of BRCA2 and RAD51 at damaged loci (PMID: 19423707). PALB2 also interacts with BRCA1, possibly functioning as an intermediary factor between BRCA1 and BRCA2 in the HR pathway (PMID: 19268590, 19584259). Preclinical data show that mutations in BRCA1 and BRCA2 can abrogate interaction with PALB2 and disrupt HR-mediated DNA repair (PMID: 19369211, 16793542). Germline heterozygous mutations in PALB2 increase susceptibility to breast cancer with possible lesser effects in ovarian, pancreatic, prostate cancer and melanoma (PMID: 17200668, 17287723, 17420451, 18053174, 19264984, 20858716, 24448499, 25099575). Biallelic mutations of PALB2 are implicated in Fanconi anemia complementation group N (PMID: 17200671, 17200672, 20858716). Although rare, deleterious somatic variants in PALB2 are observed across various tumor types. True +ENST00000366794 NM_001618.3 142 PARP1 False PARP1 encodes a nuclear protein modifier enzyme involved in the DNA repair pathway. PARP1 inhibition has been shown to be effective in germline BRCA-deficient tumors, triple-negative breast cancer (TNBC), chronic lymphocytic leukemia, and ovarian serous papillary carcinoma. PARP1 encodes a nuclear localized poly(ADP-ribose) polymerase that transfers an ADP-ribose group to target proteins. PARP1 activity has been implicated in several biological processes including DNA repair, DNA replication, transcription, and chromatin remodeling (PMID: 9315851, 26184161). After induction of DNA damage, PARP1 binds to sites of single-strand breaks and recruits DNA repair proteins to the site of damage (PMID: 9315851, 26184161). PARP1 is also a key factor in regulating other biological and oncogenic processes, including maintenance of pluripotency in embryonic development, cell reprogramming and transcriptional regulation (PMID: 17286852, 22902501, 23939864, 21095583, 19262751, 26184161). Functional studies have demonstrated that PARP1 loss leads to genomic instability and resistance to DNA damage-induced cell death (PMID: 24916104). PARP1 is highly expressed in several human cancers, however, PARP1 mutations are rare (PMID: 25528020). In the absence of PARP1, single-strand breaks cause replication fork collapse resulting in double-stranded breaks and ultimately triggering DNA repair by homologous recombination pathways involving DNA repair genes such as BRCA1/2 (PMID: 24916104, 25286972). PARP1 inhibitors have been developed to leverage the ability of PARP1 to induce double-strand breaks in cancers with mutations in DNA repair genes, such as BRCA1/2, resulting in inefficient repair and cell death (PMID: 15829967, 19351835, 20858840, 25286972). PARP inhibitors have also been shown to be efficacious in other tumor types that share clinicopathological characteristics with BRCA-mutant tumors (‘BRCAness’), such as triple-negative breast cancer (TNBC), chronic lymphocytic leukemia, and ovarian serous papillary carcinoma (PMID: 16912188). The PARP1 inhibitor rucaparib has been approved for the treatment of BRCA-mutated ovarian cancer (PMID: 28751443). True +ENST00000350526 NM_181457 5077 PAX3 True PAX3, a transcription factor, is altered by chromosomal translocation in rhabdomyosarcoma. PAX3, a member of the paired-box (PAX) family, encodes for a transcription factor that regulates expression of target genes involved in cellular proliferation, survival and differentiation (PMID: 22532290). All PAX proteins contain a paired box DNA-binding domain, a homeobox DNA-binding domain and a transactivation domain (PMID: 24496612). The expression of PAX genes is temporally and spatially restricted during organogenesis and these genes play a key role in controlling cell fate during early development (PMID: 24496612). There are seven human isoforms of PAX3, with each isoform regulating intersecting target genes (PMID: 17187370). Knockdown of PAX3 in melanoma, glioblastoma and rhabdomyosarcoma cell models suppresses cellular proliferation, migration and invasion, suggesting that PAX3 functions predominantly as an oncogene in these contexts (PMID: 36057879, 10871843, 23701726). PAX3 chromosomal rearrangements have been identified in rhabdomyosarcoma and gastric cancer (PMID: 18457914, 25653235, 12039929). False +ENST00000358127 NM_016734.2 5079 PAX5 True PAX5 encodes a transcription factor involved in B-cell development. Translocations of PAX5 are found in lymphomas and leukemias. PAX5 is a protein in the paired-box family of transcription factors that is important in early B-cell development and differentiation (PMID:10524622). PAX5 plays a key role in the commitment of bone marrow multipotent progenitors to the B-lymphoid lineage by favoring VDJ gene rearrangement and activating the expression of B-cell-specific genes (PMID: 9442394) while simultaneously repressing genes involved in other hematopoietic differentiation programs (PMID: 12479824). The oncogenic function of PAX5 is likely tissue specific. PAX5 deficiency in B-cell acute lymphoblastic leukemia cell lines and models induces leukemia development and aberrant B-cell development and differentiation, suggesting that PAX5 functions predominantly as a tumor suppressor gene in this context (PMID: 25855603, 24939936, 30643249). Inactivating mutations, hypermethylation, translocations and deletions of PAX5 have been found in B-ALL, pediatric acute lymphoblastic leukemia and breast cancer (PMID: 17344859, 8943844, 25855603, 19020546, 37403081). A germline susceptibility mutation in PAX5 for development of B-ALL has also been identified (PMID: 24013638). Conversely, expression of PAX5 in other cancer cell models induces increased cancer cell viability, promotion of c-Met transcription and confers cisplatin resistance, suggesting that PAX5 functions predominantly as an oncogene in these tissue contexts (PMID: 19139719, 9815975, 29964012). Amplification of PAX5 has been identified in neuroblastoma and B-ALL (PMID: 29296789, 15155532). True +ENST00000420770 NM_001135254 5081 PAX7 True PAX7, a transcription factor, is altered by chromosomal translocation in rhabdomyosarcoma. PAX7, a member of the paired-box (PAX) family, encodes for a transcription factor that regulates expression of target genes involved in cellular proliferation, survival and differentiation (PMID: 34571854, 31534153, 17548510). All PAX proteins contain a paired box DNA-binding domain, a homeobox DNA-binding domain and a transactivation domain (PMID: 24496612). The expression of PAX genes is temporally and spatially restricted during organogenesis and these genes play a key role in controlling cell fate during early development (PMID: 24496612). Overexpression of PAX7 in rhabdomyosarcoma models induces cellular migration and invasion, suggesting that PAX7 functions predominantly as an oncogene (PMID: 25123133). PAX7 chromosomal rearrangements have been identified in rhabdomyosarcoma (PMID: 12039929, 22089931). False +ENST00000348715 NM_003466.3 7849 PAX8 True PAX8, a transcription factor, is overexpressed in various cancer types and chromosomal rearrangements involving this gene are found in thyroid cancers. PAX8 is a protein in the paired-box (PAX) family of transcription factors that plays a key role in controlling cell fate during early development and organogenesis (PMID: 24496612). All PAX proteins contain a paired box DNA-binding domain, a homeo box DNA-binding domain and a transactivation domain (PMID: 24496612). The expression of PAX genes is temporally and spatially restricted during organogenesis and these genes play a key role in controlling cell fate during early development (PMID: 24496612). PAX8 is the only member of the family expressed in the thyroid tissue; it is involved in thyroid follicular cell development and expression of thyroid-specific genes, and also functions in very early stages organogenesis of the kidney, the gynecologic tract and the thymus (PMID: 1337742). A fusion protein, PAX8-PPARγ, is implicated in some follicular thyroid carcinomas and follicular-variant papillary thyroid carcinomas (PMID: 10958784). An array of heterogenous mutations of PAX8 have been seen in thyroid dysgenesis, which causes congenital hypothyroidism (PMID: 25231445). False +ENST00000394830 NM_018313.4 55193 PBRM1 False PBRM1 encodes a tumor suppressor and component of the SWI/SNF chromatin-remodeling complex. Inactivating mutations of PBRM1 are frequently found in renal carcinoma. The PBRM1 gene encodes the protein BAF180, which is a component of the nucleosome-remodeling complex switching defective/sucrose non-fermenting (SWI/SNF) (PMID: 21248752). Nucleosomes are histone octamers around which DNA is wrapped in order to regulate its exposure to transcription factors and RNA polymerases (PMID: 23113498). Remodeling complexes such as the SWI/SNF family serve to loosen, reposition and break DNA/histone contacts ultimately rendering the DNA accessible to modulation (PMID: 21654818). BAF180 contains 6 bromodomains, which bind to lysine residues in histone tails (PMID:19084573, PMID:22435813). Aberrations of each individual bromodomain are sufficient to disrupt the protein's function as a tumor suppressor (PMID: 22435813, PMID:24613357). Specifically, one study demonstrated that BAF180 is among the key components required for p53-dependent cellular senescence (PMID:20660729). Additional work focusing on breast cancer cell lines identified BAF180 as a critical promoter in the induction of p21 activity, which functions as a key component of cell cycle regulatory functions (PMID:18339845). PBRM1 truncation mutants can no longer bind and remodel the p21 locus leading to cell cycle defects and aberrant cell proliferation (PMID: 18339845, 22949125). Loss of PBRM1 activity is also associated with chromosomal instability due to its inability to promote cohesion (PMID: 24613357). True +ENST00000303577 NM_006196.3 5093 PCBP1 False PCBP1, an RNA binding protein, is recurrently altered by mutation in Burkitt's lymphoma and gastrointestinal adenocarcinomas. PCBP1 (also alpha-CP1 and HNRNP E1) is an RNA binding protein that mediates transcription, translation and alternative splicing of mRNA molecules in a variety of contexts (PMID: 17389360). PCBP1 functions as a poly(rc)-binding protein (PMID: 7607214) that binds cloverleaf and large stem-loop IV mRNA structures (PMID: 10608888). The proteins PCBP1 and PCBP2 are translated from the same intronless gene and can cooperate to regulate RNA binding in collaboration with other components, including the hnRNPK ribonucleoparticle (PMID: 7607214, 9257647, 10455157). PCBP1 has been implicated in the stability of a variety of mRNA substrates including alpha-globin (PMID: 9234743), the androgen receptor (PMID: 12011088), EPO (PMID: 10068686), p21(WAF1) (PMID: 12431987), the folate receptor (PMID: 14722620), histone molecules (PMID: 18656558) and STAT3 (PMID: 14722620), among others. PCBP1 activity regulates a variety of cellular processes including cell cycle progression (PMID: 19211566), metastasis (PMID: 20154680, 26096938), and alternative splicing in both normal and malignant cells (PMID: 20361869, 27746021). For example, TGF-β activity promotes PCBP1 regulation of SMAD3, a critical mediator of metastasis (PMID: 27746021, 20154680, 26096938). Somatic mutations in PCBP1 are found in Burkitt’s lymphoma and gastrointestinal adenocarcinomas and these alterations are predicted to disrupt mRNA stability and alternative splicing (PMID: 29622466, 26173642). PCBP1 regulates a diverse range of substrates implicated in oncogenesis and therefore can function as either a tumor suppressor or oncogene (PMID: 18656558). False +ENST00000334409 NM_005018.2 5133 PDCD1 True PDCD1 is a key mediator of immune self tolerance and several cancer entities highly express PDCD1 to evade anti-tumoral immune response. Anti-PD1 therapy has been successful in PD1 expressing cancer. PDCD1 (Programmed cell death protein 1) encodes the protein PD1, which is a coinhibitory receptor expressed on T-cells and pro-B cells that belongs to the immunoglobulin superfamily (PMID: 20636820, 12421930). PD1 acts to inhibit an immune response by binding to the ligands PD-L1 and PD-L2, which are expressed on other normal or malignant cells (PMID: 17629517). PD-L1 binding to PD1 leads to programmed cell death in antigen-specific T-cells and reduced apoptosis in regulatory T-cells, which results in an overall decrease in immune response (PMID: 11857337, 16382236, 20208540). Amplification or overexpression of PD1 has been identified in some tumor types and can be predictive of responses to immunotherapy (PMID: 22437870, 26918453, 28652380, 27620277). Antibodies targeting PD1 have been developed and assessed in clinical trials that block the immune evasive PD-L1/PD1 interaction. Atezolizumab, a monoclonal antibody targeting PD-L1, is FDA approved for the treatment of patients with locally advanced or metastatic urothelial carcinoma (PMID: 28424325) and metastatic non-small cell lung cancer (NSCLC) whose disease progressed during or following platinum-containing chemotherapy (PMID: 28611199). Pembrolizumab, an anti-PD-1 antibody, is considered first-line therapy for patients with non-small cell lung cancer and metastatic melanomas that express PD-L1 and may be efficacious in other tumors that express PD-L1 (PMID: 28806116). Nivolumab, an FDA-approved monoclonal antibody that targets PD-1, is also effective in tumors with high PD-L1 expression due to the blockade of the PD-1/PD-L1 interaction and activation of a robust immune response (PMID: 28806116). Tumors with defects in mismatch-repair and overexpression of PD-L1 should be considered for PD-1 blockade (PMID: 26028255). False +ENST00000397747 NM_025239.3 80380 PDCD1LG2 True PDCD1LG2, a ligand of T-cell receptors involved in immune suppression, is overexpressed in various cancer types. "The PDCD1LG2 gene encodes the ""programmed cell death 1 ligand 2"" (PD-L2) protein. PD-L2 is highly similar to PD-L1, a protein whose overexpression by tumor cells and antigen presenting cells (APC) leads to negative regulation of T-cell receptor (TCR) signaling and subsequent tumor immune evasion (PMID: 15599732, 22437870, 16864790). PD-L2 binding affinity for PD-1 is higher than PD-L1, although the biological consequences of this are unknown (PMID: 12893276). PD-L2 is also expressed in activated T-helper cells type 2 (Th2), inhibiting its function and regulating IFN-γ production (PMID: 21752471). Impaired tumor growth has been observed in several in vitro and in vivo cancer models upon dual PD-L1/PD-L2 inhibition, but the specific additive role for the latter remains elusive (PMID: 22611421). PDCD1LG2 overexpression or amplification has been reported in renal, cervical and breast cancers, among others, and in some cases predicts poor prognosis (PMID: 26464193, 26913631, 26424759, 26752545, 26317899, 24270737, 15837746). PDCD1LG2 is a putative target for cancer immunotherapy (PMID: 22658128, 22611421)." False +ENST00000331163 NM_002608.2 5155 PDGFB True 1 PDGFB, a growth factor that activates PDGFR signaling, is recurrently altered by rearrangement in dermatofibrosarcoma protuberans (DFSP), a sarcoma of the skin, and related diseases. PDGFB is a signaling ligand that is a member of the platelet-derived growth factor family (PMID: 7073684, 18483217). PDGFB encodes a precursor peptide that requires intracellular, proteolytic processing to initiate receptor binding (PMID: 16007151). Receptor binding activity of PDGFB is also dependent on ligand dimerization, either as a homodimer or a heterodimer with family member PDGFRA, to form PDGF-BB or PDGF-AB (PMID: 2836952, 18483217). PDGF dimers activate PDGF receptor kinases in a context-specific manner, dependent on ligand configuration and receptor expression (PMID: 28267575). PDGFR signaling mediates a variety of downstream signaling effectors including PI3K, MAPK, and PLC-γ, among others (PMID: 18483217). These signaling pathways regulate a variety of cellular processes including cell proliferation, cell cycle progression, differentiation, and invasion (PMID: 18483217). Overexpression of PDGFB is implicated in several cancer types and promotes tumor progression in preclinical studies (PMID: 18478301). Rearrangements involving PDGFB are found in patients with dermatofibrosarcoma protuberans, a sarcoma of the skin (PMID: 17431412, 12131162). These translocations result in enhanced expression of PDGFB and increased PDGFR signaling activity, suggesting that PDGFRB functions as an oncogene (PMID: 17431412, 12131162). Several small molecule inhibitors targeting PDGFR may be efficacious in patients with increased PDGFB signaling (PMID: 26261104, 26261104). False +ENST00000257290 NM_006206.4 5156 PDGFRA True 1 R1 PDGFRA, a receptor tyrosine kinase, is altered by mutation, chromosomal rearrangement or amplification in a diverse range of cancers. The PDGFRA gene encodes for the protein Platelet-derived growth factor alpha (PDGFRA). Binding of ligand to the extracellular domain of PDGFRA, which contains immunoglobulin (Ig)-like domains, causes dimerization followed by autophosphorylation of the receptor and activation of downstream pathways such as RAS-MAPK, PI3K and PLC-γ that are involved in developmental and cellular responses. The catalytic activity of PDGFRA is mediated through the split intracellular tyrosine kinase domain; PDGFRA binds to all PDGF ligand isoforms except PDGF-DD (PMID:18483217, 24703957). Mutations, insertions, deletions, fusions and genomic amplification of PDGFRA lead to its activation in several tumor types: ~7% of gastrointestinal stromal tumors (GISTs) have PDGFRA activating mutations and these mutations are mutually exclusive from KIT mutations (PMID: 20023271); activating mutations in PDGFRA have been been reported in ~5% of Chinese melanoma patients (PMID:24132921); amplification of PDGFRA is the second most frequent receptor tyrosine kinase amplification in glioblastoma (GBM), is found in ~7-15% of GBM tumors and is often associated with in-frame deletions (PMID:18772890,19915670, 22323597, 20129251, 20889717); amplification of the PDGFRA locus has been reported in more than 80% of intimal sarcomas (PMID:20685895), ~19% of malignant peripheral nerve sheath tumors (PMID:16357008), 3-7% of non-small cell lung adenocarcinomas and 8-10% non-small cell lung squamous cell carcinomas (PMID:19755855); activating mutations have been found in ~5% of diffuse intrinsic pontine gliomas and in ~14% of non-brain stem pediatric high-grade gliomas, around 40% of these occurring in the context of PDGFRA amplification (PMID:23970477); chimeric fusion transcripts to the catalytic domain of PDGFRA have been reported in select cases of GBM (PMID:20889717), chronic myeloid leukemia (PMID:12023981,12944919, 15034867) and hypereosinophilic syndrome (HES)/chronic eosinophilic leukemia (CEL) (PMID:12660384, 19187542, 16498388, 16845659, 17555450). PDGFRA mutations have also been reported in inflammatory fibroid polyps (PMID: 22394371), and these mutations have been characterized as activating in other disease types. R1 False +ENST00000261799 NM_002609.3 5159 PDGFRB True 1 PDGFRB, a receptor tyrosine kinase, is infrequently mutated in solid tumors. PDGFRB (platelet-derived growth factor receptor beta), is a transmembrane receptor-tyrosine kinase whose ligands are the homodimers PDGF-BB and PDGF-DD (PMID: 18483217, 20581310). Upon binding to PDGF ligand, the receptor undergoes homodimerization (or heterodimerization with PDGFRα), bringing the intracellular kinase domains into proximity and triggering kinase activation. Downstream signaling pathways include JAK/STAT, PI3K/AKT, MAPK/ERK, PLCγ, and NF-κB (PMID: 18483217, 20581310). PDGFRB is primarily expressed on cells of mesenchymal origin (e.g. fibroblasts, endothelium) and is involved in organ development, angiogenesis and wound repair (PMID: 7958864, 10375497, 18483217, 20581310). Although PDGFRB plays a role in early hematopoiesis, its role in adult hematopoietic cells is less clear (PMID: 7958864, 11264163). Pathologic overexpression of PDGFRB in hematopoietic cells contributes to neoplastic growth and progression (PMID: 20581310). Although PDGF/PDGFR signaling appears to play an important role in numerous types of solid tumors, mutations, amplifications or translocations/fusions of PDGFRB are relatively rare in most solid tumors (PMID: 18483217). False +ENST00000282077 NM_002610 5163 PDK1 True PDK1, a serine/threonine kinase, is altered by amplification in various cancer types. PDK1 encodes for a master serine/threonine kinase which functions in the regulation the activation of at least 23 other kinases, including the AKT serine/threonine kinase family and AGC serine/threonine kinase family (PMID: 24352480, 9368760, 20027184, 23448267). PDK1 can activate and control the expression of various downstream substrates, including CDKN1B, CCND1 and PI3K, to regulate critical cellular processes such as proliferation, cell cycle control and survival (PMID: 18430722, 23893244, 34646383). Overexpression of PDK1 in various types of cancer cell lines and models induces aberrant cellular proliferation, adhesion, invasion and tumor growth, suggesting that PDK1 functions predominantly as an oncogene (PMID: 31646108, 32071289, 27878287, 36474273). Amplification of PDK1 has been identified in various types of cancer, including breast cancer, prostate cancer and ovarian cancer (PMID: 21542898, 23401739, 33403023). Aberrant PDK1 expression has been implicated in conferring chemoresistance in various cancer cell models through hyperactivation of PI3K/AKT/mTOR downstream signaling (PMID: 24044505, 36474273, 37169941). False +ENST00000342085 NM_002613.4 5170 PDPK1 False PDPK1 encodes a serine/threonine kinase involved in the PI3K signaling pathway. Amplifications of PDPK1 are found in breast and thyroid cancers. PDPK1 (also known as PDK1) encodes for 3-phosphoinositide-dependent protein kinase 1 that mediates downstream signaling from phosphoinositide 3-kinase (PI3K). It is a serine-threonine kinase that responds to mitogenic and insulin signals to phosphorylate targets including the AGC family of kinases such as p70 S6K and AKT (PMID:10801415, 9094314, 9427642). Breast cancer and multiple myeloma cells have shown dependency on PDPK1 for survival and tumor progression (PMID:19573809, 25269480). In pancreatic cancer, PDPK1 signaling can contribute to Kras oncogenic activity (PMID:23453624). The PDPK1 gene has been found to be amplified in breast and thyroid cancers (PMID:19602588, 18492751). Inhibitors are in development for different tumor types, particularly in breast cancer (PMID:22491800, 24039447, 21568903, 24037523). False +ENST00000315596 NM_015032.3 23047 PDS5B False PDS5B, a cohesin regulatory protein, is recurrently altered by mutation and deletion in hematologic malignancies and solid tumors. PDS5B (also AS3 and APRIN) is a protein that binds cohesin, a ring-like structure that regulates sister chromatid segregation during cell division (PMID: 15855230). PDS5B mediates cohesin-dependent sister chromatid cohesion during mitosis or meiosis to ensure proper chromosome-spindle attachments (PMID: 26903600). In addition, PDS5B activity is important for the maintenance of the curved interface of the cohesin ring and for the dissolution of the cohesin complex during mitosis to allow for appropriate chromosome segregation (PMID: 15855230, 27549742). PDS5B mediates additional cellular functions including regulation of stem cell function (PMID: 20383194) and chromatin looping (PMID: 29217591). PDS5B also interacts with BRCA2 to mediate DNA repair and is located on a chromosomal region that contains BRCA2 that is commonly lost in breast cancer (PMID: 22293751). Loss of PDS5B expression results in chromosome missegregation, aneuploidy and developmental defects in mice (PMID: 17652350, 24141881). PDS5B also mediates androgen-dependent signals that are required for growth arrest in prostate cells (PMID: 18499069, 10215036, 10963680). Germline mutations in PDS5B are found in patients with cohesinopathies, such as Cornelia de Lange syndrome (PMID: 19412548). Somatic loss-of-function mutations in PDS5B are found in patients with myelodysplastic syndrome and acute myeloid leukemia as well as some solid tumors (PMID: 26492932, 23850494, 19737411), suggesting that PDS5B functions as a tumor suppressor. PDS5B expression is also correlated with improved patient survival and sensitivity to DNA damaging agents (PMID: 27924011, 22293751). True +ENST00000525115 NM_001258311.1 79605 PGBD5 True PGBD5, a DNA transposase that mediates transposon movement in the genome, is involved in the initiation of chromosomal rearrangements in childhood cancers. PGBD5 is a DNA transposase that is a member of the piggyBac transposase family (PMID: 24180413, 26406119). piggyBac transposases mediate the mobility of genetic elements flanked by inverted terminal repeats (ITR) and reintegrate these elements, termed transposons, into another location in the genome via a “cut and paste” mechanism (PMID: 24180413, 26406119). Transposons mediate genetic evolution and comprise half of the human genome, with PGDB5 functioning as the most conserved transposase in humans (PMID: 26406119). PGBD5 is predominantly expressed in the brain and in the central nervous system during development (PMID: 24180413). Increased expression of PGBD5 in cell lines and murine models results in transformation, suggesting that PGBD5 functions as an oncogene (PMID: 28504702). Overexpression of PGBD5 is found in childhood cancers including rhabdoid tumors, neuroblastoma, medulloblastoma and Ewing sarcoma (PMID: 28504702, 30333322). PGBD5 promotes the formation of chromosomal rearrangements by binding site-specific sequences and disrupting the expression of tumor suppressor genes (PMID: 30333322). Oncogenic PGBD5 activity requires DNA end-joining repair and is sensitive to ATM and ATR inhibition (PMID: 29093183). False +ENST00000325455 NM_000926.4 5241 PGR True PGR encodes the progesterone receptor which mediates the effects of progesterone, playing a central role in reproductive events. PGR expression is common in breast and endometrial tumors and is predictive for response to endocrine therapy. PGR encodes the progesterone receptor (PR) which is a nuclear hormone receptor. It bind to progesterone in the cytoplasm and dimerizes. The complex then enters the nucleus and binds to DNA. PR then modulates transcription depending on its isoform and on the pattern of phosphorylation at a large number of possible sites (PMID: 11110801). PR is essential in the coordination of the reproductive cycle and is especially associated with the establishment and maintenance of pregnancy. PR has been shown to interact with STAT3 (PMID: 21184768) and the SP1 transcription factor (PMID: 21184768).The PR protein is commonly expressed in breast and endometrial tumors (cBioPortal, MSKCC, Mar. 2016; PMID: 11041059, 8319181) and provides a key prognostic indicator alongside the presence and absence of estrogen receptor (ER) (PMID: 1634918). PGR can be involved in other tumor types (PMID: 26892043, 26976979) and is mutated in a range of solid tumors especially at the R740 codon in the ligand binding domain (cBioPortal, MSKCC, Mar. 2016). Germline mutations in PGR are associated with endometrial cancer (PMID: 26881523). PR is targeted to some extent by endocrine therapy, PGR expression has been associated with response to tamoxifen in ER- patients (PMID: 16497822). False +ENST00000373896 NM_015651 26147 PHF19 True PHF19, a Polycomb-group cofactor of PRC2, is infrequently altered in cancer. PHF19 encodes for a cofactor that recruits the PRC2 complex and binds histone H3K36me3 to regulate embryonic stem cell differentiation and self-renewal (PMID: 31959557, 23160351, 23104054). PHF19 binding to H3K36me3 is a mark of transcriptional activation and leads to the association of H3K36me3 demethylases and recruitment of the PRC2 complex (PMID: 23160351, 23228662). Recruiting the PRC2 complex causes PRC2-mediated H3K27 trimethylation and the demethylation of H3K36 and subsequent transcriptional silencing (PMID: 23160351). Overexpression of PHF19 in multiple myeloma and prostate cancer cell lines induces cellular proliferation, growth and metastasis, suggesting that PHF19 functions primarily as an oncogene (PMID: 32155117, 31383640). PHF19 amplification has been identified in various cancers, including multiple myeloma, plasma cell leukemia and glioblastoma, and these cancers may also be sensitive to PRC2 inhibition (PMID: 31383640, 30323224). False +ENST00000332070 NM_001015877.1 84295 PHF6 False PHF6, a chromatin binding protein, is frequently altered by mutation and deletion in a range of hematologic malignancies. PHF6 is a DNA binding protein that functions as an epigenetic remodeler (PMID: 28607179). PHF6 binds chromatin via two imperfect zinc finger domains and mediates transcription by functioning as an epigenetic reader protein (PMID: 20228800). Expression of PHF6 is highest in the thymus, ovary, and thyroid (PMID: 20228800) and PHF6 is associated with lineage-specific roles in hematopoietic differentiation (PMID: 25737277, 28607179). In biochemical experiments, PHF6 associated with the NuRD complex, an epigenetic complex involved in histone deacetylation (PMID: 22720776). Loss of PHF6 resulted in increased gamma-H2AX, a histone mark implicated in DNA repair (PMID: 20228800). PHF6 also regulates the cell cycle by mediating ribosomal RNA synthesis (PMID: 23229552). Germline PHF6 mutations have been identified in Börieson-Forssman-Lehmann syndrome (BFLS), a developmental disorder associated with severe mental retardation and epilepsy (PMID: 12415272). Somatic mutations in PHF6 are found in patients with hematopoietic malignancies, including acute myeloid leukemia and T-cell acute lymphoblastic leukemia, among others (PMID: 20228800, 21736506). PHF6 mutations are predominantly missense and truncating, resulting in loss of protein, suggesting that PHF6 is a tumor suppressor (PMID: 20228800, 21030981, 21736506, 22928734). Loss-of-function mutations in PHF6 have been associated with poorer outcome in patients with acute myeloid leukemia (PMID: 22417203). True +ENST00000262719 NM_194449 23239 PHLPP1 False PHLPP1, a protein phosphatase, is recurrently altered by deletion in cancer. PHLPP1, a member of the metal-dependent protein phosphatase family, encodes for a phosphatase which functions in regulating Akt and PKC signaling (PMID: 15808505, 18162466). PHLPP1 dephosphorylates the hydrophobic motifs of Akt and PKC isoforms to mediate increased apoptosis and inhibition of cellular proliferation (PMID: 15808505, 18162466, 17386267). Knockdown of PHLPP1 in various cancer cell lines and models induces tumorigenesis, increased metastasis and increased Akt signaling, suggesting that PHLPP1 functions predominantly as a tumor suppressor gene (PMID: 21840483, 29391600, 22044669). Downregulation of PHLPP1 has been identified in various types of cancer, including melanoma, colon cancer and prostate cancer (PMID: 29391600, 19079341, 21840483). True +ENST00000568954 NM_015020 23035 PHLPP2 False PHLPP2, a protein phosphatase, is recurrently altered by deletion in cancer. PHLPP2, a member of the metal-dependent protein phosphatase family, encodes for a phosphatase that functions in regulating AKT and PKC signaling (PMID: 15808505, 18162466). PHLPP2 dephosphorylates the hydrophobic motifs of AKT and PKC isoforms to mediate increased apoptosis and inhibition of cellular proliferation (PMID: 15808505, 18162466, 17386267). Knockdown of PHLPP2 in various cancer cell lines and models induces cellular proliferation and transformation and increases eIF2α phosphorylation, suggesting that PHLPP2 functions predominantly as a tumor suppressor gene (PMID: 32319585, 34663797, 25977341, 19079341). Loss of PHLPP2 has been identified in various types of cancer, including esophageal squamous cell carcinoma, hypopharyngeal squamous cell carcinoma and colon cancer (PMID: 26245343, 25793736, 19079341). True +ENST00000226382 NM_003924.3 8929 PHOX2B False PHOX2B encodes a transcription factor involved in neural development. Germline mutations of PHOX2B are associated with congenital central hypoventilation syndrome and Hirschprung's disease and predispose to neuroblastomas. PHOX2B (Paired-like homeobox 2b) is a homeobox transcription factor that physiologically regulates the specification of sympathic neuron neurotransmitter identity (PMID: 7910552, 10230790). It does so by regulating the transcriptional expression of important genes for the production of neurotransmitters such as tyrosin hydroxylase (TH) and others (PMID: 10230790). PHOX2B mutations can lead to congenital central hypo-ventilation syndrome (CCHS) and Hirschprung's disease (PMID: 12640453, 12631670). Patients with PHOX2B mutant CCHS have a higher incidence of neuroblastoma and a subset of hereditary as well as sporadic neuroblastoma show PHOX2B mutations (PMID: 15516980, 10360575, 15024693). In neuroblastoma PHOX2B mutations lead to impaired neuroblast differentiation, but the exact mechanisms are not yet clear (PMID: 25124476, 12612655). True +ENST00000333590 NM_002641.3 5277 PIGA False PIGA, an enzyme involved in the synthesis of GPI membrane attachments, is recurrently altered in hematologic malignancies. PIGA (also PIG-A) is an enzyme involved in the first step of the GPI anchor biosynthesis pathway (PMID: 8500164). Glycosylphosphatidylinositol (GPI) anchors are post-translational modifications that attach the C-terminal of extracellular proteins to the cellular membrane (PMID: 8500164, 22265715). Cell surface proteins require GPI anchors for attachment at the membrane as well as for protein sorting, signal transduction, and immune regulation (PMID: 25885527). GPI anchors are added to proteins in the endoplasmic reticulum (ER) prior to protein sorting (PMID: 8500164, 9463366). PIGA is the catalytic enzyme in the GPI-N-acetylglucosamine transferase (GlcNAc) complex that is responsible for the first step in GPI synthesis (PMID: 8500164, 9463366). PIG-A initiates the formation of the intermediate N-acetylglucosaminyl phosphatidylinositol by transferring GlcNAc to phosphatidylinsositol (PI) (PMID: 8500164). GPI anchoring is required during embryogenesis and loss of PIGA in mice results in embryonic lethality (PMID: 7851884). Somatic loss-of-function mutations in PIGA are found in patients with paroxysmal nocturnal hemoglobinuria (PNH), a clonal hematopoietic malignancy that leads to anemia and a predisposition for leukemia (PMID: 10220445, 10627475, 10048414). Patients with PNH present with red blood cells that cannot express proteins at the membrane that require GPI anchoring, including the complement proteins CD55 and CD59 (PMID: 10220445, 8946596). Because PIGA loss results in depletion of important cell surface proteins from the membrane, a PIG-A assay has been developed to test for mutations in response to genotoxic stress (PMID: 24798381, 27637482, 20034593). True +ENST00000367187 NM_002646 5287 PIK3C2B True PIK3C2B, a lipid phosphoinositide, is infrequently altered in cancer. PIK3C2B, a member of the phosphoinositide 3-kinase (PI3K) family, encodes for a lipid phosphoinositide which functions in regulating various cellular processes including cytoskeleton organization, cell morphology and cell survival (PMID: 16775008, 22984590). The C2 domain of PIK3C2B is a lipid-binding domain which allows for phosphorylation of lipids and lipid signaling to regulate cellular processes (PMID: 20713135). Overexpression of PIK3C2B in various cancer cell lines and models induces fibrosis and cellular invasion and migration, suggesting that PIK3C2B functions predominantly as an oncogene (PMID: 31513749, 32903879). Amplification and mutations of PIK3C2B have been identified in various cancers, including glioblastoma and non-small cell lung cancer (PMID: 14655756, 22510280). False +ENST00000433979 NM_004570.4 5288 PIK3C2G False PIK3C2G encodes a kinase involved in cell proliferation, oncogenic transformation and protein trafficking signaling pathways. Inactivating mutations of PIK3C2G are found in melanomas and lung and gastrointestinal cancers. PIK3C2G is a class II catalytic subunit of PI3-Kinase (PMID: 25785104). PIK3C2G acts as a lipid kinase to create phosphatidylinositol-3,4-bisphosphate (PtdIns(3,4)P2), which acts as a secondary messenger in key signaling pathways involved in cell cycle, motility, differentiation and transformation (PMID: 10209156). Class II PI3Ks are the least studied, however, they are defined by the presence of a carboxyl-terminal calcium-dependent phospholipid-binding motif (PMID: 22507127). PIK3C2G is mutated in a number of cancers, and a large proportion of these mutations are predicted to be inactivating mutations. False +ENST00000262039 NM_002647.2 5289 PIK3C3 False PIK3C3 encodes a kinase involved in maturation of autophagosomes and lysosomes. Inactivating mutations or deletions of PIK3C3 are found in melanoma, uterine, lung, gastrointestinal, urothelial and pancreatic cancers. PIK3C3, also known as VPS34, is a class III catalytic subunit of PI3K and is important in creating phosphatidylinositol 3-phosphate (PtdIns3P). PIK3C3 plays an important role in the maturation of autophagosomes and the transport of lysosomal enzyme precursors to lysosomes (PMID: 20562532, 22498475). PIK3C3 is also involved in mTOR signaling, which regulates autophagy in response to nutrient sensing in the cell (PMID: 24013218). Inactivating mutations of PIK3C3 are seen in multiple cancer types. False +ENST00000263967 NM_006218.2 5290 PIK3CA True 1 PIK3CA, the catalytic subunit of PI3-kinase, is frequently mutated in a diverse range of cancers including breast, endometrial and cervical cancers. Phosphatidylinositol-3-kinase (PI3K) is comprised of a regulatory subunit (p85α) as well as a catalytic subunit (p110α) and it is the catalytic subunit that is encoded by the PIK3CA gene. PIK3CA is among the most commonly mutated genes in cancer and aberrant activation of PI3K is a transforming event (PMID: 17376864). Multiple receptor tyrosine kinases, including EGFR, ERBB2 (HER2), RET, MET, and VEGFR, among others, convert extracellular cues into intracellular signals and recruit PI3K to the plasma membrane via scaffold proteins such as IRS1 or by activating RAS. Upon stimulation, PI3K-110α converts its lipid substrate PIP2 (phosphatidylinositol - 4,5 - bisphosphate) to PIP3 (phosphatidylinositol - 3,4,5 - bisphosphate), which activates several signaling cascades, including the well-characterized AKT-mTOR pathway. Once activated, AKT-mTOR downstream signaling promotes cell survival, proliferation, growth and motility (PMID: 16341083). Adding to this complexity, exposure to some PI3K/mTOR pathway-targeted drugs relieves cancer cells of self-regulatory properties inherent in the PI3K-AKT-mTOR pathway thereby promoting tumor resistance to these agents (PMID: 22576208). False +ENST00000289153 NM_006219.2 5291 PIK3CB True PIK3CB, a catalytic subunit of PI3-kinase, is altered by amplification or mutation in various cancer types. PIK3CB, also known as p110-β, is a catalytic subunit of PI3K that is important in creating phosphoinositol 3,4,5-trisphosphate (PIP3), which acts as a secondary messenger in key cellular signaling pathways such as AKT-mTOR. PIK3CB plays a critical role in tumorigenesis driven by loss of PTEN (PMID: 18755892, 18594509) and drives PI3K signaling. Roles other than oncogenic activation of PI3K/AKT pathway have also been described for PIK3CB, including effects on growth and cell metabolism, including insulin signaling (PMID: 18594509, 18780892, 26132308). In HER2-amplified and PIK3CA-mutant cancers, inhibition of PIK3CA can lead to reactivation of PI3K signaling through PIK3CB (PMID: 25544637). Hence, combined inhibition of both isoforms is a promising therapeutic strategy that blocks pathway activation and leads to successful tumor regression (PMID: 25544636, 25544637, 25409150). False +ENST00000377346 NM_005026.3 5293 PIK3CD True PIK3CD encodes a kinase involved in immune cell regulation. Inactivating mutations of PIK3CD are found in uterine, endometrial and colorectal cancers, among others. PIK3CD, also known as p110-ẟ, is a catalytic subunit of PI3K that is important in creating phosphoinositol 3,4,5-trisphosphate (PIP3), which acts as a secondary messenger in key cellular signaling pathways such as AKT-mTOR. PIK3CD primarily functions in immune cells through AKT signaling. It is required for T-cell receptor activation (PMID: 12130661), and it is also necessary for a full antibody response in B-cells (PMID: 12235209). Germline mutations in PIK3CD likely causes both immunodeficiency and lymphoproliferative disease as a result of hyperactivation of AKT-mTOR signaling, which forces the differentiation of naive CD8+ T-cells into short-lived effector cells and reduces long-term memory T- and B-cells (PMID: 24165795). Idelalisib, a specific inhibitor of PIK3CD, has been used with Rituximab (a CD20 antibody) in the treatment of chronic lymphocytic leukemia (CLL) and has been associated with significant increase in progression-free survival (PMID: 24450857). False +ENST00000359195 NM_002649.2 5294 PIK3CG True PIK3CG encodes a kinase involved in modulation of the extracellular signal. Inactivating mutations of PIK3CG are found in uterine, endometrial, skin and lung cancers, among others. PIK3CG (phosphatidelinositol-4,5-bisphophsphate3-kinase catalytic subunit gamma), also known as p110-gamma, is a class I catalytic subunit of PI3-kinase and acts as a lipid and protein kinase that phosphorylates phosphoinositides (PMID: 17290298). PIK3CG is involved in extracellular signaling and linking cell-surface receptors to intracellular signaling networks, such as the PI3-kinase/AKT pathway (PMID:12040186). Once activated, AKT-mTOR downstream signaling promotes cell survival, proliferation, growth and motility (PMID: 16341083). PIK3CG is primarily expressed in white blood cells, and through its direct interactions with RAS and G-protein coupled receptors (GPCRs) (PMID:12507995) is important in immune cell responses and inflammatory stimuli (PMID:10669418). While deletions of PIK3CG are often found in myeloid malignancies in conjunction with broad 7q22 deletion, PIK3CG is not likely a tumor suppressor in these settings (PMID: 11756194). False +ENST00000521381 NM_181523.2 5295 PIK3R1 False PIK3R1, the regulatory subunit of PI3-kinase, is mutated in various cancers, most frequently in glioma, endometrial and colorectal cancers. PIK3R1 encodes p85α, the regulatory subunit of phosphatidylinositol-3-kinase (PI3K)(PMID: 12040186). In the absence of upstream receptor tyrosine kinase (RTK) activation, p85α both stabilizes and inhibits the activity of p110α, the catalytic subunit of PI3K. Upon RTK activation, p85α binds to phosphorylated tyrosine residues on the cytoplasmic tails of RTKs. Subsequently, this recruits the PI3K enzymatic complex to the cell membrane and allows the p110α catalytic subunit to generate phosphatidylinositol-3,4,5-trisphosphate (PIP3) (PMID: 12040186, 1707345, 2833705). The production of PIP3 results in recruitment and activation of the serine/threonine kinase, AKT, which in turn activates numerous downstream targets (e.g. mTOR) involved in cell growth, proliferation and survival (PMID: 12094235). PIK3R1 mutations occur most frequently in its two SRC Homology 2 (SH2) domains, nSH2 and iSH2 (PMID: 21478295, 19962665). These mutations disrupt the ability of p85α to inhibit the PI3K catalytic subunit, thus resulting in aberrant activation of AKT-mTOR signaling (PMID: 9450999, 11606375, 15932879, 17626883, 18079394, 19962665). Across all tumor types, PIK3R1 mutations tend to be mutually exclusive with alterations in TP53, PIK3CA, SETD2 and WT1 (PMID: 24132290). PIK3R1 mutations are prevalent in glioblastoma and to a lesser extent in endometrial, breast and colorectal cancers (PMID: 23636398, 24120142, 17932254, 22810696). True +ENST00000222254 NM_005027.3 5296 PIK3R2 False PIK3R2 encodes a regulatory subunit of PI3-kinase, a component of the pro-oncogenic PI3-kinase/AKT/mTOR signaling pathway. PIK3R2 is mutated at low frequencies in a diverse range of cancer. PIK3R2, also known as p55-β, is a regulatory subunit of PI3K and functions to regulate activated receptor tyrosine kinases (RTKs) via direct interaction (PMID: 12094235). It is thus important in regulating various downstream activities in the cell, such as growth, proliferation and motility. Upon RTK activation, PIK3R2 helps recruit the PI3K enzymatic complex to the cell membrane and allows the PI3K catalytic subunit to generate phosphatidylinositol-3,4,5-trisphosphate (PIP3), which is important in activating downstream signaling pathways such as AKT-mTOR (PMID:12040186). PIK3R2 mutations are often found in endometrial cancers with wildtype PTEN, and allow for increased PI3K and downstream AKT signaling (PMID: 21984976). True +ENST00000262741 NM_003629.3 8503 PIK3R3 False PIK3R3 encodes a kinase involved in insulin-like growth factor 1 receptor signaling. Inactivating mutations of PIK3R3 are found in stomach and uterine cancers. The PIK3R3 (phosphatidylinositol 3-kinase regulatory subunit gamma) protein, also known as p55-gamma, is a regulatory subunit of PI3K and functions to regulate activated receptor tyrosine kinases (RTKs) via direct interaction (PMID: 12094235). It is thus important in regulating various downstream activities in the cell, such as growth, proliferation and motility. Upon RTK activation, PIK3R3 helps recruit the PI3K enzymatic complex to the cell membrane and allows the PI3K catalytic subunit to generate phosphatidylinositol-3,4,5-trisphosphate (PIP3), which is important in activating downstream signaling pathways such as AKT-mTOR (PMID:12040186). PIK3R3 has been shown to directly modulate IGF2 signaling in glioblastoma and is amplified in some cases (PMID: 17360667, 16530701). True +ENST00000373509 NM_002648.3 5292 PIM1 False PIM1 encodes a serine/threonine kinase involved in cell survival and proliferation. Mutations of PIM1 are found in lymphomas. The PIM1 gene encodes a serine/threonine protein kinase that is constitutively active and signals survival and growth pathways (PMID:10435626,19276681, 23712827). PIM1 cooperates with the MYC oncogene and can lead to genomic instability (PMID:21860423, 14678956). It targets many important proteins involved in cell proliferation and survival including MYC, nitric oxide synthase and Bad (PMID:18438430, 15280015, 26598507). Its expression is upregulated in multiple tumor types including leukemias, glioblastoma, pancreatic and prostate cancers (PIMD:15498859, 25155357,18708761). PIM1 expression is associated with prostate and gastric cancer prognosis (PMID:11518967, 21993851). PIM1 mutations are found in lymphomas (PMID:11460166, 24970810, 26773040). Inhibitors of PIM1 kinase are being developed for anti-tumor therapy (PMID:25505253, 17218638, 26643319). False +ENST00000373271 NM_182811.1 5335 PLCG1 True PLCG1, a phospholipase-C signaling molecule, is recurrently mutated in hematologic malignancies. PLCG1 is a membrane-associated enzyme that is a member of the phospholipase-C (PLC) family (PMID: 19665973). PLC proteins cleave phospholipid phosphatidylinositol 4,5-bisphosphate (PIP2) into the products diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3) (PMID: 25456276, 29174396, 23140367). DAG and IP3 are secondary messengers that mediate cellular signaling pathways (PMID: 29174396, 23140367). IP3 binds calcium-mediated receptors resulting in an increase in cytosolic calcium concentrations and activation of protein kinase C (PKC) (PMID: 9096335, 10373546, 19179337). PLCG1 activity is regulated by receptor tyrosine kinases, such as PDGFR, VEGFR, and EGFR, in response to hormones and growth factors (PMID: 9096335). PLCG1-regulated signal transduction pathways, such as the MAPK and JNK pathways, regulate a variety of cellular processes including migration, proliferation, oxidative stress, angiogenesis and transformation (PMID: 11931670, 15944397). Somatic mutations in PLCG1 have been identified in T-cell lymphomas (PMID: 24497536, 25304611, 26415585, 26437031), Sezary syndrome (a leukemic variant of cutaneous T-cell lymphomas) (PMID: 27121473, 26415585) and angiosarcomas (PMID: 24633157, 25252913). PLCG1 mutations typically occur in the catalytic domain of PLCG1 and are predicted to be gain-of-function alterations resulting in activation of downstream oncogenic signaling pathways (PMID: 24497536). False +ENST00000564138 NM_002661.3 5336 PLCG2 True PLCG2 encodes an enzyme involved in transmembrane signaling. Mutations of PLCG2 are associated with autoimmunity and immune dysregulation and resistance to Ibrutinib therapy in patients with CLL. PLCG2 encodes for the gene phospholipase C gamma 2, a calcium dependent enzyme that cleaves phospholipids (phosphatidylinositol 4,5-bisphosphate (PIP2)) into diacylglycerol (DAG) and inositol 1,4,5-triphosphate (IP3) (PMID:20870410). The enzyme is autoinhibited by a C-terminal SH2 domain and activated by phosphorylation (PMID:20807769). It is expressed mainly in B-cells and Natural Killer cells where it acts to transduce signals from the immunglobulin family of receptors (PMID:10933392, 16002670). It is also involved in regulating osteoclast development (PMID:17053833). Mutations and deletions have been associated with autoimmunity and immune dysregulation (PMID:22236196, 23000145). Mutations in PLCG2 are found as resistance mechanisms to Ibruitinib therapy in CLL patients (PMID:24869598). These activating mutations result in Btk independent signaling from the B-cell receptor (PMID:25972157). Polymorphisms in PLCG2 have also been associated with cancer development risk (PMID:24080446, 23874846). False +ENST00000274289 NM_006622.3 10769 PLK2 False PLK2 encodes a tumor suppressor involved in cell cycle progression. PLK2 mediates chemotherapy sensitivity and resistance, apoptosis, and proliferation in cancer cells. PLK2 encodes polo-like kinase 2 a serine/threonine kinase that controls cell cycle progression (PMID:16627997). PLK2 is involved in regulating many pathways including angiogenesis, skeletal development, neuronal differentiation, synapse formation, centrosome duplication, and mitochondrial respiration response (PMID:26004360, 12972611, 25590559, 19706541,18498738, 19700763). PLK2 also phosphorylates alpha-synuclein that may have a role in Parkinsons disease (PMID:19004816, 23983262). In cancer cells PLK2 mediates chemotherapy sensitivity and resistance, apoptosis, and proliferation (PMID:21402713,19764992,25501818,16160013, 12897130, 26640387, 23703673). Inhibitors of polo-like kinases are in development (mainly against PLK1) although their effects on each family member may bring varying responses (PMID:25263688). False +ENST00000316660 NM_021127.2 5366 PMAIP1 False PMAIP1 is involved in promoting cell death (apoptosis). Mutations and deletions of PMAIP1 are found in lymphomas and leukemias. PMAIP1, also known as NOXA, encodes for phorbol-12-myristate-13-acetate-induced protein 1, a gene involved in regulating apoptosis (PMID:15694340). PMAIP1 contains a Bcl2 homology 3 (BH3) domain that mediates interactions with Bcl-2 family member proteins to alter the balance towards pro-apoptosis (PMID:15901672). Specifically, inhibition of Mcl-1 by PMAIP1 can lead to mitochondrial cytochrome c release and cell death (PMID:17115033). PMAIP1 is induced by TP53 as a consequence of DNA damage and other death signals such as c-Myc induction (PMID:10807576, 18042711, 23948298, 23153536, 19647221). PMAIP1 function is important for the sensitivity of tumors to anti-cancer therapy (PMID: 24525728, 24030633, 23302226, 22693249, 17038534). Its expression may also determine the efficacy of BH3 mimetics in development for cancer therapy (PMID:22128299,21628457). Mutations have been identified in lymphomas but are rare in solid tumors (PMID: 16960149, 12969015, 18231856). PMAIP1 expression is frequently down-regulated in pancreatic cancer, and in Panc-1 pancreatic cancer cell line, PMAIP1 expression is negatively correlated with proliferation rate and tumorigenic potential (PMID:18231856). True +ENST00000268058 NM_033238 5371 PML False PML, a transcription factor, is recurrently altered by chromosomal rearrangement in acute promyelocytic leukemia. PML, a member of the tripartite motif (TRIM) family, encodes for a phosphoprotein transcription factor which functions primarily in regulating cell cycle processes (PMID: 10574707, 25412268). PML is interspersed between chromatin and is the core component of the subnuclear multiprotein PML nuclear bodies complex (PML-NBs) (PMID: 9448006, 1999457). Within PML-NBs, PML activates caspases and Fas to induce Fas-dependent and caspase-dependent DNA-damage-induced apoptosis (PMID: 9806545). Knockout of PML in acute promyelocytic leukemia models induces tumor formation and impairs apoptosis, suggesting that PML functions predominantly as a tumor suppressor gene (PMID: 9806545, 11181703). Translocations between RARA and PML are implicated in the pathogenesis of acute promyelocytic leukemia (PMID: 23841729). The PML-RARA fusion protein confers sensitivity to targeted treatment with all-trans retinoic acid and arsenic trioxide (PMID: 20378816). True +ENST00000441310 NM_000534.4 5378 PMS1 False PMS1 is involved in DNA mismatch repair. PMS1 is one of four MutL homologs that functions in the DNA mismatch repair (MMR) system, which is important in detecting and repairing nucleotide base mismatches. Within the MMR system, PMS1 forms a heterodimer with MLH1 (known as the MutLβ complex); in humans the specific function of this complex is unknown (PMID: 24614649, 16136382). The MMR system primarily acts as a sensory system that scans newly synthesized DNA for base pair mismatches caused by DNA polymerase strand slippage. Upon recognition of DNA mismatches, the MMR system recruits repair enzymes that excise mismatched bases and initiates resynthesis along the parental template by DNA polymerase. Loss of function of the MMR system leads to an accumulation of distinct single nucleotide mutations and alterations known as microsatellite instability (MSI), which can cause frameshift mutations or protein truncations, potentially increasing the risk of tumorigenesis (PMID: 24614649). Germline mutations in PMS1 have been shown to be involved in Lynch syndrome, which can cause a predisposition to certain types of cancer, including colorectal cancer and endometrial cancer (PMID: 15528792). Patients who are MMR-deficient have also been shown to respond well to PD-1 blockade immunotherapies, hence the FDA-approval of pembrolizumab for patients with MSI-high or MMR-deficient tumors regardless of tumor etiology (PMID: 26028255). True +ENST00000265849 NM_000535.5 5395 PMS2 False PMS2 encodes a tumor suppressor involved in DNA mismatch repair. Germline mutations of PMS2 are associated with Lynch Syndrome and predispose to colorectal cancer. PMS2 is an endonuclease that plays an essential role in the mismatch repair (MMR) pathway. Specifically, PMS2 nicks DNA to initiate excision of a mismatched strand (PMID: 20624957). Mutations in PMS2 lead to an inability to correctly repair mismatches and insertion/deletion loops in the DNA, which results in increased tumor hypermutation and a microsatellite instability-high (MSI-H) phenotype (PMID: 14871975). Germline mutations of PMS2 can cause Lynch syndrome, also known as hereditary non-polyposis colon cancer (HNPCC), which predisposes individuals to colorectal, endometrial, ovarian, urothelial, and other cancers (PMID: 428275, 1648437, 30627969, 31171120). Biallelic mutations in MSH6 also result in constitutional mismatch repair deficiency (CMMRD) (PMID: 24737826). Sporadic PMS2 mutations have also been reported in cancers from numerous tissue types (PMID: 16472587). Tumor hypermutation has been associated with response to certain immunotherapies. Specifically, pembrolizumab has been FDA-approved for all MMR-deficient and MSI tumors, irrespective of specific tumor etiology (PMID: 25409260, 26028255). True +ENST00000336032 NM_006813.2 10957 PNRC1 False PNRC1 is a nuclear receptor activator that modulates transcription of a variety of nuclear receptors. It is widely expressed in normal tissue, whereas downregulation and, in some cases, upregulation have been observed in solid cancers, including breast, gastric, hepatocellular and colorectal carcinomas. PNRC1 is a nuclear receptor coactivator that modulates the transcriptional activation of a variety of nuclear receptors. Among these, the nuclear receptors (e.g. estrogen receptor α and β, progesterone receptor, androgen receptor, glucocorticoid receptor, thyroid hormone receptor, retinoic acid receptor and retinoid X receptor) bind PNRC1 in a ligand-dependent manner, whereas the orphan receptors (e.g. steroidogenic factor 1 and estrogen-related receptor α 1) interact with PNRC1 in a ligand-independent manner (PMID: 23925889, 17068076, 15604093). PNRC1 also stimulates transcription by RNA polymerase III through direct binding of its subunit RPC39 (PMID: 7578250, 10894149, 17612402). In addition to its function as a modulator of transcription, PNRC1 plays an important role in the Ras-MAPK pathway, where it downregulates the signaling cascade through its interaction with Grb2 (PMID: 15122321). Downregulation of PNRC1 has been observed in various tumor types including breast, gastric, hepatocellular and colorectal carcinomas; however, somatic mutations in PNRC1 are infrequent in human cancers (PMID: 15122321, 11768609). False +ENST00000440232 NM_002691.3 5424 POLD1 False 2 POLD1 encodes an enzyme involved in DNA replication and repair. Germline mutations of POLD1 predispose to colorectal and endometrial cancers. POLD1 is the catalytic subunit of the DNA polymerase δ complex p125. The p125 subunit contains both polymerase and 3ꞌ to 5ꞌ exonuclease activity (PMID: 7490075, 9030545). POLD1 is involved in DNA synthesis of the lagging strand during DNA replication, proofreading activity during polymerization and DNA repair (PMID: 18439893, 10781066, 11027336). In functional studies, reduced expression of POLD1 was shown to cause genomic instability resulting from the accrual of errors during DNA replication. Furthermore, reduced expression of POLD1 was associated with fragile site instability and a high frequency of chromosomal aberrations (PMID: 11003646, 18591249). Recent studies have demonstrated that levels of POLD1 protein decrease with age, resulting in reduced DNA repair capacity (PMID: 22915169, 21556771). Alterations within the exonuclease domains of POLD1 and POLE, another proofreading protein that contributes to DNA replication fidelity, result in the accumulation of single nucleotide variants and an ultra-mutated phenotype, similar to the ultra-mutated phenotype seen in dMMR/MSI-H tumors (PMID: 35398880). Germline heterozygous loss-of-function mutations in the exonuclease domain of POLD1 cause polyposis and predispose individuals to colorectal, endometrial, and possibly brain cancers (PMID: 23263490, 23528559, 24501277, 26133394, 26493165). Note that somatic variants of POLD1 are extremely rare (PMID: 35398880, 37848928, 31479159). POLD1 mutations have been identified as drivers of hypermutation, and therefore, cancers with POLD1 variants may be increasingly sensitive to immunotherapy (PMID: 29056344). Several studies have demonstrated clinical benefit to immune checkpoint inhibitors in patients with tumors harboring POLE or POLD1 proofreading deficiency mutations (PMID: 38777726, 35780178, 35817971, 35398880). True +ENST00000320574 NM_006231.2 5426 POLE False 2 POLE, the catalytic subunit of DNA polymerase epsilon, is an enzyme involved in DNA replication and repair. Select POLE mutations lead to ultra-high mutation rates, most frequently in endometrial and colorectal cancer. "POLE is the catalytic subunit of DNA polymerase ε, the replicative DNA polymerase that extends the leading strand during DNA replication (PMID: 24861832). POLE contains an exonuclease ""proofreading"" domain, which replaces incorrectly incorporated nucleotides spontaneously during faithful replication (PMID: 24861832). Alterations within the exonuclease domains of POLE and POLD1, another proofreading protein that contributes to DNA replication fidelity, result in the accumulation of single nucleotide variants and an ultra-mutated phenotype, similar to the ultra-mutated phenotype seen in dMMR/MSI-H tumors (PMID: 35398880). Germline heterozygous loss-of-function mutations in the exonuclease domain of POLE cause polyposis and predispose individuals to colorectal cancer (PMID: 23263490, 23528559, 24501277, 26133394, 26493165). Several recurrent mutation hotspots in the exonuclease domain of POLE have been identified as impacting its proofreading capability and leading to ultra-high mutation rates, primarily in cancers of the colon, rectum and endometrium. Somatic mutations in the proofreading domain of POLE have been reported in endometrial cancers (PMID: 23636398, 25505230) and colorectal cancers (PMID: 25228659). In some contexts, POLE mutations have been associated with hypermutation, increased mutation load and better response to checkpoint inhibition in human cancers (PMID: 29056344, 29489427, 27159395, 28188185, 27486176, 31415061). Patients with mutated, proofreading-deficient POLE in endometrial cancer have been shown to have better outcomes (PMID: 25505230, 23636398). Several studies have demonstrated clinical benefit to immune checkpoint inhibitors in patients with tumors harboring POLE or POLD1 proofreading deficiency mutations (PMID: 38777726, 35780178, 35817971, 35398880)." True +ENST00000268124 NM_001126131 5428 POLG False POLG, a mitochondrial DNA polymerase, is infrequently altered in cancers. Mutations in POLG are associated with inherited mitochondrial disorders, including Alpers-Huttenlocher syndrome. POLG (DNA polymerase gamma) is a mitochondrial DNA polymerase involved in the replication and maintenance of the mitochondrial genome (PMID: 10827171). POLG contains a catalytic subunit with both polymerase and 3'-5' proofreading exonuclease domains, as well as an accessory subunit involved in maintaining processivity (PMID: 19837034, 10827171). Mutations in the polymerase domain of POLG lead to reduction in the mitochondrial DNA (mtDNA) content, decreased oxidative phosphorylation and increased cell migration in breast cancer cell lines (PMID: 19629138). Furthermore, mice with POLG mutations affecting the exonuclease domain exhibit accumulation of mtDNA mutations, earlier onset of aging phenotypes and increased apoptotic markers compared to wildtype (PMID: 16020738). Autosomal dominant or recessive mutations in POLG, mostly in the polymerase domain, are associated with mitochondrial diseases such as Alpers-Huttenlocher syndrome and progressive external ophthalmoplegia (PMID: 23545419, 11431686). POLG is mutated by missense mutations in patients with breast cancer (PMID: 19629138). False +ENST00000357628 NM_015450.2 25913 POT1 False POT1, a tumor suppressor that functions as a telomere binding protein, is altered by mutation in hematologic malignancies. POT1 is a telomere binding protein that is a component of shelterin (PMID: 29149597, 30208292). Shelterin is a protein complex that protects the ends of chromosomes, or telomeres, from inappropriate DNA repair mechanisms (PMID: 27218840). Telomeres are repetitive sequences at the end of chromosomes that prevent fusion with other chromosomes, maintain chromosome integrity, and are implicated in aging and cancer (PMID: 15181449). POT1 is an oligonucleotide binding protein that interacts with single-stranded DNA on telomeres and controls telomerase-mediated telomere elongation (PMID: 12768206). In addition, POT1 binds other telomere regulatory proteins including TRF1 (Telomere Repeat Factor 1), which inhibits unnecessary telomere extension (PMID: 15231715). POT1 also interacts with other telomere interacting proteins including PIP1 (POT-interacting protein), TIN2 (TRF1-interacting factor) and TPP1, among others, to maintain telomere stability and to recruit telomerase (PMID: 15231715, 15181449). Disruption of these protein interactions with POT1 results in aberrant mutagenic alternative non-homologous end joining (A-NHEJ) leading to genomic instability and chromosome fusions (PMID: 28393832, 27869160). Inhibition of POT1 expression also results in the activation of ATR-dependent DNA damage resulting in replication stress (PMID: 27239034). Germline loss-of-function mutations in POT1 are found in familial cutaneous melanoma, lymphoma and glioma (PMID: 24686849, 25482530, 29693246). Somatic loss-of-function POT1 mutations are found in chronic lymphocytic leukemia and disrupt oligonucleotide binding activity (PMID: 23502782). POT1 mutations are predicted to promote genome instability due to the inability of POT1 to protect telomeres from DNA repair mechanisms (PMID: 28393832). True +ENST00000526816 NM_001207025 5452 POU2F2 True POU2F2, a homeobox-containing transcription factor, is altered by amplification in various cancers. POU2F2, a member of the POU domain family, encodes for a homeobox-containing transcription factor that binds to the octamer motif (5’-ATTTGCAT-3’) found in immunoglobulin gene promoters (PMID: 2904654). POU2F2 regulates the transcriptional activation of immunoglobulin genes primarily in B lineage cells (PMID: 23045607). POU2F2 mediates B cell development, differentiation and survival by promoting transactivation of genes such as STAT3, IL-10 and MYC (PMID: 26993806). The transactivation activity of POU2F2 is enhanced through the transcriptional coactivator Obf1, which is encoded by POU2AF1 (PMID: 24688485). Overexpression of POU2F2 in various cancer cell lines and models induces cellular proliferation, migration and invasion, suggesting that POU2F2 functions predominantly as an oncogene (PMID: 33832481, 26019213, 33931589). POU2F2 amplification has been identified in various cancers including lung cancer, gastric cancer and liver cancer (PMID: 33832481, 26019213, 14576340). False +ENST00000328345 NM_005604 5454 POU3F2 True POU3F2, a transcription factor, is recurrently altered by amplification in lung adenocarcinoma. POU3F2 encodes for a class III POU-homeodomain transcription factor that functions primarily in neuronal differentiation (PMID: 8543155, 10842361). POU3F2 is a core regulator of neural gene networks that have been implicated in risk for schizophrenia and bipolar disorder (PMID: 30545964, 32929213). POU3F2 is required for the generation of tuft cells, which are chemosensory cells found in gastrointestinal and respiratory tracts that respond to external stimuli by releasing bioactive material to regulate immune cell function (PMID: 26675736, 29216297). Overexpression of POU3F2 in various types of cancer cell lines and models induces cellular proliferation, invasion and migration and confers radioresistance, suggesting that POU3F2 functions predominantly as an oncogene (PMID: 36797433, 32169117, 23358112, 27784708, 31920461). POU3F2 amplification has been identified in various types of cancer, including glioblastoma, small cell lung cancer and melanoma (PMID: 2216722, 23530560, 32632141, 7478537). False +ENST00000644024 NM_000307 5456 POU3F4 True POU3F4, a neural transcription factor, is infrequently altered in cancer. POU3F4, a member of the POU-III family, encodes for a transcription factor that functions primarily in early neural development, including neural tube and hypothalamic patterning (PMID: 1628619). POU3F4 is located on the X chromosome, and mutations in this gene have been associated with X chromosome-linked hearing loss due to its function in middle and inner ear development (PMID: 33919129, 36000053). Overexpression of POU3F4 in various cancer cell lines and models induces increased cellular proliferation, migration and viability, suggesting that POU3F4 functions predominantly as an oncogene (PMID: 31371344, 25243889, 25343275, 19307926). Amplification of POU3F4 has been identified in various cancers, including pancreatic neuroendocrine tumors and neuroendocrine prostate cancer (PMID: 19307926, 31371344). False +ENST00000287820 NM_015869.4 5468 PPARG True PPARG, a nuclear receptor, is known to behave as an oncoprotein when fused with with PAX8 in thyroid cancer. PPARG encodes the Peroxisome Proliferator-Activated Receptor- gamma (PPAR- γ) subfamily of nuclear receptors. PPAR-γ forms a heterodimer with Retinoid X Receptor-α in response to peroxisome proliferators such as clofibric acid or to RXR-α agonists such as 9-cis-retinoic acid and activates the expression of various genes involved in the regulation of adipogenesis, lipid metabolism, glucose homeostasis, atherogenesis, inflammation and tumor susceptibility (PMID: 1324435, 8536636). Chromosomal translocation (2;3)(q13;p25) resulting in a fusion between DNA binding domains of thyroid transcription factor Paired box gene 8 (PAX8) and PPAR- γ1 has been identified in a subset of thyroid follicular carcinomas (PMID: 10958784). PAX8-PPAR-γ behaves like an oncoprotein, and its transforming properties can be attributed at least in part to a dominant negative inhibition of wildtype PPAR-γ (PMID: 15077183). Ligands that activate PPAR-γ, typically thiazolidinediones, are known to sensitize a wide array of cancer cells to death receptor (DR)-mediated apoptosis, owing to de novo expression of proteins involved in regulating the cell cycle and cell survival/death, and also act as inhibitors of angiogenesis (PMID: 18615184,15041792). On the contrary, PPAR-γ agonists have also been reported to increase the frequency and size of colon tumors in APCMin/+ mouse models of colon cancer (PMID: 9734399, 9734400). False +ENST00000305921 NM_003620.3 8493 PPM1D True PPM1D, a protein phosphatase, is altered by mutation in various solid and hematologic malignancies including in therapy-related hematopoietic disorders. PPM1D (Protein Phosphatase, Mg2+/Mn2+ dependent, 1D) is a member of the protein phosphatase 2C (PP2C) family of Ser/Thr protein phosphatases. PPM1D is induced by p53 following activation in response to various environmental stresses such as radiation, H2O2, and anisomycin (PMID: 19015127, 22201816). PPM1D is emerging as an important oncogene by virtue of its negative control on several key tumor suppressor pathways including ATM, CHK2, p38 MAPK, and p53 (PMID: 19879149). PPM1D is overexpressed and/or mutated in various human primary cancers, including breast cancer, hepatocellular carcinoma, pancreatic adenocarcinoma, ovarian carcinoma and neuroblastoma (PMID: 19879149, 23242139, 17233815, 19293255). High PPM1D expression has been associated with tumor progression and poor prognosis in non-small cell lung cancer, nasopharyngeal carcinoma and prostate cancer (PMID: 25412952, 25060857, 26714478). Finally, various PPM1D inhibitors, including peptidic inhibitors derived from substrate sequences and small chemical inhibitors, were reported that suppress cancer cell growth and could be useful in the development of effective anti-cancer agents (PMID: 18845566, 21528848, 17073441, 24390428, 22115592, 25466181, 26358280). False +ENST00000322088 NM_014225.5 5518 PPP2R1A False 3A PPP2R1A encodes a serine/threonine phosphatase that regulates cell growth and division. PPP2R1A is frequently mutated in endometrial and ovarian cancers. The PPP2R1A gene encodes protein phosphatase 2A (PP2A) a serine/threonine phosphatase involved in cell growth and division (PMID: 11171037). PP2A activity has long been considered an important tumor suppressor (PMID: 2153055), although recent evidence suggests that it may function as an oncogene in some context (PMID: 27272709). The PPP2R1A gene encodes the 'scaffolding' subunit of the PP2A trimeric holoenzyme, so named because it bridges PP2A's catalytic subunit to a myriad of targeting subunits (PMID: 17055435). Targeting subunits confer specificity for substrate selection and enzyme localization in the cell. PPP2R1A mutations have recently been found to positively correlate with whole-genome doublings in human cancers (PMID: 24071852). These mutations have been identified in uterine (endometrial) carcinomas (PMID: 23636398, 21435433, 21381030, 21435433), uterine (serous) carcinomas (PMID: 21435433) , ovarian low-grade serous, low-grade endometrioid, clear cell, and mucinous carcinomas (PMID: 21435433, 20826764, 21381030). The functional impact of these mutations during tumorigenesis is limited, however, the available studies describing these mutations indicate that normal function of PPP2R1A is tumor suppressive (PMID: 22262169, PMID: 21791616). True +ENST00000380737 NM_002717.3 5520 PPP2R2A False PPP2R2A, a subunit of the PP2A phosphatase, is altered by mutation and deletion in various cancer types. PPP2R2A (also PR55α) is a subunit of the protein phosphatase 2 (PP2A) that is a member of the PP2A regulatory B subunit family (PMID: 18588945). PP2A is a trimeric enzyme, which is composed of a catalytic subunit, a scaffold subunit, and one of 18 regulatory subunits, such as PPP2R2A, functioning as the predominant serine/threonine phosphatase (PMID: 18588945). PPP2R2A binding contributes to the selectivity of the PP2A phosphatase for substrates (PMID: 18588945, 18042541). Oncogenes, such as MYC and AKT, are negatively regulated by PPP2R2A activity (PMID: 32522823). Dephosphorylation of these targets results in altered cellular functions including reduced proliferation and cellular survival (PMID: 18042541, 12932319). In addition, PPP2R2A regulates ATM dephosphorylation, leading to homologous recombination at sites of DNA damage in the genome (PMID: 23087057). PPP2R2A has additional protein targets including AP-1, HDAC4, and TFGBR1, among others (PMID: 18158287, 12912990, 18045992, 12932319, 14712210, 9774674). Somatic PPP2R2A loss-of-function mutations and deletions have been reported in many cancer types, including prostate, ovarian and non-small cell lung cancers (PMID: 21872824, 23087057, 25879784, 31349904, 27531894), and are predictive or poor survival (PMID: 32522823, 25879784, 31822657, 26893480, 25879784). In loss-of-function preclinical studies, PPP2R2A deletion corresponded to increased sensitivity to DNA damaging agents, such as ATR, CHK1, and PARP1 inhibitors, due to elevation of replication stress pathways (PMID: 32522823, 23087057). True +ENST00000356692 NM_174907.2 151987 PPP4R2 False PPP4R2, a regulatory subunit of a protein phosphatase, plays a vital role in DNA double strand break repair. PPP4R2 encodes a regulatory subunit of the protein phosphatase 4 (PPP4C), a protein serine/threonine phosphatase that has been implicated in microtubule organization at centrosomes. PPP4R2 may be instrumental in targeting PPP4 catalytic subunit (PPP4c) to the centrosomes, and may also regulate (inhibit) the activity of PPP4c at centrosomal microtubule organizing centers (PMID: 10769191). PPP4R2 interacts with Survival of Motor Neurons (SMN) protein complex and is essential for differentiation of neuronal cells (PMID: 22559936) as well as for temporal localization of small nuclear ribonucleoproteins (snRNPs), suggesting a role in maturation of spliceosomal snRNPs (PMID: 12668731). PPP4R2 is part of a conserved ternary complex including PPP4R3 and PPP4c that mediates dephosphorylation of RPA2 and γH2AX, and is required for DNA double strand break repair (PMID: 18614045, 20154705). False +ENST00000373547 NM_002721.4 5537 PPP6C False PPP6C encodes a serine/threonine phosphatase involved in cell cycle progression and DNA double-strand break repair. Aberrant expression of PPP6C is found in melanomas, hepatocellular carcinomas, mesotheliomas and glioblastomas. The PPP6C gene encodes the catalytic subunit of serine/threonine phosphatase 6 (PP6) (PMID: 9143513), which integrates signaling from multiple pathways. In normal cells, PP6 regulates cell cycle progression, and hence restricts G1 to S phase progression in cancer cells (PMID: 9013334, 21187329, 10227379). PP6 plays an important role in oocyte meiosis, and loss of PP6 protein is associated with female infertility (PMID: 26349807). In addition, PP6 is involved in the homology-directed repair of DNA double-strand breaks induced by ionizing radiation; it also plays an important role in inflammatory responses by IL-1 via dephosphorylation of Thr-187 in the activation loop of TAK1 (PMID: 21451261, 17079228). PP6 has been shown to promote replication of influenza A virus (PMID: 25187537). PP6’s involvement in cancer has been largely established. Somatic mutations that lead to inactivation of the protein, loss of heterozygosity and nonsense mutations are observed in approximately 10% of melanomas harboring NRAS or BRAF mutations; these mutations are associated with poor prognosis (PMID: 24336958, 22842228, 24755198, 23729733, 22817889). Overexpression of PPP6C in glioblastoma is associated with worse overall survival (PMID: 25332711, 22395973); downregulation of PP6, which is dependent on miR-373, is observed in hepatocellular carcinoma and mesothelioma (PMID: 21481188, 20463022). PPP6C mutations play a role in the progression of thyroid cancer (PMID: 24718460). True +ENST00000271526 NM_005973 5546 PRCC True PRCC, a proline-rich splicing protein, is altered by chromosomal rearrangement in renal cell carcinomas. PRCC encodes for a proline-rich protein that functions primarily in pre-mRNA splicing. Phosphorylated PRCC is recruited to precursor mRNA to activate the human spliceosome B complex (PMID: 21536652). PRCC can interact with the mitotic checkpoint protein MAD2B and regulates various processes, such as checkpoint control, colony formation and cell apoptosis (PMID: 34715922, 11717438). Overexpression of PRCC in non-small cell lung cancer cell lines induces cellular proliferation, migration and invasion, suggesting that PRCC functions predominantly as an oncogene (PMID: 30900418). Amplification of PRCC has been identified in non-small cell lung cancer (PMID: 16322280). PRCC has been identified as a common translocation partner for the transcription factor TFE3 in papillary renal cell carcinoma (PMID: 8872474, 12459622, 11313942, 38740306). The PRCC-TFE3 fusion is suggested to enhance the transcription factor activity of TFE3 through the N-terminal proline-rich transcriptional activation domain of PRCC (PMID: 8872474). False +ENST00000369096 NM_001198.3 639 PRDM1 False PRDM1 encodes a transcriptional repressor involved in the cellular response to viral infection and B-cell differentiation. Deletions of PRDM1 are found in diffuse large B-cell lymphomas and prostate cancer. PRDM1, also known as BLIMP-1 and PRDI-BF1, encodes PR domain zinc finger 1 (PRDM1), a DNA-binding protein with five zinc fingers (PMID: 1851123). PRDM1 was initially described as a transcriptional repressor of interferon ß, and as an essential component of B cell differentiation, wherein it represses MYC (PMID: 1851123, 9887105, 8168136, 9110979. It has been shown to function by interaction with the Groucho family of transcriptional co-repressors as well histone-modifying factors (PMID: 9887105, 14985713, 19124609). More recent results from animal studies indicate PRDM1 as an important factor in establishment in the germ cell lineage, T cell differentiation and homeostasis and heart function (PMID: 15937476, 16565720, 24821700). Two single-nucleotide polymorphisms (SNPs) located intergenic to PRDM1 and ATG5 have been associated with increased risk for radiation therapy-induced second malignant neoplasms after radiotherapy for pediatric Hodgkin's lymphoma (PMID: 21785431). True +ENST00000276594 NM_024504.3 63978 PRDM14 False PRDM14, a transcriptional regulator, is amplified and overexpressed in breast cancer. The PRDM14 gene encodes a zinc-finger protein that acts as a transcriptional regulator. It belongs to the PRDM family of genes, which exert both positive and negative roles in the transcription of genes involved in development, and either possess or enhance histone methyltransferase activity (PMID: 22669819, 22028065). PRDM14 plays an important role in the establishment of germ cell lineage in mice (PMID: 18665129, 18622394). Additionally, PRDM14 is required for the maintenance of human embryonic stem cell (hESC) identity, and enhances the reprogramming of human fibroblasts into hESC by co-regulating the expression of key genes (PMID: 20953172, 24268575). PRDM14 overexpression in breast cancer cells leads to increased growth and colony formation capabilities and decreased apoptosis (PMID: 17942894). PRDM14 is overexpressed or amplified in a subset of breast and prostate cancers (PMID: 17942894; cBioPortal, MSKCC, Dec. 2016). False +ENST00000288368 NM_024870.2 80243 PREX2 False PREX2, a positive mediator of RAC1 GTPase, is predominantly mutated in melanomas. The PREX2 gene encodes a protein that facilitates the exchange of GDP to GTP on RAC1, leading to the activation of its downstream effectors. PREX2 is activated by phosphatidylinositol 3,4,5-trisphosphate (PIP3) and G-protein coupled receptors and mediates the PI3K pathway-dependent activation of RAC1 (PMID: 15304343, 15304342, 15897194). PREX2 can activate the PI3-Kinase (PI3K) pathway by antagonizing PTEN inhibitory effects (PMID: 19729658); conversely, PTEN negatively regulates PREX2-mediated oncogenic effects (PMID: 25829446). PREX2 activation increases cell proliferation, activates PI3K signaling and downregulates tumor suppressors such as CDKN1C in NRAS-mutant melanoma (PMID: 25829446, 26884185). Oncogenic effects of PREX2 have also been described in other cancers (PMID: 26718453), as well as a role for PREX2 in the insulin signaling pathway (PMID: 26438819). PREX2 is mutated in melanomas and other skin cancers, as well as in pancreatic tumors (PMID: 22622578, 25719666; cBioPortal, MSKCC, Dec. 2016). False +ENST00000308677 NM_002730.3 5566 PRKACA True PRKACA, a catalytic subunit of protein kinase A, is predominately altered by chromosomal rearrangement in various types of hepatocellular carcinoma. PRKACA, a catalytic subunit of protein kinase A (PKA), is involved in the phosphorylation of many cellular proteins important for cell proliferation, maturation, and apoptosis. Cyclic-AMP (cAMP)-dependent activation of PKA leads to the release of PKA regulatory subunits and subsequent phosphorylation of a number of downstream substrates. Cellular substrates of PKA, including transcription factors such as cAMP response element binding protein (CREB), are involved in the activation of multiple downstream processes, typically those involved in cellular metabolism. Fusions of PRKACA to DNAJB1 are the defining oncogenic alteration in fibrolamellar hepatocellular carcinoma (FL-HCC) (PMID: 25557953, 25698061, 25605237, 25122662, 24578576, 26489647). PRKACA overexpression has been identified in HER2-targeted breast carcinoma (PMID: 24909179), and an activating hotspot mutation (L205R) in PRKACA has been frequently identified in patients with adrenal Cushing's syndrome (PMID: 24700472). False +ENST00000358598 NM_212471.2 5573 PRKAR1A False PRKAR1A, a regulatory subunit of protein kinase A, is altered by mutation or translocation in various cancers. PRKAR1A is a cyclic adenosine monophosphate (cAMP)-dependent regulatory subunit that inhibits the catalytic subunits of protein kinase A (PKA) (PMID: 15331577). Binding of cAMP to the regulatory subunit PRKAR1A releases the catalytic subunits of PKA to phosphorylate target proteins, resulting in the activation of signaling pathways that promote cell proliferation, cell division and invasion (PMID: 26042218, 27995993). Germline mutations in PRKAR1A are responsible for the Carney complex disorder characterized by skin pigmented lesions, myxomas, collagenomas and fibromas (PMID: 10973256) and for primary pigmented nodular adrenocortical disease leading to Cushing's syndrome (PMID: 17036196, 12424709). Deletions and loss-of-function mutations in PRKAR1A have been identified in adrenocortical tumors (PMID: 14500362). Missense and nonsense mutations result in decreased cAMP-dependent dissociation of PKA catalytic subunits, suggesting that PRKAR1A functions as a tumor suppressor. PRKAR1A has been identified as a translocation partner for RARA in acute promyelocytic leukemia (PMID: 17712046) and for RET in papillary thyroid carcinoma (PMID: 7678053). True +ENST00000643927 NM_002738.7 5579 PRKCB True PRKCB, a serine/threonine protein kinase, is altered by amplification in various cancers. PRKCB, protein kinase C beta, encodes for a calcium and diacylglycerol (DAG)-dependent serine/threonine protein kinase that plays an important role in angiogenesis, immunity via NF-κB signaling, apoptosis and cellular proliferation (PMID: 24795864, 9935234, 35567329). It is a member of the protein kinase C (PKC) family of proteins, which serve as major receptors of phorbol esters, a class of natural compounds that can promote tumors and are involved in the phosphorylation of various transduction pathways, including the Wnt pathway (PMID: 37505453, 28422739, 35567329). Alternative splicing of the PRKCB gene produces two isoforms, PCKβI and PCKβII, which exhibit distinct functional properties that contribute to the tissue-type specific oncogenic role of PRKCB (PMID: 24795864, 9935234, 17145886). Overexpression of both isoforms in breast and colon cancer cells increases cellular proliferation and TGF-alpha levels, suggesting that PRKCB functions as an oncogene in these contexts (PMID: 17145886, 9935234). Furthermore, PRKCB is upregulated in breast cancer and Ewing sarcoma tumors and its loss in Ewing sarcoma models, both in vitro and in vivo, induces apoptosis and prevents tumor growth (PMID: 19324060, 22930730). However, promoter methylation leading to loss of PRKCB expression is associated with worse survival in diffuse large B-cell lymphoma (DLCBL), non-small cell lung cancer (NSCLC) and prostate cancer, and patients with glioblastoma multiforme with undermethylated PRKCB show higher rates of survival, suggesting that PRKCB may function as a tumor suppressor gene in these cancer types (PMID: 35567329, 37505453, 34198725, 38606198). True +ENST00000295797 NM_002740.5 5584 PRKCI True PRKCI, a serine/threonine kinase, is frequently altered by amplification across various cancers. The PRKCI gene encodes the protein kinase C iota, an atypical serine/threonine kinase involved in multiple cellular processes. PRKCI protects BCR-ABL leukemia cells from undergoing apoptosis (PMID: 9346882). It also enhances cell proliferation and survival via NF-KB pathway activation (PMID: 10467349, 10356400). PRKCI promotes colony formation and tumor growth in vivo (PMID: 15994303) and cooperates with SOX2 to activate the Hedgehog signaling pathway in lung cancers (PMID: 24525231). PRKCI phosphorylates BAD in glioma cells, thus allowing them to evade apoptosis (PMID: 21419810). PRKCI is frequently altered by amplification in several cancers, including lung, ovarian, esophageal and head and neck carcinomas (cBioPortal, MSKCC, Dec. 2016). False +ENST00000331968 NM_002742.2 5587 PRKD1 False PRKD1, a serine/threonine kinase, is mutated in salivary gland carcinomas. The PRKD1 gene encodes the serine/threonine protein kinase D1, which is involved in a variety of cellular processes. PRKD1 is activated by diacylglycerol (DAG) and is able to phosphorylate EGFR, among other targets, leading to signaling suppression (PMID: 17703233, 10523301, 21209314). PRKD1 plays a role in apoptosis and NF-kB-mediated response to oxidative stress (PMID: 10764790, 12505989). PRKD1 has also been implicated in VEGF-induced angiogenesis in endothelial cells (PMID: 18332134) and in the KRAS-mediated methylator phenotype of colorectal cancers (PMID: 24623306). The PRKD1 gene is mutated in cutaneous squamous cell carcinomas and salivary gland adenocarcinomas (PMID: 25240283, 25303977). Small molecule inhibitors against PRKD1 and other protein kinase D isoforms are available (PMID: 20442301). False +ENST00000314191 NM_006904.7 5591 PRKDC True PRKDC, a catalytic subunit of the DNA-dependent serine/threonine protein kinase, is recurrently altered by mutation in various cancers. PRKDC, a member of the phosphatidylinositol 3-kinase-related kinase (PIKK) protein family, encodes for a catalytic subunit of the DNA-dependent serine/threonine protein kinase (DNA-PK), which functions in the non-homologous end joining pathway of DNA repair and V(D)J recombination (PMID: 31189537, 22813740, 19535303, 9398855). DNA-PK is activated by the DNA-Ku70/80 protein dimer complex, which also mediates DNA binding for DNA repair (PMID: 20023628, 18334221). DNA-PK maintains chromosome stability and telomere length by preventing end joining through interaction with Ku (PMID: 12954774, 11090128). The oncogenic function of PRKDC is likely tissue-specific. Knockdown of PRKDC in lung cancer and colorectal cancer cell lines and models induces increased DNA damage and malignant transformation, suggesting that PRKDC functions predominantly as a tumor suppressor gene in these contexts (PMID: 31055244, 26175416). Conversely, overexpression of PRKDC in breast cancer and gastric cancer cell lines and models induces cell cycle progression and cellular proliferation and migration, suggesting that PRKDC functions predominantly as an oncogene in this context (PMID: 31513357, 31255330). Mutations of PRKDC have been identified in various cancers, including lung cancer, breast cancer, liver cancer, colorectal cancer and skin cancer (PMID: 32238472, 35801800). True +ENST00000366898 NM_004562.2 5071 PRKN False PRKN encodes a tumor suppressor invovled in tagging cellular proteins for degradation. PRKN is inactivated in various cancer types, and its dysfunction is associated with hereditary Parkinson's disease. PRKN encodes the parkin protein, which is a component of an E3-ubiquitin ligase complex that serves to mark proteins for proteasomal degradation (PMID: 19946270, 24793136). The PRKN protein functions through physical interaction with ubiquitin-conjugating enzymes, including UBCH7 and UBCH7 (PMID:19946270). Through regulation of protein stability, PRKN plays a role in several molecular processes which contribute to oncogenesis, including but not limited to cell cycle progression (PMID:24793136), mitochondrial homeostasis (PMID: 25815004, 24149988) and apoptosis (PMID: 19679562). PRKN is frequently deleted across a variety of cancer types (PMID: 24793136, 24297497, 19946270); however, other forms of PRKN inactivation, including somatic mutation and promoter hypermethylation/down-regulation of expression, have also been observed (PMID: 24297497; cBioPortal, MSKCC, Nov. 2015). Recently, germline mutation in PRKN has been associated with familial lung cancer (PMID: 25640678). True +ENST00000304992 NM_006445 10594 PRPF8 False PRPF8, a core component of spliceosome complexes, is infrequently altered in cancer. PRPF8 encodes the core component of the catalytic U2- and U12-dependent spliceosome complexes. PRPF8 contains several WD domains throughout the protein that allow for protein-protein interactions to mediate the assembly of spliceosomal proteins, snRNAs and pre-mRNA splicing (PMID: 9774689). Alternative splicing of PRPF8 has been identified in various different cancers and results in dysfunction of the proofreading function when assembling spliceosome complexes (PMID: 24781015, 32547101, 35124606). PRPF8 is located close to the TP53 locus on chromosome 17p, and alternative splicing mutations of PRPF8 have been identified in cancer concomitantly with TP53 loss-of-function mutations (PMID: 24781015). True +ENST00000311737 NM_002769.4 5644 PRSS1 False PRSS1 encodes the digestive pro-enzyme trypsinogen, which is activated in the small intestine. Mutations in PRSS1 are associated with pancreatitis and increased risk of pancreatic cancer. PRSS1 encodes cationic trypsinogen which is secreted in the pancreas, making up about two-thirds of the trypsin content in normal pancreatic juice. Cationic trypsinogen is typically activated in the small intestine to become the digestive enzyme trypsin-1. Trypsin-1 cleaves peptide linkages involving the carboxyl group of lysine or arginine (PMID: 16791840, 7845208, 25010489). It is part of a family of serine protease enzymes that perform a wide variety of functions including immune response, digestion, blood coagulation and reproduction (PMID 12475199). Germline mutations in PRSS1 are associated with premature activation of trypsin-1 causing pancreatic self-digestion that results in pancreatitis and an increased risk of pancreatic cancer (PMID: 23187834, 25479140). Missense mutations in PRSS1 are relatively common in some other solid tumors, including melanoma and lung adenocarcinoma (cBioPortal, MSKCC, Mar. 2016). False +ENST00000373237 NM_002794 5690 PSMB2 True PSMB2, a subunit of the 20S core proteasome complex, is infrequently overexpressed in cancer. PSMB2 is a non-catalytic beta subunit of the 20S core proteasome complex (PMID: 15244466). The proteasome complex maintains protein homeostasis through the degradation of intracellular proteins (PMID: 15244466). PSMB2, along with the other six beta subunits, form the proteasome complex's proteolytic chamber through the assembly of two heptameric rings (PMID: 12015144). Overexpression of PSMB2 promotes tumorigenesis through decreasing homologous recombination, impairing DNA double-strand break repair, promoting cell proliferation and inhibiting apoptosis (PMID: 21660142, 36110152). In vitro knockdown of PSMB2 in cell lines suppresses proteasome complex activity and cell proliferation, and promotes apoptosis (PMID: 36110152). High levels of PSMB2 have been identified in a variety of tumor types including chronic leukemia, liver cancer and hepatocellular carcinoma (PMID: 32933107, 29780166). False +ENST00000331920 NM_000264.3 5727 PTCH1 False 3A PTCH1, a tumor suppressor and inhibitor of the hedgehog pathway, is recurrently mutated in basal cell carcinoma. PTCH1 (protein patched homolog 1) encodes a transmembrane protein that is a component of the oncogenic Hedgehog (HH) signaling pathway. PTCH1 functions as the primary receptor for sonic hedgehog (SHH), a secreted protein involved in embryonic development (PMID: 11001584, 8906787). In response to SHH, PTCH1 binds and inhibits Smoothened (SMO), a G protein-coupled receptor; this results in decreased signaling via the HH pathway (PMID: 14737121). Thus, PTCH1 functions as a classic tumor suppressor by inhibiting SMO-mediated oncogenic signaling. Germline PTCH1 mutations are associated with the nevoid basal cell carcinoma syndrome (NBCCS, Gorlin syndrome), which predisposes patients to basal cell carcinoma as well as medulloblastoma (PMID: 8658145). Recurrent somatic inactivating PTCH1 mutations have been identified in basal cell carcinoma (PMID: 26950094) and medulloblastoma, suggesting that mutant PTCH1 is a primary driver of these diseases (PMID: 21107850, 22832583, 24651015, 22820256, 21163964, 22832581). As inactivating PTCH1 mutations lead to increased SMO activity recently developed SMO inhibitors show promising responses in PTCH1 mutant tumors (PMID: 24651015, 26169613). True +ENST00000371953 NM_000314.4 5728 PTEN False 1 PTEN, a lipid and protein phosphatase, is one of the most frequently mutated genes in cancer. PTEN is a tumor suppressor that is one of the most frequently mutated genes in human cancer (PMID: 9072974, 9090379, 22473468). PTEN has several physiological functions, most notably operating as a phosphatase that converts phosphatidylinositol (3,4,5)-triphosphate (PIP3) to phosphatidylinositol (4,5)-diphosphate (PIP2) at the cell membrane (PMID: 18767981). Impairment of PTEN function through multiple mechanisms, including through non-synonymous mutations, results in PIP3 accumulation and constitutive activation of catabolic downstream AKT/mTOR signaling. Therefore, PTEN inactivation promotes cell growth, proliferation and survival (PMID: 12040186). Additionally, nuclear PTEN is thought to regulate RAD51 expression, and in this way is also associated with homologous recombination and repair of DNA strand breaks (PMID: 17218262, 23888040). Thus, loss of PTEN may also lead to greater genomic instability and provide a setting for the accumulation of other deleterious mutations. PTEN is frequently mutated in many types of human cancers (PMID: 15254063). Germline loss-of-function PTEN mutations occur in approximately 80% of patients with the cancer predisposition syndrome Cowden disease, which is associated with high-penetrance breast and thyroid cancer (PMID: 9467011, 24136893, 21430697). True +ENST00000626021 NM_003463.4 7803 PTP4A1 False PTP4A1, a protein tyrosine phosphatase, is altered by amplification at low frequencies in various cancers. The PTP4A1 gene encodes a protein tyrosine phosphatase (PTP) with a characteristic PTP domain that is necessary to dephosphorylate its substrates, and a prenylation domain that allows the protein to bind the plasma membrane (PMID: 9018080, 15571731). PRP4A1 forms part of the mitotic spindle and stimulates progression from G1 to S phases during mitosis, probably via negative regulation of the p21 tumor suppressor (PMID: 12235145, 14643450). PTP4A1 enhances cell migration, invasion and metastasis by activating SRC and ERK pathways (PMID: 12782572, 19199380,). THE PTP4A1 gene is rarely altered in human tumors, only being amplified in a small subset of tumors such as prostate cancers (cBioPortal, MSKCC, Dec. 2016). False +ENST00000371621 NM_001278618.1 5770 PTPN1 True PTPN1, a tyrosine phosphatase, is recurrently altered by mutation, fusion, deletion, and amplification in a variety of cancer types. PTPN1 (also PTP1B) is a tyrosine phosphatase that functions as a signaling protein. PTPN1 is implicated as a negative regulator of the insulin pathway and removes phosphat molecules from activated insulin receptor kinase (PMID: 11884589). In addition, PTPN1 regulates the activity of a variety of other kinases implicated in a variety of cellular contexts including EGFR (PMID: 9050838), JAK2 (PMID: 11694501), TYK2 (PMID: 11694501), and FAK (PMID: 16291744), among others. PTPN1 activity has been associated with the regulation of several cellular processes including invasion (PMID: 18332219), cytokine sensitivity (PMID: 26817397), cell adhesion (PMID: 10409197), and proliferation (PMID: 14766979). Loss of PTPN1 in preclinical studies leads to increased JAK-STAT pathway activity in hematopoietic cells (PMID: 24531327) and deletion of PTPN1 in mice results in a hematopoietic malignancy (PMID: 28111468). Somatic mutations in PTPN1 have been identified in lymphomas including B-cell acute lymphoblastic leukemia (B-ALL), primary mediastinal B cell lymphoma (PMBCL), and Hodgkin’s lymphoma (PMID: 29650799, 24531327). PTPN1 alterations are largely loss-of-function mutations that are associated with reduced PTPN1 protein expression and phosphatase activity, suggesting that PTPN1 functions as a tumor suppressor (PMID: 24531327). However, overexpression of PTPN1 truncation and splice mutations in cell lines results in transformation, implicating some alterations as dominant negative mutations (PMID: 27855221). In addition, the PTPN1 gene lies within the 20q region that is frequently deleted in myeloproliferative disorders and myelodysplastic syndromes (PMID: 7949181) and amplified in breast and ovarian cancers (PMID: 8758909, 10815905). PTPN1 fusion proteins have also been identified in non-Hodgkin lymphomas (PMID: 27268263). True +ENST00000351677 NM_002834.3 5781 PTPN11 True PTPN11, a protein tyrosine phosphatase, is altered in various solid and hematologic malignancies. PTPN11 (also known as SHP2) is a protein tyrosine phosphatase that removes phosphate groups from signaling molecules (PMID: 18286234). In its resting inactive state, PTPN11 maintains a conformation that inhibits phosphatase activity (PMID: 18286234). After growth factor or cytokine stimulation of a receptor tyrosine kinase (RTK), such as the platelet-derived growth factor receptor alpha (PDGFRA), PTPN11 is recruited to the phosphorylated tyrosine residue on the RTK leading to a conformational change and activation of phosphatase activity (PMID: 18286234, 21575863). PTPN11 regulates multiple signaling cascades and is involved in the negative regulation of the PI3K/AKT (PMID: 14644997), STAT5 (PMID: 23103841) and RAS/RAF/MEK/ERK signaling pathways (PMID: 25026279, 24618081). Germline mutations in PTPN11 have been identified in Noonan syndrome and LEOPARD syndrome, while somatic PTPN11 mutations have been identified in several cancers and are prevalent in juvenile myelomonocytic leukemia (JMML) (PMID: 11704759,16358218). PTPN11 mutations typically occur as missense mutations that disrupt phosphatase activity or have dominant negative function, leading to the activation of signaling pathways that regulate growth (PMID: 21575863). However, both gain-of-function and loss-of-function mutations can lead to pathway activation, as the open conformation of PTPN11 resulting from mutation matters more for its interaction with other proteins than does its catalytic activity (PMID: 29559584). KRAS-mediated tumorigenesis has been shown to depend on functional PTPN11 protein (PMID: 29808010, 29808006, 29808009).While PTPN11-specific therapies have not yet been developed, small molecule inhibitors targeting members of the RAF and PI3K signaling pathways have been found to be therapeutically effective in the context of PTPN11 loss (PMID: 26365186). False +ENST00000411767 NM_080683 5783 PTPN13 False PTPN13, a tyrosine phosphatase, is infrequently altered in cancer. PTPN13, a member of the PTP family, encodes for a tyrosine phosphatase that functions in apoptotic regulation (PMID: 15611135). PTPN13 interacts with FAS and NGFR through its phosphotyrosine substrate recognition pocket to negatively regulate pro-apoptotic signaling (PMID: 7536343, 20620960). PTPN13 functions in the regulation of various other cellular physiological processes, including cell-cell adhesion and cellular proliferation, by regulating phosphorylation levels of signaling pathways such as Akt and PI3K (PMID: 32919955, 23604317). Knockdown of PTPN13 in various cancer cell lines and models reduces cell-cell junction stability and cell-cell adhesion, tumor growth and invasiveness, and colony formation and invasion, suggesting that PTPN13 functions predominantly as a tumor suppressor gene (PMID: 31938048, 20501847, 17982484). Downregulation of PTPN13 has been identified in various types of cancer, including breast cancer, non-small cell lung cancer and clear cell renal cell carcinoma (PMID: 20501847, 22245727, 32919955). Hypermethylation of the PTPN13 promoter region has also been identified in lymphoma, breast cancer, liver cancer and gastric cancer (PMID: 16572203). True +ENST00000366956 NM_005401 5784 PTPN14 False PTPN14, a tyrosine phosphatase, is infrequently altered in cancer. PTPN14, a member of the PTP family, encodes for a tyrosine phosphatase that functions in development and the regulation of various cellular processes including cellular proliferation, cellular adhesion and cytoskeleton organization (PMID: 10212280, 10934049). PTPN14 modulates angiogenesis and organogenesis through the TGF-β/BMP pathway and Hippo-YAP pathway (PMID: 22233626, 17893246, 26950094). Knockdown of PTPN14 in various cancer cell lines and models induces cellular proliferation and invasion, suggesting that PTPN14 functions predominantly as a tumor suppressor gene (PMID: 29017057, 32141101, 32645410). Loss of PTPN14 has been identified in various types of cancer, including prostate cancer, pancreatic cancer and basal cell carcinoma (PMID: 32645410, 29017057, 33602785). True +ENST00000309660 NM_002828.3 5771 PTPN2 False PTPN2, a tyrosine phosphatase, is recurrently altered by mutation and deletion in lymphomas. PTPN2 (also TC-PTP) is a tyrosine phosphatase that functions as a signaling protein. PTPN2 is highly expressed in immune cells and functions to remove phosphate molecules from proteins, namely protein tyrosine kinases (PMID: 19290937). Many substrates of PTPN2 have been identified including JAK1 (PMID: 11909529), JAK3 (PMID: 11909529), STAT1/6 (PMID: 12138178, 17210636), EGFR (PMID: 11514572, 9488479), and the oncogenic fusion BCR-ABL (PMID: 14966296), among others. Predominantly, PTPN2-mediated dephosphorylation of protein tyrosine kinases results in negative regulation of downstream signaling pathways (PMID: 11514572). PTPN2 can shuttle between the nucleus and cytoplasm, which is dependent on numerous factors including the presence of cellular stress (PMID: 11479308). Activity of PTPN2 is required for a variety of cellular processes including cell cycle control (PMID: 11498795), lymphocytic proliferation (PMID: 12847239), lymphocytic lineage specification (PMID: 28798028), insulin signaling (PMID: 20484139), apoptosis (PMID: 21984578) and cytokine sensitivity (PMID: 21115548). PTPN2 also negatively regulates T cell receptor signaling, leading to attenuation of immune responses (PMID: 22080863). Loss of PTPN2 expression in mice results in hematopoietic deficiencies and dysregulation of inflammatory responses (PMID: 9271584, 29444435). Polymorphisms in PTPN2 are associated with autoimmune disorders such as Crohn’s disease, type I diabetes and ulcerative colitis (PMID: 22080863, 22457781, 24445916). Deletions and somatic loss-of-function mutations in PTPN2 have been identified in T-cell acute lymphoblastic leukemia and peripheral T-cell lymphomas (PMID: 20473312, 21551237, 21791476). In contrast, PTPN2 expression has been associated with colon cancer promotion due to reduced inflammasome activity (PMID: 29444435). Consistent with this result, deletion of PTPN2 leads to enhanced efficacy of immunotherapies as evidenced in preclinical studies by an activated inflammatory response (PMID: 28723893). True +ENST00000356435 NM_002839.3 5789 PTPRD False PTPRD, a tumor suppressor and receptor protein tyrosine phosphatase, is altered by mutation or deletion in various cancer types including skin and lung cancers. PTPRD encodes the enzyme Receptor-type tyrosine-protein phosphatase delta (PTPδ), which is a member of the family of protein tyrosine phosphatases (PTPs) that are involved in various cellular processes. Specifically, PTPRD contains extracellular, transmembrane and intracellular domains thus constituting a receptor-like PTP with a role in cell-cell adhesion (PMID: 16557282, 22977525). Identified targets for dephosphorylation by PTPRD include STAT3 and AURKA (PMID: 19478061, 22305495). PTPRD is inactivated in a large number of glioblastomas and is mutated, deleted or promoter methylated in multiple other human cancers, ranging from neuroblastomas to endometrial, lung and colon cancers and has a putative tumor suppressor function (PMID: 25263441, 19478061). True +ENST00000587303 NM_002850.3 5802 PTPRS False PTPRS encodes a tyrosine phosphatase involved in regulation of synapse structure, function and plasticity in the central nervous system. Mutations, altered expression and microdeletions of PTPRS are found in colorectal, head and neck and ovarian cancers, among others. The PTPRS gene encodes the enzyme receptor-type tyrosine-protein phosphatase T (PTPσ), which is a member of the family of protein tyrosine phosphatases (PTPs) that are involved in various cellular processes. Specifically, PTPRS contains extracellular, transmembrane and intracellular domains thus constituting a receptor-like PTP. Additionally, PTPRS is considered a member of the leukocyte common antigen-related (LAR) subfamily of PTPs, due to its role in development of the nervous system and evolutionary conservation (PMID: 15674434). PTPRS is seldom altered in cancer but its deregulation has been observed in several cancers, such as colorectal, head and neck and ovarian tumors, and it might act as a tumor suppressor through regulation of angiogenic and EMT processes (PMID: 16557282, 25998839, 26308964, 22065749). True +ENST00000373198 NM_133170.3 11122 PTPRT False PTPRT encodes a tyrosine phosphatase involved in cell adhesion. Mutations of PTPRT are found in colon, lung, skin and head and neck cancers, among others. The PTPRT gene encodes the enzyme receptor-type tyrosine-protein phosphatase T, which is a member of the protein tyrosine phosphatases (PTPs) family. PTPRT contains extracellular, transmembrane and intracellular domains, thus constituting a receptor-like PTP with a role in cell-cell adhesion (PMID: 16973135, 16557282). Identified targets for dephosphorylation by PTPRT include cadherins E, N and VE, STAT3, PXN and BCR (PMID: 16973135, 22767509, 20133777). Mutations in PTPRT are found specifically in colon cancer but also in a wide range of other human cancers, including both solid and blood tumors. PTPRT is characterized as a tumor suppressor, as PTPRT mutations in cancer are predominantly loss of function, and PTPRT knock-out mice are hypersensitive to AOM (azoxymethane)-induced colon cancer (PMID: 17223850, 25982282, 15155950, 21517784). True +ENST00000257075 NM_014676 9698 PUM1 False PUM1, an RNA binding protein involved in post-translational gene regulation, is infrequently altered in cancer. PUM1 is an RNA-binding Pumilio protein of the highly conserved PUF family of proteins, which are important mediators of post-translational gene regulation. These proteins bind to the 3’UTR of target mRNAs, promoting their degradation and thereby controlling their translation (PMID: 18411299, 28232582, 31395860). However, PUM1 has also been shown to mediate transcript-specific post-translational gene activation in certain contexts (PMID: 28232582). Due to its role in regulating gene expression, PUM1 is known to be involved in tumorigenesis, as dysregulated expression of PUM1 can lead to DNA repair damage, chromosomal instability (PMID: 29428722) and may inhibit apoptosis (PMID: 18166083). PUM1 may also regulate innate immunity (PMID: 28760986). In leukemia, PUM1 is known to promote and maintain hematopoietic stem and myeloid leukemia cell growth (PMID: 28232582). False +ENST00000361752 NM_006775 9444 QKI False QKI, an RNA-binding protein, is altered by deletion in various cancers. QKI, a member of the signal transduction and activation of RNA (STAR) family, is an RNA-binding protein which regulates cellular differentiation through control of mRNA transport, stability and splicing (PMID: 33397958, 27029405). QKI regulates myelination and oligodendrocyte differentiation, and downregulation of QKI has been implicated in schizophrenia (PMID: 16641098). QKI encodes for three major alternatively spliced transcripts, QKI-5, QKI-6 and QKI-7, that are developmentally regulated and vary in RNA processing roles in the brain (PMID: 19727426, 23319046, 11917126). Knockdown of QKI in various cancer cell lines and models induces cellular proliferation, migration and invasion, suggesting that QKI functions predominantly as a tumor suppressor gene (PMID: 33569406, 35600368, 33196842). Downregulation of QKI has been identified in various types of cancer, including colorectal cancer, prostate cancer and oral cancer (PMID: 19686745, 24153116, 24918581). True +ENST00000229340 NM_006861.6 11021 RAB35 True RAB35 encodes a member of the Ras superfamily of small GTPases that signals through the pro-oncogenic PI3-kinase pathway. RAB35 is a member of the Ras superfamily of small GTPases that collectively function in regulating the myriad of membrane transport processes in eukaryotic cells (PMID: 19931531, 20937701, 23060965). RAB35 (also named Ray or Rab1c), interacts with p53-related protein kinase and distributes in the nucleus, cytosol, and cell membrane (PMID: 16600182). RAB35 is an interacting partner for nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) in human lymphoma cells (PMID:14968112) and mediates Wnt5a-induced migration of breast cancer cells (PMID:23353182). Through mutual antagonism, RAB35 and ARF6 are geared to reciprocally balance the recycling of integrins and cadherins in order to tune cell adhesive behavior towards cell migration or intercellular contact. Consistent with that, there is a strong reduction in RAB35 expression levels in brain, breast and squamous tumors, which are all associated with EGF receptor overexpression and enhanced ARF6 activity (PMID: 23264734). A clinical investigation demonstrates a significant positive correlation between RAB35 and androgen receptor (AR) expression in ovarian cancer, making RAB35 attractive as a candidate for biomarker of AR function in ovarian cancer (PMID:19623182). Importantly, RAB35 is a critical regulator of PI3K-AKT signaling that acts upstream of PDK1 and mTORC2 and downstream of growth factor receptors (PMID:26338797). Expression of two known cancer-related RAB35 missense mutations, RAB35-A151T or RAB35-F161L, resulted in increased AKT phosphorylation, enhanced cell viability, resistance to apoptosis under growth-factor deprivation, and PI3K-dependent transformation, indicative of a gain-of-function effect (PMID: 26338797). Searches of existing human tumor sequencing databases reveal that RAB35 mutations are rare and are therefore unlikely to appear on current lists of human cancer genes that rely solely on statistical methods to distinguish between driver and passenger mutations (PMID: 26338797). Finally, RAB35 is a target gene of miR-720 in HEK293T and HeLa cells, a nonclassical miRNA involved in the initiation and progression of several tumors (PMID:26413265). False +ENST00000356142 NM_018890.3 5879 RAC1 True RAC1 encodes a RAS superfamily small GTPase involved in the regulation of cell adhesion, differentiation and migration. RAC1 is predominantly mutated in melanoma and has several well-defined hotspot mutations. The RAC1 (ras-related C3 botulinum toxin substrate 1) gene encodes a member of the Rho family of GTPases, which includes RHO, RAC1 and CDC42. Rho GTPases regulate the assembly and disassembly of the cytoskeleton; in this regard, RAC1 plays a role in cell adhesion, differentiation and migration (PMID: 24072884, 17373658). Additionally, RAC1 is involved in pathways governing proliferation (MAPK pathway), the inflammatory response (NFkB pathway) and regulation of the cell cycle (PMID: 24072884, 10816416, 17373658). The activity of RAC1 is controlled by guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs), which switch GDP for GTP and trigger catalysis of GTP to GDP, respectively (PMID: 10816416). RAC1 is ubiquitously expressed, and gain-of-function mutations are implicated in processes underlying metastasis and drug-resistance; therefore, RAC1 is a putative drug target (PMID: 22407364, 25056119, 19509242, 24072884, 25594058, 24750242). RAC1 mutations are found predominantly in melanoma, but have also been identified in other cancer types (PMID: 22817889, 22842228, 17904119, 22786680). An alternatively spliced and constitutively active version of RAC1, named RAC1B, has been detected in colon and lung cancer (PMID: 11062023, 10597294, 15516977, 22786680). False +ENST00000249071 NM_002872.4 5880 RAC2 True RAC2 is a small GTPase that is implicated in promoting tumor growth, angiogenesis and metastasis. RAC2 encodes a small signaling GTPase protein Rac2 (Ras-relatedC3 botulinum toxin substrate 2) belonging to the Rac sub-family of Rho family of GTPases. RAC2 regulates various cellular processes such as secretion, cytoskeletal reorganization, cell polarization (specifically lamellipodial extension and membrane ruffling), and phagocytosis (PMID: 16949823). RAC2 has been identified as a component of the phagocytic oxidase complex in neutrophils, and a dominant negative mutation (D57N) in RAC2is associated with phagocyte immunodeficiency in humans (PMID: 10961859, 15814684, 21167572). In addition, RAC2 is involved in multiple kinase-mediated signal transduction pathways, including the mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3-K) signaling networks (PMID: 7664330, 9042860, 10843388). Unlike RAC1 and RAC3, RAC2 is expressed specifically in cells of hematopoietic lineages (PMID: 23850828, 12370311), and RAC2-deficient mice demonstrate cellular defects in multiple hematopoietic lineages, including stem and progenitor cells, neutrophils, mast cells, T and B cells (PMID:12370311, 11057896, 11320224). Mouse models have revealed a distinct role for RAC2 in promoting tumor growth, angiogenesis and metastasis (PMID: 24770346) and loss of RAC2 causes a significant delay in the development of BCR-ABL-driven myeloproliferative disorders (PMID: 17996650). False +ENST00000380774 NM_133339 5884 RAD17 False RAD17, a cell cycle checkpoint chromatin-binding protein, is frequently altered by loss-of-function in various cancers. RAD17 is a cell cycle checkpoint chromatin-binding protein that functions as a regulator of cell cycle arrest and DNA damage repair in response to DNA damage (PMID: 20424596). When DNA damage occurs in cells, RAD17 is phosphorylated at two conserved serine motifs on its C-terminus by ATM and ATR checkpoint kinases (PMID: 11418864). Phosphorylated RAD17 in turn recruits and activates Claspin to phosphorylate CHK1 to halt mitotic entry and mediate DNA repair and replication (PMID: 16885023, 11090622, 11390642). Loss of RAD17 function promotes tumorigenesis through increased chromosomal aberrations, DNA double-strand breaks and endoreduplication, significantly reducing cell viability (PMID: 12672690). Loss of RAD17 has been frequently identified in various cancer types, including head and neck squamous cell carcinoma, adenoid cystic carcinoma and prostate adenocarcinoma (PMID: 17657792, 26437225). True +ENST00000297338 NM_006265.2 5885 RAD21 False RAD21 encodes a protein involved in DNA repair and chromosome segregation. Germline mutations of RAD21 are associated with an increased risk of developing breast cancer. RAD21 is a subunit of the cohesin complex that aligns and stabilizes sister chromatids during metaphase (PMID: 24854081). The cohesin ring is comprised of two large structural proteins, SMC1a and SMC3, and this ring opens and closes through the binding of alpha-kleisin subunits to the RAD21 adapter protein (PMID: 24854081). The cohesin complex also functions to maintain chromatin looping structures, or 3D arrangements of DNA that allow for regulatory control of gene expression (PMID: 28985562). RAD21 has been implicated as a double-stranded break DNA repair protein (PMID: 20711430). Germline mutations in RAD21 have been identified in patients with cohesinopathies leading to a spectrum of developmental defects (PMID: 22633399). Somatic RAD21 mutations have been identified in patients with acute myeloid leukemia and myelodysplastic syndromes (PMID: 24335498, 23955599, 25006131). RAD21 mutations are predominantly missense and predicted to lead to loss of function activity, however, it remains unclear if RAD21 mutations lead to aneuploidy as predicted (PMID: 25006131). True +ENST00000378823 NM_005732.3 10111 RAD50 False RAD50 encodes a component of protein complex critical to DNA double-stranded-break end processing. Select germline mutations of RAD50 predispose to breast cancer. RAD50 is a subunit of the MRE11/RAD50/NBS1 (MRN) complex. The MRN complex is recruited to the site of DNA double-strand breaks (DSBs) as part of the DNA damage response (DDR) and plays a pivotal role in the repair of damage via either the homologous recombination (HR) or non-homologous end-joining (NHEJ) pathways (PMID: 2659437, 15309560). Within this complex, RAD50 functions as a flexible and dynamic dimer with ATPase activity. Biochemical studies have demonstrated that RAD50 functions in the maintenance of genomic integrity via the bridging of multiple RAD50 molecules to DNA and subsequent recruitment of the MRN complex to damaged chromatin (PMID: 21458667, 21511873, 21441914, 12152085, 25576492). RAD50 also has a direct function in bridging the ends of DNA that are to be repaired via NHEJ (PMID: 15309560). Germline mutations in RAD50 have been identified in patients with Nijmegen breakage syndrome-like disorder, characterized by progressive microcephaly, short stature and increased risk of cancer (PMID: 19409520). Mutations in RAD50 increase tumor susceptibility, similar to mutations in other DNA repair enzymes, and RAD50 somatic mutations have been identified in several human cancers (PMID: 16385572, 24894818). RAD50 mutations are predicted to be loss-of-function leading to the reduced ability for DNA damage-induced MRN foci to form (PMID: 19409520). True +ENST00000267868 NM_002875.4 5888 RAD51 False RAD51 encodes a protein involved in DNA double-strand break repair. Germline mutations or overexpression of RAD51 are associated with an increased risk of developing breast cancer. RAD51 is a member of the RAD51 recombinase family that functions in homologous recombination (HR)-mediated repair of double-stranded DNA breaks (DSBs). RAD51 acts at an early step in the DSB pathway: the 5’ended DNA strands flanking the DSB break site are resected and the single-stranded overhangs are coated by RAD51 forming a nucleo-protein filament (PMID: 25833843). RAD51 then probes for homologous DNA and initiates the process of strand invasion and exchange between homologous DNA (PMID: 19122145, 20930833). RAD51 forms protein complexes with known tumor suppressors including BRCA1, BRCA2 and PALB2; specifically, BRCA2 loads RAD51 monomers at sites of DNA double-strand breaks (PMID: 14636569, 20729832, 20930833, 20871615, 20729858). RAD51 germline mutations may increase breast cancer risk in certain populations (PMID: 10807537, 26108708), while other studies suggest the RAD51 135 G/C single nucleotide polymorphism may increase breast cancer risk in BRCA2 mutation carriers (PMID: 11248061, 17999359). RAD51 is infrequently mutated in human cancer; however, RAD51 overexpression has been linked to increased oncogenic potential in several tumor types, including pancreatic and breast (PMID: 18243065, 24811120, 26317153, 21807066, 10851081). True +ENST00000487270 NM_133509.3 5890 RAD51B False 1 RAD51B, a DNA repair protein involved in homologous recombination, is altered by mutation in various cancer types. RAD51B (also known as RAD51L1) is a member of the RAD51 recombinase family that functions in homologous recombination (HR)-mediated repair of double-stranded DNA breaks (DSBs). RAD51B, in complex with the central homologous repair protein RAD51, acts at an early step in the DSB pathway: the 5’ ended DNA strands flanking the DSB break site are resected and the single-stranded overhangs are coated by RAD51 forming a nucleo-protein filament (PMID: 25833843). RAD51 then probes for homologous DNA and initiates the process of strand invasion and exchange between homologous DNA (PMID: 19122145, 20930833). RAD51B expression is upregulated following ionizing radiation (PMID: 9788630) and RAD51B function is required for the formation of repair complexes including RAD51 paralogs, XRCC2 and XRCC3 (PMID:11751635, 11283264, 10938124). In addition to the DNA damage repair pathway, RAD51B has been shown to influence cell cycle regulation through phosphorylation of p53, CDK2 and cyclin E, resulting in G1 cell cycle delay (PMID: 10623463). Germline RAD51B variants have been identified as risk factors in familial breast cancer (PMID: 24139550, 26261251, 27149063, 34021944, 34635660). Loss of RAD51B expression results in loss of DNA repair functions and may promote oncogenesis via genome instability (PMID: 25313082, 24390348, 19330030). True +ENST00000337432 NM_058216.2 5889 RAD51C False 1 RAD51C is a protein involved in DNA double-strand break repair. Germline mutations of RAD51C are associated with an increased risk of breast and ovarian cancer. RAD51C is infrequently mutated in human cancers; however, RAD51C gene expression was reduced in a subset of breast cancer tumor samples (PMID: 23512992). RAD51C (also known as RAD51L2) is a member of the RAD51 recombinase family that functions in homologous recombination (HR)-mediated repair of double-stranded DNA breaks (DSBs). RAD51C, in complex with RAD51, acts at an early step in the DSB pathway: the 5’ended DNA strands flanking the DSB break site are resected and the single-stranded overhangs are coated by RAD51 forming a nucleo-protein filament (PMID: 25833843). RAD51 then probes for homologous DNA and initiates the process of strand invasion and exchange between homologous DNA (PMID: 19122145, 20930833). RAD51C is a component of two DSB repair complexes, BCDX2 (including RAD51B, RAD51C, RAD51D, and XRCC2) and CX3 (including XRCC3), which have roles in damage-stabilization and assembly of RAD51 filaments, respectively (PMID: 16093548, 23149936). RAD51C activity is also important for resolving Holliday junctions (PMID: 17114795, 14716019). Germline heterozygous mutations in RAD51C increase susceptibility to ovarian cancer and possibly breast cancer (PMID: 22415235, 32107557, 32235514, 33471991, 36411032). In addition, biallelic mutations of RAD51C are implicated in Fanconi anemia complementation group O (PMID: 20400963, 20952512, 29278735, 37031326). True +ENST00000345365 NM_002878.3 5892 RAD51D False 1 RAD51D encodes a protein involved in DNA double-strand break repair. Germline mutations of RAD51D are associated with an increased risk of developing breast and ovarian cancer. RAD51D (also known as RAD51L3) is a member of the RAD51 recombinase family that functions in homologous recombination (HR)-mediated repair of double-stranded DNA breaks (DSBs). RAD51D, in complex with RAD51, acts at an early step in the DSB pathway: the 5’ended DNA strands flanking the DSB break site are resected and the single-stranded overhangs are coated by RAD51 forming a nucleo-protein filament (PMID: 25833843). RAD51 then probes for homologous DNA and initiates the process of strand invasion and exchange between homologous DNA (PMID: 19122145, 20930833). Biochemical studies demonstrate that RAD51D forms a complex with three other RAD51 paralogs: XRCC2, RAD51B and RAD51C (known as the BCDX2 complex) (PMID: 10871607, 11751635, 16236763). This complex plays a role in the early stages of HR, prior to recruitment of RAD51 to damaged DNA foci (PMID: 11751635, 21821141). RAD51D also interacts with DNA binding and replication proteins including SFPQ, NONO, MCM2, and MSH2 (PMID: 19658102) and has a role in the telomere maintenance (PMID: 15109494). RAD51D-deficient cells develop spontaneous chromosomal aberrations and exhibit G2 arrest (PMID: 11283264, 21205838, 15781618). Germline, heterozygous mutations in RAD51D increase susceptibility to ovarian cancer and possibly breast cancer (PMID: 22415235, 32107557, 33471991, 36411032). RAD51D somatic mutations are rare in human cancers; however, RAD51D variants have been associated with increased chemoresistance (PMID: 19033885). True +ENST00000358495 NM_134424.2 5893 RAD52 False RAD52, a DNA repair protein, is inactivated by mutation in hereditary breast and ovarian cancers. RAD52 is a recombinase protein involved in RAD51-mediated DNA recombination and repair (PMID: 27649245). RAD52 binds to RAD51, promoting strand exchange during homologous recombination (HR) by pairing of homologous single- and double-stranded DNA (PMID: 27649245). Biochemical studies suggest RAD52 may help recruit RAD51 to double-stranded break (DSB) loci or form RAD51 nucleoprotein filaments (PMID: 10212258, 8550550, 9450758, 8370524). Whereas RAD51 knockout is embryonic lethal in mice, depletion of RAD52 in mice or human cell lines does not render a lethal or DSB-sensitive phenotype (PMID: 9774659, 8943369, 8692798). However, preclinical studies show that inactivation of RAD52 in cells lacking BRCA2, BRCA1, RAD51 paralogs or PALB2 results in synthetic lethality (PMID: 9774659, 22964643, 23071261) indicating that RAD52 has redundant function in RAD51-mediated HR repair pathways (PMID: 22964643, 23071261). Rare germline RAD52 variants have been found in familial breast and ovarian cancer (PMID: 12883740, 10463575, 23188672), however somatic RAD52 mutations in human cancers are infrequent. False +ENST00000371975 NM_001142548.1 8438 RAD54L False 1 RAD54L encodes a protein involved in DNA double-strand break repair. Mutations of RAD54L are found in non-Hodgkin lymphoma and chronic lymphocytic leukemia, among other cancers. RAD54L is a member of the SNF2-family of helicases that functions as a chromatin remodeling protein for the repair of double-stranded breaks during homologous recombination and repair (PMID: 17417655, 19671661). RAD54L binds to RAD51, the central homologous repair protein, and facilities a topological change in the DNA leading to DNA pairing and recombination (PMID: 11030338, 12359723). The RAD54L-RAD51 interaction results in supercoiling ahead of replication factor complex movement and the stabilization of the D loops during DNA repair (PMID: 11459989, 16818238). RAD51 binding to single and double-stranded DNA is stabilized by RAD54L during recombination initiation (PMID: 12566442). There is additional evidence that RAD54L can disassociate RAD51 from duplex DNA after recombination has been initiated (PMID: 12453424). Mutations in RAD54L have been identified in breast cancers, colon cancers, and lymphomas, however, somatic alterations of RAD54L in human cancers are infrequent (PMID: 10362365). False +ENST00000251849 NM_002880.3 5894 RAF1 True 2 RAF1 (CRAF), an intracellular kinase and component of the pro-oncogenic MAP-kinase signaling pathway, is infrequently mutated in cancer. Germline mutations of RAF1 are associated with Noonan and LEOPARD syndrome. RAF1, or CRAF, is one of three RAF serine/threonine kinases that signal in the mitogen-activated protein kinase (MAPK) pathway (PMID: 17555829). In response to extracellular stimuli, RAS-mediated signaling induces the formation of CRAF homodimers or CRAF/BRAF heterodimers leading to phosphorylation of MEK and subsequently ERK, which are signaling effectors in the MAPK pathway. Activation of MAPK signaling stimulates a wide range of cellular functions such as proliferation, differentiation and migration (PMID: 21779496). CRAF is ubiquitously expressed and is necessary for normal physiology in several tissues despite partially overlapping functions with ARAF and BRAF (PMID: 9767153). Somatic mutations in RAF1 occur at a low frequency in different cancers, including uterine, stomach, colorectal and malignant melanoma (PMID: 27273450, 24957944). Several RAF1 missense mutations have been shown to be oncogenic, leading to increased MAPK signaling and oncogenic transformation in vitro (PMID: 24569458). Additionally, rare oncogenic RAF1 fusions have been found in different types of cancer (PMID: 19363522, 20526349, 25266736). CRAF-activated MAPK signaling has also been associated with resistance to the BRAF inhibitor vermurafenib in melanoma (PMID: 27327499). False +ENST00000283195 NM_006267 5903 RANBP2 True RANBP2, a RAN-binding protein, is altered by mutation and chromosomal rearrangement in various cancers. RANBP2 encodes for a RAN-binding protein which functions as a component of the nuclear pore complex and regulates the RAN-GTPase cycle (PMID: 19118815, 26251516, 9480752). RAN, a small GTP-binding protein of the RAS superfamily, functions in the regulation of nuclear protein import and export, RNA processing and cell cycle progression, and is sumoylated by RANBP2 (PMID: 17287812, 26251516). RANBP2 interacts with the E2 enzyme UBC9 and enhances SUMO1 transfer from UBC9 to SUMO1 target SP100 to regulate protein localization and stability at the nuclear pore complex (PMID: 11792325). RANBP2 mutations are implicated in the development of the neurological disorder acute-necrotizing encephalopathy type 1 (PMID: 19118815, 26923722). Knockdown of RANBP2 in various cancer cell lines and models suppresses cellular proliferation, migration and invasion, suggesting that RANBP2 functions predominantly as an oncogene (PMID: 33816306, 34298689). Conversely, downregulation of RANBP2 in HeLa cells and colorectal cancer cells induces chromosomal misalignment, improper mitotic progression and mitotic cell death, suggesting that there may be tumor suppressive roles for RANBP2 (PMID: 24113188, 27058664). RANBP2 has been identified as a recurrent fusion partner of ALK in inflammatory myofibroblastic tumors (PMID: 12661011, 25028698, 26893756). False +ENST00000254066 NM_000964.3 5914 RARA False 1 RARA, a transcription factor, is altered by mutation or amplification in various solid tumors and is recurrently altered by chromosomal rearrangement in acute promyelocytic leukemia. RARA (retinoic acid receptor alpha) is a transcription factor that plays a role in the differentiation of white blood cells. RARA heterodimerizes with the RXR nuclear receptor and is activated by binding retinoid ligands (PMID: 1310350). Binding of the ligand results in a conformational change and recruits histone acetyltransferases and chromatin remodeling ATPases that activate transcription (PMID: 8274399, 11106744). RARA signaling is involved in the development of multiple tissue types, hematopoiesis, and stem cell specification (PMID: 9053308, 10529422, 24074870). Translocations between RARA and PML is implicated in the pathogenesis of acute promyelocytic leukemia (APL) (PMID: 23841729). The fusion protein confers sensitivity to targeted treatment with all-trans retinoic acid and arsenic trioxide (PMID: 20378816). Other rarer translocations partners with RARA have also been observed in APL (PMID: 25583766, 25629986, 23287866, 26414475, 20807888, 9288109). The RARA gene can also be methylated and reduced in expression other leukemias (PMID: 17993618). RARA mutations have been observed in breast fibroepithelial tumors (PMID: 26437033). The gene is also amplified in a subset of breast cancers and can interact with the estrogen receptor (PMID: 23830798, 20080953). False +ENST00000274376 NM_002890.2 5921 RASA1 False RASA1, a GTPase-activating protein (GAP) and negative regulator of RAS, is deleted or mutated in a number of cancers. RASA1 (Ras p21 protein activator 1) encodes a RAS GAP also known as p120RasGAP (PMID: 3201259). It accelerates the conversion of Ras-GTP to Ras-GDP to terminate Ras signaling (PMID: 17540168, 18568040). The absence of RASA1 activity leads to accumulation of GTP-bound RAS and persistent MAP kinase signaling following growth factor stimulation (PMID: 9121432). Somatic alterations in RASA1 map to all regions of the gene, including the C-terminal GAP catalytic domain and the N-terminal tandem SH2-SH3-SH2-PH-C2 domains. The SH2 and SH3 domains have been shown to interact with signaling proteins, including RhoGaps. Statistical analysis of mutational profiles of more than 8,200 tumor data sets identified RASA1 as a candidate driver and a putative tumor-suppressor gene based on a high ratio of inactivating to benign mutations (PMID: 24183448). RASA1 has also been implicated as a potential tumor suppressor in aggressive cutaneous squamous cell carcinoma and several subtypes of breast cancer (PMID: 25303977, 16570289, 19372580). The highest rates of RASA1 mutations have been reported for prostate adenocarcinoma (13.1%) and cutaneous squamous cell carcinoma (13%) (PMID: 22722839, 25303977). In most cancers somatic alterations in RASA1 are infrequent (e.g. 1.6% across 21 tumor types) (PMID: 24390350). RASA1 plays an essential role in vascular system development, as loss-of-function mutations cause capillary ‘malformation-arteriovenous’ malformation syndrome (CM-AVM) (PMID: 24038909, 22913934). True +ENST00000267163 NM_000321.2 5925 RB1 False RB1, a regulator of the cell cycle, is inactivated by mutation, deletion or allelic loss in various cancer types, including retinoblastoma and lung cancer. RB1, also known as RB, is involved in the cell-cycle checkpoint and in its active form inhibits the transition from G1 to S phase of the cell cycle until the cell is ready to divide. RB is active in its unphosphorylated form where it binds to E2F family of transcription factors, which together with the E2F Dimerization Partner (E2F-DP), inhibits the transcription of S-phase promoting factors by recruiting histone deacetylases (HDACs) and induce heterochromatin formation (PMID: 1655277). At the end of G1, cyclin-dependent kinases (CDKs) phosphorylate RB to pRB which leads to its dissociation from the E2F-DP complex, thereby allowing entry into S-phase. RB remains phosphorylated until the end of mitosis at which point it is dephosphorylated by protein phosphatase 1 (PP1) to activate the G1-S-phase checkpoint (PMID: 20694007). In addition to its role in G1 cell cycle arrest, RB1 has also been shown to play a role in safeguarding genome stability and mediating apoptosis, senescence and differentiation in response to various stimuli (PMID: 22293180). As a result of its role in these essential cellular functions, loss of function of RB1 not only leads to unregulated cell division and growth but also to the abrogation of multiple mechanisms that safeguard against cellular transformation and tumorigenesis. Loss-of-function and deletions of RB1 have been associated with many human cancers including lung, breast, prostate and bladder cancers, and concomitant loss of RB1 and p53 are thought to constitute a tumor-initiating event (PMID: 12204530). Homozygous loss or inactivation of the RB1 gene is a hallmark of retinoblastoma (PMID: 22293180), and heterozygous germline mutations in RB1 predispose children to retinoblastoma (PMID: 10502774, 24688104, 27068507) and adults to sarcoma and other tumors (PMID: 16269091, 22205104). True +ENST00000628161 NM_001204468.1 8241 RBM10 False RBM10 encodes a member of the RNA-binding motif gene family that is implicated in regulating mRNA alternative splicing. RBM10 is mutated in various human cancers, and also identified as a susceptibility gene in TARP syndrome. RBM10 encodes a nuclear protein that belongs to a family of proteins with RNA-binding motif. RBM10 is located on the X chromosome and therefore subject to X-inactivation whereby the remaining active allele is widely expressed in human cell lines and tissues (PMID: 11944989, 15514923). Mutations that result in a truncated RBM10 protein are identified as the causes of TARP (Talipes equinovarus, Atrial septal defect, Robin sequence, and Persistent left superior vena cava) syndrome, which has been reported to cause pre- or postnatal death in affected males (PMID: 20451169, 21910224, 24000153). RBM10 was discovered to be among the most frequently mutated genes in lung adenocarcinoma samples (PMID: 22980975, 25079552); mutations in this gene have also been observed in breast, colon, ovary, pancreas and prostate cancers (PMID: 20668451, 16959974). RBM10 has been characterized as an RNA-binding protein both in vitro and in vivo, and identified as an important regulator of alternative splicing (PMID: 24000153, 24332178). Recently, RBM10 has been shown to regulate alternative splicing of FAS and Bcl-X, two genes involved in apoptosis (PMID: 24530524). True +ENST00000369784 NM_022768.4 64783 RBM15 True RBM15, an RNA binding protein, is altered by chromosomal rearrangement in hematologic malignancies. RBM15 (also OTT) is an RNA binding protein that is a member of the SHARP family of proteins (PMID: 17376872). RBM15 is a regulator of N6-methyladenosine methylation of RNA, an RNA modification that impacts gene expression (PMID: 17376872). RBM15 binds pre-messenger RNA at introns of important hematopoietic genes, including GATA1, MPL, and RUNX1, and recruits splicing factors to mediate alternative splicing (PMID: 26575292, 25468569). In addition, RBM15 is important in the nuclear export of mRNA via binding to the nuclear receptor NFX1, leading to nuclear envelope localization in order to coordinate messenger ribonucleoprotein binding (PMID: 17001072, 18981216, 19586903, 19786495). RBM15 is also important in the regulation of several cellular functions including X chromosome inactivation, cell fate specification, DNA damage and cellular proliferation (PMID: 26190105). RBM15 is highly expressed in hematopoietic stem cells and RBM15 expression restricts the development of myeloid and megakaryocytic cell types (PMID: 17283045). In addition, RBM15 coordinately regulates differentiation in a cell-type specific manner with NOTCH transcriptional activity (PMID: 17283045). Loss of RBM15 expression in murine models results in hematopoietic abnormalities including loss of peripheral B cells and a shift towards myeloid progenitor fate (PMID: 17376872). Recurrent RBM15 translocations are found in patients with acute megakaryocytic leukemia (PMID: 11344311). In addition, somatic loss-of-function mutations in RBM15 have been identified in phyllodes tumors, a benign fibroepithelial neoplasm of the breast (PMID: 29315289). True +ENST00000421138 NM_002907.3 5965 RECQL False RECQL, a DNA helicase, is a germline breast cancer susceptibility gene. The RECQL gene encodes a DNA helicase that localizes to sites of DNA damage where mismatch repair factors are also recruited and unwinds the DNA (PMID: 7961977, 8056767, 15886194). The precise mechanisms of action of RECQL are largely unknown, but it is thought to be required for proper DNA replication, DNA repair and genome homeostasis (PMID: 18074021, 20065033, 15886194, 23095637). Alternative functions for RECQL include a role in telomere maintenance (PMID: 24623817). RECQL has been described to regulate genes that promote cell migration and invasion and inhibit apoptosis (PMID: 25424877, 25483193). The RECQL gene is rarely altered in tumors (cBioPortal, MSKCC, Dec. 2016). Germline mutations in RECQL have been associated with breast cancer susceptibility (PMID: 25915596, 25945795). True +ENST00000617875 NM_004260.4 9401 RECQL4 False RECQL4 encodes a DNA helicase that is involved in DNA replication and repair. Germline mutations of RECQL4 are associated with Rothmund-Thomson, RAPADILINO and Baller-Gerold syndromes and predispose to osteosarcomas, among other cancers. RECQL4 appears to function both in single-stranded DNA annealing and double-stranded DNA unwinding and is involved in DNA replication and various types of DNA repair, including double-strand break repair, nucleotide excision repair, base excision repair and single strand repair (PMID: 20065033, 20222902, 17320201, 18693251, 16949575, 22508716, 19567405). RECQL4 functions as a tumor suppressor. Inheritance of two compromised alleles leads to Rothmund-Thomson Syndrome (RTS), Baller-Gerold Syndrome (BGS), or RAPADILINO syndrome, each a rare syndrome with many overlapping phenotypic features. It has been suggested that the different syndromes are a result of mutations with different effects on the protein product, with certain domains involved in specific pathways (PMID: 20301383, 20113479, 17364146). RTS and RAPADILINO have a cancer predisposition, particularly osteosarcoma. RECQL4 somatic mutations, reported in tumors of numerous tissue types, are found across the gene without any specific hotspot. There is currently no therapy targeted at RECQL4 mutations. Missense mutations make up approximately 69% of all point mutations in RECQL4 in reported tumor samples. These mutations are scattered throughout the gene, include the Sld2 (DNA replicative factor) domain and the conserved RecQ-family helicase domain (PMID: 23238538, 23899764, 20668451, 24332040). Mutations in the Sld2 domain have the potential to affect the initiation of DNA replication (PMID: 25336622). Mutations within the helicase domain may affect the ability of RECQL4 to carry out strand annealing/unwinding functions (PMID: 25336622). True +ENST00000295025 NM_002908.2 5966 REL True REL, a transcription factor, is most frequently altered by mutation or amplification in B-cell lymphomas. REL encodes a transcription factor in the NF-kappa B family of transcription factors regulating immune function (PMID:22405852). It is important for the development of regulatory T-cells, B-cell proliferation and survival, and cytokine production (PMID:19995950,10049356,12646638, 12426000). While normally expressed mainly in lymphocytes, it has also been found expressed in various solid cancer types in an oncogenic role (PMID:18037997, 21933882). Polymorphisms in REL are associated with autoimmune disease such as rheumatoid arthritis, psoriasis, and gastrointestinal autoimmune disorders (PMID:19503088, 20953190, 21425313). REL is most frequently altered by amplifications seen in both Hodgkins and non-Hodgkins lymphomas (PMID: 11433522, 12511414, 11830502). It can also be over expressed in lymphomas through translocation with the immunglobulin loci (PMID:17079453). Mutations that alter REL transactivation activity are rare but have been seen in lymphomas (PMID:17072339,1650444, 11921291). REL promotes lymphoma proliferation and cell survival and inhibitors are in development for lymphoma therapy (PMID:17567982, 26744524). False +ENST00000428762 NM_005045.3 5649 RELN False RELN, an extracellular glycoprotein involved in neuronal migration, is altered by mutation in neurological disorders and in solid and hematologic malignancies. RELN (also Reelin) is a secreted extracellular matrix glycoprotein important in neuronal function (PMID: 27303269). Expression of RELN is highest during brain development and is predominantly secreted from Cajal-Retzius neurons and regions of hypothalamic differentiation (PMID: 9182958). In addition, expression of RELN shifts dramatically postnatally, suggesting different roles of RELN during development and adulthood (PMID: 18477607). Activity of RELN is required for appropriate cell migration, aggregation, synaptic function and dendrite formation (PMID: 27803648). RELN acts as an exogenous ligand that binds the receptors VLDLR and ApoER2, resulting in the phosphorylation of DAB1, a signaling effector molecule (PMID: 27803648). Activation of DAB1 initiates the activity of downstream signaling proteins including PI3K and the Src-family protein Crk (PMID: 18477607). RELN signaling mediates the activity of RAP1-GTP and cofilin, proteins involved in cell adhesion and actin cytoskeleton (PMID: 27803648). Loss of RELN in mouse models results in central nervous system defects including aberrant motor coordination, tremors, and altered gait (PMID: 7972007, 7715726). Reduced RELN expression has been implicated in a variety of neurological diseases including schizophrenia, bipolar disorder and autism, among others (PMID: 27092053). Germline RELN mutations are found in patients with neurodevelopmental disorder autosomal recessive lissencephaly with cerebellar hypoplasia (PMID: 10973257). Somatic mutations in RELN were identified in patients with T-cell precursor acute lymphoblastic leukemia, adult T-ALL and lung cancers (PMID: 22237106, 25595890, 22980976). Epigenetic silencing of RELN expression via methylation occurs in several cancer types including gastric and hepatocellular cancer (PMID: 19956836, 20734148, 29222813), suggesting that RELN likely functions as a tumor suppressor. False +ENST00000309042 NM_001193508.1 5978 REST False REST, a transcriptional repressor, is altered by mutation in various cancer types. Germline mutations of REST are associated with Wilm's tumor. REST (also NRSF or RE-1 silencing transcription factor) is a transcriptional repressor that is a member of the Krüppel-type zinc-finger transcription factor protein family (PMID: 23414932, 15907476). REST functions to suppress the expression of neuronal genes by binding to neuron-restrictive silencer elements (NRSE) (PMID: 15907476). Epigenetic modifying proteins that facilitate gene repression are recruited to chromatin by REST, including CDYL1, EHMT2, HDACs, and SIN3a, among others, to inhibit neuronal gene expression (PMID: 10491605, 15200951, 28286748, 10734093). REST activity has been implicated in the restriction of neuroendocrine cell fate, including in neuroendocrine tumor types such as small cell lung and prostate cancer (PMID: 28489825, 28256535, 24163104). REST also regulates various cellular functions including stemness, invasion, proliferation, hypoxia, neuronal function and embryonic development (PMID: 28256535, 27531581, 28286748). Germline mutations in REST are associated with Wilm’s tumor, a pediatric cancer that affects the kidney (PMID: 26551668). Epigenetic silencing of REST expression is implicated in neurodegenerative disease and in cancer (PMID: 29351877). Somatic truncating mutations and deletions in REST have been identified in several cancer types, including colorectal cancer, suggesting that REST predominantly functions as a tumor suppressor (PMID: 15960972, 23414932). However, increased REST activity is found in neuronal cancers, such as glioblastomas, medulloblastomas and neuroblastomas, suggesting that REST activity may be context-dependent (PMID: 23414932). True +ENST00000355710 NM_020975.4 5979 RET True 1 RET, a receptor tyrosine kinase, is altered by mutation in medullary thyroid cancers and by chromosomal rearrangement in lung cancers, papillary thyroid cancers, and rarely, other solid tumors. RET is a receptor tyrosine kinase that binds ligands of the glial cell line-derived neurotrophic factor (GDNF) family and transmits intracellular signals via the pro-oncogenic mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) pathways (PMID: 24561444). RET is normally expressed in the developing embryo, playing a particularly important role in neural and neuroendocrine lineages (PMID: 8306871). In cancer, RET can be activated either through point mutations or gene rearrangements with a variety of translocation partners resulting in constitutively active cytosolic oncoproteins (PMID: 24561444). Germline heterozygous, activating mutations in RET lead to the highly penetrant familial cancer syndromes multiple endocrine neoplasia type 2A (MEN2A: medullary thyroid carcinoma, pheochromocytoma, hyperparathyroidism), multiple endocrine neoplasia type 2B (MEN2B: medullary thyroid carcinoma, pheochromocytoma, multiple mucosal neuromas and intestinal ganglioneuromas, marfanoid habitus), and familial medullary thyroid carcinoma (FMTC) (PMID: 15322516, 19469690, 25810047). Oncogenic somatic mutations include point mutations and genomic rearrangements of the RET locus leading to inversions or translocations. These have been identified in various cancers including papillary thyroid cancer, lung adenocarcinoma and chronic myelomonocytic leukemia (CMML). In addition, aberrant expression or activation of wildtype RET correlates with tumor invasion and metastasis in pancreatic cancer and endocrine therapy resistance in breast cancer (PMID: 24561444). False +ENST00000358835 NM_002912 5980 REV3L True REV3L, a catalytic component of DNA polymerase zeta involved in translesion DNA synthesis, is frequently altered in cancer. REV3L, also known as POLZ, encodes the catalytic subunit of DNA polymerase zeta and functions in translesion DNA synthesis (PMID: 9618506). The catalytic activity of REV3L requires interaction with the non-catalytic subunit of polymerase zeta, REV7, and the scaffolding protein, REV1, to allow assembly of translesion DNA polymerases at sites of DNA damage (PMID: 22859296). REV3L maintains genomic stability and proliferation of cells in response to DNA damage, however, accumulation of DNA damage occurs as a result of REV3L-mediated proliferation (PMID: 11050391, 12805232). The expression level of REV3L varies in a variety of cancer tissues (PMID: 11115544) and cell lineage plays a large role in dictating the oncogenic function of REV3L alterations. Amplification of REV3L has been identified in various cancers, including glioma, esophageal squamous cell carcinoma and cervical cancer (PMID: 19289490, 26752104, 18593951). Overexpression of REV3L in cervical cancer cells promotes tumorigenesis as measured by increased cell growth and tumor colony formation (PMID: 25781640). Loss of REV3L has been identified in various cancers, including colon cancer, non-small cell lung cancer and gastric cancer (PMID: 18622427, 15617831). In vitro studies examining the deletion of REV3L have had conflicting results on the effects on cancer cell growth. REV3L inhibition in HeLa cells demonstrated no effect on tumorigenesis as measured by no alteration in colony growth or survival, however other studies using cervical cancer, lung, breast, mesothelioma and colon tumor cells demonstrated suppressed colony growth (PMID: 20028736, 22028621). Polymorphisms of REV3L resulting in loss of REV3L function have been identified in non-small cell lung cancer, breast cancer and mesothelioma (PMID: 22349819, 21455670, 24956248). False +ENST00000262187 NM_005614.3 6009 RHEB True RHEB encodes the protein Ras homolog enriched in brain (RHEB), a GTPase that is a direct upstream activator of the mTOR pathway. While RHEB is infrequently mutated in human cancer, it has been shown to be overexpressed in many cancer types, likely due to amplifications and/or post-transcriptional regulation. RHEB encodes a small GTPase within the RAS superfamily that functions as a molecular switch by activating the mTOR pathway (specifically, mTORC1) when bound to GTP (PMID: 24863881). Specifically, RHEB is thought to enact its activation upon mTORC1 via affecting the substrate affinity of mTORC1 for 4EBP1, a downstream effector of the mTOR pathway, resulting in protein synthesis activation (PMID: 19299511). RHEB is negatively regulated by the tuberous sclerosis complex (TSC1/TSC2) which functionally activates the GTPase activity of RHEB causing exchange of the RHEB-bound GTP for GDP thus preventing RHEB from activating mTORC1 (PMID: 18708577). The TSC1/TSC2 complex is frequently mutated in human cancers, which allows for RHEB-associated upregulation of the mTOR pathway (PMID: 18708577, 15240005). RHEB is ubiquitously expressed in human cells and is localized to the lysosomal membrane along with mTORC1 and the TSC1/TSC2 complex (PMID: 24863881, 14614311). Beyond its role in the regulation and activation of the mTORC1 complex, RHEB has been suggested to have multiple other non-canonical functions, including regulation of BRAF, as well as being important in developmental functions (PMID: 24863881, 21412983). RHEB has also been postulated to play a context-dependent role in the regulation of apoptosis and autophagy (PMID: 24216995). RHEB is not a commonly mutated gene in human cancer, although hotspot, activating mutations have been discovered within the effector domain in a small number of renal cell carcinomas and endometrial cancers (PMID: 24390350, 24631838, cbioportal March, 2015). RHEB has, however, been shown to be overexpressed in multiple cancer types, including liver, lung, prostate, lymphoma and bladder cancer, and RHEB overexpression has been postulated to be associated with poor outcomes in breast cancers and head and neck squamous cell carcinomas (PMID: 18708577, 18708578, 20388784). This overexpression may result in part from copy number gains (RHEB is located at 7q36) or focal amplifications, which occur in numerous cancer types including ovarian (12%, cbioportal March, 2015). RHEB overexpression has been proposed to be a biomarker for response to mTOR pathway inhibitors (rapalogs), although clinical evidence for this is lacking at this time (PMID: 18708578, 24631838). False +ENST00000418115 NM_001664.2 387 RHOA True RHOA, a GTPase, is altered in various solid and hematologic malignancies. The RHOA gene encodes a ubiquitously expressed small GTPase protein that primarily localizes to the cytoplasm. RHOA cycles between an active, guanosine triphosphate (GTP) bound, and an inactive, guanosine diphosphate (GDP) bound state. Proteins known as guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs) facilitate activation and inactivation of RHOA respectively. RHOA mediates several cellular functions by activating a number of downstream effectors, including the ROCK-cofilin pathway which stimulates cell motility by causing actin stress fiber formation and contractility (PMID: 25660168). RHOA plays an important role in tumorigenesis and metastasis by mediating invasion of tumor cells, and inhibition of RHOA signaling has shown anti-tumor effect in preclinical models (PMID: 21622195, 25728708, 20364104, 25333508). On the contrary, recent studies have shown that several oncogenic RHOA mutations lead to inactivation of the protein, and RHOA deletion is more common than RHOA amplification in some tumors, suggesting a complex and potentially context-dependent role of RHOA in cancer (cBioPortal, MSKCC, April. 2015; PMID: 24413737, 24816253). False +ENST00000357387 NM_152756.3 253260 RICTOR True RICTOR, a core component of the oncogenic mTOR2 complex, is altered by amplification or mutation in various cancer types. The RICTOR (rapamycin-insensitive companion of mTOR) gene encodes a core component of the mTOR complex-2 (mTOR2), which also includes mTOR, mLST8, DEPTOR, PRAS40, SIN1, and PROTOR1/2 (PMID: 20418915 ). RICTOR is an upstream kinase for several AGC kinase family members, including AKT/PKB, PKC (protein kinase C) and SGK1 (serum-glucocorticoid-induced protein kinase-1). In response to growth factors, mTOR2 phosphorylates and activates these kinases to regulate cytoskeletal organization, cell proliferation and survival (PMID: 22350330, 15268862, 15718470, 18566586, 18925875, 17141160, 18566587). Included in the mTORC2 targets is AKT, a key component in the pro-oncogenic PI3-kinase signaling pathway that regulates various cellular functions including cell survival, proliferation and apoptosis (PMID: 25505994, 15718470). RICTOR also associates with factors independent of mTOR (PMID: 20832730, 18339839, 18426911), and some of the less well-characterized mTOR-independent functions of RICTOR include regulation of cell morphology, migration and protein degradation (PMID: 21670596). Overexpression of RICTOR is positively associated with tumor progression and poor survival in hepatocellular carcinoma (PMID: 25371154), endometrial carcinoma (PMID: 24966915), pituitary adenoma (PMID: 23898069) and gastric cancer (PMID: 26159923). Upregulation of RICTOR is associated with renal cell carcinoma (RCC) metastasis, suggesting RICTOR as a potential biomarker for prognosis and stratification of patients with RCC (PMID:26500094). The RICTOR locus is amplified in melanoma (PMID: 26356562) and lung cancer (PMID: 26370156). False +ENST00000283109 NM_018343.3 55781 RIOK2 True RIOK2, a transcription factor and atypical kinase, is altered in various cancers. Right open-reading-frame kinase 2 (RIOK2), also known as Rio2, is an ATPase required for ribosome subunit maturation and is also a master transcription factor that regulates hematopoietic differentiation through control of GATA1, GATA2, SPI1, RUNX3 and KLF1 (PMID: 34359076, 34937919). This atypical kinase belongs to the RIO protein family, which comprises proteins that function in ribosome biogenesis, cell cycle progression and chromosome maintenance (PMID: 36518977, 16182620). RIOK2 assists in the maturation of the pre-40S ribosomal complex by facilitating subunit export from the nucleus to the cytoplasm (PMID: 33753942, 34359076). Additionally, RIOK2 plays a regulatory role in the metaphase-anaphase transition during mitosis. When RIOK2 is overexpressed, cells remain in metaphase for longer, and when RIOK2 is knocked down, the duration of mitosis is extended (PMID: 21880710). The role of RIOK2 in ribosome maturation and protein synthesis suggests that it functions as an oncogene. RIOK2 overexpression is implicated in the development of multiple cancers, including non-small cell lung cancer (NSCLC), glioblastoma, prostate cancer and acute myeloid leukemia (PMID: 36518977, 29749434, 23459592). However, RIOK2 loss is common in myelodysplastic syndromes, which results in decreased erythroid differentiation, anemia, increased megakaryopoiesis and myelopoiesis (PMID: 33753942, 34937919). Preclinical research into RIOK2 inhibitors such as ERGi-USU and NSC139021 is ongoing and has shown efficacy in vitro and in vivo (PMID: 29712692, 36518977, 34572430). False +ENST00000368323 NM_006912.5 6016 RIT1 True RIT1 encodes a RAS-related GTPase that plays a role in neuronal development and differentiation. Activating mutations in RIT1 are frequent in Noonan syndrome and are found in a variety of cancers, including lung adenocarcinoma, hepatocellular carcinoma and myeloid malignancies. RIT1 encodes a RAS-related small GTP-binding protein that belongs to the RAS subfamily of small GTPases (PMID: 8824319, 10545207). These proteins function as binary molecular switches; in response to external stimuli, they exchange GDP with GTP, thereby triggering several intracellular signaling networks. RIT1 is widely expressed in adult and embryonic tissue, including primary neurons and the developing brain. It plays a central role in the induction of neuronal differentiation through activation of both the BRAF/ERK and the p38 MAP kinase signaling pathways (PMID: 15632082, 11914372). Additionally, RIT1 plays a role in regulating axonal versus dendritic growth, and it contributes to IFNγ-induced dendritic retraction (PMID: 17460085, 12668729, 18957053). RIT1 has been identified as a regulator of a p38/MAPK-dependent cascade that functions as a prosurvival mechanism in response to oxidative stress (PMID: 21737674, 21444726, 23123784). RIT1 gain-of-function mutations are associated with Noonan syndrome (PMID: 25049390, 24939608, 23791108); activating mutations in the Switch II domain of RIT1 have been observed in lung adenocarcinoma and myeloid malignancies (PMID: 25079552, 24469055, 23765226). The transforming potential of RIT1 is associated with the activation of a p38γ-dependent signaling pathway (PMID: 11821041, 15831491). False +ENST00000221486 NM_006397 10535 RNASEH2A True RNAseH2A, a subunit of ribonuclease RNAse H2, is frequently altered by amplification in cancer. RNAseH2A encodes the catalytic A subunit of the trimeric endoribonuclease RNAse H2 and functions in DNA replication through the degradation of RNA in RNA/DNA hybrids (PMID: 19015152). RNAseH2A interfaces with the non-catalytic C subunit, RNAseH2C, through interaction on its C-terminus, and this interaction is required for the catalytic activity of the RNAse H2 complex (PMID: 21454563). Alterations of RNAseH2A that appear on this interface disrupt interaction and enzymatic activity and have been implicated in the human auto-inflammatory disease Aicardi-Goutières syndrome (PMID: 21177854). Overexpression of RNAseH2A is associated with poor patient prognosis and has been frequently identified in various cancers (PMID: 27176716, 32509219, 29843367). RNAseH2A amplification promotes tumorigenesis through the upregulation of cell cycle progression and survival and the downregulation of apoptosis in DNA-damaged cells (PMID: 29843367, 32509219). False +ENST00000336617 NM_024570 79621 RNASEH2B False RNAseH2B, a subunit of ribonuclease RNase H2, is frequently altered by deletion in cancer. RNAseH2B encodes the non-catalytic B subunit of the trimeric endoribonuclease RNAse H2 and functions in DNA replication through the degradation of RNA in RNA/DNA hybrids (PMID: 19015152). The conserved PCNA interacting protein-box sequence located on the C-terminus of RNAseH2B allows for PCNA binding to RNAseH2B to promote hydrolyzation of ribonucleotides misincorporated during replication (PMID: 19015152). Loss of RNAseH2B is associated with poor patient prognosis and has been frequently identified in various cancers including cervical cancer, intestinal carcinoma and prostate cancer (PMID: 29642758, 30273559, 35179959). RNAseH2B loss causes impairment in nucleotide excision repair and PARP trapping, leading to significant accumulation of DNA damage, genomic instability and tumorigenesis (PMID: 35179959). RB1 and BRCA2 are physically close to RNAseH2b on chromosome 13q and both genes are frequently co-deleted with RNAseH2B (PMID: 35179959). True +ENST00000407977 NM_017763.4 54894 RNF43 False RNF43, a ubiquitin ligase, is mutated in various cancers including gastrointestinal and gynecological cancers. RNF43 encodes for ring finger protein 43 is a transmembrane protein that has ubiquitin ligase activity (PMID: 24532711). It inhibits the Wnt pathway signaling by controlling Frizzled receptor expression through ubiquitination and protein degradation (PMID:26863187, 25891077). It binds to the ligand R-spondin which inhibits its activity (PMID:22575959). RNF43 is expressed in LGR5 positive colonic stem cells and regulates their growth and differentiation through Wnt signaling (PMID:22895187). Mutations are found in colorectal, endometrial, ovarian, gastric, cholangiocarcinoma, and pancreatic neoplasms (PMID:26257827, 25344691, 24816253, 22561520, 26505881, 23847203, 24293293, 26924569). Mutations have been characterized as loss of function and may lead to susceptibility to treatment with Wnt pathway inhibitors (PMID:25901018). RNF43 truncating mutations and loss-of-function mutations have been associated with increased sensitivity and clinical benefit in patients with microsatellite stable BRAF V600E-mutant colorectal cancer treated with anti-BRAF/EGFR therapies (PMID: 38394466, 36779536, 36097219). True +ENST00000464233 NM_002941.3 6091 ROBO1 False ROBO1, a signaling protein and axon guidance receptor, is recurrently altered by mutation and deletion in a range of hematopoietic and solid tumors. Germline mutations in ROBO1 are also found in families with a predisposition for both breast and colon cancer risk. ROBO1 is an axon guidance receptor that is a member of the immunoglobulin superfamily of proteins (PMID: 9458045, 27578174). ROBO1 is expressed on axon growth cones and controls midline axon crossing between the left and right half of the central nervous system (PMID: 16254601). Slit, an extracellular matrix protein, functions as a chemorepulsive signal at the midline and is a ligand for ROBO1 (PMID: 10102267). ROBO1 signaling also mediates a variety of other cellular functions including angiogenesis, migration, cell polarity, cell proliferation and mammary gland development (PMID: 27578174). SLIT2 and ROBO1 are implicated in a signaling pathway that regulates endothelial cell polarity and migration involving the effector proteins VEGFR, CDC42, NCK, and PAK2 (PMID: 26659946). Heterozygous loss of ROBO1 expression in murine models results in tumor formation, suggesting a role of ROBO1-SLIT2 signaling in cancer (PMID: 15374951). Germline ROBO1 variants are associated with neurodevelopmental disorders including craniofacial microsomia and dyslexia, among others (PMID: 16254601, 28402530, 28286008). In addition, germline ROBO1 mutations are found in families with a predisposition for familial breast and colon cancer (PMID: 29698419, 26427657). Somatic loss-of-function mutations in ROBO1 have been identified in patients with hematopoietic malignancies including myelodysplastic syndromes and multiple myeloma (PMID: 26608094, 24429703). Deletions and hypermethylation of ROBO1 are also found in a range of cancer types including lung cancer, colorectal cancer and cholangiocarcinomas, among others (PMID: 12615722, 21603610, 19104841, 24500968, 27009864), suggesting that ROBO1 predominantly functions as a tumor suppressor. Several studies, however, propose that ROBO-SLIT signaling may also promote cancer progression in some contexts dependent on the availability of SLIT2 ligand (PMID: 12892710). True +ENST00000368508 NM_002944.2 6098 ROS1 True 1 R2 ROS1, a receptor tyrosine kinase, is altered by mutation or chromosomal rearrangement in a diverse range of cancers, including lung cancer. The ROS1 gene encodes a transmembrane protein with intracellular tyrosine kinase activity (PMID: 18778756). ROS1 is a member of the sevenless subfamily of tyrosine kinase insulin receptor genes (PMID: 27256160). The normal physiological role and ligand of this protein in humans is currently unknown (PMID: 23814043). ROS1 rearrangements where the kinase domain is retained (PMID: 22327623) are implicated in a range of human epithelial cancers including cholangiocarcinoma (PMID: 21253578), ovarian carcinoma (PMID: 22163003), gastric carcinoma (PMID: 23400546), angiosarcoma (PMID: 23637631) and most commonly non-small cell lung cancer (PMID: 22215748). Although ROS1 rearrangements were first discovered in a human glioblastoma cell line (PMID: 2827175), there is a paucity of ROS1 rearrangements in human gliomas (PMID: 24999209). The mechanism by which ROS1 rearrangements leads to dysregulated kinase activity is not clear, as its ligand has not yet been deciphered; however, it is hypothesized to occur through constitutive kinase activation (PMID: 18083107). R2 False +ENST00000370321 NM_000969 6125 RPL5 False RPL5, a ribosomal protein, is infrequently altered in cancer. RPL5 encodes for the 60S ribosomal protein L5, a component of the ribosome (PMID: 7937132, 7772601). RPL5 interacts with MDM2 to mediate protein ubiquitination and degradation in response to ribosomal stress (PMID: 16803902). RPL5 also functions as a component of the 5S RNA-protein complex through binding to 5S rRNA (PMID: 11410658). Knockdown of RPL5 in various cancer cell lines and models induces increased cellular proliferation, tumor growth and increased inflammation suggesting that RPL5 functions predominantly as a tumor suppressor gene (PMID: 28147343, 33348919). Downregulation of RPL5 has been identified in various types of cancer, including glioblastoma, breast cancer and multiple myeloma (PMID: 28147343, 27909306). RPL5 mRNA expression has been suggested as a predictive biomarker for initial response to bortezomib for newly diagnosed and relapsed patients with multiple myeloma (PMID: 27909306). True +ENST00000593052 NM_001308226 6209 RPS15 True RPS15, a ribosomal protein, is altered by mutation in chronic lymphocytic leukemia. RPS15 encodes for a ribosomal protein that is a component of the 40S ribosomal subunit (PMID: 35438042). RPS15 is essential for mRNA translation and ribosomal biogenesis as the protein mediates interaction between the 40S and 60S ribosomal subunits, facilitates binding of mRNA and tRNA during translation and mediates nuclear export and cytoplasmic processing of rRNA (PMID: 32583822, 16037817). Overexpression of RPS15 in esophageal squamous cell carcinoma cancer cell lines and models induces cellular proliferation, migration and invasion, suggesting that RPS15 functions predominantly as an oncogene (PMID: 37264021). RPS15 mutations have been identified in chronic lymphocytic leukemia (PMID: 30498067, 34251413). False +ENST00000334205 NM_003942.2 8986 RPS6KA4 True RPS6KA4 encodes a serine/threonine kinase involved in the MAPK signaling pathway. RPS6KA4 regulates several oncogenes and is a potential chemotherapeutic target. The ribosomal protein S6 kinase, 90 kDa, polypeptide 4 (RPS6KA4, also known as MSK2 or RSK-B), is a serine/threonine protein kinase, composed of two kinase domains, the N and C-terminal kinase domains and acts as an important downstream effector of mitogen-activated protein kinase (MAPK) (PMID:9003374,7498520). Many growth factors, peptide hormones, and neurotransmitters regulate RPS6KA4 through Erk1/2 signaling (PMID: 10411321,10610536). Knockdown of RPS6KA4 gene expression leads to upregulation of p53 transcriptional activity and its overexpression results in the inhibition of p53 target promoters and p53-mediated apoptosis, indicating that RPS6KA4 has a p53-inhibiting function (PMID:16929179, 19797274). Moreover, the antitumoral effect of α-Lipoic acid (α-LA) on colorectal cancer cells stems, at least partially, from its property to prevent RPS6KA4-mediated p53 inhibition (PMID:23599020). MAPKs play a major role in UV-induced skin cancer development and a phospho-MAPK array analysis indicated that p38α and its downstream target proteins, MSK2 and HSP27, were strongly activated by UVB and SUV (PMID:23382047). RPS6KA4 is also known as MSK2 (human mitogen- and stress-activated protein kinase 2) and shares 64% homology with MSK1. Activated MSK1/2 is known to induce cellular transformation in various cell lines; for instance, following induction by EGF and TPA, MSK1/2 activation leads to cellular transformation of mouse epidermal cells (JB6 cells) (PMID:18381464). The role of MSK1/2 in cellular transformation also involves its ability to activate various transcription factors such as CREB, ATF1, ER81, and the p65 subunit of NFκB, which in turn activate the transcription of genes involved in tumorigenic and metastatic progression (PMID:22983151). MSK1/2 also mediate chromatin remodeling that is required at the enhancer and upstream promoter element for TPA-induced initiation of TFF1 expression in MCF-7 breast cancer epithelial cells (PMID:23675462). Finally, an exciting new study reported that MSK1/2 is involved in an in vivo model of skin tumor development (PMID: 21314333). Mice lacking MSK1 and 2 exhibit reduced skin tumor formation by tumor promoting agents 7,12-dimethylbenz[a]anthracene (DMBA) and TPA in a multistage skin carcinogenesis model compared to wild-type mice. As such, MSK1/2 as a key regulator of expression of several oncogenes presents a potential target in chemotherapeutic development (PMID:21314333). Inhibition of MSK1/2 can be achieved by cell permeable molecules that have varying degrees of potency and selectivity. The two most common inhibitors used to study the effects of MSK in vitro are H89 and Ro 318220 (PMID:10998351,22983151). False +ENST00000312629 NM_003952.2 6199 RPS6KB2 True RPS6KB2 encodes a serine/threonine kinase involved in protein translation, cell proliferation and survival. Copy number alterations and mutations of RPS6KB2 are found in various cancers and are associated with poor prognosis. RPS6KB2 encodes the ribosomal protein S6 kinase β-2 (S6K2), a serine/threonine kinase involved in the control of cap-independent translation of a subset of proteins, in proliferation and in cell survival (PMID: 10490847, 22431522, 17786541, 16810323). In addition, S6K2 plays a role in learning, memory and synaptic plasticity (PMID: 18174371). S6K2 is activated upon stimulation of cells with insulin, serum or phorbol 12-myristate 13-acetate by effectors of the PI3K signaling pathway, such as Rac, CDC42, PDK1 and PKC-ζ (PMID: 9804755, 10490846, 11108711, 8653792, 9445476, 10082559, 12529391). Genetic variations in RPS6KB2 are associated with Alzheimer disease (PMID: 21811019). S6K2 is ubiquitously expressed, with the highest levels found in the gastrointestinal tract, lungs and central nervous system; levels in normal tissues are relatively low, compared with levels in corresponding tumor samples (PMID: 21444676, 16810323). High levels of S6K2 are found in adenocarcinoma, breast cancer, endometrial cancer, lung cancer and gastric cancer (PMID: 15627062, 21748818, 15995633, 15627061, 20953835, 16810323, 23393338). Expression and localization of RPS6KB2 are distinguishing features of cancer cells (PMID: 15627062). Amplification of RPS6KB2 has prognostic value and can help predict treatment success in breast cancer. In endometrial and gastric cancers, the level of nuclear expression of RPS6KB2 correlates with tumor grade and decreased overall survival. In lung cancer, increased expression of S6K2 is correlated with drug resistance (PMID: 15627062, 21748818, 15995633, 15627061, 20953835, 16810323). Somatic mutations are found in lung adenocarcinomas in nonsmokers and are associated with worse survival (PMID: 24894543). Polymorphisms in RPS6KB2 are associated with a risk of developing colon cancer and rectal cancer (PMID: 21035469). False +ENST00000306801 NM_020761.2 57521 RPTOR True RPTOR encodes a scaffolding protein in the mTORC1 complex that regulates protein synthesis. RPTOR (regulatory-associated protein of mTOR) encodes a scaffolding protein that regulates the assembly, localization and substrate binding of mTORC1. mTOR (mechanistic target of rapamycin) is an atypical serine-threonine protein kinase that belongs to the phosphoinositide 3-kinase (PI3K)-related kinase family (PMID: 19339977). It interacts with several proteins to form two distinct complexes named mTOR complex 1 and 2 (mTORC1 and mTORC2). RPTOR/raptor is a unique member of the mTRORC1 complex and serves as a scaffolding protein and is essential for mTORC1 complex activity (PMID: 25450580, 14684181, 26159692). mTORC1 is a key regulator of protein synthesis (PMID: 19339977). RPTOR binds to the translational regulator 4E-BP1 and mTORC1 then directly phosphorylates 4E-BP1, which, in turn, promotes protein synthesis (PMID: 19339977, 15718470). mTORC1 also controls the synthesis of lipids required for proliferating cells to generate membranes (PMID: 19948145). The mTOR pathway is of great importance in cancer pathogenesis (PMID: 25450580). Many components of the pathway upstream of mTORC1 are mutated in human cancers (PMID: 22500797). Derivatives of rapamycin (rapalogs) that potently inhibit mTOR activity are tested in different cancer types some of which are clinically approved (PMID: 21490404). False +ENST00000373001 NM_022157.3 64121 RRAGC True RRAGC, an mTORC1 activator, is mutated in follicular lymphomas. The RRAGC gene encodes a guanine-binding protein of the RAG family of GTPases; it acts as a heterodimer with RRAGCA or RRAGCB (PMID: 24095279). RRAGC targets mTORC1, a complex that responds to growth factors and various other stimuli to positively regulate cell growth that is frequently deregulated in cancer. Specifically, RRAGC regulates the intracellular localization of mTORC1 and facilitates its RHEB-dependent activation (PMID: 20381137, 27234373). RRAGC missense mutations are found in follicular lymphomas (PMID: 26691987). False +ENST00000246792 NM_006270.3 6237 RRAS True "RRAS is a small GTPase, and mutations in this gene are found in disorders termed ""RASopathies"" as well as in hematologic and pediatric cancers." "RRAS (also R-Ras) is a small GTPase protein belonging to the RRAS subfamily of Ras-like GTPases. RRAS regulates diverse cellular processes including angiogenesis, vascular homeostasis, vascular regeneration, cell adhesion and neuronal axon guidance (PMID: 28610953). In addition, RRAS regulates the organization of the actin cytoskeleton and promotes the formation of ruffling lamellipodia via its activation of phospholipase Cε (PMID: 16537651). RRAS mediates cell adhesion, cell spreading, cell polarization and phagocytosis via Integrin β1 activity (PMID: 8620538,18270267, 11257001). Loss of RRAS expression in mice results in vasculature defects, highlighting the importance of RRAS in the hematopoietic system (PMID: 27029009). Germline mutations in RRAS are found in disorders related to Noonan Syndrome collectively called ""RASopathies"" and rare somatic alterations have been associated with hematologic and pediatric cancers (PMID: 24705357)." False +ENST00000256196 NM_012250.5 22800 RRAS2 True RRAS2, a small GTPase, is altered frequently by amplification or missense mutations in various cancers. RRAS2 (also TC21) is a small GTPase protein belonging to the RRAS subfamily of Ras-like GTPases. RRAS2 primarily localizes to the plasma membrane and activates the MAPK (mitogen-activated protein kinase), PI3K (phosphatidylinositol 3-kinase), and JNK signaling cascades (PMID: 10557073,11850823). Interaction of RRAS2 with c-Raf initiates these downstream signaling pathways and mediates transformation and differentiation of diverse cell types (PMID: 10557073,11850823). Functional experiments have demonstrated that RRAS2 can function as an oncogene, as engineered gain-of-function mutations have high levels of transforming activity and induce transcriptional activation from Ras-responsive promoter elements (PMID: 8196649). Oncogenic mutations in RRAS2 are occasionally found in tumor cell lines (PMID: 8052619, 7478545) and RRAS2 amplification is found in many cell lines derived from breast cancer (PMID: 8552388); however, RRAS2 alterations are relatively rare in human cancers. False +ENST00000360203 NM_001283009.2 51750 RTEL1 False RTEL1 is a helicase important for regulating telomere length in which germline mutations are associated with dyskeratosis congenital and Hoyerall-Hreidarsson syndrome. RTEL1 (Regulator of telomere length1) encodes a DNA helicase implicated in telomere length regulation, DNA repair, and maintaining genomic stability. The helicase activity of RTEL1 is essential in disassembling telomere loops and suppressing telomere fragility to maintain the integrity of chromosome ends (PMID: 24115439). In addition, it interacts with proteins in the shelterin complex known to protect telomeres during DNA replication (PMID:23959892). It also acts as an anti-recombinase to affect the disassembly of toxic DNA recombination intermediates, and thus regulates meiotic recombination and crossover homeostasis (PMID: 18957201). Germline mutations in this gene have been associated with dyskeratosis congenital (PMID: 23329068) and Hoyerall-Hreidarssonsyndrome (PMID: 23959892). True +ENST00000300305 NM_001754.4 861 RUNX1 False RUNX1, a transcription factor involved in hematopoietic differentiation, is altered by mutation or chromosomal rearrangement in various hematologic malignancies. RUNX1, also known as AML1 or CBFA2, is a transcription factor that is a master regulator of hematopoietic differentiation. It interacts with a diverse subset of transcriptional complexes and can act as a transcriptional activator via recruitment of histone acetyltransferases or methyltransferases (PMID: 18695000, 22012064), or a repressor via recruitment of histone deacetylases or Polycomb-repressive complex 1 (PRC1) (PMID: 21059642, 22325351). Due to its important role in hematopoiesis, conditional deletion of RUNX1 in mice results in an expansion of the hematopoietic stem and progenitor population, and defective T- and B-lymphocyte development (PMID: 14966519). RUNX1 is highly regulated via alternative splicing, ubiquitination, phosphorylation, acetylation, and methylation, which has important regulatory consequences in cancer (PMID: 19386523). RUNX1 is frequently translocated and altered in acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), acute lymphoid leukemia (ALL), and Familial platelet disorder with predisposition for acute myeloid leukemia (FPD/AML) (PMID: 17290219, 15156185, 21174539). Many translocations involving RUNX1 lack the activation domain, and have a leukemogenic effect by acting as a dominant negative inhibitor of wild-type RUNX1 in transcription activation (PMID: 15156182). True +ENST00000265814 NM_001198626.1 862 RUNX1T1 True RUNX1T1, a transcriptional repressor, is recurrently altered by fusion in acute myeloid leukemias. RUNX1T1 (also ETO, MTG8, CBFA2T1) is a transcription factor that is a member of ETO/MTG family of proteins (PMID: 15649458). RUNX1T1 functions as a transcriptional repressor and interacts with several complexes involved in silencing of gene expression, including the nuclear receptor corepressor (NCoR), silencing-mediator for retinoid/thyroid hormone receptors (SMRT), mSin3a, and histone deacetylases (PMID: 9724795, 9819404, 9819405, 9724795). In addition, RUNX1T1 co-binds CEBPA, a transcription factor associated with tissue-specific differentiation programs (PMID: 19811452). RUNX1T1 is expressed in normal heart and brain tissues and is not highly expressed in hematopoietic lineages (PMID: 9661669, 9209371). Functional studies of RUNX1T1 activity have been predominantly completed in the context of leukemic fusion proteins; therefore, further work is necessary to study the cellular functions of wildtype RUNX1T1. The RUNX1-RUNX1T1 or t(8;21) fusion (most commonly termed AML-ETO fusion) is the most frequent translocation in acute myeloid leukemia (PMID: 8338940). In this fusion protein, the RUNT homology domain of the RUNX1 gene on chromosome 21 is fused to the entirety of the RUNX1T1 gene on chromosome 8 (PMID: 11607817). The AML-ETO fusion protein is insufficient to drive leukemia in murine models and human leukemias, suggesting that a second mutational hit is required for leukemogenesis (PMID: 22875638, 26666262). This translocation functions as an oncogene by enhancing self-renewal in hematopoietic stem cells and mediating transcriptional activity via the recruitment of epigenetic complexes to target genes (PMID: 28299657, 11607817). False +ENST00000481739 NM_002957.4 6256 RXRA False RXRA is a nuclear receptor and a transcriptional regulator, and deficiency of RXRA cause hyperplasia and aberrant differentiation in skin and prostate. RXRA encodes the Retinoid X Receptor Alpha, which is a member of the steroid and thyroid hormone receptor superfamily of transcriptional regulators. RXRA functions either as a homodimer or as a heterodimeric partner for a number of nuclear receptors. RXRA/PPARA (Peroxisome Proliferator-activated Receptor- alpha) heterodimers regulate PPARA-mediated transcriptional activity on genes involved with fatty acid oxidation, such as the cytochrome P450 system genes (PMID: 10195690). RXRA also heterodimerizes with the thyroid hormone receptor (T3R), Vitamin D3 receptor (VD3R) and Retinoic Acid Receptors (RARs). RXRA is required for forming stable complexes of these receptors with their cognate DNA response elements and for transactivation of genes regulating growth, differentiation, metabolism, homeostasis and neoplasia (PMID: 1314167, 1310351). In acute promyelocytic leukemia (APL) driven by PML/RARA fusion protein, RXRA is deemed essential for APL pathogenesis in vivo, even though PML/RARA can complex with DNA and transform primary hematopoietic progenitors ex vivo (PMID: 17613434). RXRA deficiency causes hyperplasia and aberrant differentiation of skin epidermis and prostate epithelium (PMID: 11171393, 12183441). False +ENST00000477973 NM_012234.5 23429 RYBP False RYBP is a transcriptional repressor with a possible tumor-suppressor function. It is frequently lost in prostate cancer. The RYBP (RING1 and YY1 binding protein) protein is a Polycomb group protein that is involved in transcriptional regulation. RYBP is part of the Polycomb-repressive complex 1 (PRC1) and interacts directly with RING1, RNF2, and YY1, to mediate H2A ubiquitylation at specific polycomb target sites to repress these genes (PMID: 22325148). It has been show to play an important role in development and stem cell programming through its role in transcriptional repression (PMID: 10369680). RYBP also has polycomb-independent roles, and can act as a tumor suppressor through interaction with MDM2 and subsequent stabilization of TP53 (PMID: 19098711). The genetic locus of RYBP is frequently deleted in prostate cancers and loss of RYBP expression has been detected in hepatocellular carcinoma and non-small cell lung cancer and is associated with poor outcome (PMID: 20579941, 25344099, 26404750). True +ENST00000379958 NM_017654.4 54809 SAMD9 False SAMD9, a cytoplasmic nuclease, is infrequently altered in various cancers. SAMD9 encodes a multi-domain, cytoplasmic anticodon nuclease that plays a role in many cell functions including immune response to viral infection, protein translation and endosome fusion (PMID: 37285440, 28545555, 28157624). An effector domain in SAMD9 preferentially binds to double-stranded nucleic acids and is crucial in its antiviral and antiproliferative functions (PMID: 35046037, 25428864). Additionally, the SAM domain located at the N-terminus of SAMD9 is able to polymerize and facilitate protein-protein interactions (PMID: 21805519). Key functions of SAMD9 include binding and cleaving the phenylalanine tRNA molecule, effectively decreasing protein translation, and binding endosome protein RGI2 to regulate endosome function (PMID: 38848876). SAMD9 expression is regulated by interferon and tumor necrosis factor-α, and activation of SAMD9 downregulates MYC and E2F targets (PMID: 33731850, 38848876). SAMD9 is implicated in the development of myeloid lineage malignancies via dysregulation of cell cycle control and endocytosis, including those characterized by deletions of chromosome 7q (PMID: 27259050, 35046037, 24029230). Knockdown of SAMD9 increases the invasion, migration and proliferation of non-small cell lung cancer (NSCLC) cells in vitro, while overexpression of SAMD9 suppresses proliferation and invasion in NSCLC cells (PMID: 25450373). However, SAMD9 silencing and knockdown in vivo reduces esophageal squamous cell carcinoma formation and metastasis and reduces migration and invasion of glioma and lung cancer cell lines in vitro (PMID: 36757050, 31646435). Gain-of-function mutations in SAMD9 that inhibit cell proliferation cause the autosomal recessive disorder normophosphatemic familiar tumoral calcinosis and the autosomal dominant disorder MIRAGE syndrome (myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes, and enteropathy) (PMID: 35046037, 16960814, 27182967). False +ENST00000318238 NM_152703.5 219285 SAMD9L False SAMD9L, a cytoplasmic nuclease, is infrequently altered in various cancers. SAMD9-like (SAMD9L) encodes a multi-domain, cytoplasmic anticodon nuclease that plays a role in many cell functions including immune response to viral infection, protein translation and endosome fusion (PMID: 37285440, 28545555, 28157624). An effector domain in SAMD9L preferentially binds to double-stranded nucleic acids and is crucial in its antiviral and antiproliferative functions (PMID: 35046037, 25428864). Additionally, the SAM domain located at the N-terminus of SAMD9L is able to polymerize and facilitate protein-protein interactions (PMID: 21805519). Key functions of SAMD9L include binding and cleaving the phenylalanine tRNA molecule, effectively decreasing protein translation, and binding endosome protein RGI2 to regulate endosome function (PMID: 38848876, 33731850). SAMD9L expression is regulated by interferon and tumor necrosis factor-α, and activation of SAMD9L downregulates MYC and E2F targets (PMID: 33731850, 38848876). Disruption of SAMD9L is associated with the development of myelodysplastic syndromes and acute myeloid leukemia, including those characterized by deletions of chromosome 7q, via dysregulation of endocytosis, hematopoietic cell proliferation and differentiation (PMID: 28346228, 24029230, 28202457, 27259050, 35046037). Knockdown of SAMD9L increases cell proliferation and colony formation in hepatocellular carcinoma cell lines and increases tumorigenicity in nude mice (PMID: 27259050). Gain-of-functions in SAMD9L that inhibit cell proliferation cause ataxia-pancytopenia and other immunodeficiency disorders with variable neurological presentations (PMID: 35046037, 28202457). False +ENST00000646673 NM_015474.3 25939 SAMHD1 False SAMHD1, a deoxynucleoside triphosphate triphosphohydrolase involved in cellular dNTP homeostasis, is recurrently altered by mutation in chronic lymphocytic leukemia. SAMHD1 (also AGS5 and Mg11) is a deoxynucleoside triphosphate triphosphohydrolase involved in cellular dNTP homeostasis (PMID: 28502830). SAMHD1 converts dNTPs, the nitrogenous bases that are required for DNA synthesis, into deoxynucleosides after stimulation by dGTP, leading to depletion of the dNTP pool (PMID: 28502830, 22056990). The activity of SAMHD1 is regulated by the concentration of dNTPs, which allosterically bind SAMHD1 to regulate tetramerization and catalytic activity (PMID: 28502830, 25760601). In addition, SAMHD1 may also have ribonuclease activity; however, this finding is controversial (PMID: 25038827, 26101257). SAMHD1 has been implicated in additional cellular functions including innate immunity and DNA end resection during DNA repair (PMID: 19525956, 28834754). SAMHD1 is also a restriction factor that renders myeloid and dendritic cells refractory to HIV infection by hydrolyzing intracellular dNTPs in non-cycling cells, decreasing the dNTP pool required for DNA synthesis (PMID: 21613998, 22926205). Germline mutations in SAMHD1 are found in patients with Aicardi-Goutières syndrome, a neurodevelopmental disorder that aberrantly activates the immune system and resembles congenital infection (PMID: 19525956). Somatic SAMHD1 mutations are found in patients with chronic lymphocytic leukemia (PMID: 24335234). SAMHD1 is predicted to function as a tumor suppressor as mutations in SAMHD1 result in reduced protein expression (PMID: 24335234). Expression of SAMHD1 can also result in resistance to nucleoside-based chemotherapies by hydrolyzing the active triphosphate metabolites, namely in acute myeloid leukemia (PMID: 28502830, 27991919). True +ENST00000300175 NM_001144757.1 6447 SCG5 True SCG5, a secreted chaperone protein, is infrequently altered by amplification and mutation in neuroendocrine tumors. Germline mutations in SCG5 are associated with hereditary mixed polyposis syndrome and predispose to colorectal cancers. SCG5 (also Secretogranin V or 7B2) is a secreted chaperone protein that is a member of the granin family (PMID: 2053134, 21862681, 22947085). SCG5 is predominantly expressed in neuroendocrine tissues and functions to reduce the aggregation of other secreted proteins (PMID: 21862681, 22947085). In addition, SCG5 activates the proprotein convertase (PC2) enzyme which initiates neuroendocrine peptide maturation by facilitating transport of protein precursors through the endoplasmic reticulum and secretory pathway (PMID: 11719503, 11439082, 10799554, 9881669). Additional studies have identified SCG5 as a β-cell associated antigen that is recognized by naïve CD8-positive T-cells (PMID: 30078552). Aberrant SCG5 activity has been implicated in neurodegenerative disorders and mediates amyloid-β and α-synuclein aggregation (PMID: 23172224). Germline duplications involving a region including SCG5 and GREM1 are found in patients with hereditary mixed polyposis syndrome and these alterations may be associated with colorectal cancer risk (PMID: 27984123, 22561515, 18084292). Various neuroendocrine tumors, including renal cell, pancreatic and small cell lung cancers, are found to have altered expression of SCG5 (PMID: 2548871, 29796168, 25023465). False +ENST00000264932 NM_004168.2 6389 SDHA False SDHA encodes a tumor suppressor involved in the electron transport chain. Germline mutations of SDHA are associated with paraganglioma and pheochromocytoma and predispose to gastrointestinal cancers. SDHA (Succinate dehydrogenase A) is one of the four components of the succinate dehydrogenase (SDH) complex and is a critical enzyme in the mitochondrial electron transport chain. SDHA localizes to the inner membrane of mitochondria and couples the oxidation of succinate to fumarate and transfers electrons directly to the ubiquinone pool (PMID: 16892081, 21771581). SDHA and other SDH complex family members function as tumor suppressors; loss of function mutations in these genes have been shown to stabilize hypoxia-inducible factors (HIF), thus leading to a hypoxic state that promotes tumorigenesis (PMID: 20484225, 11605159, 16103922). Mutations in components of the SDH complex lead to accumulation of succinate, which can competitively inhibit the action of alpha-ketoglutarate-dependent histone- and DNA-demethylases in a variety of cancers and lead to a hypermethylator phenotype (PMID: 23707781). Germline loss-of-function mutations in the SDH genes, including SDHA, cause hereditary paraganglioma and pheochromocytoma (PMID: 21771581). Mutations in SDH genes have also been linked to gastrointestinal tumors (PMID: 23730622). True +ENST00000301761 NM_017841.2 54949 SDHAF2 False SDHAF2 encodes a tumor suppressor involved in the electron transport chain. Germline mutations of SDHAF2 are associated with head and neck parangangliomas. SDHAF2 (Succinate dehydrogenase assembly factor 2) is critical to the appropriate assembly of the succinate dehydrogenase (SDH) protein complex, which is important in the mitochondrial electron transport chain. SDHAF2 physically resides in the inner membrane of mitochondria (PMID: 19628817) and ensures appropriate incorporation of flavin adenine dinucleotide (FAD) into the SDH complex (PMID:19628817). Mutations in SDHAF2 have been associated with hereditary head and neck paragangliomas and pheochromocytomas (PMID: 20071235, 21224366). Paragangliomas associated with SDHAF2 mutations typically have a young age of onset and do not co-occur with mutations in SDH components (e.g. SDHA). Notably, it was identified that children who inherited a maternal mutant SDHAF2 allele were not affected by the disease, suggesting that parent-of-origin for the mutant allele is important in the development of the disease (PMID: 21771581). True +ENST00000375499 NM_003000.2 6390 SDHB False SDHB encodes an enzyme involved in the electron transport chain. Germline mutations of SDHB are associated with pheochromocytomas and paragangliomas and gastrointestinal, renal cell and pituitary cancers. SDHB (Succinate dehydrogenase B) is one of the four components of the succinate dehydrogenase (SDH) complex and is a critical enzyme in the mitochondrial electron transport chain. SDHB localizes to the inner membrane of mitochondria and couples the oxidation of succinate to fumarate and transfers electrons directly to the ubiquinone pool (PMID: 16892081, 21771581). SDHB and other SDH complex family members function as tumor suppressors; loss of function mutations in these genes have been shown to stabilize hypoxia-inducible factors (HIF), thus leading to a hypoxic state that promotes tumorigenesis (PMID: 18978332). SDH mutations have been involved in the pathogenesis of pheochromocytomas, paragangliomas, gastrointestinal stromal tumors (GISTs), renal-cell carcinomas and pituitary adenomas (PMID: 25394176). Mutations in components of the SDH complex lead to accumulation of succinate, which can competitively inhibit the action of alpha-ketoglutarate-dependent histone- and DNA-demethylases in a variety of cancers and lead to a hypermethylator phenotype (PMID: 23707781, 23743927). Germline loss of function mutations in the SDH genes, including SDHB, cause hereditary paraganglioma and pheochromocytoma (PMID: 21771581). True +ENST00000367975 NM_003001.3 6391 SDHC False SDHC encodes an enzyme involved in the electron transport chain. Germline mutations of SDHC are associated with pheochromocytomas and paragangliomas and gastrointestinal, renal cell and pituitary cancers. SDHC (Succinate dehydrogenase C) is one of the four components of the succinate dehydrogenase (SDH) complex and is a critical enzyme in the mitochondrial electron transport chain. While SDHA and SDHB form the catalytic domain of the SDH complex, SDHC and SDHD anchor the complex to the inner mitochondrial membrane (PMID: 10657297). SDHC and other SDH complex family members function as tumor suppressors; loss of function mutations in these genes have been shown to stabilize hypoxia-inducible factors (HIF), thus leading to a hypoxic state that promotes tumorigenesis (PMID: 18978332, 17102089). SDH mutations have been involved in the pathogenesis of pheochromocytomas, paragangliomas, gastrointestinal stromal tumors (GISTs), renal-cell carcinomas and pituitary adenomas (PMID: 25394176). Mutations in components of the SDH complex lead to accumulation of succinate, which can competitively inhibit the action of alpha-ketoglutarate-dependent histone- and DNA-demethylases in a variety of cancers and lead to a hypermethylator phenotype (PMID: 23707781, 23743927 ). Germline loss of function mutations in the SDH genes can cause hereditary paraganglioma and pheochromocytoma (PMID: 21771581). True +ENST00000375549 NM_003002.3 6392 SDHD False SDHD encodes an enzyme involved in the electron transport chain. Germline mutations of SDHD are associated with pheochromocytomas and paragangliomas and gastrointestinal, renal cell and pituitary cancers. SDHD (Succinate dehydrogenase D) is one of the four components of the succinate dehydrogenase (SDH) complex and is a critical enzyme in the mitochondrial electron transport chain. While SDHA and SDHB form the catalytic domain of the SDH complex, SDHC and SDHD anchor the complex to the inner mitochondrial membrane (PMID: 10657297). SDHD and other SDH complex family members function as tumor suppressors; loss of function mutations in these genes have been shown to stabilize hypoxia-inducible factors (HIF), thus leading to a hypoxic state that promotes tumorigenesis (PMID: 18978332, 17102089). SDH mutations have been involved in the pathogenesis of pheochromocytomas, paragangliomas, gastrointestinal stromal tumors (GISTs), renal-cell carcinomas and pituitary adenomas (PMID: 25394176). Mutations in components of the SDH complex lead to accumulation of succinate, which can competitively inhibit the action of alpha-ketoglutarate-dependent histone- and DNA-demethylases in a variety of cancers and lead to a hypermethylator phenotype (PMID: 23707781, 23743927 ). Germline loss of function mutations in the SDH genes can cause hereditary paraganglioma and pheochromocytoma (PMID: 21771581). True +ENST00000283752 NM_006919.2 6317 SERPINB3 True SERPINB3, a serine protease inhibitor, is altered by mutation in solid tumors. Somatic mutations of SERPINB3 may be predictive of improved response to immunotherapy. SERPINB3 is a cysteine/serine protease inhibitor that is a member of the SERPIN protein family (PMID: 27637160). SERPIN proteins predominantly function by disrupting the active sites of proteases and forming irreversibly covalent SERPIN-protease complexes (PMID: 27637160). Specifically, SERPINB3 mainly targets papain-like cysteine proteases such as Cathepsin L, S, and K and papain (PMID: 27637160). SERPINB3, and the tandemly duplicated paralog SERPINB4, have a domain that shares sequence homology with ovalbumin, a classic model antigen (PMID: 26375851). Increased expression of SERPINB3 is found in respiratory inflammatory diseases including asthma, chronic obstructive pulmonary disease (COPD), and tuberculosis, implicating SERPINB3 in stress responses and autoimmunity (PMID: 19332150, 23325331, 25111616). In addition, SERPINB3 has been associated with the regulation of apoptosis due to altered surface antigen presentation (PMID: 19332150). SERPINB3 expression is associated with poor prognosis in several cancer types; however, functional experiments have identified both growth-promoting and inhibitory roles of SERPINB3 (PMID: 29491058, 27637160, 25544768). Somatic mutations in SERPINB3 are found in patients with cutaneous melanoma, and these alterations are associated with improved survival following immune checkpoint blockade therapies (PMID: 26091043, 27668655). Improved responses to immunotherapy may be due to the ability of mutated SERPINB3 to serve as an epitope, leading to immune recognition (PMID: 27668655). True +ENST00000341074 NM_002974.3 6318 SERPINB4 False SERPINB4, a serine protease inhibitor, is altered by mutation in solid tumors. SERPINB4 is a cysteine/serine protease inhibitor that is a member of the SERPIN protein family (PMID: 27637160). SERPIN proteins predominantly function by disrupting the active sites of proteases and forming irreversibly covalent SERPIN-protease complexes (PMID: 27637160). Specifically, SERPINB4 mainly targets chymotrypsin-like serine proteases such as chymase and cathepsin G (PMID: 27637160). SERPINB4, and the tandemly duplicated paralog SERPINB3, have a domain that shares sequence homology with ovalbumin, a classic model antigen (PMID: 26375851). SERPINB4 is not as well-studied as SERPINB3, however, the family members are predicted to have similar activities (PMID: 27637160). SERPINB3 has been implicated in stress responses, autoimmunity, and apoptosis due to altered surface antigen presentation (PMID: 19332150, 23325331, 25111616, 19332150). SERPINB4 expression is associated with poor prognosis in several cancer types; however, functional experiments have not yet delineated if SERPINB4 functions as a tumor suppressor or oncogene (PMID: 17291250, 27637160, 30376194). Somatic mutations in SERPINB4 are found in patients with cutaneous melanoma, and these alterations are associated with improved survival following immune checkpoint blockade therapies (PMID: 26091043, 27668655). Improved responses to immunotherapy may be due to the ability of mutated SERPINB4 to serve as an epitope, leading to enhanced immune recognition (PMID: 27668655). False +ENST00000436639 NM_014454.2 27244 SESN1 False SESN1, a regulator of mTORC1, is mutated at low frequencies in various cancers. The SESN1 gene encodes a member of the sestrin family. Sestrin proteins are negative regulators of mTORC1 (PMID: 27273098, 27174209). Sestrins are leucine sensors that, in absence of this amino acid, interact with GATOR2 protein, a partner of the Rag GTPase protein GATOR1. This interaction prevents mTORC1 translocation to the lysosomal surface (PMID: 25263562, 26449471, 26586190, 25819761). The presence of leucine disrupts sestrin-GATOR interaction and allows mTORC1 signaling. Sestrin-mediated mTORC1 inhibition is partly mediated by activation of AMP-activated protein kinase (AMPK) (PMID: 25457612, 27273098). Sestrins are stress-regulated proteins and also play a role in protection from oxidative stress (PMID: 23274085, 15105503). Genetic alterations of SESN1 are rare events in cancer (cBioPortal, MSKCC, Dec. 2016). True +ENST00000253063 NM_031459.4 83667 SESN2 False SESN2, a regulator of mTORC1, is mutated at low frequencies in various cancer. The SESN2 gene encodes a member of the sestrin family. Sestrin proteins are negative regulators of mTORC1 (PMID: 27273098, 27174209). Sestrins are leucine sensors that, in the absence of this amino acid, interact with GATOR2 protein, a partner of the Rag GTPase protein GATOR1. This interaction prevents mTORC1 translocation to the lysosomal surface (PMID: 25263562, 26449471, 26586190, 25819761). The presence of leucine disrupts the sestrin-GATOR interaction and allows mTORC1 signaling. Sestrin-mediated mTORC1 inhibition is partly mediated by activation of AMP-activated protein kinase (AMPK) (PMID: 25457612, 27273098). Sestrins are stress-regulated proteins and also play a role in protection from oxidative stress (PMID: 23274085, 15105503). SESN2 protein structure and mechanisms are better characterized than other sestrin family members. Genetic alterations of SESN2 are rare events in cancer (cBioPortal, MSKCC, Dec. 2016). True +ENST00000536441 NM_144665.3 143686 SESN3 False SESN3, a regulator of mTORC1, is mutated at low frequencies in various cancers. The SESN3 gene encodes a member of the sestrin family. Sestrin proteins are negative regulators of mTORC1 (PMID: 27273098, 27174209). Sestrins are leucine sensors that, in absence of this amino acid, interact with GATOR2, a partner of the Rag GTPase protein GATOR1. This interaction prevents mTORC1 translocation to the lysosomal surface (PMID: 25263562, 26449471, 26586190, 25819761). The presence of leucine disrupts the sestrin-GATOR interaction and allows mTORC1 signaling. Sestrin-mediated mTORC1 inhibition is partly mediated by activation of AMP-activated protein kinase (AMPK) (PMID: 25457612, 27273098). Sestrins are stress-regulated proteins and also play a role in protection from oxidative stress (PMID: 23274085, 15105503). Genetic alterations of SESN3 are rare events in cancer (cBioPortal, MSKCC, Dec. 2016). True +ENST00000372692 NM_001122821 6418 SET True SET, a multifunctional protein and inhibitor of histone acetyltransferase, is infrequently altered by translocation in leukemia. SET, also known as template activating factor-Iβ (TAF-Iβ), is a multi-functioning protein that acts as a template activating factor, histone chaperone and phosphatase 2A inhibitor (PMID: 34021475). SET is involved in DNA replication through processes such as transcription, nucleosome assembly and chromatin remodeling (PMID: 34021475). As a subunit of the inhibitor of histone acetyltransferase (INHAT) complex, SET inhibits the activity of histone acetyltransferase and exerts chaperone activity by binding to core histones, specifically histone 3 and histone 4 (PMID: 34021475,17360516). Inhibiting the acetylation of nucleosomes is an important event in chromatin remodeling and transcriptional regulation (PMID: 11163245). The SET complex, composed of SET and granzyme A-activated endonuclease NH23-H1, also regulates apoptosis following the attack of cytolytic T cells and NK cells (PMID: 1618237). In response to superoxide generated by granzyme A, the SET complex translocates from the endoplasmic reticulum to the nucleus and regulates apoptosis through the inhibition of phosphatase 2A (PP2A), a major mammalian protein serine-threonine phosphatase, which is a tumor suppressor that inhibits cell proliferation via the dephosphorylation of Bcl-2 (PMID: 34021475, 862667). Impaired regulation of PP2A by SET loss may lead to acute myeloid leukemia (PMID: 8626647), and translocations involving the SET gene are found in various forms of acute myeloid leukemia (PMID: 34021475, 8626647). False +ENST00000649279 NM_015559.2 26040 SETBP1 True SETBP1, an epigenetic remodeling protein, is frequently altered by mutation in a range of hematopoietic malignancies. SETBP1 is a DNA binding protein that functions as an epigenetic remodeler (PMID: 28881700). Binding of SETBP1 to proteins with SET domains, typically present in histone methyltransferases, allows for the methylation of substrates, including histone tails (PMID: 25306901). SETBP1 activates gene expression in part by mediating the recruitment of the HCF1/KMT2A/PHF8 epigenetic complex to regions of chromatin (PMID: 29875417). In addition, SETBP1 binds the protein SET, an inhibitor of the phosphatase PP2A, and overexpression of SETBP1 results in reduced PP2A expression and leukemic proliferation (PMID: 19965692). In preclinical studies, SETBP1 has been shown to mediate self-renewal in leukemia cells and to regulate the expression of the HOXA gene cluster (PMID: 22566606, 25306901). Expression of SETBP1 is also associated with organ development and neuronal activation (PMID: 29875417). Germline mutations in SETBP1 have been identified in patients with Schinzel-Giedion syndrome, a congenital disorder that presents with neurological symptoms and increased risk of malignancy (PMID: 28346496, 20436468). Somatic SETBP1 mutations are found in patients with hematopoietic malignancies, including myeloproliferative neoplasms and atypical chronic myeloid leukemia (PMID: 23832012, 23222956). Alterations in SETBP1 occur in a hotspot region that is within a degron motif that facilitates substrate recognition by the SCF-β-TrCP E3 ubiquitin ligase. These mutations disrupt SETBP1 degradation by the E3 ligase complex, suggesting that SETBP1 functions as an oncogene (PMID: 29875417, 28346496). False +ENST00000262519 NM_014712.2 9739 SETD1A True SETD1A, a histone methyltransferase that binds actively transcribed genes, is infrequently altered across a diverse range of cancers. SETD1A (also KMT2F, hSET1, SET1A, SET1) is a histone methyltransferase that is a member of the MLL family of trithorax-related chromatin remodeling enzymes (PMID: 18838538, 25550471). SETD1A modifies histone tails by trimethylating histone H3 at lysine 4, resulting in an epigenetic signal that is associated with actively transcribed genes or genes poised for transcription (PMID: 18838538, 24126056). Histone proteins, essential components of the nucleosome, consist of DNA wrapped around eight histone protein molecules (two sets of each H2A, H2B, H3, and H4 histones), and histone tail modifications provide signals for the activation or repression of gene expression (PMID: 11498575). The formation of an epigenetic complex including CFP1, RBBP5, ASH2, WDR5, and WDR82 is required for effective SETD1A enzymatic modification of histone tails (PMID: 17998332). SETD1A shares substantial homology with SETD1B, however, these two methyltransferases have non-redundant functions in the regulation of gene expression (PMID: 17355966). In addition, the SETD1A complex binds to RNA polymerase II and influences the initiation of transcription (PMID: 17998332 ). SETD1A also interacts with several additional chromatin-modifying enzymes that influence gene expression and chromatin state (PMID: 18765639, 20622854, 23353889). The activity of SETD1A is required for many stages of development including embryonic and neural stem cell survival, maternal oocyte gene expression and hematopoietic lineage specification (PMID: 24550110, 28619824, 27141965, 23754954, 25550471). In addition, SETD1A has been implicated in the maintenance of stalled replication fork and the regulation of DNA repair pathways with implications for genome stability (PMID: 29937342, 29348130). Loss-of-function mutations in SETD1A are found in patients with schizophrenia and developmental disorders (PMID: 26974950, 24853937). SETD1A is overexpressed in several cancer types and has been shown to promote cell proliferation and survival in functional studies (PMID: 19426701, 24247718, 25373480, 29474905). False +ENST00000604567 XM_005253858.3 23067 SETD1B False SETD1B, a histone methyltransferase protein, is recurrently mutated in a variety of human cancers. SETD1B (also SETB1, KMT2G) is a histone methyltransferase that is a member of the MLL family of chromatin remodeling enzymes (PMID: 17355966, 28160335). SETD1B modifies histone tails by trimethylating histone H3 at lysine 4, resulting in an epigenetic signal that is associated with actively transcribed genes or genes poised for transcription (PMID: 17355966). Histone proteins, essential components of the nucleosome, consist of DNA wrapped around eight histone protein molecules (two sets of each H2A, H2B, H3, and H4 histones), and histone tail modifications provide signals for the activation or repression of gene expression (PMID: 11498575). The formation of an epigenetic complex including CFP1, RBBP5, ASH2, WDR5, and WDR82 is required for effective SETDB1 enzymatic modification of histone tails (PMID: 17355966). The activity of SETD1B is also required for many stages of development including embryonic and neural stem cell survival and maternal oocyte gene expression (PMID: 24550110, 28619824). Microdeletions and mutations in SETD1B have been associated with disorders that result in intellectual disability and craniofacial abnormalities (PMID: 27106595, 29322246). Somatic fusion proteins and mutations have been identified in several tumor types including hematopoietic malignancies, oesophageal squamous cell carcinoma, and endometrial cancers, among others (PMID: 24925220, 24670651, 24382738, 27997699, 29967129). These SETD1B mutations predominantly occur as nonsense and/or frameshift mutations, suggesting that SETD1B may function as a tumor suppressor. False +ENST00000409792 NM_014159.6 29072 SETD2 False SETD2, an H3K36 trimethylase, is altered in a variety of cancer types. SETD2 encodes a chromatin modulating enzyme that functions by site specific trimethylation of histone H3K36. It was originally identified as a contributing enzyme in the pathogenesis of Huntington Disease and thus was initially named Huntington Interacting Protein B (HYPB) (PMID: 9700202). Histone methylation is a highly controlled biological process that regulates gene expression by altering the ability of RNA polymerase II to interact with DNA and thus initiate transcription (PMID:16118227, 25123655). Additionally, the SETD2-regulated H3K36 histone mark has been shown to play a role in regulating DNA mismatch repair. This suggests that inactivation of this protein can lead to enhanced genetic instability, enrichment of nonsense and frameshift mutations and ultimately oncogenic transformation of cells (PMID: 23622243, 25123655, 25728682, 24931610). Importantly, SETD2-mutant renal tumors failed to activate the p53 tumor suppressor, thus providing an alternative pathway for the inactivation of p53 that leads to defects in DNA damage repair (PMID: 24843002). True +ENST00000331768 NM_032233.2 84193 SETD3 False SETD3, a histone methyltransferase, is infrequently altered by fusion or mutation in a variety of human cancers. SETD3 is a histone methyltransferase that is a member of the SET domain family of chromatin remodeling enzymes (PMID: 21832073). SETD3 modifies histone tails by methylating histone H3 at lysine 4 and lysine 36, resulting in an epigenetic signal that is associated with actively transcribed genes or genes poised for transcription (PMID: 21832073). Histone proteins, essential components of the nucleosome, consist of DNA wrapped around eight histone protein molecules (two sets of each H2A, H2B, H3 and H4 histones), and histone tail modifications provide signals for the activation or repression of gene expression (PMID: 11498575). SETD3 is ubiquitously expressed and also binds and methylates non-histone substrates including PCNA, a protein involved in DNA replication (PMID: 26030842) and FOXM1, a protein involved in hypoxia (PMID: 27845446), among others. The activity of SETD3 is important in mediating muscle differentiation by activating the expression of muscle-associated genes (PMID: 21832073). Expression of SETD3 has been associated with oncogenesis and metastasis in several tumor types (PMID: 28442573, 29099276). Rare SETD3 mutations and fusion proteins have been identified in human cancers including B-cell lymphomas (PMID: 23065515). False +ENST00000332131 NM_017438.4 54093 SETD4 False SETD4, a histone methyltransferase, is infrequently altered by mutation in a variety of human cancers. SETD4 is a histone methyltransferase that is a member of the SET domain family of chromatin remodeling enzymes (PMID: 24738023). SETD4 modifies histone tails by tri-methylating histone H4 at lysine 20 as evidenced in model organisms, however, the specific methyltransferase activity of SETD4 has not yet been determined in mammalian studies (PMID: 28031330). Histone proteins, essential components of the nucleosome, consist of DNA wrapped around eight histone protein molecules (two sets of each H2A, H2B, H3, and H4 histones), and histone tail modifications provide signals for the activation or repression of gene expression (PMID: 11498575). SETD4 has been shown to be overexpressed in breast cancer cells that are estrogen receptor negative (PMID: 24738023). Knockdown of SETD4 expression in breast cancer cells results in reduced proliferation and cell cycle progression (PMID: 24738023). Infrequent SETD4 mutations have been identified in human cancers; however, additional functional experiments are necessary to determine the impact of these alterations (cbioportal, September 2018). False +ENST00000402198 NM_001080517.2 55209 SETD5 False SETD5, a histone methyltransferase, is infrequently altered by mutation in a variety of human cancers. SETD5 is a histone methyltransferase that is a member of the SET domain family of chromatin remodeling enzymes (PMID: 24680889). SETD5 is predicted to methylate histone tails to regulate gene expression, however, the specific methyltransferase activity of SETD5 has not yet been determined in mammalian studies. Histone proteins, essential components of the nucleosome, consist of DNA wrapped around eight histone protein molecules (two sets of each H2A, H2B, H3, and H4 histones), and histone tail modifications provide signals for the activation or repression of gene expression (PMID: 11498575). SETD5 interacts with the PAF1 co-transcriptional complex and the NCor-associated histone deacetylase complexes. Loss of SETD5 expression results in increased histone acetylation at transcriptional start sites, suggesting a role in histone deacetylation (PMID: 27864380). SETD5 deletion in murine models results in developmental defects including cardiac defects, aberrant neural tube development, and altered vascular structure (PMID: 27864380). Germline mutations in SETD5 have been associated with human disorders that result in intellectual disability and craniofacial abnormalities (PMID: 23613140, 24680889, 24768552, 28120103). Rare somatic mutations in SETD5 have also been identified in several human cancer types, including prostate cancer, (PMID: 24768552). False +ENST00000219315 NM_001160305.1 79918 SETD6 False SETD6, a histone methyltransferase, is infrequently altered by mutation in a variety of human cancers. SETD6 is a histone methyltransferase that is a member of the SET domain family of chromatin remodeling enzymes (PMID: 23324626). SETD6 modifies histone tails by monomethylating histone H2AZ, a histone variant, at lysine 7 (PMID: 23324626). Histone proteins, essential components of the nucleosome, consist of DNA wrapped around eight histone protein molecules (two sets of each H2A, H2B, H3, and H4 histones), and histone tail modifications provide signals for the activation or repression of gene expression (PMID: 11498575). The H2AZK7me1 mark is found at chromatin locations also marked by H3K27me3, a repressive mark, suggesting that this mark reduces gene expression in embryonic stem cells (PMID: 23324626). SETD6 can also methylate non-histone proteins including PAK4 and RELA (PMID: 26841865, 21131967), leading to altered WNT and NF-KB signaling, respectively. SETD6 monomethylates RELA, a component of the NF-KB signaling pathway, resulting in a methylated protein that binds chromatin at RELA target genes (PMID: 21131967). The methylated RELA protein reduces chromatin accessibility at NF-KB target genes, leading to a restrained NF-KB inflammatory response (PMID: 21131967, 21515635). In addition, SETD6 has been implicated in oxidative response pathways and maintenance of embryonic stem cells (PMID: 26780326, 23324626). SETD6 is overexpressed in some tumor types, including breast cancer; however, SETD6 is infrequently altered across human cancers (PMID: 24751716, 28122346). False +ENST00000274031 NM_001306199.1 80854 SETD7 False SETD7, a histone methyltransferase, is infrequently mutated in a variety of human cancers. SETD7 (also SET7, SET9, SET7/9) is a histone methyltransferase that is a member of the SET domain family of chromatin remodeling enzymes (PMID: 11779497). SETD7 modifies histone tails by methylating histone H3 at lysine 4, resulting in an epigenetic signal that is associated with actively transcribed genes or genes poised for transcription (PMID: 11779497, 11850410, 12540855). Histone proteins, essential components of the nucleosome, consist of DNA wrapped around eight histone protein molecules (two sets of each H2A, H2B, H3, and H4 histones), and histone tail modifications provide signals for the activation or repression of gene expression (PMID: 11498575). In addition to methylation of histone substrates, SETD7 can also methylate non-histone substrates in order to regulate their stability or functional activity. SETD7 methylates P53 in a mechanism that restricts P53 to the nucleus leading to transcriptional stabilization and activation (PMID: 17646389, 18280244, 21855806). SETD7 also stabilizes the estrogen receptor and NF-KB for recruitment to transcriptional targets (PMID: 18471979). In addition, SETD7 methylates DNMT1 (a DNA methyltransferase), E2F1 (a cell cycle factor involved in regulating DNA damage-induced cell death), and YAP (a transcription factor involved in WNT regulation), among others (PMID: 19282482, 19684477, 21151116, 20603083, 27046831). Somatic mutations in SETD7 are rare in human cancers; however, SETD7 has been implicated as both a tumor suppressor and oncogene in different cellular contexts (PMID: 26848522, 26779630, 26701885, 26116705, 27183310). False +ENST00000271640 NM_001145415.1 9869 SETDB1 True SETDB1, a histone methyltransferase, is altered by amplification, mutation, and fusion in melanoma, lung cancer, and mesothelioma. SETDB1 (also ESET, KMT1E) is a histone methyltransferase that is a member of the SET domain family of chromatin remodeling enzymes. SETDB1 modifies histone tails by methylating histone H3 at lysine 9, resulting in an epigenetic signal that is associated with repressed gene expression and genes poised for activation (PMID: 11959841). Histone proteins, essential components of the nucleosome, consist of DNA wrapped around eight histone protein molecules (two sets of each H2A, H2B, H3, and H4 histones), and histone tail modifications provide signals for the activation or repression of gene expression (PMID: 11498575). SETDB1-dependent H3K9me3 methylation results in the recruitment of HP1-alpha, leading chromatin remodeling to a more heterochromatic state (PMID: 11959841). In addition, SETDB1 binds protein complexes implicated in transcriptional repression including KRAB-KAP1 and MDB1-CAF1 (PMID: 11959841, 15327775). SETDB1 also interacts with several proteins involved in sister chromatid cohesion, DNA repair, and homologous recombination (PMID: 18501190, 26206670) and mediates gene repression in embryonic and hematopoietic stem cells (PMID: 19884255, 21624812, 27301860). SETDB1 can also regulate the activity of other epigenetic complexes involved in the repression of gene expression, including Polycomb Repressive Complex 2 (PRC2) (PMID: 26160163). SETDB1 can methylate non-histone substrates including p53, which leads to recognition and degradation of P53 by MDM2 (PMID: 26471002). SETDB1 has been identified within a melanoma susceptibility locus and SETDB1 expression promotes melanoma formation (PMID: 26471002, 21430779). In addition, SETDB1 is recurrently amplified in melanoma and lung cancer (PMID: 21430779, 23770855). Somatic mutations, fusion events, and splice alterations are found in mesothelioma, leading to protein inactivation, suggesting that SETDB1 can function as either a tumor suppressor or oncogene in distinct cellular contexts (PMID: 26928227, 26824986). True +ENST00000317257 NM_031915.2 83852 SETDB2 False SETDB2, a histone methyltransferase, is altered by deletion in breast cancers. SETDB2 (also CLLD8, KMT1F) is a histone methyltransferase that is a member of the SET domain family of chromatin remodeling enzymes (PMID: 20404330). SETDB2 modifies histone tails by methylating histone H3 at lysine 9, resulting in an epigenetic signal that is associated with repressed gene expression and genes poised for activation (PMID: 20404330). Histone proteins, essential components of the nucleosome, consist of DNA wrapped around eight histone protein molecules (two sets of each H2A, H2B, H3, and H4 histones), and histone tail modifications provide signals for the activation or repression of gene expression (PMID: 11498575). SETDB2 functions to recruit HP1-alpha to centromeres and maintains heterochromatin states in repetitive elements and centromere-associated repeats, implicating SETDB2 in chromosome condensation (PMID: 20404330). SETDB2 is also important in the regulation of acute immune responses, is activated during viral infection, and may mediate bacterial infection susceptibility (PMID: 27572307, 25419628). Homozygous deletions in SETDB2 have been identified in breast cancer (PMID: 25537518); however, somatic alterations in SETDB2 are relatively rare in human cancers. True +ENST00000335508 NM_012433.2 23451 SF3B1 True 4 SF3B1, a component of the spliceosome complex, is frequently mutated in hematologic malignancies. SF3B1 (splicing factor 3b subunit 1) is a component of the spliceosome complex that regulates the removal of introns from messenger RNA (PMID: 28958291). SF3B1 binds to nucleosomes to identify exon and intron junctions of coding genes (PMID: 25892229). Importantly, SF3B1 preferentially regulates alternative splicing and 3’ splice site selection (PMID: 28445500). In addition, SF3B1 plays a role in the maintenance of genomic integrity due to contributions to sister chromatid cohesion and chromosome segregation (PMID: 25257310). Somatic mutations in SF3B1 are recurrent in uveal melanoma (PMID: 26842708) and myelodysplastic syndromes (MDS) (PMID: 21909114, 21995386), especially those with refractory anemia with ring sideroblasts (RARS) and refractory cytopenia with multilineage dysplasia and ring sideroblasts (RCMD-RS) (PMID: 21995386, 21998214). Mutations in SF3B1 lead to altered gene expression and aberrant alternative splicing (PMID: 25428262) and tend to be missense mutations rather than nonsense or frameshift mutations, suggesting either gain-of-function or dominant negative activity (PMID: 22150006, 21909114). The SF3B spliceosome complex can be inhibited by naturally occurring compounds, including spliceostatin A (PMID: 17643111), and SF3B1-mutant cells are preferentially sensitive to spliceosome inhibitors (PMID: 29457796). False +ENST00000322535 NM_006842 10992 SF3B2 True SF3B2, a subunit of the splicing factor 3b protein complex, is infrequently altered in cancer. SF3B2 encodes for subunit 2 of the splicing factor 3b protein (SF3B) complex, which functions in pre-mRNA splicing (PMID: 27720643). The SF3B complex assembles with 12S RNA to form the U2 small nuclear ribonucleoprotein complex (U2 snRNP) to bind pre-mRNA upstream of the intron branch site (PMID: 12234937). Haploinsufficiency of SF3B2 has been associated with sporadic and familial craniofacial microsomia (PMID: 34344887). Knockout of SF3B2 in cancer cell lines and models suppresses tumor growth and cellular migration and invasion, suggesting that SF3B2 functions predominantly as an oncogene (PMID: 35715826, 34611311). Amplification of SF3B2 has been identified in various types of cancer, including prostate cancer, bladder cancer and acute myeloid leukemia (PMID: 31431456). SF3B2 is suggested to confer resistance to AR-targeting therapy in prostate cancer by promoting AR-V7 expression through RNA splicing (PMID: 31431456). False +ENST00000220772 NM_003012.4 6422 SFRP1 False SFRP1, a negative regulator of WNT signaling, is infrequently altered by mutation and deletion in various cancer types. SFRP1 is an extracellular signaling ligand that is a member of the secreted frizzled-related protein family (PMID: 24316024, 23258168). SFRP1 functions as a negative regulator of the WNT signaling pathway by binding to WNT or Frizzled (Fz) receptors and precluding WNT-mediated activation of downstream signaling (PMID: 24316024, 23258168). WNT signaling is a critical developmental pathway with roles in determining cell fate, tissue identity and polarity (PMID: 28218291). SFRP1-mediated antagonism of WNT results in the activation of the β-catenin destruction complex (containing APC, GSK3β, and AXIN) which targets β-catenin for degradation (PMID: 23258168). In the absence of WNT signaling, TCF and LEF transcription factors form a repressive complex, leading to inhibition of β-catenin target genes (PMID: 24316024, 23258168). In addition, SFRP1 activity has been linked to the regulation of stress-related senescence, proliferation and metastasis (PMID: 22927647, 11593386, 24316024). Somatic mutations in SFRP1 are not well studied in human cancers; however, epigenetic silencing of SFRP1 transcription has been implicated in several cancer types, including breast cancer (PMID: 28218291, 11992124, 16449975, 11593386). SFRP1 loss of heterozygosity has also been identified in some cancer types, including colorectal cancer, suggesting that SFRP1 functions predominantly as a tumor suppressor (PMID: 10086345, 22927647). True +ENST00000274063 NM_003013.2 6423 SFRP2 True SFRP2, a negative regulator of WNT signaling, is overexpressed in various cancer types. SFRP2 is an extracellular signaling ligand that is a member of the secreted frizzled-related protein family (PMID: 24316024, 23258168). SFRP2 functions as a negative regulator of the WNT signaling pathway by binding to WNT or Frizzled (Fz) receptors and precluding WNT-mediated activation of downstream signaling (PMID: 24316024, 23258168). WNT signaling is a critical developmental pathway with roles in determining cell fate, tissue identity and polarity (PMID: 28218291). SFRP2-mediated antagonism of WNT results in the activation of the β-catenin destruction complex (containing APC, GSK3β and AXIN) which targets β-catenin for degradation (PMID: 23258168). In the absence of WNT signaling, TCF and LEF transcription factors form a repressive complex, leading to inhibition of β-catenin target genes (PMID: 24316024, 23258168). In addition to roles in antagonizing WNT, SFRP2 associates with integrin complexes and mediates cell adhesion (PMID: 14709558). SFRP2 is secreted by stromal cells in the tumor microenvironment, such as by aging fibroblasts, and promotes epithelial-to-mesenchymal transition in breast cancer (PMID: 14999144, 14709558, 16791480, 27042933). Somatic mutations in SFRP2 are not well studied in human cancers; however, epigenetic silencing of SFRP2 transcription has been implicated in several cancer types, including prostate and colorectal cancer (PMID: 22175903, 25197341, 27659069, 31516566, 26291085). SFRP2 is more commonly overexpressed in other cancers and associated with poor prognosis, suggesting that SFRP2 may function as either a tumor suppressor or oncogene (PMID: 14999144, 14709558, 28218291, 30385632). True +ENST00000237305 NM_005627.3 6446 SGK1 True SGK1, a serine/threonine kinase in the PI3K signaling pathways, is altered by mutation in hematologic malignancies. SGK1 is a serine/threonine kinase that is a member of the AGC family of protein kinases (PMID: 28236975). SGK1 (serum and glucocorticoid-inducible kinase) is activated by growth factors and is a signaling effector in the phosphoinositide 3 (PI 3)-kinase signaling pathway (PI3K) (PMID: 8455596, 10357815). In the PI3K signaling pathway, SGK1 is phosphorylated and activated by the kinases PDK1 and mTORC2 (PMID: 10357815). SGK1 regulates the expression of a variety of downstream targets including NDRG1, GSK3β, FOXO3, NEDD4L, and PIKFYVE, among others (PMID: 11154281, 10191262). AKT and SGK1 signaling have some overlapping upstream and downstream effectors and SGK1 can partially compensate for AKT activity (PMID: 29055016). In addition, SGK1 increases the activity of a variety of ion channels, ion carriers and the Na+/K+ ATPases; therefore, salt levels and other environmental stimuli are predicted to activate SGK1 activity (PMID: 23467085). SGK1 signaling has been implicated in a variety of other cellular functions including cellular proliferation, apoptosis, membrane protein turnover, regulation of cell volume, transcription and macrophage recruitment (PMID: 22556335, 28236975, 9114008). Somatic gain-of-function mutations in SGK1 are found in patients with nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) and T-cell/histiocyte-rich large B-cell lymphoma (PMID: 26658840, 30213827). In addition, overexpression of SGK1 is found in patients with breast cancer (PMID: 16246546). SGK1 signaling mediates resistance to PI3Kα and AKT inhibition due to compensatory regulation of mTORC1 signaling (PMID: 27451907, 23581296). False +ENST00000341259 NM_005475.2 10019 SH2B3 False SH2B3 is an adaptor protein that regulates growth factor and cytokine signaling. Mutations are found in hematopoietic disorders including leukemias and myeloid disease. SH2B3 (also LNK) is a plasma membrane-associated adaptor protein that negatively regulates signal transduction initiated by growth factor and cytokine receptor kinases (PMID:11805142, 18753636). SH2B3 is most highly expressed in hematopoietic cells and negatively regulates the activity of several hematopoietic kinases including c-Kit, MPL (thrombopoietin receptor), JAK2 (Janus Kinase 2), PDGFR (Platelet Derived Growth Factor Receptor, and EPOR (erythropoietin receptor). Deletion of SH2B3 in murine models results in abnormal hematopoiesis characterized by expansion of the hematopoietic progenitor population (PMID: 11805142). SH2B3-regulated signaling has been implicated in B-cell development, T-cell activation, and hematopoietic stem cell proliferation and differentiation (PMID:11114373, 10799879, 11805142). Germline mutations in SH2B3 are associated with autoimmune diseases such as diabetes, celiac disease and hypertension (PMID:19430479, 18311140, 19073967) as well as predisposition to leukemia (PMID:23908464). Somatic SH2B3 alterations are found in Down syndrome-related myeloid disorders, acute lymphoblastic leukemias and myeloproliferative neoplasms (PMID:24056718, 22897847, 20404132, 22237106) and these mutations are predicted to result in loss-of-function. True +ENST00000371139 NM_002351.4 4068 SH2D1A False SH2D1A encodes a SH2 domain protein that acts to modulate signaling in lymphocytes through the SLAM receptor. Mutations are associated with X-linked immune dysfunction and lymphoproliferative diseases. SH2D1A (also SAP) is an adaptor protein that binds to the lymphocyte cell surface protein Signaling Lymphocytic Activation Molecule (SLAM) (PMID: 9774102). SLAM receptors are expressed on hematopoietic cells and regulate lymphocyte activity (PMID: 18031694). SH2D1A competes with the recruitment of signaling molecules such as SHP-2 phosphatase and also functions as a scaffold to recruit Fyn kinase (PMID: 12458214). Recruitment of SH2D1A is important for the regulation and development of B-cells, NK cells, and T-cells including humoral immunity, cytokine production, and cytotoxicity (PMID: 15711562, 20153220, 15774582, 12529646). SH2D1A plays a role in the regulation of apoptosis and mediates lymphocyte proliferation via the apoptotic pathway (PMID: 19738428). Germline mutations and deletions in SH2D1A are associated with X-linked immune dysfunction, susceptibility to EBV infection, and lymphoproliferative disease (PMID: 9771704). Patients with X-linked lymphoproliferative disease are predisposed to the development of hemophagocytosis, lymphomas, and cytopenias (PMID: 11049992, 20926771, 23589280). Somatic variants in SH2D1A are infrequent in human cancers. True +ENST00000369452 NM_007373.3 8036 SHOC2 True SHOC2, a positive regulator of Ras-MAPK activity, is rarely altered in human cancers, but germline mutations are found in patients with Noonan-like syndromes. The SHOC2 gene encodes a positive regulator of the Ras-MAPK pathway. SHOC2 forms a complex with the catalytic subunit of protein phosphatase 1 (PP1c) and enhances growth factor- and Ras-mediated MAPK pathway activation, whereas it has no effect on Raf- and MEK-induced mechanisms (PMID: 10783161, 16630891). Mechanistically, under M-ras activation, SHOC2 facilitates PP1c-mediated dephosphorylation of the Raf-1 Ser-259 inhibitory site (PMID: 16630891). SHOC2 overexpression induces proliferation and tumorigenic growth in EGF-mediated and Ras-mutant cancer cells (PMID: 25514808, 24211266). Genetic alterations of SHOC2 are rarely seen in tumors. Germline mutations at specific SHOC2 sites are causal variants of neuro-cardio-facial-cutaneous disorders such as Noonan-like syndrome and other RASopathies (PMID: 19684605, 23918763, 25137548). False +ENST00000325599 NM_018130.2 55164 SHQ1 False SHQ1 is a nucleocytoplasmic shuttle protein with function in rRNA processing pathways. Loss of SHQ1 is frequently observed in prostate cancer. SHQ1 (H/ACA ribonucleoprotein assembly factor) is located on chromosome 3p13. SHQ1 is suggested to function in rRNA processing and has been shown to be involved in the formation of a protein-RNA complex (snoRNP [small nucleolar ribonucleoprotein]) known as the H/ACA box (PMID: 19383767, 12228251). The H/ACA box is involved in processing of rRNA, modifications of species of RNAs, and stabilization of telomeres (PMID: 20227365, 19383767). SHQ1 are shown to bind NAP57, which is an essential member of H/ACA, prior to the binding of another accessory protein, NAF1, and is thought to assist in the shuttling of the complex to nucleoli (PMID: 20227365, 19383767). SHQ1 contains a protein-protein interaction domain known as the CS domain (named after CHORD-containing proteins and SGT1) which appears to be essential for H/ACA complex formation (PMID: 19426738, 19019820). The genetic locus of SHQ1 is frequently deleted in prostate cancers and one somatic mutation has been observed (PMID: 20579941). True +ENST00000308377 NM_001104587.1 91607 SLFN11 False SLFN11, an interferon-regulated DNA damage protein, is epigenetically silenced in a variety of cancer types resulting in resistance to genotoxic therapies. SLFN11 is an interferon-stimulated gene that is a member of the Schlafen family of proteins (PMID: 23570387). SLFN11 binds and negatively regulates RPA (Replication Protein Complex A), a complex that associates with single-stranded DNA at stalled replication forks and recruits repair proteins to resolve the forks (PMID: 26658330). SLFN11 mediates the destabilization of the RPA-single-stranded-DNA complex and inhibits DNA repair by altering checkpoint maintenance and homologous recombination (PMID: 26658330). In addition, SLFN11 inhibits the translation of the DNA damage kinases ATR and ATM via specific cleavage of transfer RNAs (PMID: 30374083). SLFN11 couples IFN-γ to the DNA repair pathway and loss of SLFN11 dampens T-cell responses (PMID: 30753225). Expression of SLFN11 predicts for sensitivity to PARP inhibitors, topoisomerase inhibitors, alkylating agents, and DNA synthesis inhibitors in cancer cell line datasets and in clinical studies (PMID: 22460905, 22927417, 29906251, 27708213). In small cell lung cancer, SLFN11 expression is repressed in models of chemoresistance due to chromatin-mediated silencing (PMID: 26658330). Expression of SLFN11 predicts for improved survival in a variety of cancer types including small cell lung cancer, ovarian cancer, and Ewing sarcoma, among others (PMID: 25779942, 22927417, 26525741, 26625211, 27440269, 27923837). Rare somatic mutations in SLFN11 are found in patients with Ewing sarcomas (PMID: 26179511). In addition, SLFN11-deficient cells are sensitive to ATR inhibition due to dependency on that pathway for DNA repair (PMID: 27708213, 29395061). True +ENST00000504154 NM_004787 9353 SLIT2 False SLIT2, a secreted glycoprotein, is infrequently altered in cancer. SLIT2, a member of the Slit family, encodes for a secreted glycoprotein that primarily functions in regulating cellular migration through binding to ROBO1 and ROBO2 receptors to activate the SLIT/ROBO signaling pathway (PMID: 32807784, 35550611, 34181595). SLIT2 is proteolytically processed into C-terminal fragments (SLIT2-C) and N-terminal fragments (SLIT2-N), which both function in promoting chemotaxis through regulation of chemoattractants and increasing cell migration speed (PMID: 10102266, 30510066). The oncogenic function of SLIT2 is likely tissue-specific. Knockdown of SLIT2 in various cancer cell lines and models induces cellular migration and invasion, suggesting that SLIT2 functions predominantly as a tumor suppressor gene in these tissue-specific contexts (PMID: 30648543, 18611862, 34093772, 25490006). Downregulation of SLIT2 has been identified in various types of cancer, including gastric cancer, lung cancer and breast cancer (PMID: 24297051, 20068157, 34400395). Hypermethylation of the SLIT2 promoter region has also been identified in chronic myeloid leukemia and non-small cell lung cancer (PMID: 36411451, 35053460). Conversely, upregulation of SLIT2, along with ROBO1 upregulation, has been observed in osteosarcoma, colorectal cancer, and mucoepidermoid carcinoma (PMID: 21283129, 29523788, 22366001). Overexpression of SLIT2 has been identified to promote tumorigenesis by inducing tumor cell migration and invasion in these tissue-specific contexts (PMID: 24840330, 17268810). False +ENST00000519560 NM_003062 6586 SLIT3 False SLIT3, a secreted glycoprotein, is frequently altered in various cancer types. SLIT3 is a secreted glycoprotein involved in endothelial cell migration guidance and cell-environmental interaction via its interaction with transmembrane proteins called roundabout receptors (ROBOs) (PMID: 21743955, 23720784). There are three slit guidance ligand (SLIT) proteins in humans, all of which function during embryonic development to direct the growth of axons via repulsive guidance cues (PMID: 19741192, 11804571). In addition to its function in central nervous system growth, SLIT3 also plays a role in regulating non-neuron-related processes including kidney and diaphragm formation, angiogenesis, leukocyte migration and prevention of osteoporosis (PMID: 19741192, 21078908, 34423586). The SLIT/ROBO pathway regulates apoptosis, cell migration and invasion; dysregulation of SLIT/ROBO signaling plays a part in tumor progression (PMID: 25245168, 18829537). Expression of SLIT3 inhibits migration of malignant melanoma cells in mice and suppresses tumor growth in breast cancer cells suggesting SLIT3 functions as a tumor suppressor gene (PMID: 21743955, 18829537, 31258778). SLIT3 is frequently downregulated by hypermethylation of its promoter region in various cancer types including glioma and breast cancer, and less frequently by allelic loss in colorectal and lung cancers (PMID: 15534609, 18829537). SLIT3 methylation is also found in breast, lung, colorectal, glioma and gastric cancer cell lines (PMID: 15534609, 27082735). The SLIT3 locus also encodes miR-218-2, an intronic mRNA that is downregulated in multiple types of malignant cancers (PMID: 23720784). True +ENST00000294008 NM_032444.2 84464 SLX4 False SLX4, a protein involved in DNA damage repair, is mutated in the germline of the FANCP subtype of Fanconi anemia patients. The SLX4 protein is involved in various processes related to DNA damage repair. SLX4 localizes at double-strand breaks (DSB) on DNA where it forms a multi-protein complex by recruiting proteins involved in DNA repair and genome stability, such as ERCC1/ERCC4 and SLX1 endonucleases, MSH2/MSH3 mismatch repair complex, and telomeric TRF2, among others (PMID: 19596235, 19596236, 19595721, 19595722). SLX4 is essential for several types of DNA repair including DNA interstrand crosslinks (ICLs), Holliday junction (HJ) resolution and telomere homeostasis (PMID: 24938228). The SLX4 protein is mutated at low frequencies in various tumors, and germline mutations in the gene are the cause of a subtype of Fanconi anemia (FANCP) (PMID: 21240275, 21240277). SLX4 was studied as a putative genetic factor in familial non-BRCA1/2 breast cancer patients, but several studies failed to demonstrate its contribution (PMID: 22911665, 22401137, 21805310, 23211700). True +ENST00000262160 NM_001003652.3 4087 SMAD2 False SMAD2 encodes a tumor suppressor and transcription factor that is a downstream effector in the TGF-ß signal transduction pathway. SMAD2 is infrequently mutated in a diverse range of cancers. SMAD2 is a transcription factor that functions as an effector in the transforming growth factor beta (TGFß) signal pathway. TGFß signaling controls multiple biological processes including cellular proliferation, differentiation and tissue homeostasis (PMID: 22992590, 11057902). SMAD signaling molecules are activated by membrane receptor serine kinases following binding of TGFß superfamily of cytokines (e.g. TGFß1, TGFß2, TGFß3, activin and nodal) (PMID: 25935112, 9759503). Following dimerization and activation of TGFß receptors, two phosphorylated receptor-regulated SMAD proteins, including SMAD2, form a trimeric complex with a co-SMAD, such as SMAD4, to allow for binding to DNA (PMID: 9759503). The SMAD trimeric complex can translocate to the nucleus and regulate TGFß-mediated gene transcription in a cell-type dependent manner specified, in part, by the availability of transcriptional co-activators and chromatin accessibility (PMID: 22992590, 9759503). The contextual nature of TGFß-dependent transcription allows the TGFß pathway to suppress tumorigenesis in premalignant states and promote invasiveness and metastasis during cancer progression (PMID: 22992590, 18662538, 20495575). Loss of SMAD2 expression occurs at a low frequency in colorectal, gastric and ovarian cancer and correlates with poor prognosis (PMID: 25935112, 23139211, 9679244, 8752209, 12967141, 22539990, 12894231). Notably, both elevated and decreased levels of phosphorylated SMAD2 are associated with poor prognosis in several cancer types (PMID: 21110833, 22539990, 16788944, 25373709). Although infrequent, SMAD2 mutations are found in colorectal cancer and less frequently in various other cancer types, such as lung and hepatocellular cancer (PMID: 23139211, 22895193, 22810696, 8752209, 8971158, 10490821, 16959974). True +ENST00000327367 NM_005902.3 4088 SMAD3 False SMAD3 encodes a tumor suppressor and transcription factor that is a downstream effector in the TGF-ß signal transduction pathway. SMAD3 is infrequently mutated in a diverse range of cancers. SMAD3 is a transcription factor that functions as a critical effector in the transforming growth factor beta (TGFß) signal pathway. TGFß signaling controls multiple biological processes including cellular proliferation, differentiation and tissue homeostasis (PMID: 22992590, 11057902). SMAD signaling molecules are activated by membrane receptor serine kinases following binding of TGFß superfamily of cytokines (e.g. TGFß1, TGFß2, TGFß3, activin and nodal) (PMID: 25935112, 9759503). Following dimerization and activation of TGFß receptors, two phosphorylated receptor-regulated SMAD proteins, including SMAD3, form a trimeric complex with a co-SMAD, such as SMAD4, to allow for binding to DNA (PMID: 9759503). The SMAD trimeric complex can translocate to the nucleus and regulate TGFß-mediated gene transcription in a cell-type dependent manner specified, in part, by the availability of transcriptional co-activators and chromatin accessibility (PMID: 22992590, 9759503). The contextual nature of TGFß-dependent transcription allows the TGFß pathway to suppress tumorigenesis in premalignant states and promote invasiveness and metastasis during cancer progression (PMID: 22992590, 18662538, 20495575). Germline SMAD3 mutations are found in hereditary syndromes in the Loeys-Dietz phenotypic series of diseases (PMID: 22167769, 21217753, 21778426). Although infrequent, somatic SMAD3 loss-of-function mutations and deletions have been identified in colorectal cancer, in accordance with studies in transgenic mice (PMID: 22810696, 23139211, 9753318, 16959974). SMAD3 alterations have also been observed in various other tumor types (PMID: 16959974, 14647420, 21771027, 15295048, 12161532). True +ENST00000342988 NM_005359.5 4089 SMAD4 False SMAD4 encodes a tumor suppressor and transcription factor that is a downstream effector in the TGF-ß signal transduction pathway. SMAD4 is frequently mutated in pancreatic and colorectal cancer and infrequently mutated in various other cancers. SMAD4 is a transcription factor that functions as a critical effector in the transforming growth factor beta (TGFß) signal pathway. TGFß signaling controls multiple biological processes including cellular proliferation, differentiation and tissue homeostasis (PMID: 22992590, 11057902). The SMAD receptor-regulated signaling molecules (such as SMAD2 and SMAD3) are activated by membrane receptor serine kinases following binding of TGFß superfamily of cytokines (e.g. TGFß1, TGFß2, TGFß3, activin and nodal) (PMID: 25935112, 9759503). Following dimerization and activation of TGFß receptors, two phosphorylated receptor-regulated SMAD proteins form a trimeric complex with SMAD4 to allow for binding to DNA (PMID: 9759503). The SMAD trimeric complex can translocate to the nucleus and regulate TGFß-mediated gene transcription in a cell-type dependent manner specified, in part, by the availability of transcriptional co-activators and chromatin accessibility (PMID: 22992590, 9759503). The contextual nature of TGFß-dependent transcription allows the TGFß pathway to suppress tumorigenesis in premalignant states and promote invasiveness and metastasis during cancer progression (PMID: 22992590, 18662538, 20495575). Germline mutations in SMAD4 have been associated with juvenile polyposis syndrome (JPS) (PMID: 9545410, 8553070, 8673134, 18662538). Loss of SMAD4 expression or somatic mutations in SMAD4 are found in pancreatic cancer and are associated with tumor grade (PMID: 8553070, 8673134, 9766641, 9135016, 10327057, 19273710, 12821112). Somatic alterations in SMAD4 are observed at lower frequencies in multiple tumor types, including colon and lung adenocarcinoma (PMID: 23139211, 19841540, 16959974, 22810696, 15867212, 25589618, 25890228). True +ENST00000371122 NM_003069 6594 SMARCA1 True SMARCA1, an ATPase involved in chromatin remodeling, is infrequently altered in cancer. SMARCA1, a member of the switch/sucrose non-fermentable (SWI/SF) family, encodes for an ATPase that functions primarily in the chromatin remodeling complex (PMID: 28801535, 15310751). SMARCA1 is a catalytic subunit of the imitation SWI (ISWI) chromatin remodeling complex, which facilitates access to DNA for processes such as DNA replication, transcription and repair (PMID: 28801535). An isoform of SMARCA1 has been identified in humans to be catalytically inactive and function as a negative regulator to chromatin remodeling through forming inactive complexes (PMID: 15310751). Loss-of-function germline mutations of SMARCA1 are associated with the multisystem disorder Schimke immuno-osseous dysplasia (PMID: 20013129). The oncogenic function of SMARCA1 is likely dependent on tissue-specific contexts. Knockdown of SMARCA1 in myoepithelial cell lines induces DNA damage, growth inhibition and cancer cell death, suggesting that SMARCA1 functions predominantly as an oncogene in this context (PMID: 19996304). SMARCA1 upregulation has been identified in colon adenocarcinoma, cervical squamous cell carcinoma and endocervical adenocarcinoma (PMID: 36126083). In contrast, knockdown of SMARCA1 in gastric cancer and melanoma cell lines induces cellular growth, migration, invasion and downregulation of genes related to cellular homeostasis, suggesting that SMARCA1 functions predominantly as a tumor suppressor gene in this context (PMID: 25462860, 22508985). SMARCA1 has been identified to be silenced through DNA methylation in gastric cancer (PMID: 25462860). True +ENST00000349721 NM_001289396.1 6595 SMARCA2 False SMARCA2, a tumor suppressor involved in chromatin remodeling, is infrequently altered by mutation in various cancer types. Germline mutations of SMARCA2 are associated with Nicolaides-Barraitser syndrome. SMARCA2 (also BRM) is an ATP-dependent helicase that is a catalytic subunit of the SWI/SNF chromatin remodeling complex (PMID: 28391084, 21654818, 26601204). The SWI/SNF complex plays a role in altering chromatin structure, a process that is necessary for various cellular functions, including gene regulation, DNA repair, differentiation, and lineage specification (PMID: 28391084, 21654818, 26601204). SMARCA2, or the ATP helicase SMARCA4, form a multicomponent complex by partnering with 15 core and adaptor proteins to mediate interactions with DNA and chromatin (PMID: 28391084, 26601204). Germline heterozygous mutations in SMARCA2 are found in patients with Nicolaides-Baraitser syndrome (NCBRS), a disorder characterized by intellectual disabilities and altered development (PMID: 22366787, 31375262). NCBRS-associated SMARCA2 mutations result in enhancer reprogramming, leading to a redistribution of SMARCA4 on chromatin (PMID: 31375262). Somatic mutations in SMARCA2 in human cancers are more uncommon than SMARCA4 alterations; however, SMARCA2 has been found to be silenced by epigenetic mechanisms in several cancer types (PMID: 29391527, 28391084, 17546055). Because SMARCA2 can replace SMARCA4 in SMARCA4-deficient tumors, SMARCA2 inhibition may be efficacious in cancer types with SMARCA4 mutations (PMID: 24421395, 24520176). Furthermore, inhibitors targeting Polycomb Repressive Complex 2 (PRC2) have been found to have activity in cancers with low SMARCA2 expression (PMID: 28391084). True +ENST00000646693 NM_001128849.3 6597 SMARCA4 False 3A SMARCA4, a tumor suppressor involved in chromatin remodeling, is recurrently altered in small cell carcinoma of the ovaries, hypercalcemic type (SCCOHT). SMARCA4 is an ATP-dependent helicase that is a catalytic subunit of the SWI/SNF chromatin remodeling complex (PMID: 21654818). This complex plays a role in altering chromatin structure, a process that is necessary for various cellular functions, including transcription, DNA synthesis and DNA repair (reviewed in PMID: 25387058). Secondary to ARID1A, SMARCA4 is the most frequently mutated gene among the SWI/SNF subunits and is significantly altered in malignant rhabdoid tumors, lymphoma, medulloblastoma, lung and ovarian cancer (PMID: 23644491, 25060813, 23143597). Mutations in the SMARCA4 gene result in loss of function, suggesting its tumor suppressor properties. Germline SMARCA4 mutations predispose to pediatric atypical teratoid/rhabdoid tumors (AT/RT) (PMID: 20137775, 25060813) and small cell carcinoma of the ovaries, hypercalcemic type (SCCOHT) (PMID: 24658002, 24658004). Almost all SCCOHT cases have mutations in the SMARCA4 gene. In the majority of cases this is the only mutation present, and thus thought to be a driver mutation for this disease (PMID: 24658002, 24658004, 24658001). True +ENST00000618915 NM_003073.3 6598 SMARCB1 False 1 SMARCB1, a protein involved in chromatin remodeling, is inactivated by mutation or deletion in various cancer types including soft tissue sarcomas and CNS cancers. SMARCB1 (INI1, BAF47, SNF5) is present in all known variants of the SWI/SNF chromatin remodeling complex, and is thus considered a core subunit (PMID: 10078207). SWI/SNF complexes are ATP dependent nucleosome remodelers which are required for efficient accessibility of genes to the transcriptional machinery (PMID: 14964309). SWI/SNF complexes are important for normal human development and are required for the transition of transcriptional programs during cellular differentiation(PMID: 23568486). In cancer, SMARCB1 acts as a strong tumor suppressor. It is mutated in rhabdoid tumours, familial schwannomatosis, small-cell hepatoblastomas, extraskeletal myxoid chondrosarcomas, undifferentiated sarcomas, epitheliod sarcomas, meningiomas and poorly differentiated chordomas (PMID: 9671307, 21057957, 17357086, 18985717, 18580682, 18997735, 15899790, 20930055). Heterozygous SMARCB1 mutations are found in patients with rhabdoid predisposition syndrome, which is characterized by the inheritance of a defective SMARCB1 allele followed by the loss of the remaining allele in the tumours (PMID: 10521299). Mouse models of SMARCB1 mutations recapitulate the tumor suppressor functions observed in humans (PMID: 11095756, 12450796, 16301525). The exact mechanism by which SMARCB1 loss leads to malignant transformation is not yet well understood, however, expression analyses have shown that one consequence of SMARCB1 loss is the activation of gene expression programmes that are associated with proliferation and dedifferentiation (PMID: 21076395). Recently, it was found that SMARCB1 mutant cells depend on the PRC2 component EZH2 which has lead to clinical trials of EZH2 inhibitors in patients with SMARCB1 mutant cancers (PMID: 21654818, 20951942, 26552009, 23620515). True +ENST00000394963 NM_003076.4 6602 SMARCD1 False SMARCD1 (also known as BAF60A), is a member of the SWI/SNF family, and acts in recruiting transcription factors and nuclear receptors to the SWI/SNF chromatin remodeling complex. The SMARCD1 gene has been found mutated in breast cancer and the SMARCD1 protein is derepressed in gastric and prostate cancer. The SMARCD1 gene encodes the protein SMARCD1, (SWI/SNF related, Matrix associated, Actin dependent Regulator of Chromatin, subfamily D, member 1) also known as BAF60A (BRG1-Associated Factor 60A). The SMARCD1 protein is a member of the SWI/SNF (SWItch/Sucrose NonFermentable) complex, an ATP-dependent chromatin remodeling complex that alters the location or conformation of nucleosomes by using the energy of ATP hydrolysis and thus can regulate transcription of certain genes. To this end, SMARCD1 interacts with a wide repertoire of transcription factors including Oct3/4, Sox2, Sox10, c-Fos/c-Jun, peroxisome proliferator-activated receptor α, vitamin D receptor, glucocorticoid receptor, retinoid-related orphan receptor α, androgen receptor and recruits them to the SWI/SNF complex (PMID: 11053448, 12917342, 14698202, 18680712, 19762545, 20508149, 21725993, 22334693). SMARCD1 is required for Tbx1-driven expression of Wnt5a, a non-canonical Wnt ligand that promotes cell migration and invasion in gastric cancer (PMID: 22438823, 17079465). Moreover, SMARCD1 interacts directly and indirectly with key regulators of pluripotency in embryonic stem cells, which in some cases maintains pluripotency (PMID:19279220) and in other cases restricts it (PMID: 25818293). A series of recent studies showed that SMARCD1 is a direct target of tumor-suppressive miRNA (micro RNAs), namely miR-99 in prostate cancer (PMID: 21212412), miR-490-3p in gastric and ovarian cancer (PMID: 25503559, 25819031) and miR-100 in breast cancer stem-like cells (PMID: 25217527). On the other hand, tumor-suppressive properties of SMARCD1 have been reported; interaction between SMARCD1 and p53 is required for p53-mediated cell-cycle arrest and apoptosis (PMID: 18303029) and SMARCD1 is frequently inactivated by truncating mutations in breast cancer (PMID: 22722201). It becomes therefore obvious that the function of SMARCD1 in carcinogenesis is complex and context-dependent. False +ENST00000348513 NM_003079.4 6605 SMARCE1 True SMARCE1, an adaptor protein involved in chromatin remodeling, is infrequently altered by mutation and amplification in various cancer types. Germline mutations of SMARCE1 are associated with spinal meningiomas and Coffin-Siris syndrome. SMARCE1 (also BAF57) is a core subunit of the SWI/SNF chromatin remodeling complex (PMID: 28391084, 21654818, 26601204). The SWI/SNF complex plays an important role in altering chromatin structure, a process that is necessary for various cellular functions, including gene regulation, DNA repair, differentiation, and lineage specification (PMID: 28391084, 21654818, 26601204). The SMARCE1 subunit has the ability to bind cruciform structures in DNA which might lead to SWI/SNF targeting to sites with distinct chromatin architecture (PMID: 26601204, 27149204). In addition, SMARCE1 is predicted to have a role in mediating chromatin relaxation and disassembly of the SWI/SNF complex (PMID: 27149204). SMARCE1 also has roles in lymphocyte development and in both androgen and estrogen-mediated transcription (PMID: 12110891, 16769725, 18559499, 23493350). Familial alterations in SMARCE1 are found in patients with Coffin-Siris syndrome, a developmental disorder (PMID: 25168959, 31273213). Germline loss-of-function mutations in SMARCE1 are also found in almost all patients in non-NF2 driven spinal meningiomas (PMID: 23377182, 26601204). In human cancer, somatic mutations in SMARCE1 are rare (PMID: 26601204). However, amplification of SMARCE1 is found in some cancer types, including in breast cancer, and is implicated in metastatic progression (PMID: 26601204, 27149204). True +ENST00000322213 NM_006306.3 8243 SMC1A False SMC1A, an ATPase that functions as a subunit of the cohesin complex, is recurrently mutated in Cornelia de Lange syndromes, hematologic malignancies, and solid tumors. SMC1A (also SMC1L1) is an ATPase that is a member of the SMC family of proteins. SMC1A functions as a subunit of the cohesin complex that aligns and stabilizes sister chromatids during metaphase (PMID: 24854081). Cohesion between sister chromatids is initiated during DNA replication and must be maintained throughout mitosis or meiosis to ensure proper chromosome-spindle attachments (PMID: 26903600). The cohesin ring that encircles sister chromatids is comprised of two large structural proteins, SMC1A and SMC3, and this ring opens and closes through the binding of alpha-kleisin subunits to the RAD21 and STAG adapter proteins (PMID: 24854081, 22885700). The cohesin complex also functions to maintain chromatin looping structures or 3D arrangements of DNA that allow for regulatory control of gene expression (PMID: 19468298). SMC1A localizes to chromatin sites bound by the insulator protein CTCF, which inhibits tissue-specific enhancer-promoter interactions (PMID: 19468298, 23704192). Germline mutations in SMC1A have been identified in patients with cohesinopathies, including Cornelia de Lange syndrome, leading to a spectrum of developmental defects (PMID: 17221863, 17273969, 18996922). Somatic mutations and deletions in SMC1A have been identified in acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), bladder cancers, and additional hematopoietic malignancies, among others (PMID: 23955599, 24121791, 24335498, 25080505, 24056718, 18299561, 20514443). Mutations in SMC1A are predicted to be loss-of-function and impact the association of SMC proteins with chromatin (PMID: 18996922). Alterations in SMC1A are also predicted to be initiating events in acute myeloid leukemia (PMID: 22932223). True +ENST00000361804 NM_005445.3 9126 SMC3 False SMC3, an ATPase that functions as a subunit of the cohesin complex, is recurrently mutated in Cornelia de Lange syndromes, hematologic malignancies, and solid tumors. SMC3 is an ATPase that is a member of the SMC family of proteins. SMC3 functions as a subunit of the cohesin complex that aligns and stabilizes sister chromatids during metaphase (PMID: 24854081). Cohesion between sister chromatids is initiated during DNA replication and must be maintained throughout mitosis or meiosis to ensure proper chromosome-spindle attachments (PMID: 26903600). The cohesin ring that encircles sister chromatids is comprised of two large structural proteins, SMC1A and SMC3, and this ring opens and closes through the binding of alpha-kleisin subunits to the RAD21 and STAG adapter proteins (PMID: 24854081, 22885700). The cohesin complex also functions to maintain chromatin looping structures or 3D arrangements of DNA that allow for regulatory control of gene expression (PMID: 19468298). SMC3 localizes to chromatin sites bound by the insulator protein CTCF, which inhibits tissue-specific enhancer-promoter interactions (PMID: 19468298, 28467304). Loss of SMC3 in murine models results in aberrant hematopoietic stem cell function and altered expression of genes important in lineage commitment (PMID: 26438361). Germline mutations in SMC3 have been identified in patients with cohesinopathies, including Cornelia de Lange syndrome, leading to a spectrum of developmental defects (PMID: 17221863, 17273969, 18996922, 25655089). Somatic mutations and deletions in SMC3 have been identified in acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), bladder cancers, and additional hematopoietic malignancies, among others (PMID: 23955599, 24335498, 24056718, 18299561, 28152414, 27470916, 27207471). Mutations in SMC3 are predicted to be loss-of-function and impact the association of SMC proteins with chromatin (PMID: 26438361, 25006131). True +ENST00000446231 NM_015092.4 23049 SMG1 False SMG1, a serine/threonine kinase involved in nonsense-mediated decay, is infrequently altered across a diverse range of cancers. SMG1 is a serine/threonine kinase that is a member of the Phosphatidylinositol 3-kinase-related kinase family (PIKK) (PMID: 11544179). SMG1 is an essential protein that regulates nonsense-mediated mRNA decay (NMD), a process that removes incorrect mRNAs that contain premature translation termination codons, and hence encode for aberrant proteins (PMID: 11544179). SMG1 phosphorylates UPF1, an ATPase and RNA helicase involved in NMD, and binds additional proteins involved in mRNA surveillance (PMID: 11544179, 12554878, 18160036). UPF1 and SMG1 form a complex with translation release factors and function as a translation termination complex (PMID: 19417104). SMG1 activity is required for various cellular functions including cell cycle progression, mRNA export, translation, DNA repair, genome stability, apoptosis, and telomere maintenance (PMID: 16199763, 16488880, 16861888, 18326048, 18332866). In addition, NMD or disruption of SMG1 mRNA surveillance activity can lead to alternative splicing to circumvent premature translation termination codons (PMID: 17693403, 20566848). Loss or overexpression of SMG1 results in accumulation or degradation of mRNAs with premature termination codons as demonstrated in functional experiments (PMID: 11544179). NMD can exacerbate developmental disorders that result in mRNAs with premature translation termination codons, such as Ullrich’s disease, and inhibition of SMG1 can restore some normal cellular function (PMID: 16807116). SMG1 is infrequently mutated in human cancers, however, heterozygous loss of SMG1 in murine models results in tumor formation (PMID: 23277562) suggesting that SMG1 functions as a tumor suppressor. Expression of SMG1 is found in several tumor types including acute myeloid leukemia (AML) and head and neck squamous cell carcinomas (PMID: 22247495, 25257528). In kinase screens, SMG1 was identified as a possible target in multiple myeloma (PMID: 19996089). True +ENST00000249373 NM_005631.4 6608 SMO True SMO, a G-protein coupled receptor, is mutated in various cancers including basal cell carcinoma and medulloblastoma. Smoothened (SMO) is a conserved signal transducer of the hedgehog signaling pathway, playing important roles in normal embryonic and neuronal development as well as tumorigenesis (PMID: 23719536, 21614026, 26912893). SMO is a seven-transmembrane domain protein bearing some structural and functional similarity to G-protein coupled receptors (PMID: 23636324). SMO activity is normally inhibited by patched (PTCH1), an upstream component of the Hedgehog pathway, via poorly understood mechanisms (PMID: 23719536). Binding of extracellular Hedgehog ligands to PTCH1 leads to consecutive activation of SMO, which in turn induces modifications of the downstream GLI transcription factors leading to their activation. Activating mutations in SMO lead to constitutive activation of GLI-mediated transcription of important oncogenic genes. Such mutations have been implicated in sporadic basal cell carcinoma (PMID: 9422511, 26950094) and medulloblastoma (PMID: 21614026) and have been identified in many other tumor types. Recent efforts have been made to specifically target SMO (PMID: 26781311, 26931153, 26919418, 26843616, 26527777). A distinct set of mutations in the ligand binding pocket of SMO, however, has been described to confer resistance to SMO inhibitors such as vismodegib and related cyclopamine drugs (PMID: 25759014, 26960983). False +ENST00000490107 NM_001167740.1 64754 SMYD3 True SMYD3, a histone methyltransferase and transcriptional activator, is amplified in a subset of breast and other cancers. The SMYD3 gene encodes a histone lysine methyltransferase. SMYD3 specifically di- and trimethylates lysine-4 of histone 4 (H3K4me2/3), as well as the lysine-5 residue of the same histone. SMYD3-induced methylation generates transcription activating marks that induce gene expression. SMYD3 itself is part of the RNA polymerase complex, present on genes being actively transcribed (PMID: 15235609, 22419068). SMYD3 activity induces cell proliferation, migration and carcinogenesis in various in vitro and in vivo cancer systems via transcriptional activation of different target genes (PMID: 15235609, 25980436, 24174655, 22194464). SMYD3 is altered by amplification in a subset of breast cancers and other tumors (cBioPortal, MSKCC, Dec. 2016). False +ENST00000332029 NM_003745.1 8651 SOCS1 False SOCS1, a negative regulator of cytokine signaling, is altered in various hematologic malignancies, most frequently in diffuse large B-cell lymphoma. SOCS1 is an adaptor protein that suppresses cytokine signaling and functions in negative feedback inhibition of the JAK-STAT signaling pathway (PMID:9202125). SOCS1 binds the phosphotyrosines on receptor and non-receptor kinases to mediate inhibition of cytokine signaling (PMID:10064597). In addition, SOCS1 can target proteins for degradation via the SOCS box domain (PMID: 9202125). Regulation of cytokine signaling by SOCS1 is important for effective immune regulation and lymphocyte development (PMID:10490100, 14499118, 12433373, 16415872, 24086733). Somatic loss-of-function SOCS1 mutations have been found in Hodgkin’s lymphoma and primary mediastinal lymphomas (PMID:17652621, 23296022,19734449). SOCS1 mutations present as truncating mutations and lead to activated JAK-STAT kinase signaling (PMID:16532038), suggesting that SOCS1 functions as a tumor suppressor. Silencing of SOCS1 transcription has also been identified in myeloid diseases, leukemias, ovarian cancer and breast cancer (PMID: 25123164, 15327527, 15361843). True +ENST00000330871 NM_003955.4 9021 SOCS3 False SOCS3, a negative regulator of cytokine signaling, is infrequently mutated in various cancer types. SOCS3 is an adaptor protein that suppresses cytokine signaling and functions in negative feedback inhibition of the JAK-STAT signaling pathway (PMID: 17525754). SOCS3 binds phosphotyrosines on receptor and non-receptor kinases to mediate inhibition of cytokine signaling (PMID:10064597, 24600449). Namely, SOCS3 negatively regulates the activity of the JAK non-receptor tyrosine kinase family, leading to reduced translocation of activated STAT3 transcription factor complexes to the nucleus (PMID: 22342841, 24600449, 22566904). In addition, SOCS3 can target proteins for degradation via interactions with E3 ubiquitin ligase complexes (PMID: 29712772, 25939384). Regulation of cytokine signaling by SOCS3 is an important mediator of various cellular functions including immune homeostasis, inflammation, proliferation, and survival (PMID: 24069550, 24600449, 22566904). Somatic mutations in SOCS3 are relatively rare in human cancer; however, epigenetic silencing of SOCS3 transcription has been identified in several hematopoietic malignancies and solid tumors including mantle cell lymphomas, myeloproliferative neoplasms and prostate cancer, among others (PMID: 23432547, 26216197, 18440067, 20717995). Deletion of SOCS3 in myeloid suppressor populations in the tumor microenvironment also promotes tumor progression in solid tumors, due to dampening of anti-tumor immune responses (PMID: 26967393, 25649351, 29626115). True +ENST00000402219 NM_005633.3 6654 SOS1 True SOS1, a RAS activator, is altered at low frequencies in various cancers. SOS1 is a guanine exchange factor (GEF) that positively regulates the activation of the RAS proteins in the MAP-kinase (MAPK) pathway. SOS1 is recruited to the plasma membrane, binds the adaptor molecule GRB2 and facilitates the activated, GTP-bound state of RAS, which in turn initiates the MAPK pathway signaling cascade (PMID: 8493579). The activity of SOS1 is required to mediate cell proliferation, cell cycle progression, oxidative stress, cell migration, and invasion (PMID: 27157612). SOS1 also activates the G protein RAC by promoting the exchange of GDP for GTP (PMID: 9438849, 22042618). Germline mutations in SOS1 have been identified in certain forms of Noonan syndrome, a hereditary disorder of congenital heart disease (PMID: 17143285, 17143282). However, somatic alterations in SOS1 are rare events in human cancers (PMID: 18064648; cBioPortal, MSKCC, Jan. 2018). False +ENST00000360880 NM_006941 6663 SOX10 True SOX10, a transcription factor involved in embryonic development and cell fate, is altered by amplification in melanoma. SOX10 encodes a member of the SRY-related HMG-box (SOX) family of transcription factors that functions as a regulator of organogenesis and histogenesis during embryonic development (PMID: 28751573, 33082503). During embryogenesis, SOX10 is localized to neural crest cells and regulated by WNT signaling (PMID: 12812785). SOX10 is a transcriptional target of the WNT pathway, but also functions as a regulator of WNT pathway target genes (PMID: 25301735). Due to its role during embryogenesis, deleterious mutations of SOX10 have been implicated in various developmental disorders (PMID: 9462749, 11454798, 23643381). Knockdown of SOX10 in melanoma cell lines and models suppresses cellular proliferation, tumor growth and cell cycle progression, suggesting that SOX10 functions predominantly as an oncogene (PMID: 34557039, 22772081, 23913827). SOX10 amplification has been identified in various cancers, including melanoma, bladder cancer and nasopharyngeal carcinoma (PMID: 27051302, 28258492, 23197006). False +ENST00000297316 NM_022454.3 64321 SOX17 False SOX17 encodes a transcription factor involved in embryonic development and cell fate. Methylation and downregulation of SOX17 are found in colon, liver, lung and breast cancers. SOX17 encodes a member of the SRY-related HMG-box (SOX) family of transcription factors and acts as an important antagonist of the canonical Wnt/beta-catenin signaling pathway by promoting the degradation of β-catenin/TCF via a GSK3β-independent mechanism. The Wnt signaling pathway is involved in many biological processes including embryonic development to stem cell maintenance. For example, conditional ablation of SOX17 in mouse uterine tissue resulted in inhibition of endometrial adenogenesis and a loss of reproductive capacity (PMID:27102016). Interestingly, conditional deletion of SOX17 from mouse hematopoietic stem cells (HSCs) led to the loss of fetal and neonatal but not adult HSCs, proving its importance in the maintenance of fetal and neonatal HSCs but not adult HSCs (PMID:17655922). True +ENST00000325404 NM_003106.3 6657 SOX2 True SOX2 encodes a transcription factor involved in embryonic development and cell fate. Amplifications of SOX2 are found in glioblastomas, small cell lung cancers and squamous cell carcinomas. SOX2 encodes a transcriptional factor essential to embryonic stem cell development and the determination of cell fate. It functions as an activator or suppressor of gene transcription through a highly specific DNA binding (high-mobility group) domain (PMID: 20016762). Together with Oct-4 and Nanog, Sox2 positive regulates transcription of pluripotency factors involved in the Leukemia inhibitory factor signaling pathway (PMID:19571885). SOX2 has recently been implicated in cancer development, by promoting oncogenic signaling and maintaining cancer stem cells. It has been shown to promote cellular proliferation in breast (PMID: 22561374), prostate (PMID: 24659665), pancreatic (PMID: 23917223) and cervical cancers (PMID: 21415100); and to evade apoptotic signaling in prostate (PMID: 24325912), gastric cancer (PMID: 21415100) and non small cell lung cancer (PMID: 24233838). SOX2 has also been associated with an increased in the metastatic potential of these cancers (PMID: 22069467, 22184093, 22912670, 23895273). SOX2 amplification is observed in several cancer types including glioblastoma, small-cell lung cancer and many forms of squamous cell carcinoma (PMID: 20126410, 21518820, 22069467, 20372069, 19801978, 21334718, 22941189, 19787784). Its heterozygous mutations have been associated with developmental disorders, such as aanophthalmia-esophagel-genital (AEG) syndrome (PMID: 16543359) and syndromic microphthalmia, a structural eye malformation (PMID: 23463581). False +ENST00000245479 NM_000346.3 6662 SOX9 True SOX9 encodes a putative tumor suppressor and transcription factor involved in organ and skeletal development. This gene is frequently mutated in colorectal cancer. The SOX9 (Sex-determining Region Y box 9) gene encodes a transcription factor involved in organ and skeletal development. It is expressed widely throughout the body and regulates multiple developmental processes, such as embryonal cell-fate determination, chondrogenesis and testis formation; however, SOX9 also functions in developed tissues (PMID: 25685828). SOX9 is a transcriptional target of the WNT pathway, but also functions as a regulator of WNT pathway target genes (PMID: 17698607). Additionally, SOX9 can facilitate β-catenin degradation by promoting its phosphorylation (PMID: 19047045). Due to its role in development, deleterious mutations of SOX9 can cause developmental disorders; mutations of SOX9 are also implicated in various other disorders (PMID: 25685828). SOX9 mutations are frequent in colorectal cancer and dysregulation of SOX9 is implicated in cancer development in multiple tissue types (PMID: 22810696, 24302456, 22246670, 15084848, 20049725). True +ENST00000392045 NM_007237.4 11262 SP140 False SP140, a protein that associates with nuclear bodies, is altered by mutation in hematologic malignancies. SP140 is a nuclear protein that is a member of the SP100 family of proteins (PMID: 8695863). SP140 is predominantly expressed in lymphoid cells and associates with nuclear bodies, which are suborganelles that carry out specific nuclear functions (PMID: 28577509). These functions include the processing of pre-ribosomal RNA, oxidative stress response, gene expression regulation, cellular proliferation and innate immunity, among others (PMID: 21068152). SP140 shares homology with SP100, a protein known to associate with PML in nuclear bodies to mediate various cellular processes (PMID: 8910577, 10913195). In acute promyelocytic leukemia, SP140 co-localizes with PML in nuclear bodies and this association increases after treatment with retinoic acid (PMID: 8910577). SP140 can also function as an epigenetic reader protein, which is important in mediating the repression of immune response related genes (PMID: 24267382, 28783698). Loss of SP140 in macrophages results in altered expression of transcriptional programs and compromises the immune response to microbe infection (PMID: 28783698). SP140 is predicted to function as a tumor suppressor in chronic lymphocytic leukemia (CLL) and several variants in SP140 have been associated with increased risk for CLL (PMID: 18758461, 22235315). In addition, SP140 is hypomethylated in acute myeloid leukemia and chronic myeloid leukemia, leading to decreased gene expression (PMID: 22395470, 26568194). Somatic mutations in SP140 are also found in patients with multiple myeloma (PMID: 25743686). True +ENST00000375759 NM_015001.2 23013 SPEN False SPEN encodes a tumor suppressor that regulates transcription of ERα-target genes and has been associated with tumor growth inhibition. Somatic mutations and loss of heterozygosity of SPEN have been found in breast cancer. The SPEN gene encodes the protein, SMRT/HDAC1-associated repressor protein (SHARP), mainly involved in transcriptional repression, embryogenesis and development through regulation of the Notch, TCF/LEF, and EGFR signaling pathways. SHARP is a large 402 kDA protein composed of four N-terminal RNA-binding domains and a conserved C-terminal Spen Paralog and Ortholog C-terminal (SPOC) domain. Through these domains, SHARP directly interacts with SMRT, HDAC1, and HDAC2. SPEN also acts as an estrogen-inducible cofactor by binding the steroid receptor RNA coactivator SRA which enhances ERα activity and ultimately modulates the transcription of ERα target genes. (PMID: 11331609, 26297734) Recent studies studying ERα-expressing breast cancer cell lines have identified mutations and LOH in SPEN that lead to underexpression that may be a predictive biomarker of tamoxifen response. ERα-positive breast cell lines expressing higher levels of SPEN correlated with better outcome in patients who received adjuvant tamoxifen therapy. (PMID: 26297734). True +ENST00000347630 NM_001007228.1 8405 SPOP False SPOP encodes an adaptor protein involved in targeting proteins for degradation. SPOP mutations are predominantly found in prostate and endometrial cancers; however, the full functional consequence of these mutations remains under investigation. SPOP (Speckle-type POZ protein) is an adaptor protein in the CUL3 ubiquitin ligase complex that recognizes substrates for ubiquitination and subsequent degradation via the proteasome (PMID: 19818708). The repertoire of SPOP substrates is not well characterized; however, notable proteins include SRC3, DAXX, H2AFY, AR, BMI1, DEK, ESR1 and TRIM24 (PMID: 25278611, 15897469, 25274033, 21577200, 25766326). The CUL3-SPOP complex negatively regulates the transcriptional repressor DAXX, hence impacting the expression of endothelial pathway genes that are regulated by DAXX (PMID: 28216678). Somatic mutations in SPOP are reported in approximately 5% of endometrial cancers (PMID: 23104009) and 10% of prostate cancers (PMID: 21307934, 22610119). SPOP-mediated degradation has also been implicated in the regulation of PD-L1, a key regulatory immune ligand (PMID: 29160310). SPOP mutations in both endometrial and prostate cancer cluster in conserved residues of the MATH domain important for substrate recognition, suggesting that the mutations either alter substrate recognition or act as a dominant negative to prevent substrate degradation (PMID: 21307934, 22610119). There is emerging evidence that SPOP may be a more general tumor suppressor in glioblastoma, gastric and colorectal cancers, as SPOP expression is decreased through tumor progression (PMID: 25351530, 23216165). True +ENST00000299084 NM_152594.2 161742 SPRED1 False SPRED1, a negative regulator of the MAP-kinase pathway, is mutated at low frequencies in various cancers. The SPRED1 gene encodes a member of the Sprouty family of proteins. SPRED1 is a negative regulator of the MAP-kinase (MAPK) pathway (PMID: 15683364, 21364986). The mechanism by which SPRED1 inhibits MAPK signaling involves NF1 (neurofibromatosis type 1), which, upon interaction with SPRED1, localizes to the plasma membrane and facilitates RAS inactivation (PMID: 22751498, 26635368). Overexpression of SPRED1 in a hepatocellular carcinoma model leads to a decrease in cell motility and an increase in the expression of metalloproteinases, which are involved in invasion and metastasis (PMID: 16652141). SPRED1 is rarely mutated in cancers (cBioPortal, MSKCC, Dec. 2016). However, germline loss-of-function mutations in SPRED1 are the cause of Legius syndrome, a familial disorder with neurofibromatosis-like features (PMID: 24334617, 17704776, 19366998) and SPRED1 has been shown to act as a tumor suppressor in mucosal melanoma (PMID: 30385465). True +ENST00000295050 NM_032018.6 83932 SPRTN False SPRTN, a metalloprotease that functions as a DNA repair protein, is recurrently altered by mutation in early-onset hepatocellular carcinoma. SPRTN (also C1orf124, Spartan, or DVC1) is a metalloprotease that functions as a DNA repair adaptor protein (PMID: 25496645, 27852435). SPRTN recruits the protein segregase p97 to stalled replication forks, allowing for p97 to remove the translesional synthesis polymerase (Pol η) and for DNA replication to bypass lesions (PMID: 23042605). The activity of SPRTN is required to block excessive translesional DNA synthesis and reduce mutations caused by DNA damage (PMID: 23042607, 23042605). SPRTN associates with monoubiquitinated PCNA, the processivity factor that promotes translesional synthesis, to remove p97 from blocked replication forks (PMID: 23042605, 27084448). SPRTN also has the ability to resolve DNA-protein crosslinks, which contributes to the role of SPRTN in the DNA damage response (PMID: 27852435, 27871365). Loss of SPRTN expression results in increased mutagenesis after UV light stimulation, cellular senescence, hypersensitivity to replication stress-inducing agents and age-related phenotypes in mice (PMID: 23042605, 25501849, 27871366, 28199696). Germline mutations in SPRTN are found in patients with Ruijs-Aalfs syndrome, which presents with early-onset hepatocellular carcinoma, premature aging and genomic instability (PMID: 25261934). Patient samples with SPRTN mutations have reduced cell cycle checkpoint control when treated with genotoxic agents (PMID: 25261934). True +ENST00000389805 NM_003900 8878 SQSTM1 True SQSTM1, an autophagy adaptor protein, is infrequently altered by translocation in cancer. SQSTM1 (or p62) is a stress-inducible adaptor protein that regulates the activation of various signaling pathways such as the Nrf2, mTORC1, NF-kB and autophagy signaling pathways via feedback loops (PMID: 22264792, 20452972, 21617040, 24462201, 21258367, 24011591). Multiple kinases, including mTORC1 and MEKK3, phosphorylate SQSTM1 and allow it to bind to ubiquitin-associated proteins (PMID: 24011591). Phosphorylated SQSTM1 then sequesters or degrades via selective autophagy proteins that negatively regulate important signaling pathways, thus activating these pathways (PMID: 25609235). Examples of this are the binding of KEAP1, the negative regulator of Nrf2, or the binding of the ubiquitin-editing enzyme A20, the negative regulator of NF-kB (PMID: 28842501, PMID: 25609235). SQSTM1, therefore, serves as a regulator for diverse cellular processes such as inflammatory response, antioxidant response, anabolism and catabolism (PMID: 21981924, 10747026, 20173742, 24462201). Accumulation of SQSTM1 promotes tumorigenesis through the overactivation of these cellular processes (PMID: 27345495, 24332042, 27246794). SQSTM1 translocations have been identified in a variety of tumor types including papillary thyroid cancer, ALK-positive large B-cell lymphoma, adult T-cell acute lymphoblastic leukemia and lung adenocarcinoma (PMID: 28351223, 21134980, 20851865, 33768710). False +ENST00000358208 NM_198291.2 6714 SRC True SRC encodes a tyrosine kinase involved in cell cycle control, cytokinesis, cell survival/proliferation and migration/motility. Amplification of SRC is found in colorectal, breast, brain and pancreas cancers, among others. SRC encodes the c-SRC proto-oncogene, a non-receptor tyrosine protein kinase implicated in cell cycle control, cytokinesis, cell survival/ proliferation and migration/motility (PMID: 25662515). Furthermore, c-SRC has been strongly correlated with a variety of human malignancies including colorectal and breast cancer among others (PMID:19581523). The c-SRC protein consists of a N-terminal myristolation sequence, important for membrane localization and subsequent functionality, followed by an unique SH4 domain, a SH3 domain, a SH2 domain, a linker to the protein-tyrosine kinase domain and a C-terminal regulatory domain (PMID: 8672527). c-SRC is closely related to nine additional non-receptor tyrosine kinases that share homology with c-SRC, the SRC Family Kinases (SFK), which exert similar functions and are also implicated in human cancers (PMID: 25207369, 24948875, 24574860, 24522479, 24388104, 24361441). False +ENST00000642900 NM_006947 6731 SRP72 True SRP72, a subunit of the signal recognition particle complex, is infrequently altered in cancer. Germline SRP72 mutations are associated with familial aplasia and myelodysplasia. SRP72 encodes for a subunit of the signal recognition particle (SRP) ribonucleoprotein complex, which functions in translocation of the secretory and membrane proteins to the endoplasmic reticulum (PMID: 34020957). The SRP complex interacts with the signal sequence in nascent proteins to mediate transportation to the endoplasmic reticulum (PMID: 34020957). SRP72 contains an RNA-binding domain to interact with the signal recognition particle RNA, also known as the 7SL RNA, and mediate protein trafficking (PMID: 21073748, 15588816). SRP72 germline mutations have been implicated in familial aplasia and myelodysplasia (PMID: 22541560, 26492932). Overexpression and hypomethylation of SRP72 was frequently identified in thyroid cancer, suggesting that SRP72 may function as an oncogene in this context (PMID: 26718127). SRP72 expression is suggested to confer radioresistance as knockdown of SRP72 in preclinical studies demonstrate increased radiosensitivity (PMID: 28494188). False +ENST00000359995 NM_003016.4 6427 SRSF2 False 4 SRSF2, an RNA splicing factor, is frequently mutated in hematological malignancies. SRSF2 (serine/arginine-rich splicing factor 2) is an RNA splicing factor that mediates constitutive or alternative splicing of pre-mRNA (PMID: 25965569). As a member of the spliceosome, SRSF2 interacts with splicing factors and mediates mRNA splicing by binding to pre-mRNA via an RNA recognition motif (PMID: 22262462). Loss of SRSF2 expression in cell lines and murine hematopoietic models results in abnormal differentiation, cell cycle, apoptosis and mis-splicing of target mRNAs (PMID: 25965569). SRSF2 has also been implicated in the nuclear transport of mRNAs to and from the nucleus (PMID: 22262462). Somatic mutations in SRSF2 have been found in myelodysplastic syndrome, acute myeloid leukemia and myeloid disorders (PMID: 21909114, 25550361, 25231745, 26464169, 23660863). Alterations in SRSF2 are predominantly heterozygous missense mutations that impact the RNA recognition domain (PMID: 26261309). SRSF2 mutations result in aberrant pre-mRNA splicing at differential splicing enhancer sequences leading to exon misrecognition (PMID: 26124281, 25965569). In hematopoietic cells, key regulatory genes such as EZH2 are mis-spliced in cells with SRSF2 mutations, leading to degradation of EZH2 (PMID: 25965569). Inhibitors of the spliceosome are in preclinical and clinical testing and may be a therapeutic strategy in spliceosome-mutant disease (PMID: 26575690). False +ENST00000415083 NM_001007559.2 6760 SS18 True SS18, a transcription factor, is frequently altered by chromosomal rearrangement in synovial sarcoma. SS18 encodes a transcription factor that is a member of a SWI/SNF complex, which is a global transcription co-activator. Co-purification studies have confirmed that SS18 is specifically part of the BAF-type SWI/SNF complexes (PMID: 22442726, 11734557). SWI/SNF complexes remodel chromatin in an ATP-dependent manner to re-position and/or facilitate the binding of transcriptional activator proteins to nucleosomes (PMID: 11734557). The proteins of SWI/SNF complexes are known to be mutated and/or altered in multiple types of cancer due to the potential oncogenic effects of chromatin remodeling and transcriptional activation. False +ENST00000383202 NM_005862.2 10274 STAG1 False STAG1, a subunit of the cohesin complex, is altered by mutation in acute myeloid leukemia. STAG1 (also SA-1) is a subunit of cohesin, a multi-protein complex that mediates sister chromatid separation during cell division. Cohesin is a ring-shaped structure that regulates sister chromatid cohesion at the centromere from DNA replication to prometaphase during both meiosis and mitosis (PMID: 12034751, 19822671, 21444719). STAG1, or the homolog STAG2, in collaboration with SMC1A, SMC3, and RAD21, make up the cohesin ring-structure that surrounds chromatin (PMID: 24856830). During metaphase, cohesin subunits are released from chromosomes leading to the dissolution of cohesion between sister chromatids (PMID: 19056890). STAG1 also binds CTCF, a protein that mediates chromatin looping and has been implicated as a regulator of insulator regions (PMID: 18550811, 27219007). The cohesin complex is also important for other cellular functions including mediating epigenetic state and transcription in post-mitotic cells and regulation of the DNA damage response (PMID: 19056890). Germline mutations in STAG1 are found in cohesinopathies, developmental syndromes associated with loss of cohesin activity (PMID: 28119487). Loss of STAG1 in mice results in transcriptional changes consistent with Cornelia de Lange syndrome and other cohesinopathies (PMID: 22415368). Somatic mutations in STAG1 have been identified in acute myeloid leukemia (PMID: 24335498) and these mutations are predicted to be loss-of-function (PMID: 28430577). STAG1 overexpression has also been identified in several human cancers (PMID: 11568975). STAG1 and STAG2 have a synthetic lethal relationship, suggesting that targeting both components could be therapeutically valuable (PMID: 28691904). True +ENST00000218089 NM_001042749.1 10735 STAG2 False STAG2, a component of the cohesin complex, is recurrently altered by mutation in various cancer types,. STAG2 is a component of the cohesin complex that is required for cohesion of the sister chromatids at the centromere after DNA replication in both meiosis and mitosis (PMID: 12034751, 19822671, 21444719). Microduplication of the Xq25 chromosome, containing the locus of STAG2, is seen in some types of cohesinopathies that are characterized by abnormal behavior, intellectual disability, distinctive facial appearance and disorders in speech (PMID: 23637084, 25677961, 25450604, 26443594). Inactivating mutations in STAG2 lead to aneuploidy and chromosomal instability in cancer (PMID: 21852505). Nonsense mutations and deletions of STAG2 are found together in melanoma, Ewing sarcoma, glioblastoma, head and neck carcinoma, bladder carcinoma and myeloid neoplasms, whereas deletions alone are observed in gastric, colorectal and prostate cancers (PMID: 24856830, 21852505, 26122845, 25010205, 24270882, 24121792, 25186949, 22668012, 25223734, 23955599, 25501392, 24121789, 20687102, 24056718, 24335498, 24121791, 25867412). Somatic mutations of STAG2 are observed in myeloid malignancies, such as myelodysplastic syndrome and acute myeloid leukemia, and are associated with worse overall survival and better response to some therapeutic treatments (PMID: 25501392, 25006131, 24335498). STAG2 mutations are prevalent in leukemia patients with IDH2 mutations and are found in more than 95% of patients with secondary leukemia (PMID: 25836588, 25550361). Nonsynonymous mutations are found in glioblastoma, uterine carcinoma and breast carcinoma (PMID: 26352260). Of importance, glioblastomas harboring STAG2 mutations are more sensitive to PARP inhibition (PMID: 24356817). True +ENST00000361099 NM_007315.3 6772 STAT1 False STAT1, a transcription factor, is altered by mutation in immunodeficiency disorders. STAT1 is a transcription factor that is activated by cytokine and growth factor stimulation of receptor kinases (PMID: 26631912). Activated non-receptor JAK tyrosine kinases phosphorylate STAT1 in response to receptor kinase stimulation, leading to dimerization and nuclear translocation of STAT complexes (PMID: 22520844). STAT1 functions as a homodimer known as the IFN-gamma activator complex, or heterodimerizes with STAT2 molecules (PMID: 28184222). The latter can complex with interferon-regulated genes such as IRF9 to regulate context-specific transcriptional programs known as the interferon-stimulated gene factor 3 or ISGF3 (PMID: 28184222). JAK-STAT signaling is initiated by various cytokines, including interleukin and interferon molecules, which stimulate STAT-mediated transcription in the nucleus (PMID: 29921905). STAT1 signaling is critical for regulation of innate and adaptive immunity, including protection from pathogen infections (PMID: 26631912, 29921905). In addition, STAT1 regulates the expression of the immune recognition molecule MHC-I, which promotes clearance of tumor cells by NK and cytotoxic T cells (PMID: 30796216, 19811323). Loss of STAT1 in murine models results in depleted responses to interferon signaling, leading to aberrant T-cell function (PMID: 30796216). STAT1 also regulates various other cellular functions including differentiation, proliferation and cell death (PMID: 26631912). Germline, heterozygous, gain-of-function mutations in STAT1 result in chronic mucocutaneous candidiasis, a malignancy that results in persistent infections (PMID: 22651901, 21714643, 21727188). Somatic mutations in STAT1 are not well-studied in human cancers; however, loss of STAT1 in mammary tumor models promotes tumor progression, suggesting STAT1 may function as a tumor suppressor (PMID: 26631912, 21076615, 21311224). Additional studies have indicated that STAT1 may also have context-specific growth promoting roles (PMID: 24726362, 26631912). False +ENST00000314128 NM_005419.3 6773 STAT2 False STAT2, a transcription factor, is altered by mutation in immunodeficiency disorders. STAT2 is a transcription factor that is activated by cytokine and growth factor stimulation of receptor kinases (PMID: 27053489). Activated non-receptor JAK tyrosine kinases phosphorylate STAT2 in response to receptor kinase stimulation, leading to dimerization and nuclear translocation of STAT complexes (PMID: 26631912). STAT2 functions as a homodimer or heterodimerizes with STAT1 molecules (PMID: 28184222, 27053489). The latter can complex with interferon-regulated genes such as IRF9 to regulate context-specific transcriptional programs known as the interferon-stimulated gene factor 3, or ISGF3 (PMID: 28184222, 8621447, 31266943). JAK-STAT2 signaling is initiated by various cytokines, including interferon type I (IFN-I) molecules, which stimulate STAT-mediated transcription in the nucleus (PMID: 29921905, 30671054, 28165510). STAT2 signaling is critical for the regulation of anti-viral, immune, apoptotic, and proliferative responses initiated by IFN-I stimulation (PMID: 31605750, 30337919). Loss of STAT2 in murine models leads to deficiencies in various immune cell populations, leading to an ineffective host response to viral infection (PMID: 30134157, 27233962). Germline mutations in STAT2 are found in patients with susceptibility to viral infections due to deficiencies in IFN-I immunity (PMID: 23391734, 28087227, 23391734). STAT2 alterations have also been linked to neurodegeneration following viral infection due to mitochondrial fission defects (PMID: 26122121). Somatic mutations in STAT2 are not well-studied in human cancers; however, STAT2 activity has a critical role in regulating interferon signaling in various contexts in cancer cells (PMID: 30940163, 31605750, 29581268). False +ENST00000264657 NM_139276.2 6774 STAT3 True STAT3, a transcription factor, is altered by mutation or amplification in various solid and hematologic malignancies. STAT3 (Signal transducer and activator of transcription 3) is a transcription factor that is activated by cytokine and growth factor stimulation of receptor kinases (PMID: 26464811). Non-receptor JAK tyrosine kinases subsequently phosphorylate STAT3, leading to dimerization and nuclear translocation of STAT complexes (PMID: 25527793). STAT3 is involved in regulating development of the skin, central nervous system and mammary tissue (PMID:11994402, 10342556). Activated STAT3 is found in various cancer types, most notably in breast cancer, and is implicated in pathways important for survival, immune dysregulation, tumor microenvironment modulation and invasion (PMID: 25342631, 11420660, 21310826, 16463269). Germline mutations in STAT3 are associated with autoimmunity and lymphoproliferation (PMID: 25359994). STAT3 germline mutations have also been identified in hyper-IgE syndrome characterized by elevated IgE levels, connective tissue abnormalities and immunodeficiency (PMID: 17881745). Somatic activating STAT3 mutations are found in large granular lymphocytic leukemia and more rarely in myelodysplastic syndrome, aplastic anemia and lymphomas (PMID: 22591296, 23926297, 25586472). STAT3 mutations have also been found in inflammatory hepatocellular adenomas and copy number alterations are present in breast cancer samples (PMID: 21690253, 25470049). False +ENST00000358470 NM_001243835 6775 STAT4 True STAT4, a transcription factor, is altered by mutation in autoimmune disorders. STAT4 is a transcription factor that is a member of the signal transducer and activator of transcription (STAT) protein family (PMID: 8007943). Activated non-receptor JAK tyrosine kinases phosphorylate STAT4 in response to receptor kinase stimulation, leading to dimerization and nuclear translocation of STAT complexes (PMID: 25527793). STAT4 functions predominantly as a mediator of the innate and adaptive immune response (PMID: 15356157, 34138758). STAT4-dependent signaling to modulate Tfh cell secretion of IL-21 and IFN-y is activated by type I interferon signaling (PMID: 33512094). Mutations of STAT4 have been implicated in various autoimmune diseases (PMID: 27178308, 23755762). Knockdown of STAT4 in cancer cell lines and models suppresses tumor growth, cellular proliferation, migration and invasion, suggesting that STAT4 functions predominantly as an oncogene (PMID: 33636177, 25864744, 28114283). Amplification of STAT4 has been identified in various cancers, including ovarian cancer and lung cancer (PMID: 28114283, 30987235). Conversely, up-regulation of STAT4 in patients with hepatocellular carcinoma and cell lines demonstrate better prognosis and inhibits cellular proliferation, suggesting that there may be tissue-specific tumor suppressive roles for STAT4 (PMID: 24965572, 25852285). False +ENST00000345506 NM_003152.3 6776 STAT5A True STAT5A encodes a transcription factor involved in the JAK signaling cascade. Mutations of STAT5A are found in prostate and breast cancers and leukemias, among others. STAT5A (Signal transducer and activator of transcription 5A) is a transcription factor that is activated by cytokine and growth factor stimulation of receptor kinases (PMID:15313458, 9630227). Activated non-receptor JAK tyrosine kinases subsequently phosphorylate STAT5A, leading to the dimerization and nuclear translocation of STAT complexes (PMID:25527793). STAT5A regulates the development and differentiation of tissues and cell types including the mammary gland, hepatocytes, erythrocytes, platelets, B-cells and T-cells (PMID:15711548, 23773921, 8961260, 8906870, 18347089, 16418296). In cancer, STAT5A signaling is important for tumor progression, therapy resistance and transformation in various cancers including prostate cancer, breast cancer, myeloproliferative neoplasms and leukemias (PMID:22234689, 23660011, 18508994). STAT5A copy number alterations have been identified in breast cancer samples (PMID: 25470049), however, somatic mutations in STAT5A are infrequent in human cancers. In leukemias and myeloproliferative neoplasms, STAT5A signaling is hyperactivated through mutations in the JAK proteins or the FLT3 receptor (PMID:17356133, 17379095, 22234689). False +ENST00000293328 NM_012448.3 6777 STAT5B True STAT5B, a transcription factor, is altered in various solid and hematologic malignancies. STAT5B (Signal transducer and activator of transcription 5B) is a transcription factor that is activated by cytokine and growth factor stimulation of receptor kinases (PMID:15313458, 9630227). Activated non-receptor JAK tyrosine kinases subsequently phosphorylate STAT5B, leading to the dimerization and nuclear translocation of STAT complexes (PMID: 25527793). STAT5B regulates the development and differentiation of tissues and cell types including the mammary gland, hepatocytes, erythrocytes, platelets, B-cells and T-cells (PMID:15711548, 23773921, 8961260, 8906870, 18347089, 16418296). In cancer, STAT5B signaling is important for tumor progression, therapy resistance, and transformation in various cancers including prostate cancer, breast cancer, myeloproliferative neoplasms and leukemias (PMID:22234689, 23660011, 18508994). Somatic activating STAT5B mutations have been identified in large granular lymphocytic leukemia and subtypes of lymphomas (PMID:23596048, 25586472, 24972766). STAT5B is also found in rare translocations with RARA in cases of acute promyelocytic leukemia (PMID:22749039). False +ENST00000300134 NM_001178078.1 6778 STAT6 True STAT6, a transcription factor involved with immune regulation, is recurrently altered by mutation and amplification in lymphomas and solid tumors. STAT6 fusions are found in all patients with solitary fibrous tumor and meningeal haemangiopericytoma. STAT6 is a transcription factor that is a member of the signal transducer and activator of transcription (STAT) protein family (PMID: 8085155). STAT6 is activated by cytokine and growth factor stimulation of receptor kinases (PMID: 11345192). Activated non-receptor JAK tyrosine kinases subsequently phosphorylate STAT6, leading to the dimerization and nuclear translocation of STAT complexes (PMID: 8085155, 25527793). In the nucleus, STAT6 binds DNA and regulates the expression of a range of transcriptional targets involved in T-cell mediated inflammatory signaling (PMID: 8816495, 20620946). STAT6 activity mediates the development of T-helper type 2 (Th2) cells and IL-4 stimulated T cell responses (PMID: 8624821, 8085155). In addition, STAT6 is involved in a variety of other cellular functions including immunoglobulin class switching in B cells, lymphocyte homeostasis, apoptosis, chromatin state changes and transcriptional regulation (PMID: 8602264, 12023955, 21442426). STAT6 fusions are found in all patients with solitary fibrous tumor (SFT), a metastasizing mesenchymal cancer, and meningeal haemangiopericytoma, a soft tissue sarcoma in the meninges (PMID: 23313952, 29703757, 28295484, 25482924, 23575898). Somatic activating mutations in STAT6 are found in hematopoietic malignancies including diffuse large B cell lymphoma, follicular lymphoma, and mediastinal B cell lymphomas (PMID: 25428220, 26647218, 19423726). Amplification and overexpression of STAT6 have also been identified in a range of cancers (PMID: 24457460, 15044251), suggesting that STAT6 predominantly functions as an oncogene. False +ENST00000326873 NM_000455.4 6794 STK11 False 4 STK11, a tumor suppressor and intracellular kinase, is frequently mutated in lung cancer. STK11 encodes serine/threonine kinase 11, also known as liver kinase B1 (LKB1), that functions as a tumor suppressor. STK11 activates the AMPK (adenine monophosphate-activated protein kinase) pathway via formation of a biologically active heterotrimer with the pseudokinase, STRAD, and the adaptor protein, MO25. Activated AMPK phosphorylates TSC2 and Raptor, which leads mTORC1 hyperactivation (PMID: 14651849, 18439900). STK11-AMPK signaling regulates cell metabolism and energy homeostasis, as well as cellular stress responses to DNA damage and nutrient scarcity (PMID: 21396365). In response to the metabolic stress and hypoxic conditions that often exist within tumors, STK11-AMPK signaling is activated, resulting in inhibition of anabolism, induction of cell cycle arrest and ultimately, suppression of tumor growth (PMID: 25244018). Loss of STK11 has been shown to lead to disorganized cell polarity and tumor growth in nutrient poor conditions. Activation of STK11 by ATM under conditions of DNA damage leads to downstream inhibition of the mTOR pathway (PMID: 20160076). Mutations in STK11 have been found in lung, breast, cervical, testicular, and liver cancers, as well as malignant melanoma, and pancreatic and biliary carcinoma (PMID: 25244018). In addition, the hereditary disease Peutz-Jeghers syndrome, in which STK11 mutations were initially discovered, is characterized by an increased risk of developing both benign and malignant gastrointestinal tumors, other cancer types and mucocutaneous pigmentation (PMID: 20581245). True +ENST00000375331 NM_004197.1 8859 STK19 True STK19, a nuclear protein, is mutated in a subset of skin cancers. STK19 encodes for a nuclear DNA-binding protein that was originally misidentified as a serine/threonine kinase (PMID: 9812991). STK19 is located on chromosome 6, close to the major histocompatibility complex, a region frequently associated with several traits in case-control studies (PMID: 21323541, 23263863, 19851445, 23535732, 19423540). Despite being named as a serine/threonine kinase, STK19 has no intrinsic kinase activity and previous research of STK19’s kinase activity is suggested to be due to an STK19-associated kinase (PMID: 32531245, 32531246). STK19 is tightly chromatin-associated, however its functions as a nuclear protein are currently unknown (PMID: 32531245). STK19 is suggested to bind with an unknown kinase, leading to the phosphorylation and activation of NRAS to drive melanomagenesis, which may be sensitive to STK19 small molecule inhibition (PMID: 30712867, 32531246). STK19 mutations have been identified in a subset of skin cancers (PMID: 22817889, 25600636, 25303977). False +ENST00000373129 NM_032017.1 83931 STK40 False STK40 encodes a serine/threonine kinase involved in regulation of NF-κB- and p53-mediated transcription. Altered expression of STK40 is found in ovarian and esophageal cancers, among others. STK40 (Serine/Threonine Kinase 40) is a pseudokinase that functions predominantly as an adaptor signaling molecule (PMID: 26663584,13679039). Structural studies demonstrate that while STK40 has a serine/threonine kinase domain, the protein cannot bind ATP (PMID: 28089446). Overexpression of STK40 inhibits NF-κB activation and p53-mediated transcription, suggesting that STK40 functions as a negative regulator of NF-κB and p53 (PMID:26663584,13679039). STK40 also has been shown to bind the E3 ligase COP1, implicating the adaptor in regulation of protein stability (PMID: 28089446). Loss of STK40 expression in several cell line and murine models suggests a role for STK40 in cell differentiation including in hematopoietic cells and skeletal muscle (PMID: 28358362, 27899448). Somatic mutations in STK40 are infrequent in human cancer, however, STK40 expression has been found to be upregulated in several cancer cell line models (PMID: 26286729). False +ENST00000369902 NM_016169.3 51684 SUFU False SUFU encodes the protein suppressor of fused, which is a negative regulator of hedgehog signaling. Truncating mutations in SUFU are strongly associated with pediatric medulloblastoma. SUFU encodes the protein suppressor of fused which is part of the hedgehog signaling pathway, one of the key regulators of embryonic development (PMID: 23686138). SUFU can sequester GLI transcription factors in the cytoplasm repressing their activity (PMID: 19055941, 10564661, 10559945). SUFU can repress Wnt signaling by exporting beta-catenin from the nucleus (PMID: 11477086) it also can serve as a point of interaction between the hedgehog and p63 pathways which may be an important part of the regulation of keratinocyte differentiation (PMID: 23686138). SUFU is a tumor-suppressor in which truncating germline or somatic mutations, often accompanied by loss of the wildtype allele, are strongly associated with pediatric medulloblastoma (PMID: 12068298, 24651015). Germline mutations in SUFU can cause Gorlin syndrome (PMID: 25403219). No drugs specifically target SUFU although there are drugs that target the hedgehog signaling pathway (PMID: 23291299). True +ENST00000322652 NM_015355.2 23512 SUZ12 False SUZ12, a component of the polycomb group of transcriptional repressors, is altered in hematologic diseases and sarcomas. The SUZ12 (Suppressor of Zeste 12) is a component of the Polycomb Repressive Complex 2 (PRC2), which is responsible for transcriptional repression by catalyzing di- and tri-methylation of Histone H3 lysine 27 (H3K27) (PMID: 16630818). SUZ12 is necessary for both the histone methyltransferase activity and silencing function of PRC2 (PMID: 15225548), which are important in regulating development and expression of cell identity genes, including the HOX cluster of genes (PMID: 16625203). SUZ12 is commonly mutated in malignant peripheral nerve sheath tumors, T-cell acute lymphoblastic leukemia, and myeloid neoplasms (PMID: 25240281, 22237151, 22237106, 23486531). Translocations involving SUZ12 have been identified in endometrial stromal tumors (PMID: 11371647). Mutations in SUZ12 can cooperate with Ras pathway signaling in cellular transformation and may sensitize tumor cells to bromodomain inhibitors (PMID: 25119042). True +ENST00000375746 NM_003177.5 6850 SYK True SYK encodes a tyrosine kinase involved in signal transduction. Upregulation of SYK is found in lymphomas, leukemias and select epithelial tumors. SYK is a cytoplasmic tyrosine kinase that is recruited to the cell membrane through binding of its SH2 domain to membrane receptors and is subsequently activated via phosphorylation (PMID:7538118). SYK is predominantly expressed in hematopoietic cells and activation of SYK-mediated signaling pathways is necessary for B-cell and lymphatic system development (PMID:10963601,17699797, 23609194). In B- and T-cell signal transduction, SYK binds ITAM adaptor molecules that complex with the B-cell receptor (BCR) and T-cell receptor (TCR) mediating critical immune regulatory pathways (PMID:7477353,12522250). SYK activity is required to activate various other signaling pathways that mediate cellular adhesion, osteoclast maturation, platelet activation and vascular development (PMID: 20467426). Somatic mutations in SYK are rare in human cancers; however, activated SYK signaling has been identified in leukemias and lymphomas (PMID: 24525236,19800574, 26575169, 23764004). In addition, activation of SYK signaling has been described as a mechanism of ovarian cancer chemoresistance (PMID:26096845). Case reports have reported translocations in SYK in myelodysplastic syndromes (MDS) and lymphomas (PMID:11159536,16341044). The SYK tyrosine kinase inhibitor fostamatinib is currently being evaluated in clinical trials for efficacy in hematopoietic malignancies (PMID: 26575169, 23764004). False +ENST00000562955 NM_015284 23334 SZT2 False SZT2, a multifunctional protein, is infrequently altered in cancer. SZT2 encodes the seizure threshold 2 homolog protein, which is expressed in the brain, predominantly in the parietal frontal cortex and dorsal root ganglia, and in other tissues at lower levels (PMID: 34685691). Expression of SZT2 in the brain suggests that it may play a role during early brain development through neuronal migration, axon guidance, and synapse formation (PMID: 30970654, 19624305). While its biological function is not fully understood, the SZT2 protein is highly conserved and has been implicated in the regulation of endoplasmic reticulum homeostasis and protein quality control. Other potential functions of SZT2 include involvement in calcium homeostasis, mitochondrial function and the cellular stress response pathway (PMID: 30970654). Mutations in the SZT2 gene cause severe epileptic and neurological encephalopathy (PMID: 34685691, 36250465, 28199315, 30970654). SZT2 is a component of the KICSTOR complex which is required for the localization of the GATOR1 complex on the lysosome surface. Both the KICSTOR and GATOR1 complexes act as negative regulators of mTORC1 activity (PMID: 33685991, 30970654). In hematopoietic stem cells, loss of SZT2 causes an elevation of mTORC1 activity and reactive oxygen species production and impairs the repopulating capacity of the cells (PMID: 36250465). Mutations in the SZT2 gene have been identified in patients with PIK3CA-mutated ER+ breast cancer and head and neck squamous cell carcinoma (PMID: 33685991, 30970654). False +ENST00000423759 NM_004606.5 6872 TAF1 True TAF1, a transcription factor, is infrequently altered in cancer. TAF1 encodes for a subunit of the transcription factor polymerase II (TFIID) basal transcription factor complex, which functions in the initiation of RNA polymerase II-dependent transcription (PMID: 33795473). The TFIID multi-subunit complex is composed of the TATA binding protein and multiple TATA binding protein associated factors (TAFs) (PMID: 8340360). TAF1 is the largest subunit of the TFIID complex and functions as the core scaffold and forms the promoter DNA binding subcomplex of TFIID through interaction with TAF7 and TAF2 (PMID: 33795473). TAF1 mediates cell cycle progression through transcriptional activity regulation (PMID: 25412659, 15053879). Overexpression of TAF1 in various cancer cell lines and models induces epithelial-to-mesenchymal transition, cellular proliferation, migration and invasion, suggesting that TAF1 functions predominantly as an oncogene (PMID: 20181722, 30854104, 36368153, 31664040). Amplification and mutations of TAF1 have been identified in various cancers, including prostate cancer, non-small cell lung cancer and gastric cancer (PMID: 20181722, 36368153, 27571988). False +ENST00000294339 NM_001287347.2 6886 TAL1 True TAL1, a transcription factor, is recurrently altered by chromosomal rearrangement in T-lymphoblastic leukemias. TAL1 (also SCL) is a transcription factor that is a member of the class II basic helix-loop-helix family (bLHL) (PMID: 28179281). TAL1 is expressed in many hematopoietic cell types including hematopoietic stem cells, multipotent progenitors, megakaryocytes, and erythroid cells; however, TAL1 is silenced in lymphoid lineages (PMID: 7678994, 28179281). Like other bLHL transcription factors, TAL1 functions as a heterodimer with class I bHLH transcription factors and binds E-box motifs to regulate gene expression (PMID: 9214632). TAL1 regulates the activity of numerous genes via interaction with other hematopoietic transcription factors including LMO2, GATA1, LDB1, RUNX1, ETS family proteins, among others (PMID: 20887958). Binding of TAL1 across the genome is distinct depending on hematopoietic cell type, suggesting that TAL1 transcriptional regulation is context dependent (PMID: 21179004). In addition, TAL1 likely has additional roles in the activation of transcription factor partners beyond the role in DNA binding (PMID: 10498694). Loss of TAL1 in mice results in the absence of blood formation during early hematopoietic development and the depletion of differentiated hematopoietic cells in adults, demonstrating that TAL1 is critical in early hematopoietic lineage specification (PMID: 7830794, 8689686). TAL1 overexpression is common in patients in T-acute lymphoblastic leukemia (T-ALL), and recurrent translocations that result in TAL1 activation are also found in T-ALL, suggesting that TAL1 functions predominantly as an oncogene (PMID: 19562638, 21057528). False +ENST00000354258 NM_000593.5 6890 TAP1 False TAP1, a transport protein, is altered by amplification in various cancers. The TAP1 gene encodes a membrane-associated protein that belongs to the family of ATP-binding cassette (ABC) transporters. TAP1 is involved in the transport of antigens from the cytoplasm to the endoplasmic reticulum, as well as their association with MHC class I molecules (PMID: 14679198, 12594855, 17947644, 22638925). TAP1 overexpression has been associated with prostate cancer progression and breast cancer metastasis (PMID: 22065046, 25403418). Mechanistically, the role of TAP1 in cancer is unclear, but it likely has a role in cell proliferation (PMID: 25398693). TAP1 is altered by amplification in various cancers (cBioPortal, MSKCC, Dec. 2016). False +ENST00000383119 NM_018833.2 6891 TAP2 False TAP2, a transport protein, is altered by amplification in various cancers. The TAP2 gene encodes a membrane-associated protein that belongs to the family of ATP-binding cassette (ABC) transporters. TAP2 is involved in the transport of antigens from the cytoplasm to the endoplasmic reticulum, as well as their association with MHC class I molecules (PMID: 14679198, 12594855, 17947644, 22638925). TAP2 expression is deregulated in several cancers, and it correlates with differential antigen processing and immune system response (PMID: 18385764, 26799285, 14558951, 23302073). TAP2 is altered by amplification in various cancers (cBioPortal, MSKCC, Jan. 2017). False +ENST00000430069 NM_024665.4 79718 TBL1XR1 True TBL1XR1, a transcriptional repressor that binds the NCoR/SMRT protein complex, is recurrently altered by mutation and fusion in hematologic malignancies. TBL1XR1 (also TBLR1) is a transcriptional regulatory protein that is a member of the WD40 repeat-containing protein family (PMID: 26069883). TBL1XR1 functions as a transcriptional co-repressor by binding the NCoR (nuclear receptor corepressor)/SMRT (silencing mediator of retinoic acid and thyroid hormone receptors) complex and mediates histone deacetylation at target genes (PMID: PMID: 26069883). TBL1XR1, in collaboration with TBL1X, stabilizes the NCoR/SMRT complex on chromatin via interactions with histone H2B and H4 (PMID: 28687524, 18202150). In addition, TBL1XR1 mediates the ubiquitination and subsequent degradation of the NCoR/SMRT complexes after ligand binding to nuclear receptors (PMID: 26069883, 14980219). Ligand binding initiates activation of several hormone receptors, including the androgen receptor and retinoic acid receptor (PMID: 26069883, 16893456). TBL1XR1 also functions as a transcriptional regulator of NF-κB and WNT signaling genes (PMID: 26069883). Familial mutations in TBL1XR1 are found in patients with intellectual disability disorders including Pierpont syndrome, Rett’s syndrome and autism (PMID: 30365874, 28687524, 26769062, 28687524, 29038029, 28152507, 23160955). Somatic loss-of-function mutations in TBL1XR1 are found in patients with diverse forms of lymphoma including MALT lymphomas (PMID: 29674500), primary central nervous syndrome lymphomas (PMID: 25991819), marginal zone lymphomas (PMID: 28152507, 27248180) and relapsed/refractory diffuse large B-cell lymphomas (PMID: 26608593), among others. TBL1XR1 mutations have been found to increase binding to the NCoR/SMRT complex, enhance degradation of NCoR, and dysregulate NF-κB and WNT signaling (PMID: 28588275, 28348241, 28152507). In addition, TBL1XR1 is a recurrent fusion partner in acute promyelocytic leukemia, acute myeloid leukemia, and other hematologic malignancies (PMID: 29921692, 29437595, 28509585, 24782508, 22496164). Overexpression of TBL1XR1 may be associated with increased invasion and metastasis in solid tumors, including breast, gastric and colorectal cancers (PMID: 29091326, 28127799, 27694893, 24874481). False +ENST00000257566 NM_016569.3 6926 TBX3 False TBX3, a transcription factor, is altered in various cancers including breast cancer. TBX3 is a transcription factor that binds DNA using a T-box domain and mediates transcriptional repression (PMID:25294936). Transcriptional regulation by TBX3 is important for embryonic patterning, stem cell specification, maintenance of pluripotency and organ system development including the cardiac conduction system, mammary gland and liver (PMID: 24319661, 15158141,12668638, 18356246, 19571885, 20139965). Loss of TBX3 expression corresponds to an increased invasive phenotype in breast cancer models (PMID: 27553211). TBX3 is expressed in various cancer types and has been implicated in cell survival, interactions with the TP53 pathway and tumor invasiveness (PMID:17283120,16222716,18245468,18829543, 24316392). Germline mutations in TBX3 have been identified in Ulnar-mammary syndrome leading to defects of the limbs, apocrine gland, teeth and genital systems (PMID: 9207801). Somatic alterations in TBX3 have been found in breast cancer and predominantly result in frameshift mutations, suggesting loss-of-function (PMID:22722201, 26451490, 26249178). True +ENST00000588136 NM_001136139.2 6929 TCF3 False TCF3, a transcription factor involved in lymphopoiesis, is altered by mutation or deletion in various cancer types. TCF3 is a member of the E protein family of helix-loop-helix transcription factors (Transcription factor 3, E2A immunoglobulin enhancer-binding factors E12/E47), which activate transcription by binding to regulatory E-box sequences on target genes. TCF3 expression is essential for lymphopoiesis, and B and T lymphocyte development. It has been shown to play a role in repressing Wnt signaling, specifically beta-catenin expression, during neuronal differentiation and proliferation of neural precursor cells (PMID 24832538, 21730189). Together with p53, TCF3 enforces p21 expression and cell-cycle arrest in response to genotoxic stress (PMID: 23684607). Its deletions or diminished protein activity have been associated with several lymphoid malignancies, including pre-B-cell acute lymphoblastic leukuemia, childhood leukemia and acute leukemia (PMID: 12700034). The TCF3 locus is a common target of chromosome rearrangements in diverse leukemias, leading to E2A chimeric proteins (PMID: 17311319, 17593026, 11588043, 11243406). True +ENST00000627217 NM_001146274.1 6934 TCF7L2 False TCF7L2, a tumor suppressor and transcription factor, is altered by mutation or deletion in various cancer types, most frequently in colorectal cancer. TCF7L2 (also known as TCF4) is a transcription factor that positively regulates the WNT/beta-catenin pathway (PMID: 22934027, 23260145). WNT-ligand induced pathway activation results in destabilization of the beta-catenin destruction complex, leading to stabilization of beta-catenin. TCF7L2 forms a bipartite transcription factor complex in the nucleus with beta-catenin to activate WNT-dependent target genes (PMID: 22934027). Loss of TCF7L2 activity in murine models results in reduced hepatic glucose production and dysregulation of metabolic gene expression programs (PMID: 23260145). TCF7L2 has also been found to regulate gene expression programs in a variety of cell types that impact cellular proliferation and metabolism (PMID: 26955760, 29301589, 29190896, 18289012). A single nucleotide polymorphism (SNP) within TCF7L2 has been identified as the most significant genetic marker associated with risk of Type 2 diabetes (PMID: 22872755) and gestational diabetes (PMID: 23690305). Germline mutations in TCF7L2 have been associated with predisposition to colorectal cancer (PMID: 18398040, 18478343) and genome-wide sequencing studies have identified TCF7L2 frameshift mutations in colorectal cancer (PMID: 8621708). TCF7L2 is hypothesized to function as a tumor suppressor by repressing cell growth-promoting genes in several contexts (PMID: 18621708). True +ENST00000402399 NM_001098725.1 8115 TCL1A True TCL1A, a co-activator of the AKT signaling pathway, is frequently altered by chromosomal rearrangement in hematologic malignancies. TCL1A is a signaling molecule that is a member of the T-Cell Leukemia/Lymphoma 1 (TCL1) protein family (PMID: 16056259, 30151355). TCL1A is predominantly expressed during development and in immature lymphocytes (PMID: 12181493, 15479728). TCL1A functions as an intracellular protein that stabilizes AKT heterodimers at the cytoplasmic membrane, augments effector signaling and mediates AKT nuclear localization (PMID: 10716693, 10983986). The concentration of TCL1A proteins is important to regulate signaling pathways that control proliferation, survival, and immune regulation (PMID: 10716693, 10983986, 9285687). TCL1A also interacts with a variety of proteins including NF-κB, Hsp70, ATM, TP63, and DNMT3A, among others, implicating TCL1A in the regulation of additional cellular activities (PMID: 19668332, 23160471, 22065599, 29048125, 22308499). In murine models, increased expression of TCL1A results in the transformation of B and T cells, leading to the development of T-cell leukemias (PMID: 9520462, 12011454, 12672960). Overexpression of TCL1A in T- and B-cell malignancies are common, suggesting that TCL1A predominantly functions as an oncogene (PMID: 9407948, 16056259). Rearrangements involving TCL1A are recurrent in T-acute lymphoblastic leukemias (T-ALL), typically due to aberrant VDJ recombination of T-cell receptor genes and leading to TCL1A activation (PMID: 3258192). False +ENST00000340722 NM_004918.3 9623 TCL1B True TCL1B, a co-activator of the AKT signaling pathway, is commonly altered by chromosomal rearrangement in hematologic malignancies. TCL1B is a signaling molecule that is a member of the T-Cell Leukemia/Lymphoma 1 (TCL1) protein family (PMID: 16056259, 10344735, 10077617). TCL1B is predominantly expressed during development and immature lymphocytes (PMID: 10077617, 10588720). Like the more well-studied family member TCL1A, TCL1B functions as an intracellular protein that stabilizes AKT heterodimers at the cytoplasmic membrane, augments effector signaling and mediates AKT nuclear localization (PMID: 10716693, 10983986). The concentration of TCL1B proteins is important to regulate signaling pathways that control proliferation, survival, and immune regulation (PMID: 10716693, 10983986, 9285687, 11839817). Further biochemical experiments are required to more clearly delineate the function of TCL1B. Over-expression of TCL1A in T- and B-cell malignancies is common, suggesting that TCL1A predominantly functions as an oncogene (PMID: 11839817). Rearrangements involving TCL1B are recurrent in T-acute lymphoblastic leukemias (T-ALL), typically due to aberrant VDJ recombination of T-cell receptor genes and leading to TCL1A activation (PMID: 24042734, 3258192). False +ENST00000380036 NM_000459.3 7010 TEK False TEK, a receptor tyrosine kinase involved in angiogenesis, is rarely mutated in cancers. The TEK gene encodes a receptor tyrosine kinase (RTK) protein also known as angiopoietin-1 receptor. Signaling via the TEK receptor has roles in angiogenesis, cell migration and proliferation (PMID: 12816861, 9204896, 14665640, 18425120, 19223473). The role of TEK in cancer depends on the predominant ligand binding the receptor, with angiopoietin-1 having an agonist effect and promoting angiogenesis and angiopoietin-2 having an antagonistic role (PMID: 20651738). TEK mutations are rare events in human cancers (cBioPortal, MSKCC, Dec. 2016). False +ENST00000369448 NM_017709.3 54855 TENT5C False TENT5C, a non-canonical poly(A) polymerase, is most frequently altered by mutation and deletion in multiple myelomas. TENT5C is a protein that belongs to the group XXV nucleotidyltransferase superfamily and functions as a non-canonical poly(A) polymerase (PMID: 27060136). TENT5C expression has been shown to regulate cell cycle progression, cell differentiation, and regulation of RAS/MAPK signaling (PMID: 28341836). Loss-of-function TENT5C mutations and deletions have been identified in multiple myeloma, suggesting that TENT5C is a tumor suppressor (PMID: 21430775, 26282654, 20616218, 24434212). Mutations or deletions in TENT5C are associated with reduced overall survival in patients with multiple myleoma (PMID: 21994415). Rearrangements between MYC and TENT5C have also been found in patients with multiple myeloma (PMID: 24632883). True +ENST00000310581 NM_198253.2 7015 TERT True TERT is an enzyme that functions to maintain telomere length and genomic stability. The TERT promoter is frequently mutated in various cancer types. The TERT gene encodes the catalytic subunit of telomerase, an enzyme that maintains telomere length and genomic integrity. TERT expression is low or absent in somatic cells; however, telomerase activity is upregulated in a vast majority of tumors and likely contributes to cancer cell immortality (PMID: 24657534, 9282118). Sequencing of the TERT promoter identified activating mutations in a number of cancer types including melanoma, hepatocellular carcinoma, urothelial carcinoma, medulloblastoma and glioma (PMID: 23348506, 23530248). Tumors with highly recurrent TERT promoter mutations tend to originate from tissues with lower rates of self-renewal (PMID: 23530248). TERT promoter mutations, C228T and C250T, account for the majority of the somatic TERT promoter alterations and occur 124 and 146 base pairs upstream of the ATG start codon of TERT, respectively. Both promoter mutations create binding motifs for erythroblast transformation-specific (ETS)/ T-cell factor (TCF) transcription factors and enhance telomerase activity (PMID: 23348503, 23348506, 26194807). In addition to promoter mutations, TERT, located on chromosome 5p, is amplified across many cancer types (PMID: 20164920). False +ENST00000373644 NM_030625.2 80312 TET1 False TET1 encodes a tumor suppressor and DNA demethylase involved in the epigenetic regulation of gene expression. TET1 is infrequently mutated in solid tumors. TET1 is an iron- and alpha-ketoglutarate-dependent enzyme that is involved in converting 5-methylcytosine to 5-hydroxymethylcytosine (5hmC) (PMID: 19372391). This conversion of the DNA base to 5hmC is the initial step in active DNA methylation, which is important in gene regulation, cellular reprogramming, and mammalian development (PMID: 20639862). TET enzyme activity is inhibited by 2-hydroxyglutarate (2-HG), an inhibitory metabolite produced by specific mutations in IDH1 and IDH2 whose production results in a highly specific DNA methylation profile and is often found in certain glioblastomas and leukemias (PMID: 21383741). TET1 was first identified as a translocation partner of the MLL gene and a key oncogenic driver in acute myeloid leukemias (PMID: 23818607). Reduced TET1 expression has also been observed in various human cancers. In breast cancer, reduced TET1 levels were shown to associate with increased tumor growth and metastasis (PMID: 23716660), and in colon cancer cell lines, reduced TET1 expression was associated with an aberrant CpG methylation profile and WNT pathway activation (PMID: 27977763, 25362856). Reduced TET1 expression has also been associated with KRAS-induced cellular transformation (PMID: 25466250). True +ENST00000380013 NM_001127208.2 54790 TET2 False TET2, a tumor suppressor and DNA demethylase, is frequently mutated in hematologic malignancies. TET2 belongs to a family of alpha-ketoglutarate and iron-dependent enzymes involved in converting 5-methylcytosine to 5-hydroxymethylcytosine (PMID: 19372391). This modification is implicated in active DNA demethylation, a process that is important for cellular reprogramming and gene regulation (PMID: 20639862). TET2 has been shown to function as a tumor suppressor with mutations leading to loss-of-function, particularly those affecting the C-terminal catalytic domain (PMID: 21057493). In animal models, TET2 loss cooperates with other mutations such as JAK2 and FLT3-ITD mutations to promote cancer progression and can induce genomic hypermethylation and increase stem cell self-renewal (PMID:21723200, 25281607, 25873173, 25886910). TET2 mutations are most often found in hematologic malignancies (PMID: 24220273). Isolated mutations in TET2 have also been found in individuals with clonal hematopoiesis but with no apparent hematologic disease (PMID: 23001125). However, these patients are at a higher risk of developing hematologic cancer with aging (PMID: 25426837, 25426838). TET family enzyme activity is also inhibited by specific mutations in IDH1 and IDH2 that produce an inhibitory co-factor, 2-hydroxyglutarate (PMID: 21130701). Mutations in WT1 may also affect TET2 function as an associated co-factor (PMID: 25482556, 25601757). True +ENST00000409262 NM_144993 200424 TET3 False TET3, an epigenetic enzyme that catalyzes cytosine oxidation, is altered by mutation in hematopoietic malignancies. TET3 is an enzyme that belongs to a family of alpha-ketoglutarate and iron-dependent enzymes involved in converting 5-methylcytosine (5-mc) to 5-hydroxymethylcytosine (5-hmc) (PMID: 19372391). The 5-hmc modification is implicated in active DNA demethylation, a process that is important for cellular reprogramming and gene regulation (PMID: 20639862). The TET enzymes, including TET1 and TET2, are also involved in the oxidation of 5-mc to other cytosine derivatives (PMID: 21778364). TET3 also bind O-GlcNAc transferase (OGT) and REST to promote the binding of methyltransferases to chromatin (PMID: 23353889, 24304661, 25843715). In addition, TET3 physically associates with WT1 to mediate DNA methylation in leukemic cells (PMID: 25482556 ). TET-mediated hydroxymethylation has been implicated in a variety of cellular process including the regulation of somatic cell reprogramming (PMID: 24529596), hematopoietic differentiation (PMID: 24619230, 26257178), DNA damage response (PMID: 28325772), and telomere elongation (PMID: 25223896). Altered TET family member expression and 5-hmc levels have been correlated with tumor progression and prognosis in a variety of cancer types (PMID: 23671639, 26207381, 27848178). Somatic loss-of-function mutations in TET3 have been found in myelodysplastic syndromes, acute myeloid leukemia and colon cancer, among others (PMID: 19388938, 19420352, 22895193, 28452984, 29531217). TET3-mutant cancers may be sensitive to DNA methylation inhibitors, such as 5-azacytidine (PMID: 28193779). True +ENST00000315869 NM_006521.5 7030 TFE3 True TFE3, a transcription factor involved in nutrient sensing and lysosomal biogenesis, is recurrently altered by fusion in renal cell carcinomas and alveolar soft part sarcomas. TFE3 is a transcription factor that is a member of the MTF/TFE family of proteins (PMID: 24448649). TFE3 functions as a critical transcriptional regulator of lysosomal homeostasis, energy metabolism, nutrient sensing and cellular stress (PMID: 22297304, 24448649, 26813791, 24448649). When nutrients are abundant, TFE3 is retained in the cytoplasm by mTORC1 phosphorylation and binding to the scaffolding protein 14-3-3 (PMID: 24448649). Activity and localization of TFE3 are also mediated by Rag GTPases, under control of the amino acid sensor Ragulator (PMID: 24448649, 22980980). In response to nutrient deprivation, TFE3 regulates the number of lysosomes in the cell (PMID: 24448649). TFE3 translocates to the nucleus upon starvation and upregulates a variety of genes involved in autophagy and lysosomal biogenesis (PMID: 24448649, 22576015). In addition, TFE3 mediates a variety of immune-related activities including autophagy, proinflammatory cytokine expression and antibody production, among others (PMID: 26813791, 26813791, 30917316). Expression of TFE3 is implicated in hematopoietic and osteoclast differentiation (PMID: 17046750, 23599343). Overexpression of TFE3 is found in patients with pancreatic cancer, resulting in increased lysosomal function to maintain intracellular amino acid pools (PMID: 26168401). Oncogenic fusion proteins that place TFE3 downstream of a strong promoter are found in an aggressive subtype of renal cell carcinoma and alveolar soft part sarcomas, a rare soft tissue tumor (PMID: 22705279, 8872474, 30849994). False +ENST00000374994 NM_004612.2 7046 TGFBR1 False TGFBR1 encodes a receptor kinase that signals to downstream effectors in the TGFß signaling pathway. TGFBR1 is infrequently mutated in cancer; however, germline mutations in this gene are associated with Marfans syndrome and Loeys-Dietz syndrome. TGFBR1 is a serine/threonine protein kinase that belongs to the transforming growth-factor β (TGF β) family (PMID: 22992590). TGFß signaling controls multiple biological processes including cellular proliferation, differentiation and tissue homeostasis (PMID: 22992590, 11057902). TGFBR1 is a type I receptor that heterodimerizes with other TGFß receptor family members to initiate ligand binding (PMID: 22992590). Following ligand activation, TGFBR1 phosphorylates its dimerization partner and induces phosphorylation of downstream effectors such as the SMAD proteins, which control gene regulation (PMID: 22992590, 18662538). Germline mutations in TGFBR1 have been identified in the autosomal Loeys-Dietz syndrome type 1 and Marfan syndromes (PMID: 16928994,16791849, 16596670, 18781618). Other hereditary variants have been found to be associated with non-small cell lung cancer (PMID: 21225232, 19690145). Somatic mutations in TGFBR1 are infrequent in human cancer; however, loss-of-function mutations and deletions have been identified in colorectal cancer and several other cancer types (PMID: 22992590, 11057902). Targeting of the TGFß pathway is being explored as a therapeutic approach in multiple cancers (PMID: 11057902, 18662538) and small molecule inhibitors targeting the kinase activity of TGFBR1 have entered into clinical trials (PMID: 11057902, 18662538). True +ENST00000295754 NM_003242.6 7048 TGFBR2 False TGFBR2 encodes a receptor kinase that signals to downstream effectors in the TGFß signaling pathway. TGFBR2 is infrequently mutated in cancer; however, germline mutations in this gene are associated with Marfan syndrome and Loeys-Dietz syndrome. TGFBR2 is a serine/threonine protein kinase that belongs to the transforming growth-factor β (TGFβ) family (PMID: 22992590). TGFß signaling controls multiple biological processes including cellular proliferation, differentiation and tissue homeostasis (PMID: 22992590, 11057902). TGFBR2 is a type II receptor that heterodimerizes with other TGFß receptor family members to initiate downstream signaling (PMID: 22992590). Following TGFß-family ligand activation, TGFBR2 phosphorylates its dimerization partner and induces phosphorylation of downstream effectors such as the SMAD proteins, which control gene regulation (PMID: 22992590, 18662538). Germline mutations in TGFBR2 have been identified in the autosomal Loeys-Dietz syndrome type 2 and Marfan syndromes (PMID: 15731757, 15235604, 8317497). TGFBR2 mutations associated with Loeys-Dietz syndrome were shown in cell lines to inactive the receptor function (PMID: 15235604). Somatic mutations in TGFBR2 are infrequent in human cancer; however, loss-of-function mutations have been identified in gastrointestinal and pancreatic cancers (PMID: 22992590, 11057902). Targeting of the TGFß pathway is being explored as a therapeutic approach in multiple cancers (PMID: 11057902, 18662538) and small molecule inhibitors targeting the kinase activity of TGFß receptors have entered clinical trials (PMID: 11057902, 18662538). True +ENST00000179259 NM_020375 57103 TIGAR True TIGAR, a TP53-regulated phosphatase, is infrequently altered in cancer. TIGAR, also known as C12orf5, encodes for a phosphatase that primarily functions in the inhibition of glycolysis by reducing fructose 2,6-bisphosphate through its conserved catalytic domain (PMID: 19015259). Through translocation to various organelles under different stress stimuli, TIGAR has been identified to regulate other cellular processes including cell cycle arrest, DNA damage repair regulation, apoptosis and production of reactive oxygen species (PMID: 25928429, 24872551, 25085248, 23185017). Overexpression of TIGAR in various cancer cells and xenograft models induces increased cellular proliferation, cellular invasion, tumor progression and suppression of apoptosis and autophagy, suggesting that TIGAR functions predominantly as an oncogene (PMID: 31799200, 31983610, 19713938, 26212201). Amplification of TIGAR has been identified in various types of cancer, including colon cancer, breast cancer and glioblastoma (PMID: 23726973, 21820150, 22887998). False +ENST00000376499 NM_001303103.1 7088 TLE1 False TLE1, a transcriptional repressor, is altered by overexpression and deletion in various cancer types. TLE1 is a transcriptional co-repressor that is a member of the Groucho (Gro)/Transducin-like enhancer (TLE) of split family proteins (PMID: 1303260, 27852056). The TLE family of transcriptional regulators cannot bind DNA but function as adaptor proteins that modulate the activity of transcription factors, such as RUNX, NKX and HES family transcription factors (PMID: 27852056, 10825294). TLE1 functions as a homotetramer that recruits both epigenetic and transcriptional effector proteins to allow for remodeling of chromatin and repression of gene expression (PMID: 27852056, 29069783). TLE1 binds cofactors that mediate the activity of several signaling pathways including NOTCH, WNT and NF-KB (PMID: 27852056, 30563890). Expression of TLE1 has been implicated in a variety of cellular activities including cell fate specification, inflammation, hematopoiesis and apoptosis, among others (PMID: 27852056, 29069783, 30045946). TLE1 can function as either a tumor suppressor or oncogene in different cancer types, suggesting that TLE1 has context-specific roles in cancer progression (PMID: 27852056). Overexpression of TLE1 is found in patients with synovial sarcoma, lung cancer or invasive breast cancer, while the TLE1 gene is located in the 9q region that is commonly deleted in acute myeloid leukemia (PMID: 30563890, 27568668, 17255769, 27655370, 18258796). Specifically, in synovial sarcomas, TLE1 interacts with the SS18-SSX fusion to promote WNT-mediated gene expression programs (PMID: 26905812). False +ENST00000262953 NM_003260.4 7089 TLE2 False TLE2, a transcriptional repressor, is altered by overexpression in various cancer types. TLE2 is a transcriptional co-repressor that is a member of the Groucho (Gro)/Transducin-like enhancer (TLE) of split family proteins (PMID: 1303260, 27852056). The TLE family of transcriptional regulators cannot bind DNA but function as adaptor proteins that modulate the activity of transcription factors, such as RUNX, NKX and HES family transcription factors (PMID: 27852056, 10825294, 11283267). TLE2 functions as a homotetramer that recruits both epigenetic and transcriptional effector proteins to DNA to allow for remodeling of chromatin and repression of gene expression (PMID: 27852056, 29069783). While TLE1 is the most well-studied TLE family member, TLE2 has been shown to bind cofactors that mediate the activity of several signaling pathways including NOTCH and WNT (PMID: 27852056, 9874198, 8808280). Expression of TLE2 has been implicated in a variety of cellular activities including cell fate specification, neuronal development and inflammation, among others (PMID: 9572356, 18778483, 20356955, 9887105). Overexpression of TLE2 is found in patients with early grade astrocytomas and pituitary adenomas (PMID: 16896313, 16288009). False +ENST00000558939 NM_005078.3 7090 TLE3 False TLE3, a transcriptional repressor, is altered by mutation in various cancer types. TLE3 is a transcriptional co-repressor that is a member of the Groucho (Gro)/Transducin-like enhancer (TLE) of split family proteins (PMID: 27852056, 8989517). The TLE family of transcriptional regulators cannot bind DNA but function as adaptor proteins that modulate the activity of transcription factors, such as RUNX, NKX, and WNT family transcription factors (PMID: 27852056). TLE3 functions as a homotetramer or heterooligomer that recruits both epigenetic and transcriptional effector proteins to DNA to allow for remodeling of chromatin and repression of gene expression (PMID: 28689657, 25223786). TLE3 binds cofactors that mediate the activity of several signaling pathways including NOTCH and WNT (PMID: 30894540, 30894540). Expression of TLE3 has been implicated in a variety of cellular activities including cell fate specification, adipocyte development, osteoblast differentiation, proliferation and metastasis, among others (PMID: 28607151, 27298623, 26172616, 25779673, 21459326). TLE3 predominantly functions as a tumor suppressor by repressing gene targets involved in metastasis; however, TLE3 has also been found to promote proliferation in some cancer types, suggesting context-specific roles in cancer progression (PMID: 30719233, 29374067, 27669982). In prostate cancer, specific FOXA1 mutations disrupt an interaction with TLE3, resulting in loss of TLE3-mediated repression of WNT signaling and metastasis (PMID: 31243372). False +ENST00000376552 NM_007005.4 7091 TLE4 False TLE4, a transcriptional repressor, is altered by mutation and deletion in various cancer types. TLE4 is a transcriptional co-repressor that is a member of the Groucho (Gro)/Transductin-like enhancer (TLE) of split family proteins (PMID: 27852056). The TLE family of transcriptional regulators cannot bind DNA but function as adaptor proteins that modulate the activity of transcription factors, such as RUNX, NKX, and WNT family transcription factors (PMID: 27852056, 27486062, 10825294). TLE4 functions as a homotetramer or heterooligomer that recruits both epigenetic and transcriptional effector proteins to DNA to allow for remodeling of chromatin and repression of gene expression (PMID: 22169276). TLE4 binds cofactors that mediate the activity of several signaling pathways including NOTCH and WNT (PMID: 27486062, 15499562). Expression of TLE4 has been implicated in a variety of cellular activities including cell fate specification, immune regulation, neuronal development, metastasis and inflammation, among others (PMID: 30045946, 29395907, 27486062, 25153823). TLE4 can function as either a tumor suppressor or oncogene in different cancer types, suggesting that TLE4 has context-specific roles in cancer progression. The TLE4 gene is located in the 9q region that is commonly deleted in acute myeloid leukemia, while loss of TLE4 expression has found to be growth promoting in other cancer types such as colorectal cancer (PMID: 26701208, 18258796). False +ENST00000370196 NM_005521.3 3195 TLX1 True TLX1, a transcription factor, is recurrently altered by chromosomal rearrangement in T-cell acute lymphoblastic leukemia. TLX1 (also HOX11) is a transcription factor that is a member of the NK-like subfamily of homeobox genes (PMID: 19835636). TLX1 functions predominantly as a transcriptional repressor at T-cell lineage-specific enhancers and antagonizes NOTCH1 (PMID: 26108691). In collaboration with the transcription factor STAT5, TLX1 binds enhancer regions of genes that drive leukemic gene expression programs including BCL2 and MYC (PMID: 19835636). TLX1 is not expressed in the hematopoietic system; however, TLX1 activation is observed in several hematopoietic malignancies (PMID: 21326611). Transcriptional activity of TLX1 has been associated with several cellular functions including transformation, mitotic checkpoint control, and genome stability (PMID: 20972433, 9009195, 7905617). TLX1 downregulates the mitotic checkpoint gene CHEK2, leading to aneuploidy in TLX1-positive human and murine leukemic tumors (PMID: 20972433). Expression of TLX1 in several distinct murine models results in the development of T-ALL, with T cells typically arresting at the cortical stage of development (PMID: 20972433, 21326611). Recurrent TLX1 fusions are found in patients with T-acute lymphocytic leukemia (T-ALL) (PMID: 1676542). These rearrangements place TLX1 under the control of T-cell strong enhancers, suggesting that TLX1 functions predominantly as an oncogene (PMID: 27451956). False +ENST00000296921 NM_021025.2 30012 TLX3 True TLX3, a transcription factor involved in neuronal differentiation, is recurrently altered by chromosomal rearrangement in T-cell acute lymphoblastic leukemia. TLX3 (also HOX11L2) is a transcription factor that is a member of the NK-like subfamily of homeobox genes (PMID: 19835636). Expression of TLX3 is highest in the central nervous system, where it mediates glutamatergic neuronal differentiation (PMID: 11581159, 15064766, 27452274). TLX3 also functions as a transcriptional repressor at T-cell lineage-specific enhancers, similar to the closely related family member TLX1 (PMID: 30107177, 22516263, 22366949). TLX3 is not expressed in the hematopoietic system; however, TLX3 activation is found in leukemias (PMID: 12086890, 12454747). Expression of TLX3 in hematopoietic assays demonstrates restricted T cell differentiation at the cortical stage, likely due to transcriptional interactions with ETS1 and reduced T-cell receptor activity (PMID: 22516263). TLX3 mediates the expression of genes involved in T-cell differentiation and interacts with chromatin modifiers to regulate transcription (PMID: 29296717, 26258652). Transcriptional activity of TLX3 has been associated with several cellular functions including transformation, proliferation, and invasion (PMID: 16804919, 29296717). Recurrent TLX3 fusions are found in patients with T-cell acute lymphocytic leukemia (T-ALL) (PMID: 27451956, 28671688). These rearrangements lead to TLX3 activation by positioning TLX3 under the control of T-cell mediated regulatory units, suggesting that TLX3 functions predominantly as an oncogene (PMID: 27451956). False +ENST00000258439 NM_001193304.2 55654 TMEM127 False TMEM127 is a transmembrane protein and tumor suppressor identified in pheochromocytoma and paraganglial tumors, in which hereditary variants are found. TMEM127 (transmembrane protein 127) encodes a tumor suppressor protein with three predicted transmembrane domains. In vitro experiments confirm the localization of TMEM127 at the plasma membrane and indicate a tumor-suppressor role through reduction of mTORC1 activity, demonstrated by phosphorylation of the mTOR effector, S6K, upon TMEM127 depletion (PMID: 20923864, 20154675, 21156949). The latter has also been shown in a tissue sample from a patient with pheochromocytoma (PMID: 20923864). Cell line studies suggest that the failure of mutated TMEM127 to inhibit mTORC1 is due to loss of association with the mTOR inhibitor RAB5. Truncating germline variants in TMEM127, often in concert with loss of heterozygosity at its genomic locus, confer increased risk for pheochromocytoma and paraganglial tumors (PMID: 20923864, 20154675, 21156949, 22541004, 21613359). TMEM127 mutations have also been observed in renal cancer. True +ENST00000398585 NM_001135099.1 7113 TMPRSS2 False TMPRSS2, a transmembrane serine protease, is recurrently altered by chromosomal rearrangements in prostate cancer. TMPRSS2 is a transmembrane serine protease that functions to cleave substrates in epithelial cells. Although its role in normal epithelial cells is not well understood, TMPRSS2 is highly expressed in the prostate epithelium and is an androgen responsive gene (PMID:11245484). TMPRSS2 can cleave components of the tumor microenvironment, such as pro-HGF (hepatocyte growth factor) to promote invasion and metastasis (PMID: 25122198). TMPRSS2 is recurrently fused to ETS-family transcription factors in about 50% of primary prostate cancers, including the TMPRSS2-ERG and TMPRSS2-ETV1 fusions, resulting in overexpression of these ETS family members (PMID: 16254181). TMPRSS2 gene fusions in prostate cancer often occur in the setting of PTEN loss and subsequent PI3-kinase pathway activation (PMID:19396168,19396167). In these cancers, ETS transcription factors modify the chromatin landscape of prostate cancer cells, allowing for increased androgen receptor (AR) binding and priming prostate cancer initiation in response to PTEN loss (PMID: 23817021, 28783165). False +ENST00000237289 NM_006290.3 7128 TNFAIP3 False TNFAIP3 encodes an enzyme involved in regulation of the NF-κB pathway. Mutations of TNFAIP3 are found in lymphomas and leukemias. TNFAIP3 encodes TNF alpha induced protein 3 that is induced by Tumor necrosis factor (TNF) alpha and regulates the NF-κB pathway (PMID: 11009421). TNFAIP3 has ubiquitin ligase and de-ubiquitination activities that suppress the NF-κB pathway (PMID: 15258597). Its activity is important in regulating B-cell survival and apoptosis, inflammatory response, and dendritic cell function in regulating T-cells (PMID: 20705491, 18311150, 25043000). Polymorphisms in TNFAIP3 are associated with many autoimmune diseases such as systemic lupus erythematosus, Sjögren's syndrome, multiple sclerosis, and rheumatoid arthritis (PMID:19165919, 25684197, 24097067,17982455). Germline loss of function mutations are associated with autoimmune disease (PMID: 26642243). Mutations are found in B-cell lymphomas, T-cell large granular lymphocytic (LGL) leukemia, and peripheral T-cell lymphomas (PMID: 19412163, 21115979, 21625233, 26199174). TNFAIP3 mutation has been associated with transformation of lymphomas to more aggressive disease and varying prognosis depending on subtype (PMID: 24362818, 23327292, 21266526). True +ENST00000355716 NM_003820.2 8764 TNFRSF14 False TNFRSF14, a cell surface receptor in the tumor necrosis factor family, is recurrently altered by mutation and deletion in hematologic malignancies. TNFRSF14 (also HVEM) is a cell surface receptor in the tumor necrosis factor family (PMID: 8898196). It is expressed on several types of cells, including T cells, B cells, NK cells, dendritic cells, and myeloid cells, as well as non-lymphoid organs including lung, liver and kidney (PMID: 9162061). TNFRSF14 is a tumor suppressor and immunogenicity regulation factor and is capable of sending both stimulatory and inhibitory signals to T cells depending on the particular ligand it binds (PMID: 23023713, 20884631). Mutations in TNFRSF14 has been demonstrated in the pathogenesis of both diffuse large B-cell lymphoma (PMID: 22343534 ) and follicular lymphoma (FL) (PMID: 20884631, 24435047, 24162788, 21941365). These mutations are associated with high-risk clinical features, and patients with a mutation in TNFRSF14 responded poorly to rituximab (PMID: 20884631). Recurrent copy number loss of the region containing TNFRSF14 was observed in 42% of the cases with classical Hodgkin lymphoma (CHL) (PMID:26650888). Finally, TNFRSF14 expression is deregulated in colorectal cancer (PMID: 25750286), hepatocellular carcinoma (PMID: 25468715) and esophageal squamous cell carcinoma (PMID:24249528). True +ENST00000053243 NM_001192 608 TNFRSF17 True TNFRSF17, a transmembrane glycoprotein primarily expressed on the surface of B lymphocytes, is altered by amplification in multiple myeloma. TNFRSF17, a member of the TNF-receptor superfamily, encodes for a transmembrane glycoprotein TNF receptor expressed primarily on mature B lymphocytes and functions in B-cell activating factor (BAFF) recognition (PMID: 8165126, 1396583). TNFRSF17 mediates the development of the B lymphocytes and their autoimmune response through interaction with ligands BAFF and APRIL (PMID: 16116167). Overexpression of TNFRSF17 in various cancer cell lines and models induces tumor growth and angiogenesis, suggesting that TNFRSF17 functions predominantly as an oncogene (PMID: 27127303, 21642598, 30131941). TNFRSF17 amplification has been identified in multiple myeloma (PMID: 22804669, 27127303, 26960399). False +ENST00000338784 NM_003808 8741 TNFSF13 True TNFSF13, a tumor necrosis factor receptor ligand, is infrequently altered in cancer. TNFSF13, a member of the tumor necrosis factor (TNF) ligand family, encodes the proliferation-inducing ligand for the TNF receptors TNFRSF13B and TNFRSF17 (PMID: 33036273, 30131941). Through binding these receptors, TNFSF13 functions in B cell and T cell activation, survival and proliferation to regulate humoral immunity response (PMID: 19828625, 10973284, 14707116). TNFSF13 has been identified to have three transcript variants encoding distinct isoforms as a result of alternative splicing (PMID: 10706119). Overexpression of TNFSF13 in mouse models and cancer cell lines induces increased tumor growth, migration and proliferation, suggesting that TNFSF13 functions primarily as an oncogene (PMID: 24436270, 17190854, 19573525, 16793914, 30819903). Amplification of TNFSF13 can also be accompanied by the amplification of driver oncogenes, such as EGFR and PDK4, and the deletion and mutation of tumor suppressor genes, such as CDKN2A and PTEN (PMID: 34712225). TNFSF13 overexpression and mutation has been identified in various cancers, including breast cancer and multiple myeloma (PMID: 18366696, 30135465, 25750171). False +ENST00000409379 NM_013432 4796 TONSL False TONSL, a DNA repair protein, is altered by amplification in breast cancer. TONSL encodes the Tonsoku-like DNA repair protein, which is a multi-domain scaffold protein that plays a critical role in resistance to replication stress and maintaining genome integrity. TONSL interacts with various DNA replication and repair factors including anti-silencing function 1 (ASF1), minichromosome maintenance complex component helicases (MCM helicases), H3 and H4 histones and methanesulfonate sensitivity protein 22-like protein (MMS22L) (PMID: 32959051, 30773278). TONSL, in a heterodimer complex with MMS22L, is involved in repairing spontaneous DNA lesions through homologous recombination (PMID: 30773278). The MMS22L-TONSL complex functions in the DNA damage response upon replication fork collapse and to mediate recovery from replicative stress (PMID: 36622344, 37057595). The MMS22L-TONSL complex is recruited by replication protein A (RPA1, RPA2, and RPA3) to sites of stalled replication forks during normal S-phase replication and promotes homologous recombination by facilitating the assembly of RAD51 (PMID 30773278, 30773277, 32959051). TONSL is thought to negatively regulate NF-kappa-B by binding to NF-kappa-B complexes and trapping them in the cytoplasm, preventing them from interacting with DNA ((PMID: 30723051, 31158361). NF-kappa-B complexes can then enter the nucleus upon phosphorylation and ubiquitination of TONSL (PMID: 30723051). Overexpression of TONSL in human gastric cancer cell lines reduces cellular proliferation and colony formation and negatively regulates migration and invasion compared to control cells (PMID: 31158361). Breast primary cells overexpressing TONSL have demonstrated upregulated DNA repair via homologous recombination (PMID: 37057595). Amplification of the TONSL gene is found in breast, liver, lung, esophageal, and cervical cancer (PMID: 37057595, 30723051, 31158361) and mutations in TONSL have been identified in individuals with Sponastrime dysplasia (PMID 32959051, 30773278). False +ENST00000361337 NM_003286.2 7150 TOP1 True TOP1, a DNA topoisomerase, is infrequently altered in cancer. TOP1 (DNA topoisomerase 1) is a DNA topoisomerase that catalyzes the decatenation of DNA entanglements that occur during transcription (PMID: 12042765). This transesterification reaction results in the breaking of a DNA strand and subsequent rejoining (PMID: 25693836). Amplification of TOP1 in yeast and cancer cell lines induces genomic instability and susceptibility to DNA damage, suggesting that TOP1 functions primarily an oncogene (PMID: 11353773, 28961461, 36170822). TOP1 overexpression has been identified in various cancers, including breast cancer, ovarian cancer and liver cancer (PMID: 33144457, 26207989, 30132517). TOP1 amplification may be sensitive to treatment with TOP1 inhibitors, such as evodiamine and nitidine chloride (PMID: 26207989, 30132517). Acquired mutations in TOP1 have been identified to confer resistance to TOP1 inhibition (PMID: 21619602, 23836376, 11844605, 16546964, 21978643). False +ENST00000423485 NM_001067 7153 TOP2A True TOP2A, a DNA topoisomerase, is altered in various cancers. TOP2A is one of two isoforms of DNA topoisomerase II that plays a key role in resolving topological DNA entanglements during transcription by creating temporary double stranded breaks in the DNA phosphodiester backbone (PMID: 31216997, 36678591). In normal cells, TOP2A assists chromosome condensation and chromatid separation during interphase and mitosis and expression levels of TOP2A peak during the G2/M phase of the cell cycle (PMID: 31216997). Cancer cells take advantage of TOP2A function to alleviate DNA replication and transcription stress created by the rapid pace of malignant cell growth (PMID: 36678591). Suppression of TOP2A lengthens the duration of mitosis and causes severe defects in chromosome separation, rendering cells unable to complete the cell cycle (PMID: 35778520, 22067657, 25328138). Overexpression of TOP2A is seen in many cancer types including carcinomas, sarcomas, diffuse large B-cell lymphoma, and lower-grade glioma, and is usually associated with aggressive disease and a less favorable prognosis (PMID: 35778520, 23533247). Multiple studies have demonstrated that knockdown of TOP2A reduces oncogenesis suggesting that TOP2A functions as an oncogene (PMID: 29761838, 2976183). Anthracycline agents that target TOP2A, including aclarubicin, have demonstrated efficacy in adrenocortical carcinoma cell lines (PMID: 23533247, 30519354). While topoisomerase II inhibitors such as doxorubicin, etoposide, and teniposide are widely used in clinical practice, optimizing selective topoisomerase II agents is an ongoing area of research (PMID: 37094479). TOP2A is also the target of a preclinical vaccine that both reduces tumor incidence and decreases tumor growth of triple-negative breast cancer in mice (PMID: 37880313). False +ENST00000269305 NM_000546.5 7157 TP53 False 3A TP53, a tumor suppressor in the DNA damage pathway, is the most frequently mutated gene in cancer. TP53 encodes the p53 tumor suppressor protein, a transcription factor that responds to cellular stresses, including DNA damage and oncogenic activation, by inducing downstream anti-tumor responses such as DNA repair and apoptosis (PMID: 11099028). p53 levels are kept low in healthy cells due to negative regulation by MDM2/4, Cop1 and Trim24 and constant degradation by the ubiquitin-proteasome system (PMID: 36859359, 36207426). When DNA is damaged, a network of pathways is activated to detect and repair lesions in a cell- and context-specific manner (PMID: 36207426). p53 is rapidly phosphorylated by upstream regulators such as ATM, ATR, and CHL1/2, which results in the accumulation of stable p53 (PMID: 36207426). p53 then binds to specific DNA sequences to direct the expression of a wide variety of genes, including those involved in apoptosis, cell cycle arrest, DNA repair, senescence, stem cell differentiation, autophagy, cellular metabolism, and others (PMID: 27141080, 36859359, 36207426). Oncogenic mutations of TP53 often result in the dysregulation of p53 function, usually due to structural changes in the DNA binding domain (PMID: 36859359). Loss of p53 function can have various outcomes including tumorigenesis, invasion and metastasis, drug resistance, metabolic reprogramming, immune evasion and overall genomic instability (PMID: 36859359). TP53 is the most commonly mutated gene in human cancers, and germline mutations occur in the cancer predisposition syndrome Li-Fraumeni (PMID: 22713868, 21765642). Clinical and preclinical research into drugs that target TP53 is ongoing, notably with MDM2 inhibitors that aim to restore p53 function and are being tested in combination with other cancer therapies (PMID: 36859359, 37818252). True +ENST00000382044 NM_001141980.1 7158 TP53BP1 False TP53BP1, a tumor suppressor and DNA repair protein, is altered by mutation or deletion in various cancer types, most frequently in skin cancers. The TP53BP1 gene encodes a protein originally identified as a partner of tumor suppressor gene TP53. TP53BP1 plays a role in DNA damage recognition and DNA repair (PMID: 12364621, 21144835, 17190600, 18804090). Tumor suppressor roles for TP53BP1 have been described in several cancers, mostly related to functions of TP53, BRCA1 and ATM, although some contradictory results exist (PMID: 15970701, 17546051, 15279780, 12447382, 22266878, 20453858, 24681733). TP53BP1 is predominantly mutated in skin cancers such as cutaneous squamous cell carcinomas and melanomas (cBioPortal, MSKCC, Dec. 2016). True +ENST00000264731 NM_003722.4 8626 TP63 True TP63, a transcription factor, is recurrently altered by chromosomal rearrangement in hematologic malignancies. TP63 is a member of the TP53 family of transcription factors. The TP63 protein exists as two different isoforms due to usage of alternative promoters, producing variants with (TAp63) and without (ΔNp63) the N-terminal transactivation domain (TAD) (PMID: 23344544). TP63 transactivates downstream target genes in collaboration with TP53 and TP73, however, the TAp63 and ΔNp63 isoforms have opposing cellular functions (PMID: 24488880). TAp63 has been implicated as a tumor suppressor and plays a role in the regulation of apoptosis, cell cycle arrest, response to DNA damage, suppression of metastasis, and transactivation of TP53 family target genes (PMID: 16601753, 21760596). ΔNp63 antagonizes TP53/TAp63/TP73 transactivation of target genes by competing for TAp63 binding sites and blocking transactivation, leading to cellular proliferation (PMID: 23344544). ΔNp63 has been shown to inhibit oxidative-stress induced death and inhibits apoptosis (PMID: 29212036). TP63 is most highly expressed in epithelial cells and neurons and loss of TP63 in mouse models result in depletion of epithelial patterning (PMID: 10227293, 10227294). Expression of TP63 has also been identified as a stem cell marker in several contexts (PMID: 23344544). Germline alterations in TP63 have been associated with several disorders including ectodermal dysplasia and cleft lip/ palate syndrome (EEC) and limb mammary syndrome (LMS), among others; however, these patients do not have increased cancer risk (PMID: 17224651). Somatic mutations in TP63 are relatively infrequent in human malignancies. However, TP63 has been associated with overexpression and amplification in squamous tumors (PMID: 15754296). Translocations of TP63 have also been found in hematopoietic malignancies (PMID: 24893616, 22496164). True + 6955 TRA True TRA, the α-chain of the T-cell receptor, is recurrently altered by chromosomal rearrangement in T-cell acute lymphoblastic leukemia. TRA is the T-cell receptor A locus which encodes the α-chain of the T-cell receptor (TCR) (PMID: 29261409, 25484883). TCRs are protein complexes found on the surface of T cells that engage antigens associated with major histocompatibility complex (MHC) molecules on antigen presenting cells (PMID: 16087711). T cells are important in coordinating effector and memory immune responses in response to antigen display (PMID: 24292902). MHC class I molecules are recognized by TCRs on CD8+ T cells and MHC class II molecules are recognized by TCRs on CD4+ T cells (PMID: 6504140, 25484883). Most TCRs are composed of α and β heterodimers (encoded by TRA and TRB), with a fraction of TCRs composed of γ and δ subunits (PMID: 29261409, 20164930). TRA proteins share substantial homology to immunoglobulin proteins and exhibit sequence diversity following recombination and thymic selection (PMID: 24830344). Engagement of antigen-presenting MHC class proteins with TRA/TRB heterodimers results in conformational changes and activation of downstream pathways leading to activation of TCR-mediated signaling (PMID: 29261409). TRA rearrangements are recurrently found in patients with T-acute lymphoblastic leukemias, typically leading to activation of the fusion partner (PMID: 29279377, 28671688). Chimeric antigen receptor T cell (CAR-T) therapy is FDA-approved for patients with non-Hodgkin lymphoma and diffuse large B-cell lymphoma, in which cancer cells from patients are engineered to express TCRs that are recognized by the immune system (PMID: 29914976, 29539277, 29113977). False +ENST00000247668 NM_021138.3 7186 TRAF2 False TRAF2 is a protein that mediates signaling from members of the TNF receptor family and regulates downstream NFkB pathway activation. Mutations are found in meyloma, lymphomas, and more rarely in epithelial cancers. TRAF2 is an adaptor molecule that interacts with and transduces signals from the Tumor necrosis factor (TNF) receptor (PMID:8565075, 8985011, 8898208). Following TNF engagement, TRAF2 mediates the assembly of signaling scaffolds to activate the NF-κB pathway, JNK (Jun amino-terminal kinases), and anti-apoptotic pathways (PMID:8565075, 8985011, 8898208). TRAF2 also has ubiquitin ligase activity that can regulate protein stability (PMID: 23142077, 20577214). Signaling cascades mediated by TRAF2 have been implicated in lymphocyte proliferation and survival, immune response, and hematopoietic stem cell activation (PMID: 9390693, 9390694, 11435475). In cell line and murine cancer models, TRAF2 expression is involved in NF-κB activation leading to tumor cell survival and resistance to targeted therapy (PMID: 25843712,19336568, 22589389). Somatic mutations in TRAF2 have been identified multiple myeloma, lymphomas, and nasopharyngeal carcinomas (PMID:17692805, 24362935,19412164, 23868181). TRAF2 mutations are predicted to be loss-of-function and dysregulate NF-κB signaling (PMID: 24362935,19412164, 23868181). Amplification of TRAF2 has also been identified in epithelial cancers (PMID: 24362534). False +ENST00000392745 NM_003300.3 7187 TRAF3 False TRAF3, a signaling molecule and E3 ligase, is recurrently mutated and deleted in B cell lymphoma and multiple myeloma. TRAF3 is an E3 ligase and signaling molecule that is a member of the tumor necrosis factor (TNFR)-associated factor (TRAF) family (PMID: 21660053). TRAF3 functions downstream of Interleukin-1 (IL-1) or Toll-like receptor (TLR) pathways, which are important in the regulation of innate immunity and inflammation (PMID: 21660053). TRAF3 can function as an E3 ligase in TLR pathways, promoting K63-linked polyubiquitination in order to maintain protein-protein interactions (PMID: 21660053, 25847972). Alternatively, TRAF3 can function as a negative regulator of cytokine activity by binding MAPK effectors; degradation of TRAF3 releases MAPK-regulatory proteins, such as MAP3K1, leading to MAPK pathway activation (PMID: 30140268). In addition, TRAF3 can bind TRAF2 and cIAPs to negatively regulate the NF-κB pathway, and TRAF3 degradation results in the release of NF-κB effector molecules, such as NIK (PMID: 21660053, 15383523). TRAF3 also positively regulates the expression of IRF3 and IRF7, proteins that activate the transcription of type I interferon cytokines (PMID: 16306937). Loss of TRAF3 results in the overproduction of inflammatory cytokines (PMID: 16306937) and reduced B cell homeostasis (PMID: 17723217). TRAF3 can also bind CD40, a costimulatory protein on T cells that is required for T cell activation, and the TRAF3/CD40 interaction mediates class switching (PMID: 8934568, 12354380). Alterations of TRAF3 have been associated with immune deficiencies in response to primary infection (PMID: 20832341). Loss-of-function mutations in TRAF3 are found in multiple myeloma (PMID: 17692804, 17692805), resulting in activation of NF-κB signaling. Deletions of TRAF3 have also been identified in B cell lymphomas (PMID: 19693093, 22033491, 22469134, 25468570). True +ENST00000261464 NM_001033910.2 7188 TRAF5 False TRAF5, a signaling adaptor molecule, is infrequently altered by mutation in lymphomas. TRAF5 is a signaling molecule that is a member of tumor necrosis factor (TNFR)-associated factor (TRAF) family (PMID: 8663299). TRAF5 functions downstream of TNFR and Toll-like receptor (TLR) pathways, which are important in the regulation of innate immunity and inflammation (PMID: 12842894). TRAF5 functions as an adaptor molecule in signaling complexes that negatively regulate TLR signaling, in part by activating downstream signaling cascades and mediating cytokine signaling (PMID: 10623461). TRAF5 predominantly acts as an adaptor molecule that binds a complex including TRAF2, leading to activation of downstream NF-κB, JNK and MAPK signaling pathways (PMID: 8790348, 8999898). In addition, TRAF5 can also bind CD40, a costimulatory protein on T cells that is required for T cell activation (PMID: 8790348). An interaction between TRAF2 and TRAF5 is also associated with inhibition of JAK kinase dimerization, leading to inhibition of JAK-STAT signaling (PMID: 29668931). TRAF5 has also been implicated in the regulation of inflammation, as loss of TRAF5 leads to a marked reduction in immune cell infiltration in several tissue types (PMID: 29596835). Mutations in TRAF5 are relatively rare in human cancers; however, loss-of-function alterations have been identified in diffuse large B cell lymphoma (PMID: 19412164). True +ENST00000326181 NM_032271.2 84231 TRAF7 False TRAF7, an E3 ubiquitin ligase, is frequently altered in meningiomas. TRAF7 is an E3 ligase and signaling molecule that is a member of the tumor necrosis factor receptor-associated factor (TRAF) family (PMID: 27808423). TRAF7 activity is important for the regulation of the MAPK and NF-kB signal transduction pathways (PMID: 27808423). TRAF7 binds and potentiates the activity of MEKK3, a protein implicated in the activation of downstream MAPK and NF-kB signaling (PMID: 15001576). Additional functional studies have demonstrated that TRAF7 can mediate the stability of several NF-kB pathway members including NEMO and p65 (PMID: 21518757). TRAF7 has also been identified as an agonist for the JNK-AP1 pathway (PMID: 14743216). In addition, TRAF7 targets ubiquitination of c-FLIP, an antiapoptotic molecule, as well as p53, implicating TRAF7 in apoptosis and cellular proliferation (PMID:14743216, 23128672). Recurrent somatic mutations in TRAF7 have been identified meningiomas, including in 93% of secretory meningiomas (PMID: 23348505, 23404370), and predominantly occur as loss-of-function mutations. TRAF7 mutations commonly co-occur with KLF4 and AKT1 mutations and are mutually exclusive with NF2 alterations (PMID: 23404370). TRAF7 is also mutated in Merkel cell carcinomas and mesotheliomas (PMID: 27808423, 26655088). False + 6957 TRB True TRB, the β-chain of the T-cell receptor, is recurrently altered by chromosomal rearrangement in patients with T-cell acute lymphoblastic leukemia. TRB is the T-cell receptor B locus which encodes the β-chain of the T-cell receptor (TCR) (PMID: 29261409, 25484883). TCRs are protein complexes found on the surface of T cells that engage antigens associated with major histocompatibility complex (MHC) molecules on antigen presenting cells (PMID: 16087711). T cells are important in coordinating effector and memory immune responses in response to antigen display (PMID: 24292902). MHC class I molecules are recognized by TCRs on CD8+ T cells and MHC class II molecules are recognized by TCRs on CD4+ T cells (PMID: 6504140, 25484883). Most TCRs are composed of α and β heterodimers (encoded by TRA and TRB), with a fraction of TCRs composed of γ and δ subunits (PMID: 29261409, 20164930). TRB proteins share substantial homology to immunoglobulin proteins and exhibit sequence diversity following recombination and thymic selection (PMID: 24830344). Engagement of antigen-presenting MHC class proteins with TRA/TRB heterodimers results in conformational changes and activation of downstream pathways leading to activation of TCR-mediated signaling (PMID: 29261409). TRB rearrangements are recurrently found in patients with T-acute lymphoblastic leukemias, typically leading to activation of the fusion partner (PMID: 23033986, 19841179, 15470492). Chimeric antigen receptor T cell (CAR-T) therapy in FDA-approved for patients with non-Hodgkin lymphoma and diffuse large B-cell lymphoma, in which cancer cells from patients are engineered to express TCRs that are recognized by the immune system (PMID: 29914976, 29539277, 29113977). False + 6964 TRD True TRD, the δ-chain of the T-cell receptor, is recurrently altered by chromosomal rearrangement in B- and T-cell acute lymphoblastic leukemia. TRD is the T-cell receptor D locus which encodes the δ-chain of the T-cell receptor (TCR) (PMID: 29261409, 25484883). TCRs are protein complexes found on the surface of T cells that engage antigens typically associated with major histocompatibility complex (MHC) molecules on antigen presenting cells (PMID: 16087711). T cells are important in coordinating effector and memory immune responses in response to antigen display (PMID: 24292902). Most TCRs are composed of α and β heterodimers, but a small fraction of TCRs are composed of γ and δ subunits (encoded by TRG and TRD, termed γδ T-cells). (PMID: 29261409, 20164930). γδ T-cells are unconventional in that that recognize non-peptide stress antigens in the absence of MHC molecules (PMID: 20539306). γδ T-cell responses are commonly initiated following stress, leading to cytokine production, inflammatory responses, and pathogen clearance via direct or indirect cytotoxic activity (PMID: 28713381, 20539306). TRD proteins undergo programming during thymic maturation, restricting the expression of specific TCRs (PMID: 20539306). Engagement of antigens with TRD/TRG heterodimers results in conformational changes and activation of downstream pathways leading to activation of TCR-mediated signaling (PMID: 29261409). TRD rearrangements are recurrently found in patients with B- and T-acute lymphoblastic leukemias, typically leading to activation of the fusion partner (PMID: 16572206, 16386788, 16531254). Chimeric antigen receptor T cell (CAR-T) therapy is FDA-approved for patients with non-Hodgkin lymphoma and diffuse large B-cell lymphoma, in which cancer cells from patients are engineered to express TCRs that are recognized by the immune system (PMID: 29914976, 29539277, 29113977). False + 6965 TRG True TRG, the γ-chain of the T-cell receptor, is recurrently altered by chromosomal rearrangement in B- and T-cell acute lymphoblastic leukemia. TRG is the T-cell receptor G locus which encodes the γ-chain of the T-cell receptor (TCR) (PMID: 29261409, 25484883). TCRs are protein complexes found on the surface of T cells that engage antigens typically associated with major histocompatibility complex (MHC) molecules on antigen presenting cells (PMID: 16087711). T cells are important in coordinating effector and memory immune responses in response to antigen display (PMID: 24292902). Most TCRs are composed of α and β heterodimers, but a small fraction of TCRs are composed of γ and δ subunits (encoded by TRG and TRD, termed γδ T-cells) (PMID: 29261409, 20164930). γδ T-cells are unconventional in that they recognize non-peptide stress antigens in the absence of MHC molecules (PMID: 20539306). γδ T-cell responses are commonly initiated following stress, leading to cytokine production, inflammatory responses, and pathogen clearance via direct or indirect cytotoxic activity (PMID: 28713381, 20539306). TRG proteins undergo programming during thymic maturation, restricting the expression of specific TCRs (PMID: 20539306). Engagement of antigens with TRD/TRG heterodimers results in conformational changes and activation of downstream pathways leading to activation of TCR-mediated signaling (PMID: 29261409). TRG rearrangements are recurrently found in patients with B-cell and T-cell acute lymphoblastic leukemias, typically leading to activation of the fusion partner (PMID: 11972513, 15470492, 18245528). Chimeric antigen receptor T cell (CAR-T) therapy is FDA-approved for patients with non-Hodgkin lymphoma and diffuse large B-cell lymphoma (PMID: 29914976, 29539277, 29113977). False +ENST00000217233 NM_001301188 57761 TRIB3 True TRIB3, a pseudokinase, is infrequently altered in cancer. TRIB3 encodes for a pseudokinase that functions primarily in the regulation of the integrated stress response in the endoplasmic reticulum (PMID: 15775988, 15781252). TRIB3 inhibits the transcriptional activity of DDIT3 and ATF4, nuclear proteins that function in programmed cell death and regeneration, and upregulates the PI3K/AKT/mTOR signaling pathway through binding at both the C-terminal and N-terminal regions of TRIB3 (PMID: 15775988, 33717256, 33896816). TRIB3 has also been identified to stabilize and inhibit the ubiquitination of TWIST1, an epithelial-mesenchymal transition-inducing transcription factor (PMID: 31235507). Overexpression of TRIB3 in various cancer cell lines and mouse models induces upregulation of phosphorylated ERK1/2, JAG1 and SMAD3, and increases cellular proliferation, migration and invasion, suggesting that TRIB3 functions predominantly as an oncogene (PMID: 23319603, 23632994, 30745845). TRIB3 amplification has been identified in various types of cancer, including breast cancer, renal cell carcinoma and gastric cancer (PMID: 31844113, 30745845, 27573078). False +ENST00000377199 NM_006510 5987 TRIM27 True TRIM27, an E3 ubiquitin ligase, is frequently altered by amplification in cancer. TRIM27, also known as RFP, encodes an E3 ubiquitin ligase that is part of the zinc finger protein superfamily, and contains a tripartite motif that consists of a RING finger, B-box zinc finger and coiled-coil domain (PMID: 9247190). TRIM27 induces the ubiquitination of proteins such as PTEN, RIP1 and JAK1 to regulate signaling pathways, which includes promoting the PI3K/AKT and NF-kB signaling pathways (PMID: 30143645, 27612028, 26607717, 31719796, 34284744). Overexpression of TRIM27 in cancer cell lines results in tumor invasion, metastasis and cell proliferation, suggesting that TRIM27 predominantly functions as an oncogene (PMID: 29767249, 31719796). TRIM27 amplification has been identified in various cancer types, including colorectal cancer and ovarian cancer (PMID: 23342271, 29767249). Fusion of TRIM27 with the receptor tyrosine kinase RET has also been identified in various cancer types, including salivary intraductal carcinoma and papillary thyroid cancer (PMID: 31162284, 32326537). False +ENST00000166345 NM_004237.3 9319 TRIP13 True TRIP13, an ATP hydrolase involved in meiosis and spindle checkpoint assembly, is recurrently altered by mutation in Wilms tumor and overexpression in a variety of cancer types. TRIP13 (also PCH2) is an ATP hydrolase that is a member of the AAA+ ATPase family (PMID: 24367111, 26832417). TRIP13 is localized to the nucleolus and mediates strand invasion and crossover events that occur during homologous chromosome segregation in meiosis (PMID: 17696610, 20711356). TRIP13 is required for the appropriate distribution of meiotic proteins along chromosomes that mediate a variety of functions including crossover formation, double-strand break (DSB) repair, mitotic checkpoint regulation, synaptonemal complex formation and higher order chromatin regulation (PMID: 19851446, 19851446, 22072981, 25092294, 23382701, 25012665, 26324890). Importantly, TRIP13 regulates the switch of the checkpoint protein MAD2 from an active to inactive conformation (PMID: 25918846, 29208896, 29973720). Loss of TRIP13 results in spermatocyte death and recombination defects in murine models (PMID: 17696610, 20711356, 25768017,10319812, 25768017). In addition, increased expression of TRIP13 in cell lines results in transformation, enhanced error-prone nonhomologous end joining and chemoresistance (PMID: 25078033). Biallelic loss-of-function mutations are found in patients with Wilms tumors (PMID: 28553959). Patient samples with TRIP13 mutations have impaired spindle assembly checkpoint function and chromosomal missegregation (PMID: 28553959). Overexpression of TRIP13 is also found in several tumor types including colorectal, head and neck squamous cancer (PMID: 28105232, 25078033, 28968952, 28424416, 28157697, 29567476). TRIP13 is also included in an amplified region in non-small cell lung cancer, suggesting that TRIP13 may function both as a tumor suppressor and oncogene (PMID: 18328944). True +ENST00000298552 NM_000368.4 7248 TSC1 False 1 TSC1, a tumor suppressor in the mTOR signaling pathway, is inactivated by mutation or deletion in a diverse range of cancers. Germline and somatic TSC1 mutation are a feature of the disease Tuberous sclerosis complex (TSC). TSC1 (also hamartin) is a key negative regulator of the pro-oncogenic mTOR signaling pathway (PMID: 23485365, 20301399, 10205261). The mTOR signaling pathway has a central role in promoting cellular growth and regulating protein synthesis. TSC1 acts as a scaffold to form a heteromeric complex with TBC1D7 and TSC2; the resulting TSC complex functions as a GTPase activating protein (GAP) and inhibits RHEB (PMID: 22795129, 24529379, 24714658), which is a GTPase that functions as a small molecular switch, activating mTORC1 when bound to GTP (PMID: 24863881). Both TSC1 and TSC2 are also phosphorylated by several kinases (e.g., AKT, RSK1, ERK, AMPK, and GSK3) thus providing regulatory inhibition of the mTOR pathway via several different signaling pathways (PMID: 16959574). Germline mutations in TSC1 are associated with tuberous sclerosis, a disorder that results in benign and occasionally malignant tumor growths (PMID: 23485365, 9242607). Somatic TSC1 mutations have been identified in several cancers, including hepatocellular carcinoma, and predominantly present as truncating loss-of-function mutations (PMID: 25526364). TSC1 loss-of-function mutations result in constitutive activation of the mTORC1 complex resulting in sensitivity to mTOR-inhibiting agents (i.e., rapamycin analogs) (PMID: 22923433). True +ENST00000219476 NM_000548.3 7249 TSC2 False 1 TSC2, a tumor suppressor in the mTOR signaling pathway, is inactivated by mutation or deletion in a diverse range of cancers. Germline and somatic TSC2 mutations are a feature of the disease Tuberous sclerosis complex (TSC). TSC2 (also tumerin) is a key negative regulator of the pro-oncogenic mTOR signaling pathway (PMID: 23485365, 20301399, 10205261). The mTOR signaling pathway has a central role in promoting cellular growth and regulating protein synthesis. TSC2 acts as a scaffold to form a heteromeric complex with TBC1D7 and TSC1; the resulting TSC complex functions as a GTPase activating protein (GAP) and inhibits RHEB (PMID: 22795129, 24529379, 24714658), which is a GTPase that functions as a small molecular switch, activating mTORC1 when bound to GTP (PMID: 24863881). Both TSC1 and TSC2 are also phosphorylated by several kinases (e.g., AKT, RSK1, ERK, AMPK, and GSK3) thus providing regulatory inhibition of the mTOR pathway via several different signaling pathways (PMID: 16959574). Both TSC1 and TSC2 are also phosphorylated by several kinases (e.g., AKT, RSK1, ERK, AMPK, and GSK3) thus providing regulatory inhibition of the mTOR pathway via several different signaling pathways (PMID: 16959574). Germline mutations in TSC2 are associated with tuberous sclerosis, a disorder that results in benign and occasionally malignant tumor growths (PMID: 23485365, 9242607). Somatic TSC2 mutations have been identified in several cancers, including liver and endometrial cancers, and predominantly present as truncating loss-of-function mutations (cBioPortal, MSKCC, February 2018). TSC2 loss-of-function mutations result in constitutive activation of the mTORC1 complex resulting in sensitivity to mTOR-inhibiting agents (i.e., rapamycin analogs) (PMID: 22923433). True +ENST00000541158 NM_000369.2 7253 TSHR True TSHR (thyroid stimulating hormone receptor) is mutated in various cancers, including skin cancer. TSHR (thyroid stimulating hormone receptor) is a transmembrane protein that binds thyrotropin and thyrostimulin (PMID: 2556796). TSHR is expressed in the thyroid gland and regulates the growth of thyroid cells and the release of thyroid hormone (PMID:24931193). It belongs to the family of G-protein coupled receptors (PMID: 18719020). Activation of the receptor results higher cAMP levels, increased Protein Kinase A activity and phosphorylation of nuclear transcription factors such as cAMP regulatory element-binding protein (CREB) (PMID:11158328). TSHR may also activate other pathways including the RAS-MAPK, Protein Kinase C, and NFkB pathways (PMID: 11039907, 15062572, 18719020). Germline activating mutations result in hyperthyroidism while loss-of-function mutations lead to hypothyroidism (PMID: 7920658, 23154162, 20926595). Activating mutations are found in thyroid carcinomas (PMID:7478621,26260781). TSHR pathway activation has been found to cooperate with BRAF mutations in thyroid tumor initiation (PMID:21220306). False +ENST00000264818 NM_003331.4 7297 TYK2 True TYK2, a non-receptor kinase, is infrequently altered by mutation and rearrangement in hematopoietic malignancies. TYK2 is a non-receptor tyrosine kinase that is a member of the JAK kinase family (PMID: 17721432, 18682296). TYK2 requires a cognate cytokine receptor to initiate extracellular cytokine signaling cascades, including interferon signaling (PMID: 24654603). Activation of TYK2 leads to the recruitment and phosphorylation of downstream effectors, such as STAT3/5 and MAPK, enabling the translocation of these signaling molecules to the nucleus to activate transcription (PMID: 29162862, 28295194). TYK2 is an important mediator of inflammation and loss of TYK2 in murine models results in reduced cytokine responses (PMID: 11070173). Mutations in TYK2 have been identified in patients with hyper-IgE syndrome (HIES), a malignancy in which patients have increased mycobacterial and viral infections due to impaired cytokine signaling (PMID: 26304966). Fusion proteins containing TYK2 have been identified in patients with hematopoietic malignancies (PMID: 25207766). Germline mutations in TYK2 have been found in acute myeloid leukemia patients; however, somatic TYK2 mutations are relatively rare (PMID: 18270328). While somatic mutations in TYK2 are uncommon, activation of the TYK2/STAT pathway has been found to be oncogenic in many tumor types, including in T-cell acute lymphoblastic leukemia (T-ALL) and breast cancer (PMID: 23471820, 21864028). TYK2 can also mediate drug resistance to the JAK2 inhibitor ruxolitinib via the formation of drug-resistant TYK2/JAK2 heterodimers (PMID: 22820254). False +ENST00000291552 NM_006758.2 7307 U2AF1 True 4 U2AF1, a splicing factor, is recurrently mutated in hematologic malignancies. U2AF1 (U2 small nuclear RNA auxiliary factor 1) is the splicing factor subunit protein, U2AF35, which together with its binding partner, U2AF65, regulates the removal of introns from pre-mRNAs to produce mature mRNAs that will be translated during protein synthesis (PMID:1388271). The U2AF1 protein is essential for constitutive and enhancer-dependent splicing since it recruits the whole U2AF complex to the 3' end of the pre-mRNA intron that will be spliced (PMID: 8647433, 10617206, 10617208). Mutations in the U2AF1 gene have been found recurrently similarly in hematological malignancies such as myelodysplastic syndromes (MDS) (PMID:22389253) and Acute Myeloid Leukemia (AML) (PMID: 22158538) or Chronic Myelomonocytic leukemia (CMML) (PMID: 22323480). Interestingly it has been proposed that mutations in RNA splicing genes are drivers of the transition from MDS to different sort of myeloid leukemias (PMID:24030381). Therefore, the U2AF1 protein has been proposed as a potential therapeutic target (PMID: 21909114, 22158538, 22323480, 25965570, 25326705). Importantly, it has been shown that mutations in the U2AF1 gene happen early in leukemia development as it has been shown in secondary acute myeloid leukemia (s-AML) and can persist during disease progression (PMID:25550361). False +ENST00000308924 NM_007279.2 11338 U2AF2 False U2AF2, an mRNA splicing protein, is altered by mutation in hematopoietic cancers. U2AF2 (also U2AF65) is an RNA binding protein that functions as the large component of the U2 auxiliary factor (U2AF) protein complex (PMID: 1285125, 21753750, 25901584). The U2AF complex is necessary for the binding of U2 small nuclear RNA molecules to the pre-mRNA branch site, which is required for formation of the pre-spliceosome complex and 3’ splice site selection (PMID: 7685763, 9528748). U2AF2 specifically coordinates the annealing of complementary sequences, RNA binding and regulation of RNA helicases to mediate the formation of duplex RNA (PMID: 7685763). U2AF regulates the splicing of many genes at enhancer-dependent introns including WT1 (PMID: 9784496) and FAS (PMID: 16109372), among others (PMID: 11421359). In addition, U2AF2 has a role in the nuclear export of mRNA (PMID: 11724776) and immune regulation (PMID: 29275860). Altered U2AF2 function has been linked to diseases associated with neurodegeneration due to the presence of CAG repeats in mRNA (PMID: 21725067). U2AF2 mediates alternative splicing of CD44 in melanoma, resulting in CD44 alternative isoforms that mediate tumor progression and metastasis (PMID: 27041584). Somatic U2AF2 mutations are found in myeloproliferative neoplasms (MPN), myelodysplastic syndromes (MDS), and acute myeloid leukemia (AML) (PMID: 22389253). U2AF2 alterations reduce the affinity of U2AF2 for the splice acceptor site resulting in mis-spliced mRNA transcripts (PMID: 25311244, 28850223). False +ENST00000335972 NM_003334.4 7317 UBA1 True UBA1, a ubiquitin-like enzyme, is altered by mutation in hematological malignancies. UBA1 encodes for a ubiquitin-like enzyme which functions primarily in the ubiquitin-proteasome system as a catalyst (PMID: 1447181, 24816100). UBA1 catalyzes the first step of three in the E1-E2-E3 enzymatic cascade and adenylates ubiquitin at the C-terminal glycine (PMID: 1447181, 18662542). UBA1 is a required component in ubiquitylation-dependent signaling for DNA repair and recruits TP53BP1 and BRCA1 in response to DNA damage (PMID: 22456334). Mutations in UBA1 are associated with X-linked infantile spinal muscular atrophy and the prototypical hematoinflammatory disease VEXAS syndrome (PMID: 35996994, 35793467). VEXAS syndrome is characterized by vacuoles in myeloid and erythroid precursor cells and predisposes to myelodysplastic syndrome and plasma cell dyscrasias (PMID: 38398362, 37084382). Knockdown of UBA1 in liver cancer, leukemia and myeloma cell lines reduces cellular proliferation, migration and invasion, suggesting that UBA1 functions predominantly as an oncogene (PMID: 20075161, 33344241). UBA1 mutations have been identified in hematological malignancies (PMID: 36823397, 38687605). UBA1 inhibitors have demonstrated sensitivity in preclinical studies and are currently in clinical development (PMID: 19360080, 29884901, 36959858, 30344936, 38091008). False +ENST00000371558 NM_003336 7319 UBE2A True UBE2A, an E2 ubiquitin-conjugating enzyme, is infrequently altered in cancer. UBE2A, a member of the E2 ubiquitin-conjugating enzyme family, functions in the ubiquitin-proteasome pathway of protein degradation (PMID: 26476408). UBE2A accepts ubiquitin from the E1 complex UBE1 via a trans-thioesterification reaction to catalyze association with E3 ligases and ubiquitination of target proteins (PMID: 20061386, 19325620). DNA polymerase cofactor PCNA is a target for UBE2A ubiquitination, activating the protein’s translesion DNA repair following DNA damage (PMID: 36162503, 30531907). UBE2A amplification in cancer cell lines induces chromosomal instability and transformation, suggesting that UBE2A functions primarily as an oncogene (PMID: 11929833). UBE2A overexpression and point mutations have been identified in various cancer types, including ovarian cancer, breast cancer and melanoma (PMID: 26679603, 12640129, 24891954). False +ENST00000520539 NM_015902.5 51366 UBR5 True UBR5, an E3 ubiquitin ligase, is recurrently altered by mutation in mantle cell lymphomas. UBR5 (also EDD, HYD) is an E3 ubiquitin ligase that is a member of the HECT ligase family (PMID: 10030672). E3 ligase proteins define substrate specificity for proteins targeted to the proteasome for degradation. UBR5 appears to target proteins for degradation via the N-end rule for substrates, identifying proteins for degradation based on N-terminal amino acids (PMID: 16055722, 17462990). UBR5 is responsible for the degradation of a variety of substrates including PAIP2, a poly-A tail regulatory binding protein, and TOPBP1, a DNA damage protein (PMID: 16601676, 11714696). UBR5 has also been implicated in the regulation of WNT activity by directly ubiquitinating β-catenin (PMID: 28689657). UBR5 has a number of additional substrates that are involved in translational elongation, telomerase activity, gluconeogenesis, epigenetic regulation and histone degradation after DNA damage (PMID: 21127351, 21726808, 23362280, 27647897, 27647897). In addition, UBR5 is an important regulator of the cell cycle DNA damage checkpoint and loss of UBR5 results in the accumulation of polyploid cells, suggesting a role in genome stability (PMID: 17074762, 18073532, 21383020, 25833949). Overexpression of UBR5 has been identified in patients with breast and ovarian cancer and is associated with poorer patient outcome (PMID: 28330927, 12902990, 18349819). Increased UBR5 expression is linked to metastasis and cisplatin resistance in ovarian and breast cancer cells (PMID: 28330927, 24379240). However, somatic mutations in UBR5 are found in patients with mantle cell lymphomas and are predicted to be loss-of-function (PMID: 23407552). False +ENST00000436088 NM_014233.4 7343 UBTF True UBTF, an rRNA transcription factor, is recurrently altered in acute myeloid leukemia and other hematologic malignancies. UBTF, upstream binding transcription factor, encodes for a high mobility group (HMG)-box DNA binding protein that is essential in the transcription of ribosomal RNA (rRNA) genes by RNA polymerase I (PMID: 26317157, 34663332, 36448876, 28692053). UBTF mediates the binding of pre-initiation factor SL1-TIF1B (Selectivity Factor 1/Transcription Initiation Factor IB) and the assembly of the pre-initiation complex at the rRNA gene promoter (PMID: 26317157, 34663332). UBTF also plays a role in chromatin remodeling and pre-RNA processing through the formation of a nucleosome-like structure that replaces histone chromatin throughout the transcribed region of rRNA genes, allowing for the regulation of RNA polymerase I transcription (PMID: 26317157, 34663332). In addition, UBTF is indirectly involved in cell growth and proliferation, as ribosome biogenesis is driven by the synthesis of rRNA by RNA polymerase I (PMID: 26317157, 21151873). UBTF promotes cellular proliferation in colorectal cancer and osteosarcoma by facilitating ribosomal DNA transcription (PMID: 28692053, 21151873). Loss of UBTF in fibroblasts and lymphoma cells has been shown to suppress cellular proliferation and DNA replication, resulting in cell cycle arrest (PMID: 26317157, 30701204). Overexpression of UBTF in melanoma cells promotes cell growth, while knockdown of UBTF suppresses cell growth and promotes apoptosis, supporting its role as an oncogene (PMID: 34663332). UBTF-ITD (internal tandem duplications) in exon 13 of the UBTF gene have been described as a recurrent alteration and poor prognostic factor in pediatric patients with acute myeloid leukemia (AML) (PMID: 36448876, 37085611, 35176137, 37236968). False +ENST00000284440 NM_004181 7345 UCHL1 True UCHL1, a deubiquitinating enzyme, is infrequently altered in cancer. UCHL1 encodes for ubiquitin C-terminal hydrolase L1, a deubiquitinating enzyme that has dual effects on the regulation of protein degradation. This protein can stabilize other proteins by removing ubiquitin or add ubiquitin to proteins to mark them for degradation (PMID: 38244540). UCHL1 can enhance or inhibit multiple ubiquitin-dependent biological processes in normal cells (PMID: 37032833, 38244540). UCHL1 expression is highest in the nervous system. In the brain, UCHL1 maintains normal neuronal activity by removing abnormal proteins via interactions with components of the autophagy machinery and the ubiquitin-proteasome system (PMID: 36218038). In cancer cells, overexpression of UCHL1 activates the MAPK/ERK and AKT signaling pathways enhancing tumor invasion, metastasis and drug resistance, suggesting its role as a potential oncogene (PMID: 26293643, 18820707). UCHL1 overexpression in mice results in spontaneous development of lymphomas and lung tumors (PMID: 20574456, 31497243). Additionally, knockdown of UCHL1 in breast cancer cells, lung adenocarcinoma cells, and high-grade glioma cells demonstrates decreased cell proliferation and invasiveness, further supporting its role as an oncogene (PMID: 23664488, 28472177, 31497243). UCHL1 overexpression has been found in many cancers including brain, lung, breast, colorectal, kidney, pancreas, prostate and bladder cancers, non-small cell lung cancer, lymphomas, and neuroendocrine carcinomas (PMID: 36218038, 37815895, 28472177, 38244540). However, UCHL1 promoter hypermethylation has been reported in multiple cancer types, including esophageal, gastric, renal, prostate, head and neck squamous cell carcinoma, hepatocellular, ovarian, and colorectal cancers, which may indicate a dual role in tumor suppression (PMID: 20395212, 26293643, 20574456). False +ENST00000262803 NM_002911.3 5976 UPF1 False UPF1, involved in mRNA surveillance, is rarely mutated in cancers. UPF1 is an RNA helicase involved in mRNA surveillance. UPF1 is essential for nonsense-mediated mRNA decay, which is a pathway that degrades aberrant mRNA transcripts (PMID: 11163187, 16086026, 21145460, 21419344). Following recruitment of UPF1 to target mRNA substrates, UPF1 scans the mRNA transcript, remodels the messenger ribonucleoprotein complex, and regulates the degradation of target transcripts (PMID: 21145460). Disruption of UPF1 function results in decreased nonsense-mediated mRNA decay and contributes to epithelial-mesenchymal transition (PMID: 28663146). Somatic mutations in the UPF1 gene have been identified in pancreatic adenosquamous carcinoma (PMID: 24859531) and decreased levels of UPF1 in lung adenocarcinoma has been associated with tumor progression (PMID: 28663146). UPF1 function is associated with prostate cancer metastasis (PMID: 23881279) and with SMAD7-mediated tumorigenesis in hepatocellular carcinoma (PMID: 26759305). False +ENST00000339950 NM_003368.5 7398 USP1 True USP1, a protein deubiquitinase, is overexpressed in various cancers. USP1 is a protein deubiquitinase that regulates DNA repair, most notably in the Fanconi anemia pathway (PMID: 18082604, 16531995). In conjunction with its cofactor UAF1, USP1 deubiquitinates the FANCD2-FANCI homodimer, which disrupts the recruitment of DNA repair proteins to sites of interstrand crosslinking (PMID: 18082604, 15694335). Similarly, USP1 deubiquitinates PCNA, which prevents the recruitment of translesion synthesis polymerases to sites of DNA damage and halts DNA repair (PMID: 16531995). In osteosarcoma cells, USP1 is implicated in maintaining stemness and reducing differentiation by deubiquitinating and stabilizing ID1, ID2 and ID3, which are normally expressed during the development of undifferentiated and proliferating cells (PMID: 22387046, 21925315). Inhibition of USP1 in mouse models increases the sensitivity of B-cell lymphoma and ovarian cancer cells to chemotherapy and enhances the sensitivity of colorectal cancer and renal cell carcinoma cells to chemotherapy in vitro (PMID: 36352191, 31086816, 31921663, 36153316). There are preclinical and early clinical studies examining the efficacy of USP1 inhibition in various malignancies (Abstract: Yap et al. Abstract# 3005, ASCO 2024. https://ascopubs.org/doi/10.1200/JCO.2024.42.16_suppl.3005) (PMID: 36228090, 30531833). False +ENST00000250066 NM_004505 9098 USP6 True USP6, a deubiquitinase, is altered by chromosomal translocation in various neoplasms. USP6, a member of the ubiquitin-specific peptidases and deubiquitinases families, encodes for deubiquitinase that functions in regulating various cellular functions such as intracellular trafficking, inflammatory signaling, cell transformation and protein turnover (PMID: 12604796, 29061731, 27162353). USP6 is a hominoid-specific gene predominantly expressed in the testes (PMID: 12604796). Overexpression of USP6 in various cancer cell lines and models induces tumorigenesis, epithelial-to-mesenchymal transition and increased pathway activation, suggesting that USP6 functions predominantly as an oncogene (PMID: 15026324, 20418905, 27162353, 22081069, 35926707). USP6 chromosomal rearrangements have been identified in various neoplasms, collectively known as USP6-associated neoplasms (PMID: 36727055, 36404122, 32583473, 33558945). False +ENST00000307179 NM_001128610.2 9101 USP8 True USP8, a ubiquitin hydrolase involved in protein stabilization, is altered by mutation in Cushing's disease and by overexpression in various cancer types. USP8 (also UBPY) is a ubiquitin isopeptidase that is a member of the UBP hydrolase family (PMID: 9628861). Ubiquitin hydrolases deubiquitinate target proteins, protecting them from degradation via the proteasome or lysosome (PMID: 16120644). USP8 mediates the stabilization of numerous proteins, including growth factor receptors such as EGFR (PMID: 16120644, 25675982, 30221684, 29933386, 29626091). Because USP8 is important in the regulation of a variety of proteins, USP8 activity mediates various cellular processes including cellular proliferation, apoptosis, DNA repair, and ciliogenesis, among others (PMID: 29472535, 27321185, 26683461). USP8 phosphorylation recruits the adaptor molecule 14-3-3, leading to inactivation of USP8 catalytic activity (PMID: 17720156, 20736164, 29473952). Stabilization of USP8 results in the inability of target substrates to be appropriately targeted for degradation (PMID: 25675982). Recurrent gain-of-function mutations in USP8 are found in patients with Cushing's disease, a disorder that results in the overproduction of cortisol and development of associated tumors that localize to the pituitary gland (PMID: 25675982, 28505279, 28982703, 30315484). USP8 mutations that are associated with Cushing's disease commonly occur in the 14-3-3 binding region, resulting in uncontrolled activation of USP8 (PMID: 25675982). Altered USP8 expression results in the increased expression of proopiomelanocortin (POMC), the precursor of adrenocorticotropic hormone (ACTH), which is overproduced in Cushing’s disease (PMID: 25675982). Overexpression of USP8 has been identified in several cancer types (PMID: 29880877, 23748694). False +ENST00000602142 NM_005428.3 7409 VAV1 True VAV1, a guanine nucleotide exchange factor involved in hematopoiesis, is recurrently altered by mutation and rearrangement in hematologic malignancies and solid tumors. VAV1 is a guanine nucleotide exchange factor (GEF) that is a member of the VAV family of proteins (PMID: 26353933). GEFs are proteins that regulate the activity of monomeric GTPases by coordinating the binding of GTP and the release of GDP (PMID: 26353933). VAV1 is expressed predominantly in the hematopoietic system and has selective substrate specificity for the GTPase Rac (PMID: 11781818). The activity of VAV1 is regulated by tyrosine phosphorylation (PMID: 11781818) via several tyrosine kinases dependent on cellular context including TCR (T cell receptor), BCR (B cell receptor), and chemokine receptors (PMID: 1531699, 1375396, 10092764, 15872091). VAV1 signaling is required for appropriate lineage commitment and differentiation in a variety of hematopoietic cell types (PMID: 26353933). VAV1 has been implicated in a variety of cellular functions including T cell function, actin cytoskeleton reorganization, MAPK signaling and transcriptional regulation (PMID: 15886116, 10669724). In a hematopoietic screen, VAV1 was determined to have activity as a proto-oncogene (PMID: 2477241), but can also have tumor suppressive activity in functional studies (PMID: 23342133, 30297765, 26353933). Somatic mutations in VAV1 are found in T-cell leukemias/lymphomas and lung adenocarcinomas, among others (PMID: 26437031, 27369867, 28062691, 27158780, 25426554) and are predicted to be gain-of-function. Fusion proteins containing VAV1 have also been identified in peripheral T-cell lymphomas and other hematopoietic malignancies (PMID: 28062691, 28832024). Overexpression of VAV1 is found across a range of solid tumors, suggesting VAV1 predominantly functions as an oncogene in this context (PMID: 19533802, 23342133, 15652748). False +ENST00000371850 NM_001134398.1 7410 VAV2 True VAV2, a guanine nucleotide exchange factor involved in hematopoiesis, is infrequently altered in a range of cancer types. VAV2 is a guanine nucleotide exchange factor (GEF) that is a member of the VAV family of proteins (PMID: 26353933). GEFs are proteins that regulate the activity of monomeric GTPases by coordinating the binding of GTP and the release of GDP (PMID: 26353933). VAV2 is ubiquitously expressed across many cell types and has selective substrate specificity for the GTPase RAC (PMID: 17996485). The activity of VAV2 is regulated by phosphorylation (PMID: 11781818) via several tyrosine kinases dependent on cellular context including BCR (B cell receptor) and chemokine receptors (PMID: 11376343, 14623913). VAV2 signaling is required for appropriate lineage commitment and differentiation in a variety of hematopoietic cell types, with some redundant and non-redundant roles with family members VAV1 and VAV3 (PMID: 14623913, 15941910). In transformation assays, VAV2 was implicated as an oncogene and mediates cell proliferation and foci formation (PMID: 8710375). Overexpression of VAV2 is implicated in a variety of cancer types including breast cancer and head and neck squamous cell carcinomas (HNSCC) (PMID: 26910843, 17234718, 23033540). Somatic mutations in VAV2 are rare; however, VAV2 coordinates cellular proliferation and invasion in various cancer models via an EGFR/RAC1 signaling pathway (PMID: 20940296). False +ENST00000523873 NM_001171623.1 7422 VEGFA True VEGFA encodes a homodimeric glycoprotein that can be an essential component of tumor initiation and the primary stimulus for angiogenesis. VEGFA is commonly over-expressed in many solid tumors. VEGFA (also VEGF) is a growth factor that is a member of the family of vascular endothelial growth factors (VEGFs) and platelet-derived growth factors (PDGFs). VEGFA binds the receptor tyrosine kinases VEGFR1 and VEGFR2 to mediate downstream signaling, with almost all of the known cellular responses mediated by VEGFR2 (PMID: 16951216). Other types of receptors contribute to VEGFA signaling, including platelet-derived growth factor receptors (PMID: 17470632) and neuropilins (PMID: 22948112, 23116416). Expression of VEGFA is critical for mediating angiogenesis and vascular permeability, stimulating the migration and proliferation of vascular endothelial cells (PMID: 24263190). Autocrine VEGF signaling contributes to angiogenesis and cell proliferation (PMID: 22693250) and has been shown to promote the function of cancer stem cells (PMID: 22012397, 20141840). Paracrine VEGFA signaling also impacts the function of nearby immune cells (PMID: 23045606) and fibroblasts (PMID: 22738912, 21057529). Overexpression of VEGFA has been associated with the familial disorder Crow-Fulcase syndrome that is characterized by reduced vasopermeability (PMID: 9771661). VEGFA predominantly functions as an oncogene in human cancers and is commonly overexpressed in many solid tumor types, likely mediating enhanced tumor angiogenesis (PMID: 24263190). The VEGFA inhibitors bevacizumab (PMID: 17212999) and aflibercept (PMID: 22446028) are FDA-approved for the treatment of metastatic colorectal cancer and glioblastoma. False +ENST00000256474 NM_000551.3 7428 VHL False VHL is a tumor suppressor involved in protein degradation. Germline mutations of VHL are associated with Von Hippel-Lindau syndrome and predispose to renal cell carcinoma. VHL is an E3 ligase that functions predominantly as a tumor suppressor gene (PMID: 10102622, 9671762). The VHL protein forms a ternary complex with transcription elongation factors B and C, which is critical for the stabilization and activity of VHL (PMID: 25533676). VHL mutations that disrupt this complex lead to an unstable VHL protein that is aberrantly degraded (PMID: 7660130, 7660122). Under normal oxygen conditions, VHL plays a crucial role in the regulation of the hypoxia-inducible transcription factors (HIFs); VHL binds HIF proteins and targets them for ubiquitination and degradation via the proteasome (PMID: 10878807). HIFs are responsible for the transcription of numerous genes in response to hypoxic conditions, including pro-angiogenic factors such as vascular endothelial growth factor (VEGF) (PMID: 25533676). Loss of VHL leads to activation of HIF downstream target genes and can promote tumorigenesis in normoxic conditions (PMID: 21386872). VHL loss can cause hereditary and sporadic forms of von Hippel-Lindau disease, which is associated with hemangioblastomas, renal cysts, renal cell carcinoma, pheochromocytomas, paragangliomas, pancreatic cysts, neuroendocrine tumors and endolymphatic sac tumors (PMID: 25533676, 35579632, 35709961). Somatic functional inactivation of VHL has been reported through biallelic loss of the VHL gene in cases of 3p deletion (PMID: 2885753), heterozygous VHL mutations (PMID: 7915601, 21715564) or promoter methylation (PMID: 7937876) in human cancers. Inhibitors that target VEGF receptors and HIF proteins may have therapeutic efficacy in tumors with VHL loss (PMID: 25533676). True +ENST00000369458 NM_024626.3 79679 VTCN1 False VTCN1 encodes B7-H4, a T-cell regulator of the immunoglobulin superfamily. B7-H4 is highly expressed in various human tumors. VTCN1 encodes the V-set domain containing T cell activation inhibitor 1, also known as B7-H4 and plays critical roles in regulating T cell-mediated immune response through inhibiting T cell proliferation, cytokine secretion, and the development of cytotoxicity (PMID: 19641607, 12818166, 14568939). B7-H4 is highly expressed in various human tumors, including breast (PMID: 15756008, 15878339), ovarian (PMID: 19955922), lung (PMID: 16782226, 23874109), pancreatic (PMID: 25170273), gastric (PMID: 20872810, 21748517) and urothelial cell carcinoma (PMID: 25400757, 25364421). Soluble B7-H4 (sB7-H4) has been detected in blood samples from various cancer patients, including ovarian (PMID: 16452214, 17490732), gastric (PMID: 24947047), lung (PMID: 25636447), renal cell carcinoma (PMID: 18676826), bladder urothelial carcinoma (PMID: 25364421), hepatocellular carcinoma (PMID:25963168) and high levels of sB7-H4 were a significant prognostic indicator. Moreover, the VTCN1 genetic variants rs10754339, rs10801935, and rs3738414 indicate they could be connected with the risk of breast cancer (PMID: 25385143). False +ENST00000286574 NM_007191.4 11197 WIF1 False WIF1, a negative regulator of WNT signaling, is altered by mutation and rearrangement in various cancer types. WIF1 is an extracellular lipid-binding protein that functions as a WNT antagonist (PMID: 10201374, 24316024, 23258168). WIF1 functions as a negative regulator of the WNT signaling pathway by binding to WNT or Frizzled (Fz) receptors and precluding WNT-mediated activation of downstream signaling (PMID: 24316024, 23258168). WNT signaling is a critical developmental pathway with roles in determining cell fate, tissue identity and polarity (PMID: 28218291). WIF1-mediated antagonism of WNT results in the activation of the β-catenin destruction complex (containing APC, GSK3β and AXIN), which targets β-catenin for degradation (PMID: 23258168). In the absence of WNT signaling, TCF and LEF transcription factors form a repressive complex, leading to inhibition of β-catenin target genes (PMID: 24316024, 23258168). In addition to roles in antagonizing WNT, WIF1 has roles in mesodermal specification, cellular senescence, tissue homeostasis and proliferation (PMID: 24853424, 10201374, 30574494). Germline mutations in WIF1 have been found in families with a predisposition to cancer, as well as in patients with Nail-Patella syndrome (PMID: 25716654, 28383544). Somatic mutations in WIF1 are not well studied in human cancers; however, rare alterations are found in patients with diffuse large B-cell lymphomas (PMID: 23292937). Epigenetic silencing of WIF1 transcription and WIF1 overexpression have both been implicated in distinct cancer types, suggesting that WIF1 may function as a tumor suppressor or oncogene in different cellular contexts (PMID: 20596629, 26291085, 25432628, 15579438). Fusion proteins involving WIF1 are also found in adenomyoepitheliomas, a rare breast cancer, and in salivary gland tumors (PMID: 30675516, 17171686, 18828159). True +ENST00000298139 NM_000553 7486 WRN False WRN, a DNA helicase, is altered by mutation in various cancer types. WRN, a member of the RecQ helicase family, encodes for an ATP-dependent DNA helicase that functions in supporting genome stability through DNA repair, replication, transcription and telomere maintenance (PMID: 16264192, 17284601, 9774636, 36583333). WRN unwinds DNA strands to target abnormalities. Additionally, WRN functions as a 3’ to 5’ exonuclease for double-stranded DNA and plays a role in DNA end processing (PMID: 9771700, 10954593, 16622405). Germline mutations of WRN are associated with the autosomal recessive disorder Werner syndrome, which is characterized by a predisposition to cancer and accelerated aging (PMID: 20443122). Loss of WRN function in various microsatellite instability-high cancer cell lines and models induces accumulation of DNA damage and increased tumor mutational burden, suggesting that WRN functions predominantly as a tumor suppressor gene (PMID: 37662356, 32455893). Loss of function WRN mutations have been identified in various cancers, including colorectal cancer and soft-tissue sarcomas (PMID: 32455893, 8722214). True +ENST00000452863 NM_024426.4 7490 WT1 True WT1, a transcription factor, is overexpressed in various cancer types including leukemias. WT1 (Wilms tumor 1 gene) is a transcription factor expressed in a tissue-specific manner throughout development (PMID: 20013787, 17524167, 17361230, 12835718). WT1 has been implicated in the protein stabilization of TP53 and regulates the expression of several target genes include MYC and BCL2, which are important for cellular growth and metabolism (PMID: 7585606, 8389468). In hematopoietic cells, WT1 interacts with the epigenetic proteins TET2 and TET3 that regulate hydroxymethylation of DNA, an epigenetic modification of DNA that may also serve as a methylation state intermediate (PMID: 25482556). Loss of WT1 expression results in depletion of global 5-hydroxymethylation levels (PMID: 25482556), implicating WT1 in the regulation of DNA methylation. WT1 was initially discovered as a tumor suppressor in Wilms’ tumor (PMID: 2163761, 9090524); however, WT1 loss only contributes to the pathogenesis of a fraction of Wilms' tumors (PMID: 16110318). Somatic WT1 mutations have been identified in patients with acute myeloid leukemia (AML) and are predicted to be loss-of-function, leading to decreased DNA binding activity (PMID: 25482556). Importantly, TET and IDH family mutations are mutually exclusive with WT1 mutations in AML patients, suggesting that WT1 functions as a regulator of DNA methylation (PMID: 25482556). Patients with WT1 mutations may be increasingly sensitive to hypomethylating agents, such as azacytidine, due to the role of WT1 in the regulation of methylation (PMID: 27252512). WT1 is overexpressed in a large percentage of patients with myeloid and lymphoid leukemias (PMID: 27252512, 16461320, 15084694). Vaccines that target overexpression of WT1 are currently in clinical development (PMID: 23486779, 26389576). True +ENST00000265428 NM_007013.3 11059 WWP1 True WWP1, an E3 ubiquitin ligase, is infrequently altered by amplification in prostate and breast cancers. WWP1 (WW domain-containing E3 ubiquitin protein ligase 1) is an E3 ubiquitin ligase that regulates diverse processes in the cell, including protein trafficking and signaling (PMID: 22051607). WWP1 is responsible for mediating the polyubiquitination of PTEN. When polyubiquitinated, PTEN is prevented from dimerizing, localizing to the membrane and functioning as a tumor suppressor (PMID: 31097636). Thus, WWP1 is responsible for PTEN inactivation. WWP1 is also involved in TGF-beta signaling by regulating the degradation of Smad2 (PMID: 15221015). WWP1 knockout in cell lines leads to decreased colony formation and increased apoptosis compared to wildtype, while xenograft tumors carrying WWP1 mutations exhibit increased growth rate compared to wildtype (PMID: 31097636, 32459922). WWP1 is amplified and/or overexpressed in breast, prostate and gastric cancers, among others (PMID: 17330240, 17016436, 25293520). Germline WWP1 variants are enriched in patients with Cowden syndrome and patients with PTEN-related cancers including colorectal adenocarcinoma and thyroid cancer (PMID: 32459922). False +ENST00000360632 NM_001168280.1 25937 WWTR1 True WWTR1, a transcriptional coactivator, is altered by amplification in various cancers. The WWTR1 gene encodes the WWTR1/TAZ protein, a transcriptional coactivator involved in the Hippo signaling pathway (PMID: 26045258, 25266986). TAZ, which shares homology and function with the Yes-associated protein (YAP), is able to translocate to the nucleus and interact with TEAD1-4 to activate a transcriptional program that promotes cell proliferation and epithelial to mesenchymal transition (EMT) (PMID: 11118213, 18227151, 19324877). The Hippo signaling pathway negatively regulates TAZ function via LATS1/2 phosphorylation, which prevents TAZ nuclear translocation (PMID: 18227151). WWTR1/TAZ is considered a novel oncogene in breast and lung cancer (PMID: 18413727, 21258416). WWTR1 is amplified in several tumors, such as lung, ovarian and head and neck cancer (cBioPortal, MSKCC, Nov 2016). Cancers with defective Hippo signaling pathway and subsequent TAZ activation are good candidates for novel small-molecule Hippo modulator drugs (PMID: 27262779, 24336504). False +ENST00000216037 NM_005080.3 7494 XBP1 True XBP1, a transcription factor involved in the unfolded protein response, is infrequently altered in a range of human cancers. XBP1 is a transcription factor that is an important regulator of the unfolded protein response (UPR) (PMID: 28741511). XBP1 undergoes unconventional splicing after the accumulation of unfolded or misfolded proteins in the endoplasmic reticulum (ER) resulting in the activation of UPR (PMID: 28741511). The function of the UPR is to stop protein translation, degrade abnormal proteins, and increase chaperone production in response to ER stress; otherwise, the cell is targeted for apoptosis (PMID: 21061914). The transmembrane protein IRE1α coordinates the splicing of XBP1 upon ER stress, resulting in a newly spliced transcript that contains a transactivation domain, which is critical for mediating UPR transcriptional activity in the nucleus (PMID: 28741511, 19609461). XBP1 has been implicated in a variety of cellular functions including adaptive immunity, innate immunity, glycolysis, gluconeogenesis, DNA repair, lipid metabolism, cellular differentiation, and DNA replication, among others (PMID: 17612490, 21061914, 12612580). Variants in XBP1 have been linked to inflammatory bowel syndrome and Crohn’s disease (PMID: 18775308). Overexpression of XBP1 expression has been found in leukemias and breast cancers (PMID: 16491124, 19470730, 20028872). Increased XBP1 activity is important for the growth of tumor cells in hypoxic conditions (PMID: 15342372) and can mediate drug resistance (PMID: 17660348). Somatic mutations in XBP1 are found in patients with follicular lymphoma (PMID: 27959929), however, these alterations have not been functionally characterized. False +ENST00000355640 NM_001167.3 331 XIAP True XIAP encodes a protein that is involved in inhibiting cell death (apoptosis). Germline mutations and overexpression of XIAP are associated with X-linked lymphoproliferative syndrome and resistance to various cancer treatments. XIAP encodes for the gene X-linked inhibitor of apoptosis, an anti-apoptotic protein belonging to the family of baculovirus IAP domain repeat-containing proteins (PMID:25065885). The IAP domain mediates anti-apoptotic activity by binding and inhibiting caspases and is blocked by SMAC protein binding (PMID:9230442, 11242052). XIAP also contains a RING domain that mediates ubiquitination through E3 ligase activity (PMID:15803136, 18708583). It regulates Tumor necrosis factor (TNF) response, MAPK signaling, copper metabolism, and cellular differentiation (PMID: 24975362, 24497535, 20154138, 19011619, 23928917). In cancer, XIAP can mediate resistance to therapy (PMID:23727860, 22491673, 11280739, 12384799). Gerrmline mutations are associated with X-linked lymphoproliferative syndrome characterized by lymphohystiocytosis, hypogammaglobulinaemia, lymphomas, and immune disorders (PMID: 17080092, 23973892). Inhibitors of XIAP are in development for cancer therapy by inducing an apoptosis response (PMID: 15353805, 14749124). False +ENST00000375128 NM_000380 7507 XPA False XPA, a DNA damage repair factor involved in the nucleotide excision repair (NER) pathway, is infrequently altered in cancer. XPA encodes for a zinc finger protein that functions primarily in the nucleotide excision repair (NER) pathway as a scaffolding protein (PMID: 12897146, 25056193). XPA coordinates the assembly of other NER repair factors, such as RPA and the ERCC1-XPF endonuclease, around the site of DNA damage to prepare for lesion excision (PMID: 21148310, 7697716). Germline mutations of XPA are associated with the autosomal recessive disease xeroderma pigmentosum, resulting in a decreased ability to repair DNA damage caused by ultraviolet (UV) rays (PMID: 24135642, 8814338, 20574439). Loss of XPA in various cancer cell lines and models induces increased UV-induced mutations and disruption to DNA repair pathways, suggesting that XPA functions predominantly as a tumor suppressor gene (PMID: 11376684, 38664429, 32170071). Downregulation of XPA has been identified in bladder cancer (PMID: 28222669). True +ENST00000285021 NM_004628 7508 XPC False XPC, a DNA damage repair factor involved in the nucleotide excision repair (NER) pathway, is frequently altered by mutation or deletion in squamous cell carcinoma. Germline mutations of XPC are associated with xeroderma pigmentosum and predispose to skin cancers. XPC encodes for a DNA damage repair factor which functions as a DNA binding component of the XPC-RAD23B complex (PMID: 10873465, 20028083, 20798892). The XPC-RAD23B complex is a part of the nucleotide excision repair mechanism and recognizes DNA lesions to initiate DNA repair (PMID: 33035795, 31372632). Germline mutations of XPC are associated with the autosomal recessive disease xeroderma pigmentosum, resulting in a decreased ability to repair DNA damage caused by ultraviolet rays (PMID: 27413738). Knockdown of XPC in various cancer cell lines and models induces tumor formation, oxidative DNA damage and cellular proliferation and migration, suggesting that XPC functions predominantly as a tumor suppressor gene (PMID: 21763452, 9540983, 25871391). Downregulation of XPC has been identified in various types of cancers, including squamous cell carcinoma and melanoma (PMID: 20616346, 17575131). True +ENST00000401558 NM_003400.3 7514 XPO1 True XPO1, a nuclear export protein, is altered by mutation in some leukemias and lymphomas. The XPO1 (Exportin 1) encodes a protein that mediates nuclear export of proteins and RNA (PMID: 9323132, 10786834). XPO1 recognizes proteins containing a nuclear export signal (NES) and leads to their export from the nucleus to the cytoplasm. XPO1 has been reported to be involved in ribosome biogenesis by exporting the 60S ribosome subunit through binding to NMD3 (PMID: 26048327, 12724356). In the context of cancer, XPO1 has oncogenic properties. This has been mostly attributed to the fact that proteins exported by XPO1 include important tumor suppressors (eg. APC, TP53, SMARCB1 etc.)(PMID: 12070164, 11782423, 17891139, 20803015). High nuclear XPO1 expression is associated with adverse prognosis in various tumor entities (PMID: 18306389, 19082467, 20003838) and XPO1 mutations have been reported in some cases of chronic lymphatic leukemia (CLL) as well as diffuse large B-cell lymphoma (DLBCL) (PMID: 21642962, 26608593). XPO1 translocations have been reported in T-ALL (PMID: 25377562). Small molecule inhibitors of nuclear export (SINEs) have been developed and tested in preclinical studies in various tumor types and show promising therapeutic efficacy (PMID: 23034282, 23373539, 23970380, 25057921, 24431073, 23588715, 25366336). False +ENST00000262887 NM_006297 7515 XRCC1 False XRCC1, a scaffold protein, is infrequently altered in cancer. XRCC1, X-ray repair cross complementing 1, encodes a scaffold protein that is involved in maintaining genomic stability through the repair of both damaged nucleotide bases and single-stranded breaks in DNA (PMID: 16550161, 31324530). The protein participates in the base excision repair pathway through interactions with DNA ligase III, DNA polymerase beta, and poly (ADP-ribose) polymerase (PARP) (PMID: 31324530, 35055077, 36573562). XRCC1 has essential roles in microhomology-mediated end joining (MMEJ) repair of double-strand breaks and replication fork restart in the absence of BRCA2 (PMID: 31324530, 35055077). Mutations in the gene have been associated with neurological disorders and cancer predisposition as a result of unrepaired DNA damage (PMID: 35055077). The risk of various cancers, including breast and head and neck squamous cell carcinoma, have been associated with polymorphisms in this gene (PMID: 32562117, 36573562). True +ENST00000359321 NM_005431.1 7516 XRCC2 False XRCC2 encodes a protein involved in DNA double-strand break repair. Germline mutations of XRCC2 are associated with an increased risk developing of breast cancer. XRCC2 is a member of the RAD51 recombinase family that functions in homologous recombination (HR)-mediated repair of double-stranded DNA breaks (DSBs). RAD51 acts at an early step in the DSB pathway: the 5’ended DNA strands flanking the DSB break site are resected and the single-stranded overhangs are coated by RAD51 forming a nucleo-protein filament (PMID: 25833843). XRCC2 is a member of the BCDX2 complex that includes the RAD51 paralogs RAD51B, RAD51C, and RAD51D. The BCDX2 complex stabilizes the sites of damaged DNA and recruits RAD51 to initiate strand repair by homologous recombination (PMID: 9126486,10517641). Knockdown of XRCC2 activity in cell line and murine models results in a 100-fold decrease in DSB repair function through defective homologous recombination repair (PMID: 10517641, 14678973, 14645207, 24627042). There is conflicting data on whether germline variants of XRCC2 increase the risk of breast cancer (PMID: 22464251, 23054243,12023982,17141189) and XRCC2 is infrequently mutated in human cancers. True +ENST00000282441 NM_001130145.2 10413 YAP1 True YAP1 is a transcriptional co-activator and downstream effector of the Hippo pathway. High expression of YAP due to gene amplification or epigenetic activation is found in a diverse range of human cancers. YAP1 is a transcriptional co-activator and downstream effector of the Hippo pathway. The Hippo pathway is involved in several processes of cancer progression and physiologically has important regulatory functions in organ development and regeneration (PMID: 23467301, 24825474, 24336504). YAP1 largely mediates the downstream transcriptional effects of Hippo signaling (PMID: 20951342) by shuttling between the cytoplasm and the nucleus. In the nucleus, YAP1 induces expression of proliferative and anti-apoptotic genes via interactions with transcription factors, namely TEAD family members (PMID: 20951342). Hyperactivation of YAP1 leads to contact-inhibition, epithelial-mesenchymal transition, metastatic potential and stem cell defects (PMID: 17974916, 24336504, 25702974). Germline mutations in YAP1 have been identified in patients with coloboma, a familial disorder resulting in ocular defects (PMID: 24462371). Overexpression of YAP1 is widespread in human cancer; however, somatic mutations are rare (PMID: 25592648, 24336504). Reports of YAP1 gene amplification and epigenetic activation in cancer support the role of YAP1 as a classic oncogene (PMID: 25592648, 24336504). YAP1 fusions have also been identified in ependymomas (PMID: 29258295). Although YAP1 behaves as an oncogene in most cancers, data suggest that YAP1 can also act as a tumor suppressor in certain cellular contexts (PMID: 24976009, 22234184). Overexpression of YAP1 has been associated with resistance to MEK and BRAF inhibitors (PMID: 25665005). Verteporfin, a small molecule inhibitor that targets the YAP1-TEAD interaction, has demonstrated efficacy in preclinical models of YAP1 overexpression and is synthetic lethal with MEK and BRAF inhibition (PMID: 29299145). False +ENST00000314574 NM_005433.3 7525 YES1 True YES1 encodes a tyrosine kinase involved in regulation of cell growth and survival, apoptosis, cell-cell adhesion, cytoskeleton remodeling and differentiation. Overexpression of YES1 is found in colorectal, hepatocellular, breast and esophageal cancers and melanomas. YES1 is a non-receptor SRC protein tyrosine kinase that is activated by growth-factor binding to receptor tyrosine kinases, including PDGFR, EGFR and VEGFR (PMID: 8356071, 12496267, 16400523). Following activation, YES1 phosphorylates various substrates, including CDK4 and PAR3 to control cell cycle progression and regulate cell-cell adhesion (PMID: 18479465, 17053785). Additionally, YES1 stimulates chemokine-directed T-cell migration by phosphorylating collapsin response mediator protein 2 (CRMP2), promotes cell migration through activation of the PI3K/AKT signaling pathway and induces apoptosis in hepatocytes through its participation in the CD95L signaling pathway (PMID: 19276087, 21713032, 15917250). YES1 plays a central role in malignant mesothelioma cell growth (PMID: 22948717) and has been shown to act as an oncogene in several tumor models through increased expression and kinase activity (PMID: 7690925, 9816313, 17007035, 7690926). YES1 is amplified in basal-like breast cancer and esophageal squamous carcinoma (PMID: 21779430, 11756219) and has been implicated in resistance to trastuzumab and lapatinib in HER2-positive breast cancer (PMID: 28158234). In colorectal carcinoma, increased YES1 activation correlates with poor prognosis, as YES1 activity is elevated in adenomas with the highest risk (PMID: 7806032). However, somatic YES1 mutations are rare in human cancers. False +ENST00000262238 NM_003403.4 7528 YY1 True YY1, a transcription factor, is rarely altered by chromosomal alteration in mesothelioma. YY1 is a ubiquitously expressed zinc-finger transcription factor of the Polycomb Group family. The protein contains a DNA binding domain as well as two distinct domains involved in transcriptional activation and repression (PMID: 16314846) of multiple cellular pathways. YY1 has been shown to be a SMAD-interacting protein, involved in the regulation of TGFβ and BMP-induced cell differentiation (PMID:12808092) as well as DNA repair (PMID: 11394900). Additionally, YY1 has been suggested to play roles in the regulation of the cell cycle through interaction with cyclins and p53, apoptosis through interactions with NFkB and Fas, and inflammatory response through IFN-γ (PMID: 16314846). Mouse studies have confirmed the importance of YY1 activity in later stages of mouse embryogenesis (PMID: 10490658). False +ENST00000474710 NM_001164342.2 26137 ZBTB20 True ZBTB20, a transcription factor involved in immune regulation and pituitary function, is altered by overexpression in various cancer types. Germline mutations in ZBTB20 are found in patients with Primrose syndrome and other neurodevelopmental disorders. ZBTB20 is a transcription factor that is a member of the BTB/POZ family of DNA binding proteins. ZBTB20 is most highly expressed during hippocampus development and in mature endocrine cells (PMID: 26782407, 27079169). Deletion of ZBTB20 in mice results in decreased secretion of pituitary growth hormones, such as prolactin (PRL), and loss of mature lactotrope cells in the anterior pituitary (PMID: 26782407, 27079169). ZBTB20 directly binds the promoter of PRL and activates transcription (PMID: 27079169) and PRL overexpression has been implicated in ZBTB20-dependent models of autoimmune encephalomyelitis (PMID: 31570595). Expression of ZBTB20 is important in immune regulation in B cells, including in plasma cell differentiation and longevity (PMID: 29616049, 24711583, 23776228). The deletion of ZBTB20 in murine models can result in long-term antibody defects (PMID: 29616049). The activity of ZBTB20 has been implicated in other cellular functions including liver regeneration, lipogenesis, neuronal development and maintenance of circadian rhythms, among others (PMID: 29700307, 27657167, 27000654, 25564625, 28327662). Germline mutations in ZBTB20 are associated with Primrose syndrome, a congenital malformation syndrome associated with abnormal immunoglobulin levels, as well as other neurodevelopmental disorders (PMID: 31821719, 31321892, 29681083, 25017102). These loss-of-function alterations lead to alterations in dendritic spine morphology (PMID: 30281617). ZBTB20 has been implicated as a tumor suppressor in the context of PTEN loss (PMID: 28319090); however, overexpression of ZBTB20 is also associated with poor prognosis and metastatic progression in several cancer types including hepatocellular and lung cancers (PMID: 31556767, 26893361, 21702992, 25311537). True +ENST00000322357 NM_015898 51341 ZBTB7A True ZBTB7A, a zinc finger transcription factor, is infrequently altered in cancer. ZBTB7A, a member of the POK family of transcriptional repressors, encodes for a zinc finger transcription factor that functions in the repression of genes involved in cellular proliferation and differentiation (PMID: 17595526, 14701838, 11865059). ZBTB7A negatively regulates SMAD4 transcriptional activity in the TGF-β signaling pathway through recruitment of chromatin regulator HDAC1 to the SMAD4-DNA complex and by preventing further recruitment of transcriptional activators (PMID: 25514493). ZBTB7A can function as an AR transcriptional corepressor through the recruitment of NCOR1 and NCOR2 to suppress AR-mediated signaling and cellular proliferation (PMID: 20812024). The oncogenic function of ZBTB7A is likely tissue-specific. Overexpression of ZBTB7A in various types of cancer cell lines and models induces cellular proliferation and migration and epithelial-to-mesenchymal transition, suggesting that ZBTB7A functions predominantly as an oncogene in these tissue contexts (PMID: 17907153, 31385585, 21176152, 33167891). Amplification of ZBTB7A has been identified in various cancers, including non-small cell lung cancer, hepatocellular carcinoma and colorectal cancer (PMID: 17907153, 27982429, 33167891). In contrast, the knockdown of ZBTB7A in other types of cancer cell lines and models induces cellular proliferation and tumor metastasis, suggesting that ZBTB7A functions predominantly as a tumor suppressor gene in these tissue contexts (PMID: 36596853, 25184678, 29699474). Downregulation of ZBTB7A has been identified in various cancers, including melanoma, prostate cancer and glioblastoma (PMID: 25995384, 31444154, 36596853). True +ENST00000268489 NM_006885.3 463 ZFHX3 False ZFHX3, a tumor suppressor and transcription factor, is altered by mutation or deletion in various cancer types, most frequently in endometrial and skin cancers. ZFHX3 is a transcription factor expressed in the brain, liver, lung and the gastrointestinal tract. Normally, ZFHX3 suppresses transcription of alpha-fetoprotein by binding to an enhancer motif (PMID: 7507206, 11786962) and negatively regulates expression of the proto-oncogene MYB (PMID: 10318867). ZFHX3 is mutated in advanced gastric cancers (PMID: 17671116, 20599712) and prostate cancer (PMID: 15750593). Functional studies support a tumor suppressor role for this protein. Specifically, a ZFHX3 conditional knockout mouse develops hyperplasia and prostatic intraepithelial neoplasia (PMID: 24934715). Suppression of ZFHX3 in a prostate cell line increases proliferation, while exogenous expression of ZFHX3 decreases soft agar colony formation (PMID: 15750593). In breast cancer, ZFHX3 is not frequently mutated (PMID: 16932943, 18796146), however, it can inhibit estrogen receptor-mediated cell proliferation (PMID: 20720010). True +ENST00000336440 NM_001244698.1 677 ZFP36L1 False ZFP36L1, an RNA binding protein involved in mediating mRNA decay, is altered by mutation in various cancer types. ZFP36L1 is an RNA binding protein that is a member of the zinc-finger containing ZFP36 protein family (PMID: 29426877, 23428348). ZFP36L1 is a critical regulator of mRNA decay and binds to adenylate-uridylate-rich elements (ARE), which are located in the 3’ untranslated region (UTR) of mRNAs (PMID: 31551365, 25106868). ZFP36L1 binds the 3’ UTR of many cancer and cell-cycle related genes including HIF1A, CCND1, and E2F1 (PMID: 31551365, 29709483, 29426877). In addition, ZFP36L1 can bind to other proteins involved in mRNA degradation including mRNA decapping subunits, the exosome component RRP4, and deadenylases, among others (PMID: 15687258). Overexpression of ZFP36L1 in cancer cell lines results in reduced proliferation and cell cycle progression, suggesting that ZFP36L1 predominantly functions as a tumor suppressor (PMID: 31551365, 26542173). Deletion of ZFP36L1 in mice results in a severe defect in B-cell development, due to the role of ZFP36L1 in mediating cellular quiescence, which is required for the maintenance of genomic integrity during V(D)J recombination (PMID: 27102483, 28394372). ZFP36L1 has also been implicated in thymocyte development, and loss of ZFP36L1 results in T-acute lymphoblastic leukemias in mice (PMID: 20622884, 27566829). ZFP36L1 is also involved in the regulation of other cellular functions including differentiation, apoptosis, fate specification and hypoxia (PMID: 31551365, 30982771, 28206953, 26542173, 25014217, 26542173). Somatic mutations of ZFP36L1 have been identified in several cancer types, including breast and bladder cancer (PMID: 31551365). Epigenetic silencing of ZFP36L1 is another mechanism identified in cancer cells that results in ZFP36L1 downregulation (PMID: 31551365). True +ENST00000282388 NM_006887.4 678 ZFP36L2 False ZFP36L2, a zinc finger RNA-binding protein, is frequently altered by deletion in cancer. ZFP36L2, or TIS11D, encodes a zinc finger RNA-binding protein that negatively regulates protein synthesis through poly(A) tail deadenylation for cytoplasmic AU-rich element (ARE)-containing mRNA transcripts (PMID: 25106868). ZFP36L2 binds to the 3'-untranslated region of mRNA transcripts and recruits the CCR4-NOT-deadenylase complex to promote destabilization of the mRNA transcript (PMID: 25106868). Phosphorylation of the C-terminus of ZFP36L2 by p90 ribosomal S6 kinase results in the dissociation of the CCR4-NOT-deadenylase complex and stabilization of the mRNA transcript (PMID: 25106868). Overexpression of ZFP36L2 in cancer cell lines results in decreased cell viability and cell cycle arrest, suggesting that ZFP36L2 predominantly functions as a tumor suppressor (PMID: 21109922, 29426877). Loss of ZFP36L2 has been identified in various cancer types, including T-cell acute lymphoblastic leukemia, acute myeloid leukemia and colorectal cancer (PMID: 20622884, 21109922, 27463018). Epigenetic silencing of ZFP36L2 through hypermethylation in cancer cell lines results in ZFP36L2 downregulation (PMID: 28860350). ZFP36L2 overexpression is a prognostic marker in gastric cancer and low-grade glioma (PMID: 31048690, 35910229). True +ENST00000314425 NM_005096 9203 ZMYM3 False ZMYM3, a zinc finger protein, is infrequently altered in cancer. ZMYM3 encodes a zinc finger protein that functions primarily in transcriptional regulation and is a component of histone-deacetylase-containing multiprotein complexes (PMID: 22011512, 33173136). ZMYM3 regulates BRCA1 localization to chromatin in the DNA-damage response pathway (PMID: 28242625). Knockdown of ZMYM3 in cancer cell lines induces impaired homologous recombination repair and genomic instability, suggesting that ZMYM3 functions predominantly as a tumor suppressor gene (PMID: 28242625). Downregulation and loss function mutations of ZMYM3 have been identified in various types of cancer, including prostate cancer, chronic lymphocytic leukemia and medulloblastoma (PMID: 33115829, 22150006, 22722829). True +ENST00000302342 NM_006526 7764 ZNF217 True ZNF217, a transcription factor, is altered by amplification in various cancers. ZNF217 encodes for a Krüppel-like zinc finger transcription factor which functions as a DNA-binding transcriptional repressor through interaction with epigenetic regulators (PMID: 19242095, 16940172, 18625718). ZNF217 interacts with CTBP2, RCOR1 and various histone modifying enzymes to form a DNA-binding core transcriptional complex to regulate target genes (PMID: 18625718, 17259635). ZNF217 can attenuate pro-apoptotic signals from telomere dysfunction and DNA damage to promote cell survival (PMID: 16203743). Overexpression of ZNF217 in breast cancer and ovarian cancer cell lines and models induces cellular proliferation and tumor growth, suggesting that ZNF217 functions predominantly as an oncogene (PMID: 25031722, 21059223, 22593193, 22728437). Amplification of ZNF217 has been identified in breast cancer, ovarian cancer and prostate cancer (PMID: 22728437, 22139760, 27768596). False +ENST00000369577 NM_015021.3 23036 ZNF292 False ZNF292, a zinc finger transcription factor, is recurrently altered by mutation or downregulation in various cancers. ZNF292, a zinc finger protein, encodes a highly conserved, growth hormone-dependent transcription factor that is highly expressed in the developing brain and is critical for neurodevelopment (PMD: 27150435, 25559195, 31723249, 35125808). While the exact role of ZNF292 in neurodevelopment is still unknown, mutations have been linked to intellectual disability and autism spectrum disorder (PMID: 31723249). Mutations in ZNF292, including deletions and frameshift mutations, have been identified in gastric cancer, colorectal cancer, liver cancer and chronic lymphocytic leukemia (PMID: 27150435, 25559195, 33194728, 26200345). Loss of ZNF292 in various cancer cell lines and models results in increased cell proliferation, colony formation, and tumor growth, suggesting that ZNF292 functions predominantly as a tumor suppressor gene (PMID: 25559195, 35125808). Furthermore, loss of ZNF292 expression in esophageal squamous cell carcinoma (ESCC) and chronic lymphocytic leukemia (CLL) is associated with poor prognosis (PMID: 35125808, 33194728). True +ENST00000269394 NM_024702.2 79755 ZNF750 False ZNF750, a transcription factor, is altered by mutation and deletion in various cancer types. ZNF750 is a transcription factor that functions as a regulator of epidermal differentiation (PMID: 27819679, 22364861). ZNF750 modulates epithelial homeostasis by controlling the activation of key late-stage epidermal differentiation gene programs (PMID: 27819679, 30466065, 26545810, 22936986). Binding of ZNF750 to target genes is important for various cellular activities including differentiation, apoptosis, angiogenesis, metastasis and barrier function (PMID: 32341351, 30518868, 29113187, 26527742). ZNF750 cooperates with other transcriptional and chromatin regulators, such as FOXC2, KDM1A, and HDAC1, to activate gene expression (PMID: 32341351, 32313225, 25805135, 25228645). Through p63-mediated activation, ZNF750 coordinates the expression of KLF4 in skin cells to regulate cellular identity (PMID: 22364861). Germline alterations in ZNF750 have been detected in patients with psoriasis and psoriasiform dermatitis (PMID: 22185198). Decreased expression of ZNF750 is detected in various cancer types, including esophageal squamous cancers, suggesting that ZNF750 functions as a tumor suppressor (PMID: 27819679, 32341351, 32246873). Somatic mutations and deletions in ZNF750 are found in patients with cutaneous and squamous carcinomas of varied origins, including esophageal, cervix, head and neck, and lung, among others (PMID: 27819679, 31148199, 30563911, 29760388, 29216641, 28608921, 27749841, 25839328). True +ENST00000544604 NM_001206998.1 84133 ZNRF3 False ZNRF3, a transmembrane E3 ligase that negatively regulates WNT signaling, is altered by deletion or mutation in adrenocortical and colorectal carcinomas. ZNRF3 is a transmembrane E3 ubiquitin ligase that negatively regulates the WNT signaling pathway (PMID: 30692207, 24225776, 22575959). WNT signaling is activated following ligand engagement of WNT receptors and co-receptors, including Frizzled (FZD) and LRP5/6, resulting in increased downstream signaling (PMID: 30692207, 24225776, 22575959). ZNRF3 antagonizes WNT signaling by targeting FZD and LRP6 for degradation via ubiquitin-mediated endocytosis (PMID: 30692207, 22575959, 24349440). Other WNT signaling molecules, including the phosphoprotein Dishevelled (DSH), are required to mediate the activity of ZNRF3 at the membrane (PMID: 22575959, 22895187, 25891077). In addition, the RSpondin (RSPO) family of proteins, which function as agonists of the WNT pathway, promote membrane clearance of ZNRF3 and stability of FZD, leading to WNT pathway activation (PMID: 22575959, 22895187, 24165923, 29769720). WNT signaling is a critical regulator of tissue homeostasis, proliferation, and maintenance of the stem cell niche (PMID: 22895187, 27088858, 30692207) and loss of ZNRF3 expression results in expansion of the intestinal stem cell zone (PMID: 22895187). Downregulation of ZNRF3 is found in a variety of cancer types and overexpression leads to reduced cellular proliferation, suggesting that ZNRF3 functions as a tumor suppressor (PMID: 29088784). Somatic loss-of-function mutations and deletions are found in patients with adrenocortical carcinomas and serrated pathway colorectal cancers, among others (PMID: 24747642, 25490274, 29879932, 27661107, 24236197). True +ENST00000307771 NM_005089.3 8233 ZRSR2 False 4 ZRSR2, a splicing factor, is altered in various hematological malignancies. ZRSR2 encodes a splicing factor U2 small nuclear ribonucleoprotein auxiliary factor 35 kDa subunit-related protein 2. It is involved in the splicing of introns and is important for recognizing the 3' splice site and assembly of the spliceosome (PMID:21041408). Mutation in hematopoietic cells results in mis-splicing and retention of the U12 type intron in pre-messenger RNA (PMID:25586593). Mutations are found in myelodysplastic syndrome, secondary acute myeloid leukemia, and other myeloid dysorders (PMID: 22389253, 25550361, 25212276). Targeted inhibition of the spliceosome may be a therapeutic strategy in spliceosome mutant disease (PMID:26575690). False diff --git a/data/common_input/oncokb_cancer_genes_list.txt b/data/common_input/oncokb_cancer_genes_list.txt index 552de12..c8e81a4 100644 --- a/data/common_input/oncokb_cancer_genes_list.txt +++ b/data/common_input/oncokb_cancer_genes_list.txt @@ -61,11 +61,11 @@ MLH1 4292 ENST00000231790 NM_000249.3 ENST00000231790 NM_000249.3 No Yes 7 Yes Y MPL 4352 ENST00000372470 NM_005373.2 ENST00000372470 NM_005373.2 Yes No 7 Yes Yes Yes Yes Yes Yes Yes CD110, THPOR, TPOR MSH2 4436 ENST00000233146 NM_000251.2 ENST00000233146 NM_000251.2 No Yes 7 Yes Yes Yes Yes Yes Yes Yes COCA1, HNPCC1 MSH6 2956 ENST00000234420 NM_000179.2 ENST00000234420 NM_000179.2 No Yes 7 Yes Yes Yes Yes Yes Yes Yes GTBP -MYD88 4615 ENST00000396334 NM_002468.4 ENST00000396334 NM_002468.4 Yes No 7 Yes Yes Yes Yes Yes Yes Yes +MYD88 4615 ENST00000396334 NM_002468.4 ENST00000396334 NM_002468.5 Yes No 7 Yes Yes Yes Yes Yes Yes Yes NF1 4763 ENST00000356175 NM_000267.3 ENST00000356175 NM_000267.3 No Yes 7 Yes Yes Yes Yes Yes Yes Yes NF2 4771 ENST00000338641 NM_000268.3 ENST00000338641 NM_000268.3 No Yes 7 Yes Yes Yes Yes Yes Yes Yes ACN, BANF, SCH, merlin, merlin-1 NFE2L2 4780 ENST00000397062 NM_006164.4 ENST00000397062 NM_006164.4 Yes No 7 Yes Yes Yes Yes Yes Yes Yes -NOTCH1 4851 ENST00000277541 NM_017617.3 ENST00000651671 NM_017617.3 Yes Yes 7 Yes Yes Yes Yes Yes Yes Yes TAN1 +NOTCH1 4851 ENST00000277541 NM_017617.3 ENST00000651671 NM_017617.5 Yes Yes 7 Yes Yes Yes Yes Yes Yes Yes TAN1 NOTCH2 4853 ENST00000256646 NM_024408.3 ENST00000256646 NM_024408.3 Yes Yes 7 Yes Yes Yes Yes Yes Yes Yes NPM1 4869 ENST00000296930 NM_002520.6 ENST00000296930 NM_002520.6 No Yes 7 Yes Yes Yes Yes Yes Yes Yes B23, NPM NRAS 4893 ENST00000369535 NM_002524.4 ENST00000369535 NM_002524.4 Yes No 7 Yes Yes Yes Yes Yes Yes Yes N-ras @@ -86,7 +86,7 @@ SETD2 29072 ENST00000409792 NM_014159.6 ENST00000409792 NM_014159.6 No Yes 7 Yes SF3B1 23451 ENST00000335508 NM_012433.2 ENST00000335508 NM_012433.2 Yes No 7 Yes Yes Yes Yes Yes Yes Yes Hsh155, PRPF10, Prp10, SAP155, SF3b155 SMAD2 4087 ENST00000262160 NM_001003652.3 ENST00000262160 NM_001003652.3 No Yes 7 Yes Yes Yes Yes Yes Yes Yes JV18-1, MADH2, MADR2 SMAD4 4089 ENST00000342988 NM_005359.5 ENST00000342988 NM_005359.5 No Yes 7 Yes Yes Yes Yes Yes Yes Yes DPC4, MADH4 -SMARCA4 6597 ENST00000358026 NM_001128849.1 ENST00000646693 NM_001128849.1 No Yes 7 Yes Yes Yes Yes Yes Yes Yes BRG1, FLJ39786, SNF2-BETA, SNF2L4, hSNF2b +SMARCA4 6597 ENST00000358026 NM_001128849.1 ENST00000646693 NM_001128849.3 No Yes 7 Yes Yes Yes Yes Yes Yes Yes BRG1, FLJ39786, SNF2-BETA, SNF2L4, hSNF2b SMARCB1 6598 ENST00000263121 NM_003073.3 ENST00000618915 NM_003073.3 No Yes 7 Yes Yes Yes Yes Yes Yes Yes BAF47, Ini1, PPP1R144, RDT, SNF5, SNF5L1, Sfh1p, Snr1, hSNFS SMO 6608 ENST00000249373 NM_005631.4 ENST00000249373 NM_005631.4 Yes No 7 Yes Yes Yes Yes Yes Yes Yes FZD11, SMOH SOCS1 8651 ENST00000332029 NM_003745.1 ENST00000332029 NM_003745.1 No Yes 7 Yes Yes Yes Yes Yes Yes Yes Cish1, JAB, SOCS-1, SSI-1, TIP3 @@ -100,7 +100,7 @@ TSC1 7248 ENST00000298552 NM_000368.4 ENST00000298552 NM_000368.4 No Yes 7 Yes Y U2AF1 7307 ENST00000291552 NM_006758.2 ENST00000291552 NM_006758.2 Yes No 7 Yes Yes Yes Yes Yes Yes Yes RNU2AF1, U2AF35, U2AFBP VHL 7428 ENST00000256474 NM_000551.3 ENST00000256474 NM_000551.3 No Yes 7 Yes Yes Yes Yes Yes Yes Yes VHL1 WT1 7490 ENST00000332351 NM_024426.4 ENST00000452863 NM_024426.4 Yes Yes 7 Yes Yes Yes Yes Yes Yes Yes AWT1, GUD, NPHS4, WAGR, WIT-2 -AKT2 208 ENST00000392038 NM_001626.4 ENST00000392038 NM_001626.4 Yes No 6 Yes Yes Yes Yes Yes No Yes PKB? +AKT2 208 ENST00000392038 NM_001626.4 ENST00000392038 NM_001626.4 Yes No 6 Yes Yes Yes Yes Yes No Yes PKBβ ARID2 196528 ENST00000334344 NM_152641.2 ENST00000334344 NM_152641.2 No Yes 6 Yes Yes Yes No Yes Yes Yes BAF200, DKFZp686G052, FLJ30619, KIAA1557 ATR 545 ENST00000350721 NM_001184.3 ENST00000350721 NM_001184.3 No Yes 6 Yes Yes Yes Yes Yes No Yes FRP1, MEC1, SCKL, SCKL1 B2M 567 ENST00000558401 NM_004048.2 ENST00000559916 NM_004048.2 No Yes 6 Yes Yes Yes No Yes Yes Yes @@ -125,7 +125,7 @@ CDK6 1021 ENST00000265734 NM_001145306.1 ENST00000265734 NM_001145306.1 Yes No 6 CDKN1B 1027 ENST00000228872 NM_004064.3 ENST00000228872 NM_004064.3 No Yes 6 Yes Yes Yes Yes Yes No Yes KIP1, P27KIP1 CDKN2C 1031 ENST00000262662 NM_078626.2 ENST00000262662 NM_078626.2 No Yes 6 Yes Yes Yes Yes Yes No Yes INK4C CHEK2 11200 ENST00000328354 NM_007194.3 ENST00000404276 NM_007194.3 No Yes 6 Yes Yes Yes Yes Yes No Yes CHK2, HuCds1, PP1425, RAD53, bA444G7 -CRLF2 64109 ENST00000381566 NM_022148.2 ENST00000381566 NM_022148.2 Yes No 6 Yes Yes Yes No Yes Yes Yes CRL2, TSLPR +CRLF2 64109 ENST00000381566 NM_022148.2 ENST00000381566 NM_022148.4 Yes No 6 Yes Yes Yes No Yes Yes Yes CRL2, TSLPR CSF1R 1436 ENST00000286301 NM_005211.3 ENST00000286301 NM_005211.3 No No 6 Yes Yes Yes Yes Yes Yes No C-FMS, CD115, CSFR, FMS CSF3R 1441 ENST00000361632 NM_000760.3 ENST00000361632 NM_000760.3 Yes No 6 Yes Yes Yes Yes Yes No Yes CD114, GCSFR CTCF 10664 ENST00000264010 NM_006565.3 ENST00000264010 NM_006565.3 No Yes 6 Yes Yes Yes Yes Yes No Yes CFAP108, FAP108 @@ -143,11 +143,11 @@ FGFR4 2264 ENST00000292408 NM_213647.1 ENST00000292408 NM_213647.1 Yes No 6 Yes FLCN 201163 ENST00000285071 NM_144997.5 ENST00000285071 NM_144997.5 No Yes 6 Yes Yes Yes Yes Yes No Yes BHD, DENND8B, MGC17998, MGC23445 FUBP1 8880 ENST00000370768 NM_003902.3 ENST00000370768 NM_003902.3 No Yes 6 Yes Yes Yes Yes No Yes Yes FUBP GATA1 2623 ENST00000376670 NM_002049.3 ENST00000376670 NM_002049.3 No No 6 Yes Yes Yes No Yes Yes Yes ERYF1, GATA-1, GF1, NF-E1, NFE1 -GATA2 2624 ENST00000341105 NM_032638.4 ENST00000341105 NM_032638.4 Yes No 6 Yes Yes Yes No Yes Yes Yes NFE1B +GATA2 2624 ENST00000341105 NM_032638.4 ENST00000341105 NM_032638.4 Yes Yes 6 Yes Yes Yes No Yes Yes Yes NFE1B H3-3A 3020 ENST00000366813 NM_002107.4 ENST00000366815 NM_002107.4 Yes No 6 Yes Yes Yes Yes No Yes Yes H3.3A, H3F3, H3F3A H3C2 8358 ENST00000244661 NM_003537.3 ENST00000621411 NM_003537.3 No No 6 Yes Yes Yes No Yes Yes Yes H3/l, H3FL, HIST1H3B HGF 3082 ENST00000222390 NM_000601.4 ENST00000222390 NM_000601.4 Yes No 6 Yes Yes Yes Yes Yes No Yes DFNB39, F-TCF, HGFB, HPTA -IKZF1 10320 ENST00000331340 NM_006060.4 ENST00000331340 NM_006060.4 No No 6 Yes Yes Yes Yes Yes No Yes Hs.54452, IKAROS, LyF-1, PPP1R92, ZNFN1A1, hIk-1 +IKZF1 10320 ENST00000331340 NM_006060.4 ENST00000331340 NM_006060.6 No No 6 Yes Yes Yes Yes Yes No Yes Hs.54452, IKAROS, LyF-1, PPP1R92, ZNFN1A1, hIk-1 IRF4 3662 ENST00000380956 NM_002460.3 ENST00000380956 NM_002460.3 Yes No 6 Yes Yes Yes Yes Yes No Yes LSIRF, MUM1 JUN 3725 ENST00000371222 NM_002228.3 ENST00000371222 NM_002228.3 Yes No 6 Yes Yes Yes Yes Yes No Yes AP-1, c-Jun KDM5A 5927 ENST00000399788 NM_001042603.1 ENST00000399788 NM_001042603.1 Yes No 6 Yes Yes Yes Yes Yes No Yes JARID1A, RBBP2 @@ -160,7 +160,7 @@ MAP2K4 6416 ENST00000353533 NM_003010.3 ENST00000353533 NM_003010.3 No Yes 6 Yes MAPK1 5594 ENST00000215832 NM_002745.4 ENST00000215832 NM_002745.4 Yes No 6 Yes Yes Yes Yes Yes No Yes ERK2, MAPK2, PRKM1, PRKM2, p41mapk MDM2 4193 ENST00000462284 NM_002392.5 ENST00000258149 NM_002392.5 Yes No 6 Yes Yes Yes Yes Yes No Yes HDM2, MGC5370 MDM4 4194 ENST00000367182 NM_002393.4 ENST00000367182 NM_002393.4 Yes No 6 Yes Yes Yes Yes Yes No Yes HDMX, MDMX -MITF 4286 ENST00000394351 NM_000248.3 ENST00000394351 NM_000248.3 Yes Yes 6 Yes Yes Yes Yes Yes No Yes MI, WS2, WS2A, bHLHe32 +MITF 4286 ENST00000394351 NM_000248.3 ENST00000394351 NM_000248.4 Yes Yes 6 Yes Yes Yes Yes Yes No Yes MI, WS2, WS2A, bHLHe32 MTOR 2475 ENST00000361445 NM_004958.3 ENST00000361445 NM_004958.3 Yes No 6 Yes Yes Yes Yes Yes No Yes FLJ44809, FRAP, FRAP1, FRAP2, RAFT1, RAPT1 MUTYH 4595 ENST00000372115 NM_001048171.1 ENST00000372115 NM_001048171.1 No Yes 6 Yes Yes Yes Yes Yes No Yes MYH MYC 4609 ENST00000377970 NM_002467.4 ENST00000621592 NM_002467.4 Yes No 6 Yes Yes Yes Yes Yes No Yes MYCC, bHLHe39, c-Myc @@ -177,7 +177,7 @@ PDCD1LG2 80380 ENST00000397747 NM_025239.3 ENST00000397747 NM_025239.3 Yes No 6 PDGFRB 5159 ENST00000261799 NM_002609.3 ENST00000261799 NM_002609.3 Yes No 6 Yes Yes Yes Yes Yes No Yes CD140b, JTK12, PDGFR, PDGFR1 PHF6 84295 ENST00000332070 NM_001015877.1 ENST00000332070 NM_001015877.1 No Yes 6 Yes Yes Yes No Yes Yes Yes BFLS, BORJ, CENP-31, KIAA1823, MGC14797 PIM1 5292 ENST00000373509 NM_002648.3 ENST00000373509 NM_002648.3 No No 6 Yes Yes Yes Yes Yes No Yes PIM -PRKAR1A 5573 ENST00000358598 NM_212471.2 ENST00000358598 NM_212471.2 No No 6 Yes Yes Yes Yes Yes No Yes CNC1, PRKAR1, TSE1 +PRKAR1A 5573 ENST00000358598 NM_212471.2 ENST00000358598 NM_212471.2 No Yes 6 Yes Yes Yes Yes Yes No Yes CNC1, PRKAR1, TSE1 RAD21 5885 ENST00000297338 NM_006265.2 ENST00000297338 NM_006265.2 No Yes 6 Yes Yes Yes Yes Yes No Yes KIAA0078, SCC1, hHR21 RAF1 5894 ENST00000251849 NM_002880.3 ENST00000251849 NM_002880.3 Yes No 6 Yes Yes Yes Yes Yes No Yes CRAF, Raf-1, c-Raf RARA 5914 ENST00000254066 NM_000964.3 ENST00000254066 NM_000964.3 No No 6 Yes Yes Yes Yes Yes No Yes NR1B1 @@ -195,7 +195,7 @@ STAT3 6774 ENST00000264657 NM_139276.2 ENST00000264657 NM_139276.2 Yes No 6 Yes SUFU 51684 ENST00000369902 NM_016169.3 ENST00000369902 NM_016169.3 No Yes 6 Yes Yes Yes Yes Yes No Yes PRO1280, SUFUH, SUFUXL SYK 6850 ENST00000375746 NM_003177.5 ENST00000375746 NM_003177.5 Yes No 6 Yes Yes Yes Yes Yes No Yes TENT5C 54855 ENST00000369448 NM_017709.3 ENST00000369448 NM_017709.3 No Yes 6 Yes Yes Yes Yes Yes No Yes FAM46C, FLJ20202 -TGFBR2 7048 ENST00000295754 NM_003242.5 ENST00000295754 NM_003242.5 No Yes 6 Yes Yes Yes Yes Yes No Yes MFS2, TBR-ii, TBRII +TGFBR2 7048 ENST00000295754 NM_003242.5 ENST00000295754 NM_003242.6 No Yes 6 Yes Yes Yes Yes Yes No Yes MFS2, TBR-ii, TBRII TMPRSS2 7113 ENST00000398585 NM_001135099.1 ENST00000398585 NM_001135099.1 No No 6 Yes Yes Yes Yes Yes No Yes PRSS10 TNFRSF14 8764 ENST00000355716 NM_003820.2 ENST00000355716 NM_003820.2 No Yes 6 Yes Yes Yes Yes Yes No Yes ATAR, CD270, HVEA, HVEM, LIGHTR TSC2 7249 ENST00000219476 NM_000548.3 ENST00000219476 NM_000548.3 No Yes 6 Yes Yes Yes Yes Yes No Yes LAM, PPP1R160, TSC4, tuberin @@ -207,9 +207,9 @@ AURKA 6790 ENST00000312783 NM_003600.2 ENST00000312783 NM_003600.2 Yes No 5 Yes AURKB 9212 ENST00000585124 NM_004217.3 ENST00000585124 NM_004217.3 Yes No 5 Yes Yes Yes Yes Yes No No ARK2, Aik2, AurB, IPL1, PPP1R48, STK12, STK5 AXL 558 ENST00000301178 NM_021913.4 ENST00000301178 NM_021913.4 Yes No 5 Yes Yes Yes Yes Yes No No JTK11, Tyro7, UFO BCL10 8915 ENST00000370580 NM_003921.4 ENST00000648566 NM_003921.4 No Yes 5 Yes Yes Yes No Yes No Yes CIPER, CLAP, c-E10, mE10 -BCORL1 63035 ENST00000218147 ENST00000218147 No Yes 5 Yes No Yes Yes Yes No Yes CXorf10, FLJ11362 +BCORL1 63035 ENST00000218147 ENST00000218147 NM_021946.4 No Yes 5 Yes No Yes Yes Yes No Yes CXorf10, FLJ11362 BCR 613 ENST00000305877 NM_004327.3 ENST00000305877 NM_004327.3 Yes No 5 Yes No Yes Yes Yes No Yes ALL, BCR1, CML, D22S11, D22S662, PHL -BIRC3 330 ENST00000263464 NM_182962.2 ENST00000263464 NM_182962.2 No No 5 Yes Yes Yes No Yes No Yes API2, MALT2, MIHC, RNF49, c-IAP2, cIAP2, hiap-1 +BIRC3 330 ENST00000263464 NM_182962.2 ENST00000263464 NM_182962.2 Yes Yes 5 Yes Yes Yes No Yes No Yes API2, MALT2, MIHC, RNF49, c-IAP2, cIAP2, hiap-1 BLM 641 ENST00000355112 NM_000057.2 ENST00000355112 NM_000057.2 No Yes 5 Yes Yes Yes No Yes No Yes BS, RECQ2, RECQL3 BTG1 694 ENST00000256015 NM_001731.2 ENST00000256015 NM_001731.2 No Yes 5 Yes No Yes Yes Yes No Yes APRO2 CDK8 1024 ENST00000381527 NM_001260.1 ENST00000381527 NM_001260.1 Yes No 5 Yes Yes Yes Yes Yes No No K35 @@ -224,7 +224,7 @@ EPHA3 2042 ENST00000336596 NM_005233.5 ENST00000336596 NM_005233.5 No Yes 5 Yes EPHB1 2047 ENST00000398015 NM_004441.4 ENST00000398015 NM_004441.4 Yes Yes 5 Yes Yes Yes Yes Yes No No EPHT2, Hek6 ERCC4 2072 ENST00000311895 NM_005236.2 ENST00000311895 NM_005236.2 No Yes 5 Yes Yes Yes Yes No No Yes FANCQ, XPF ETV1 2115 ENST00000405192 NM_001163147.1 ENST00000405192 NM_001163147.1 Yes No 5 Yes Yes Yes No Yes No Yes ER81 -FAS 355 ENST00000355740 NM_000043.4 ENST00000652046 NM_000043.4 No Yes 5 Yes No Yes Yes Yes No Yes APO-1, APT1, CD95, FAS1, TNFRSF6 +FAS 355 ENST00000355740 NM_000043.4 ENST00000652046 NM_000043.6 No Yes 5 Yes No Yes Yes Yes No Yes APO-1, APT1, CD95, FAS1, TNFRSF6 FGF19 9965 ENST00000294312 NM_005117.2 ENST00000294312 NM_005117.2 Yes No 5 Yes Yes Yes Yes Yes No No FGF3 2248 ENST00000334134 NM_005247.2 ENST00000334134 NM_005247.2 Yes No 5 Yes Yes Yes Yes Yes No No HBGF-3, INT2 FGF4 2249 ENST00000168712 NM_002007.2 ENST00000168712 NM_002007.2 Yes No 5 Yes Yes Yes Yes Yes No No HBGF-4, HST, HST-1, HSTF1, K-FGF, KFGF @@ -293,7 +293,7 @@ BCL11B 64919 ENST00000357195 NM_138576.3 ENST00000357195 NM_138576.3 No Yes 4 Ye BCL2L1 598 ENST00000307677 NM_138578.1 ENST00000307677 NM_138578.1 No No 4 Yes Yes Yes Yes No No No BCL2L, BCLX, Bcl-X, PPP1R52, bcl-xL, bcl-xS BMPR1A 657 ENST00000372037 NM_004329.2 ENST00000372037 NM_004329.2 No Yes 4 Yes Yes Yes No No No Yes ACVRLK3, ALK3, CD292 CDKN1A 1026 ENST00000244741 NM_078467.2 ENST00000244741 NM_078467.2 No Yes 4 Yes Yes Yes Yes No No No CAP20, CDKN1, SDI1, WAF1, p21CIP1, p21Cip1/Waf1 -CIITA 4261 ENST00000324288 NM_001286402 ENST00000324288 NM_001286402 No Yes 4 Yes No Yes No Yes No Yes MHC2TA, NLRA +CIITA 4261 ENST00000324288 NM_001286402 ENST00000324288 NM_000246.3 No Yes 4 Yes No Yes No Yes No Yes MHC2TA, NLRA CUL3 8452 ENST00000264414 NM_003590.4 ENST00000264414 NM_003590.4 No Yes 4 Yes Yes Yes Yes No No No CUX1 1523 ENST00000292535 NM_181552.3 ENST00000292535 NM_181552.3 No Yes 4 Yes No Yes No Yes No Yes CDP, CDP/Cut, CDP/Cux, CDP1, CUT, CUTL1, CUX, Clox, Cux/CDP, GOLIM6 DDX3X 1654 ENST00000399959 NM_001356.4 ENST00000478993 NM_001356.4 No Yes 4 Yes No Yes No Yes No Yes DBX, DDX14, DDX3 @@ -307,7 +307,7 @@ EPHA5 2044 ENST00000273854 NM_004439.5 ENST00000273854 NM_004439.5 No No 4 Yes Y EPHA7 2045 ENST00000369303 NM_004440.3 ENST00000369303 NM_004440.3 Yes Yes 4 Yes Yes Yes No Yes No No Hek11 ERCC2 2068 ENST00000391945 NM_000400.3 ENST00000391945 NM_000400.3 No Yes 4 Yes Yes Yes No No No Yes EM9, MGC102762, MGC126218, MGC126219, XPD ERCC3 2071 ENST00000285398 NM_000122.1 ENST00000285398 NM_000122.1 No Yes 4 Yes Yes Yes No No No Yes RAD25, XPB -ERCC5 2073 ENST00000355739 NM_000123.3 ENST00000652225 NM_000123.3 No Yes 4 Yes Yes Yes No No No Yes ERCM2, XPGC +ERCC5 2073 ENST00000355739 NM_000123.3 ENST00000652225 NM_000123.4 No Yes 4 Yes Yes Yes No No No Yes ERCM2, XPGC ERRFI1 54206 ENST00000377482 NM_018948.3 ENST00000377482 NM_018948.3 No Yes 4 Yes Yes Yes Yes No No No GENE-33, MIG-6, RALT ETV4 2118 ENST00000319349 NM_001079675.2 ENST00000319349 NM_001079675.2 Yes No 4 Yes No No Yes Yes No Yes E1A-F, E1AF, PEA3 ETV5 2119 ENST00000306376 NM_004454.2 ENST00000306376 NM_004454.2 Yes No 4 Yes No No Yes Yes No Yes ERM @@ -354,7 +354,7 @@ RAD51C 5889 ENST00000337432 NM_058216.2 ENST00000337432 NM_058216.2 No Yes 4 Yes RAD51D 5892 ENST00000345365 NM_002878.3 ENST00000345365 NM_002878.3 No Yes 4 Yes Yes Yes Yes No No No HsTRAD, R51H3, RAD51L3, Trad RAD52 5893 ENST00000358495 NM_134424.2 ENST00000358495 NM_134424.2 No No 4 Yes Yes Yes Yes No No No RAD54L 8438 ENST00000371975 NM_001142548.1 ENST00000371975 NM_001142548.1 No No 4 Yes Yes Yes Yes No No No RAD54A, hHR54, hRAD54 -RECQL4 9401 ENST00000428558 NM_004260.3 ENST00000617875 NM_004260.3 No Yes 4 Yes Yes Yes No No No Yes RecQ4 +RECQL4 9401 ENST00000428558 NM_004260.3 ENST00000617875 NM_004260.4 No Yes 4 Yes Yes Yes No No No Yes RecQ4 RRAS2 22800 ENST00000256196 NM_012250.5 ENST00000256196 NM_012250.5 Yes No 4 Yes Yes Yes No No No Yes TC21 RUNX1T1 862 ENST00000265814 NM_001198626.1 ENST00000265814 NM_001198626.1 Yes No 4 Yes No Yes No Yes No Yes AML1T1, CBFA2T1, ETO, MTG8, ZMYND2 SDHAF2 54949 ENST00000301761 NM_017841.2 ENST00000301761 NM_017841.2 No Yes 4 Yes Yes Yes No No No Yes C11orf79, FLJ20487, PGL2, SDH5 @@ -374,17 +374,21 @@ XRCC2 7516 ENST00000359321 NM_005431.1 ENST00000359321 NM_005431.1 No Yes 4 Yes ZFHX3 463 ENST00000268489 NM_006885.3 ENST00000268489 NM_006885.3 No Yes 4 Yes Yes Yes No No No Yes ATBF1, C16orf47, FLJ26184, ZNF927 ABL2 27 ENST00000502732 NM_007314.3 ENST00000502732 NM_007314.3 Yes No 3 Yes No No No Yes No Yes ABLL ABRAXAS1 84142 ENST00000321945 NM_139076.2 ENST00000321945 NM_139076.2 No Yes 3 Yes Yes Yes No No No No ABRA1, ABRAXAS, CCDC98, FAM175A, FLJ13614 +AFDN 4301 ENST00000351017 ENST00000683244 NM_001386888.1 No Yes 3 Yes No No No Yes No Yes AF-6, AF6, MLLT4 AFF4 27125 ENST00000265343 NM_014423 ENST00000265343 NM_014423 Yes No 3 Yes No No No Yes No Yes AF5Q31, MCEF AGO2 27161 ENST00000220592 NM_012154.3 ENST00000220592 NM_012154.3 No No 3 Yes Yes Yes No No No No CASC7, EIF2C2, LINC00980, Q10, hAGO2 ANKRD11 29123 ENST00000301030 NM_013275.5 ENST00000301030 NM_013275.5 No Yes 3 Yes Yes Yes No No No No LZ16, T13 +ARHGAP26 23092 ENST00000274498 NM_015071 ENST00000274498 NM_015071 Yes Yes 3 Yes No No No Yes No Yes GRAF, KIAA0621, OPHN1L, OPHN1L1 ARHGAP35 2909 ENST00000404338 NM_004491.4 ENST00000404338 NM_004491.4 Yes Yes 3 Yes Yes No No No No Yes GRF-1, GRLF1, KIAA1722, P190A, p190ARhoGAP, p190RhoGAP ARHGEF12 23365 ENST00000397843 NM_015313 ENST00000397843 NM_015313 Yes Yes 3 Yes No No No Yes No Yes KIAA0382, LARG ARID5B 84159 ENST00000279873 NM_032199.2 ENST00000279873 NM_032199.2 No Yes 3 Yes Yes Yes No No No No FLJ21150, MRF2 ASXL2 55252 ENST00000435504 NM_018263.4 ENST00000435504 NM_018263.4 No Yes 3 Yes Yes Yes No No No No ASXH2, FLJ10898, KIAA1685 ATF1 466 ENST00000262053 NM_005171.4 ENST00000262053 NM_005171.4 Yes No 3 Yes No No No Yes No Yes TREB36 +ATIC 471 ENST00000236959 NM_004044 ENST00000236959 NM_004044 Yes No 3 Yes No No No Yes No Yes AICARFT, IMPCHASE, PURH BABAM1 29086 ENST00000359435 NM_001033549.1 ENST00000359435 NM_001033549.1 No No 3 Yes Yes Yes No No No No C19orf62, FLJ20571, HSPC142, MERIT40, NBA1 BBC3 27113 ENST00000449228 NM_001127240.2 ENST00000449228 NM_001127240.2 No Yes 3 Yes Yes Yes No No No No JFY1, PUMA BCL2L11 10018 ENST00000393256 NM_138621.4 ENST00000393256 NM_138621.4 No Yes 3 Yes Yes Yes No No No No BIM, BOD, BimEL, BimL, BimS +BCL2L2 599 ENST00000250405 NM_004050 ENST00000250405 NM_004050 Yes No 3 Yes No No Yes Yes No No BCL-W, KIAA0271, PPP1R51 BCL3 602 ENST00000164227 NM_005178 ENST00000164227 NM_005178 Yes No 3 Yes No No No Yes No Yes BCL4, D19S37 BCL7A 605 ENST00000261822 NM_001024808 ENST00000261822 NM_001024808 No Yes 3 Yes No No No Yes No Yes BCL7 BCL9 607 ENST00000234739 NM_004326.3 ENST00000234739 NM_004326.3 Yes No 3 Yes No No No Yes No Yes @@ -395,20 +399,21 @@ CCNQ 92002 ENST00000576892 NM_152274.4 ENST00000576892 NM_152274.4 No Yes 3 Yes CD22 933 ENST00000085219 NM_001771 ENST00000085219 NM_001771 No No 3 Yes No No Yes Yes No No SIGLEC-2, SIGLEC2 CD276 80381 ENST00000318443 NM_001024736.1 ENST00000318443 NM_001024736.1 Yes No 3 Yes Yes Yes No No No No B7-H3, B7H3, B7RP-2 CD58 965 ENST00000369489 NM_001779.2 ENST00000369489 NM_001779.2 No Yes 3 Yes No Yes No Yes No No LFA3 +CD70 970 ENST00000245903 NM_001252 ENST00000245903 NM_001252 Yes No 3 Yes No No Yes Yes No No CD27L, CD27LG, TNFSF7 CD74 972 ENST00000009530 NM_001025159 ENST00000009530 NM_001025159 Yes No 3 Yes No No Yes No No Yes DHLAG CDC42 998 ENST00000344548 NM_001791.3 ENST00000344548 NM_001791.3 Yes No 3 Yes Yes Yes No No No No CDC42Hs, G25K CENPA 1058 ENST00000335756 NM_001809.3 ENST00000335756 NM_001809.3 No No 3 Yes Yes Yes No No No No CENP-A, CenH3 CLTCL1 8218 ENST00000427926 NM_007098 ENST00000427926 NM_007098 No No 3 Yes No No No Yes No Yes CHC22, CLH22, CLTCL, CLTD -CNTRL 11064 ENST00000238341 NM_007018 ENST00000373855 NM_007018 No No 3 Yes No No No Yes No Yes CEP1, CEP110 +CNTRL 11064 ENST00000238341 NM_007018 ENST00000373855 NM_007018.6 No No 3 Yes No No No Yes No Yes CEP1, CEP110 COL1A1 1277 ENST00000225964 NM_000088 ENST00000225964 NM_000088 Yes No 3 Yes No No No Yes No Yes -COP1 64326 ENST00000367669 NM_022457.5 ENST00000367669 NM_022457.5 Yes No 3 Yes Yes Yes No No No No CFAP78, FAP78, FLJ10416, RFWD2, RNF200 +COP1 64326 ENST00000367669 NM_022457.5 ENST00000367669 NM_022457.5 Yes Yes 3 Yes Yes Yes No No No No CFAP78, FAP78, FLJ10416, RFWD2, RNF200 CSDE1 7812 ENST00000438362 NM_001242891.1 ENST00000438362 NM_001242891.1 No No 3 Yes Yes Yes No No No No D1S155E CTLA4 1493 ENST00000302823 NM_005214.4 ENST00000648405 NM_005214.4 Yes No 3 Yes Yes Yes No No No No CD152, CELIAC3, CTLA-4, GSE, IDDM12 CTNNA1 1495 ENST00000302763 NM_001903 ENST00000302763 NM_001903 No Yes 3 Yes No No Yes Yes No No CAP102 CYSLTR2 57105 ENST00000282018 NM_020377.2 ENST00000282018 NM_020377.2 Yes No 3 Yes Yes Yes No No No No CYSLT2R, CysLT(2) DCUN1D1 54165 ENST00000292782 NM_020640.2 ENST00000292782 NM_020640.2 Yes No 3 Yes Yes Yes No No No No DCUN1L1, RP42, SCCRO, SCRO, Tes3 DDIT3 1649 ENST00000346473 NM_001195057.1 ENST00000346473 NM_001195057.1 No No 3 Yes No No No Yes No Yes CHOP, CHOP10, GADD153 -DEK 7913 ENST00000397239 NM_003472.3 ENST00000652689 NM_003472.3 Yes No 3 Yes No No No Yes No Yes D6S231E +DEK 7913 ENST00000397239 NM_003472.3 ENST00000652689 NM_003472.4 Yes No 3 Yes No No No Yes No Yes D6S231E DNM2 1785 ENST00000355667 NM_001005360 ENST00000355667 NM_001005360 Yes No 3 Yes No No No Yes No Yes CMT2M, CMTDI1, CMTDIB, DI-CMTB, DYN2, DYNII DNMT3B 1789 ENST00000328111 NM_006892.3 ENST00000328111 NM_006892.3 No Yes 3 Yes Yes Yes No No No No DTX1 1840 ENST00000257600 NM_004416.2 ENST00000257600 NM_004416.2 No Yes 3 Yes No Yes No Yes No No RNF140, hDx-1 @@ -436,7 +441,7 @@ FGF10 2255 ENST00000264664 NM_004465 ENST00000264664 NM_004465 Yes No 3 Yes No N FGF14 2259 ENST00000376143 NM_004115 ENST00000376143 NM_004115 No Yes 3 Yes No No Yes Yes No No FHF4, SCA27 FGF23 8074 ENST00000237837 NM_020638 ENST00000237837 NM_020638 Yes No 3 Yes No No Yes Yes No No FGF6 2251 ENST00000228837 NM_020996 ENST00000228837 NM_020996 Yes No 3 Yes No No Yes Yes No No -FHIT 2272 ENST00000468189 NM_001166243 ENST00000492590 NM_001166243 No Yes 3 Yes No No No Yes No Yes FRA3B +FHIT 2272 ENST00000468189 NM_001166243 ENST00000492590 NM_002012 No Yes 3 Yes No No No Yes No Yes FRA3B FLI1 2313 ENST00000527786 NM_002017.4 ENST00000527786 NM_002017.4 Yes No 3 Yes No No No Yes No Yes SIC-1 FOXO3 2309 ENST00000343882 NM_001455 ENST00000343882 NM_001455 No No 3 Yes No No No Yes No Yes AF6q21, FKHRL1, FOXO2, FOXO3A FUS 2521 ENST00000254108 NM_004960 ENST00000254108 NM_004960 Yes No 3 Yes No No No Yes No Yes ALS6, HNRNPP2, TLS, hnRNP-P2 @@ -447,13 +452,13 @@ GPS2 2874 ENST00000380728 NM_004489.4 ENST00000380728 NM_004489.4 No Yes 3 Yes Y GREM1 26585 ENST00000300177 NM_013372.6 ENST00000300177 NM_013372.6 Yes No 3 Yes Yes Yes No No No No CKTSF1B1, CRAC1, DAND2, DRM, HMPS, gremlin H1-3 3007 ENST00000244534 NM_005320.2 ENST00000244534 NM_005320.2 No Yes 3 Yes No Yes No Yes No No H1.3, H1F3, H1d, H1s-2, HIST1H1D H1-4 3008 ENST00000304218 NM_005321.2 ENST00000304218 NM_005321.2 Yes No 3 Yes No Yes No Yes No No H1.4, H1F4, H1e, H1s-4, HIST1H1E -H2AC11 8969 ENST00000359193 NM_021064.4 ENST00000359193 NM_021064.4 No No 3 Yes No Yes No Yes No No H2A.1b, H2A/p, H2AFP, HIST1H2AG -H2AC16 8332 ENST00000357320 NM_003511 ENST00000613174 NM_003511 No No 3 Yes No Yes No Yes No No H2A/i, H2AFI, HIST1H2AL, dJ193B12.9 +H2AC11 8969 ENST00000359193 NM_021064.4 ENST00000359193 NM_021064.5 No No 3 Yes No Yes No Yes No No H2A.1b, H2A/p, H2AFP, HIST1H2AG +H2AC16 8332 ENST00000357320 NM_003511 ENST00000613174 NM_003511.3 No No 3 Yes No Yes No Yes No No H2A/i, H2AFI, HIST1H2AL, dJ193B12.9 H2AC17 8336 ENST00000359611 NM_003514 ENST00000359611 NM_003514 Yes No 3 Yes No Yes No Yes No No H2A.1, H2A/n, H2AFN, HIST1H2AM H2AC6 8334 ENST00000314088 NM_003512.3 ENST00000314088 NM_003512.3 No No 3 Yes No Yes No Yes No No H2AFL, HIST1H2AC H2BC11 8970 ENST00000339812 NM_021058.3 ENST00000339812 NM_021058.3 No No 3 Yes No Yes No Yes No No H2B/r, H2BFR, HIST1H2BJ H2BC12 85236 ENST00000356950 NM_080593.2 ENST00000356950 NM_080593.2 No No 3 Yes No Yes No Yes No No H2BFAiii, H2BFT, HIST1H2BK -H2BC17 8348 ENST00000616182 No No 3 Yes No Yes No Yes No No H2B.2, H2B/n, H2BFN, HIST1H2BO +H2BC17 8348 ENST00000616182 NM_003527.4 No No 3 Yes No Yes No Yes No No H2B.2, H2B/n, H2BFN, HIST1H2BO H2BC4 8347 ENST00000314332 NM_003518.3 ENST00000314332 NM_003518.3 No No 3 Yes No Yes No Yes No No H2B/l, H2BFL, HIST1H2BC H2BC5 3017 ENST00000289316 NM_021063.3 ENST00000289316 NM_021063.3 No No 3 Yes Yes Yes No No No No H2B/b, H2BFB, HIST1H2BD H3-4 8290 ENST00000366696 NM_003493.2 ENST00000366696 NM_003493.2 No No 3 Yes Yes Yes No No No No H3.4, H3/g, H3FT, H3t, HIST3H3 @@ -475,6 +480,7 @@ HIF1A 3091 ENST00000337138 NM_001530.3 ENST00000337138 NM_001530.3 Yes No 3 Yes HLA-B 3106 ENST00000412585 NM_005514.6 ENST00000412585 NM_005514.6 No Yes 3 Yes Yes Yes No No No No AS HMGA1 3159 ENST00000311487 NM_145899 ENST00000311487 NM_145899 Yes No 3 Yes No No No Yes No Yes HMGIY HMGA2 8091 ENST00000403681 NM_003483 ENST00000403681 NM_003483 Yes No 3 Yes No No No Yes No Yes BABL, HMGIC, LIPO +HOXA11 3207 ENST00000006015 NM_005523 ENST00000006015 NM_005523 No Yes 3 Yes No No No Yes No Yes HOX1, HOX1I HOXB13 10481 ENST00000290295 NM_006361.5 ENST00000290295 NM_006361.5 Yes Yes 3 Yes Yes Yes No No No No HSP90AA1 3320 ENST00000216281 NM_005348 ENST00000216281 NM_005348 Yes No 3 Yes No No No Yes No Yes FLJ31884, HSP90N, HSPC1, HSPCA, Hsp89, Hsp90 ICOSLG 23308 ENST00000407780 NM_015259.4 ENST00000407780 NM_015259.4 Yes No 3 Yes Yes Yes No No No No B7-H2, B7H2, B7RP-1, B7RP1, B7h, CD275, GL50, ICOS-L, ICOSL, KIAA0653 @@ -492,8 +498,8 @@ IRS1 3667 ENST00000305123 NM_005544.2 ENST00000305123 NM_005544.2 Yes No 3 Yes Y JARID2 3720 ENST00000341776 NM_004973.3 ENST00000341776 NM_004973.3 Yes Yes 3 Yes No Yes No Yes No No JMJ KAT6A 7994 ENST00000265713 NM_006766.4 ENST00000265713 NM_006766.4 No No 3 Yes No No No Yes No Yes MOZ, MYST3, RUNXBP2, ZC2HC6A, ZNF220 KLHL6 89857 ENST00000341319 NM_130446 ENST00000341319 NM_130446 Yes Yes 3 Yes No No Yes Yes No No FLJ00029 -KMT2B 9757 ENST00000222270 NM_014727.1 ENST00000420124 NM_014727.1 No Yes 3 Yes Yes Yes No No No No CXXC10, HRX2, KIAA0304, MLL1B, MLL4, TRX2, WBP7 -KMT5A 387893 ENST00000330479 NM_020382.3 ENST00000402868 NM_020382.3 No No 3 Yes Yes Yes No No No No PR-Set7, SET07, SET8, SETD8 +KMT2B 9757 ENST00000222270 NM_014727.1 ENST00000420124 NM_014727.3 No Yes 3 Yes Yes Yes No No No No CXXC10, HRX2, KIAA0304, MLL1B, MLL4, TRX2, WBP7 +KMT5A 387893 ENST00000330479 NM_020382.3 ENST00000402868 NM_020382.7 No No 3 Yes Yes Yes No No No No PR-Set7, SET07, SET8, SETD8 KNSTRN 90417 ENST00000249776 NM_033286.3 ENST00000249776 NM_033286.3 No No 3 Yes Yes Yes No No No No C15orf23, FLJ14502, SKAP, TRAF4AF1, kinastrin LCK 3932 ENST00000336890 NM_001042771.2 ENST00000336890 NM_001042771.2 Yes No 3 Yes No Yes No No No Yes LEF1 51176 ENST00000265165 NM_016269 ENST00000265165 NM_016269 Yes No 3 Yes No No No Yes No Yes TCF10, TCF1ALPHA, TCF7L3 @@ -508,6 +514,7 @@ MECOM 2122 ENST00000468789 NM_001105078.3 ENST00000468789 NM_001105078.3 Yes No MGA 23269 ENST00000219905 NM_001164273.1 ENST00000219905 NM_001164273.1 No Yes 3 Yes Yes Yes No No No No FLJ12634, KIAA0518, MAD5, MXD5 MLLT10 8028 ENST00000307729 NM_001195626.1 ENST00000307729 NM_001195626.1 Yes No 3 Yes No No No Yes No Yes AF10 MLLT3 4300 ENST00000380338 NM_004529 ENST00000380338 NM_004529 Yes No 3 Yes No No No Yes No Yes AF-9, AF9, YEATS3 +MN1 4330 ENST00000302326 NM_002430 ENST00000302326 NM_002430 Yes No 3 Yes No No No Yes No Yes MGCR, MGCR1, MGCR1-PEN MSI1 4440 ENST00000257552 NM_002442.3 ENST00000257552 NM_002442.3 Yes No 3 Yes Yes Yes No No No No MST1 4485 ENST00000449682 NM_020998.3 ENST00000449682 NM_020998.3 No Yes 3 Yes Yes Yes No No No No D3F15S2, DNF15S2, HGFL, NF15S2 MTAP 4507 ENST00000380172 NM_002451.3 ENST00000644715 NM_002451.3 No Yes 3 Yes Yes No Yes No No No MSAP, c86fus @@ -521,7 +528,7 @@ NR4A3 8013 ENST00000395097 NM_006981.3 ENST00000395097 NM_006981.3 Yes No 3 Yes NTHL1 4913 ENST00000219066 NM_002528.5 ENST00000219066 NM_002528.5 No Yes 3 Yes Yes Yes No No No No NTH1, OCTS3 NUF2 83540 ENST00000271452 NM_031423.3 ENST00000271452 NM_031423.3 Yes No 3 Yes Yes Yes No No No No CDCA1, CT106, NUF2R NUP214 8021 ENST00000359428 NM_005085 ENST00000359428 NM_005085 Yes No 3 Yes No No No Yes No Yes CAIN, CAN, D9S46E, N214 -NUP98 4928 ENST00000359171 XM_005252950.1 ENST00000355260 XM_005252950.1 Yes No 3 Yes No No No Yes No Yes NUP96, Nup98-96, Nup98-Nup96 +NUP98 4928 ENST00000359171 XM_005252950.1 ENST00000355260 NM_139132.4 Yes No 3 Yes No No No Yes No Yes NUP96, Nup98-96, Nup98-Nup96 NUTM1 256646 ENST00000333756 XM_011521429.1 ENST00000333756 XM_011521429.1 No No 3 Yes No No Yes No No Yes C15orf55, DKFZp434O192, FAM22H, NUT PAK1 5058 ENST00000356341 NM_002576.4 ENST00000356341 NM_002576.4 Yes No 3 Yes Yes Yes No No No No PAK5 57144 ENST00000353224 NM_177990.2 ENST00000353224 NM_177990.2 Yes No 3 Yes Yes Yes No No No No KIAA1264, PAK7 @@ -538,6 +545,7 @@ PIK3R3 8503 ENST00000262741 NM_003629.3 ENST00000262741 NM_003629.3 No Yes 3 Yes PLCG1 5335 ENST00000373271 NM_182811.1 ENST00000373271 NM_182811.1 Yes No 3 Yes No Yes No No No Yes NCKAP3, PLC-II, PLC1, PLC148, PLCgamma1 PLK2 10769 ENST00000274289 NM_006622.3 ENST00000274289 NM_006622.3 No No 3 Yes Yes Yes No No No No SNK PMAIP1 5366 ENST00000316660 NM_021127.2 ENST00000316660 NM_021127.2 No Yes 3 Yes Yes Yes No No No No NOXA +PML 5371 ENST00000268058 NM_033238 ENST00000268058 NM_033238 No Yes 3 Yes No No No Yes No Yes MYL, RNF71, TRIM19 PMS1 5378 ENST00000441310 NM_000534.4 ENST00000441310 NM_000534.4 No Yes 3 Yes Yes Yes No No No No MLH2, PMSL1 PNRC1 10957 ENST00000336032 NM_006813.2 ENST00000336032 NM_006813.2 No No 3 Yes Yes Yes No No No No B4-2, PROL2, PRR2 PPP4R2 151987 ENST00000356692 NM_174907.2 ENST00000356692 NM_174907.2 No No 3 Yes Yes Yes No No No No @@ -556,10 +564,10 @@ RECQL 5965 ENST00000421138 NM_002907.3 ENST00000421138 NM_002907.3 No Yes 3 Yes RHEB 6009 ENST00000262187 NM_005614.3 ENST00000262187 NM_005614.3 Yes No 3 Yes Yes Yes No No No No RHEB2 RIT1 6016 ENST00000368323 NM_006912.5 ENST00000368323 NM_006912.5 Yes No 3 Yes Yes Yes No No No No MGC125864, MGC125865, RIBB, RIT, ROC1 RPS6KA4 8986 ENST00000334205 NM_003942.2 ENST00000334205 NM_003942.2 Yes No 3 Yes Yes Yes No No No No MSK2, RSK-B -RPS6KB2 6199 ENST00000312629 NM_003952.2 ENST00000312629 NM_003952.2 Yes No 3 Yes Yes Yes No No No No KLS, P70-BETA, S6KB, S6Kbeta, S6K?, STK14B, p70S6Kb +RPS6KB2 6199 ENST00000312629 NM_003952.2 ENST00000312629 NM_003952.2 Yes No 3 Yes Yes Yes No No No No KLS, P70-BETA, S6KB, S6Kbeta, S6Kβ, STK14B, p70S6Kb RRAGC 64121 ENST00000373001 NM_022157.3 ENST00000373001 NM_022157.3 Yes No 3 Yes Yes Yes No No No No FLJ13311, GTR2 RRAS 6237 ENST00000246792 NM_006270.3 ENST00000246792 NM_006270.3 Yes No 3 Yes Yes Yes No No No No R-Ras -RTEL1 51750 ENST00000360203 NM_001283009.1 ENST00000360203 NM_001283009.1 No Yes 3 Yes Yes Yes No No No No C20orf41, DKFZP434C013, KIAA1088, NHL, RTEL, bK3184A7.3 +RTEL1 51750 ENST00000360203 NM_001283009.1 ENST00000360203 NM_001283009.2 No Yes 3 Yes Yes Yes No No No No C20orf41, DKFZP434C013, KIAA1088, NHL, RTEL, bK3184A7.3 RXRA 6256 ENST00000481739 NM_002957.4 ENST00000481739 NM_002957.4 No No 3 Yes Yes Yes No No No No NR2B1 RYBP 23429 ENST00000477973 NM_012234.5 ENST00000477973 NM_012234.5 No Yes 3 Yes Yes Yes No No No No AAP1, DEDAF, YEAF1 SESN1 27244 ENST00000436639 NM_014454.2 ENST00000436639 NM_014454.2 No Yes 3 Yes Yes Yes No No No No PA26, SEST1 @@ -590,6 +598,7 @@ TFE3 7030 ENST00000315869 NM_006521.5 ENST00000315869 NM_006521.5 Yes No 3 Yes N TGFBR1 7046 ENST00000374994 NM_004612.2 ENST00000374994 NM_004612.2 No Yes 3 Yes Yes Yes No No No No ALK-5, ALK5, ESS1, MSSE, TBR-i, TBRI TLX1 3195 ENST00000370196 NM_005521.3 ENST00000370196 NM_005521.3 Yes No 3 Yes No No No Yes No Yes HOX11, TCL3 TLX3 30012 ENST00000296921 NM_021025.2 ENST00000296921 NM_021025.2 Yes No 3 Yes No No No Yes No Yes HOX11L2, RNX +TNFRSF17 608 ENST00000053243 NM_001192 ENST00000053243 NM_001192 Yes No 3 Yes No No No Yes No Yes BCM, BCMA, CD269, TNFRSF13A TP53BP1 7158 ENST00000382044 NM_001141980.1 ENST00000382044 NM_001141980.1 No Yes 3 Yes Yes Yes No No No No 53BP1, TDRD30, p202 TRAF3 7187 ENST00000392745 NM_003300.3 ENST00000392745 NM_003300.3 No Yes 3 Yes No Yes No Yes No No CAP-1, CD40bp, CRAF1, LAP1, RNF118 TRAF5 7188 ENST00000261464 NM_001033910.2 ENST00000261464 NM_001033910.2 No Yes 3 Yes No Yes No Yes No No RNF84 @@ -597,6 +606,7 @@ TYK2 7297 ENST00000264818 NM_003331.4 ENST00000264818 NM_003331.4 Yes No 3 Yes N U2AF2 11338 ENST00000308924 NM_007279.2 ENST00000308924 NM_007279.2 No No 3 Yes No Yes No Yes No No U2AF65 UBR5 51366 ENST00000520539 NM_015902.5 ENST00000520539 NM_015902.5 Yes No 3 Yes No Yes No No No Yes DD5, EDD, EDD1, HYD, KIAA0896 UPF1 5976 ENST00000262803 NM_002911.3 ENST00000262803 NM_002911.3 No No 3 Yes Yes Yes No No No No HUPF1, KIAA0221, NORF1, RENT1, pNORF1, smg-2 +USP6 9098 ENST00000250066 NM_004505 ENST00000250066 NM_004505 Yes No 3 Yes No No No Yes No Yes HRP1, TRE17, TRESMCR, Tre-2, Tre2 USP8 9101 ENST00000307179 NM_001128610.2 ENST00000307179 NM_001128610.2 Yes No 3 Yes Yes No No No No Yes HumORF8, KIAA0055, SPG59, UBPY VTCN1 79679 ENST00000369458 NM_024626.3 ENST00000369458 NM_024626.3 No No 3 Yes Yes Yes No No No No B7-H4, B7H4, B7S1, B7x, FLJ22418 XBP1 7494 ENST00000216037 NM_005080.3 ENST00000216037 NM_005080.3 Yes No 3 Yes No Yes No Yes No No XBP2 @@ -607,13 +617,13 @@ ZNF217 7764 ENST00000302342 NM_006526 ENST00000302342 NM_006526 Yes No 3 Yes No ABI1 10006 No No 2 No No No No Yes No Yes ABI-1, E3B1, SSH3BP1 ACKR3 57007 ENST00000272928 NM_020311 ENST00000272928 NM_020311 Yes Yes 2 Yes No No No No No Yes CMKOR1, CXCR7, GPR159, RDC1 ACTG1 71 ENST00000331925 NM_001199954.1 ENST00000573283 NM_001199954.1 No Yes 2 Yes No Yes No No No No ACTG, DFNA20, DFNA26 -AFDN 4301 No No 2 No No No No Yes No Yes AF-6, AF6, MLLT4 +ACVR2A 92 ENST00000241416 NM_001278579 ENST00000241416 NM_001278579 Yes Yes 2 Yes No No No No No Yes ACTRII, ACVR2 +ADGRA2 25960 ENST00000412232 NM_032777 ENST00000412232 NM_032777 Yes No 2 Yes No No No Yes No No DKFZp434C211, DKFZp434J0911, FLJ14390, GPR124, KIAA1531, TEM5 AFF1 4299 No No 2 No No No No Yes No Yes AF-4, AF4, MLLT2, PBM1 AGO1 26523 ENST00000373204 NM_012199.2 ENST00000373204 NM_012199.2 Yes No 2 Yes Yes No No No No No EIF2C1, hAGO1 ALB 213 ENST00000295897 NM_000477.5 ENST00000295897 NM_000477.5 No No 2 Yes Yes No No No No No APLNR 187 ENST00000257254 NM_005161.4 ENST00000257254 NM_005161.4 Yes Yes 2 Yes Yes No No No No No AGTRL1, APJ, APJR, FLJ90771 ARFRP1 10139 No No 2 No No No Yes Yes No No ARL18, ARP, Arp1 -ARHGAP26 23092 No No 2 No No No No Yes No Yes GRAF, KIAA0621, OPHN1L, OPHN1L1 ARHGEF28 64283 ENST00000426542 NM_001177693.1 ENST00000426542 NM_001177693.1 Yes No 2 Yes No Yes No No No No RGNEF, RIP2, p190RhoGEF ARID3A 1820 ENST00000263620 NM_005224.2 ENST00000263620 NM_005224.2 No Yes 2 Yes No Yes No No No No BRIGHT, DRIL1 ARID3B 10620 ENST00000346246 NM_001307939.1 ENST00000346246 NM_001307939.1 Yes No 2 Yes No Yes No No No No BDP, DRIL2 @@ -622,7 +632,6 @@ ARID4A 5926 ENST00000355431 NM_002892.3 ENST00000355431 NM_002892.3 No Yes 2 Yes ARID4B 51742 ENST00000264183 NM_001206794.1 ENST00000264183 NM_001206794.1 No Yes 2 Yes No Yes No No No No BCAA, BRCAA1, RBP1L1, SAP180 ARID5A 10865 ENST00000357485 NM_212481.1 ENST00000357485 NM_212481.1 No No 2 Yes No Yes No No No No MRF-1, RP11-363D14 ARNT 405 No No 2 No No No No Yes No Yes HIF-1beta, bHLHe2 -ATIC 471 No No 2 No No No No Yes No Yes AICARFT, IMPCHASE, PURH ATP1A1 476 ENST00000295598 NM_000701 ENST00000295598 NM_000701 Yes Yes 2 Yes No No No No No Yes ATP6AP1 537 ENST00000369762 NM_001183.5 ENST00000369762 NM_001183.5 No No 2 Yes No Yes No No No No 16A, ATP6IP1, ATP6S1, Ac45, CF2, ORF, VATPS1, XAP-3, XAP3 ATP6V1B2 526 ENST00000276390 NM_001693.3 ENST00000276390 NM_001693.3 No Yes 2 Yes No Yes No No No No ATP6B2, HO57 @@ -630,16 +639,16 @@ ATXN2 6311 ENST00000377617 NM_002973.3 ENST00000550104 NM_002973.3 No Yes 2 Yes ATXN7 6314 ENST00000295900 NM_000333.3 ENST00000295900 NM_000333.3 Yes No 2 Yes Yes No No No No No ADCAII, OPCA3, SCA7, SGF73 BACH2 60468 ENST00000257749 NM_001170794.1 ENST00000257749 NM_001170794.1 No Yes 2 Yes No Yes No No No No BTBD25 BCL11A 53335 No No 2 No No No No Yes No Yes BCL11A-L, BCL11A-S, BCL11A-XL, CTIP1, EVI9, HBFQTL5, ZNF856 -BCL2L2 599 No No 2 No No No Yes Yes No No BCL-W, KIAA0271, PPP1R51 BRD3 8019 ENST00000303407 NM_007371 ENST00000303407 NM_007371 Yes No 2 Yes No No No No No Yes KIAA0043, ORFX, RING3L BRSK1 84446 ENST00000309383 NM_032430 ENST00000309383 NM_032430 No Yes 2 Yes No No No Yes No No KIAA1811 +BUB1B 701 ENST00000287598 NM_001211.5 ENST00000287598 NM_001211.6 Yes No 2 Yes No No No No No Yes BUBR1, Bub1A, MAD3L, SSK1 CACNA1D 776 ENST00000350061 NM_001128840 ENST00000350061 NM_001128840 Yes No 2 Yes No No No No No Yes CACH3, CACN4, CACNL1A2, CCHL1A2, Cav1.3 CAD 790 ENST00000264705 NM_001306079 ENST00000264705 NM_001306079 Yes No 2 Yes No No No Yes No No GATD4 CAMTA1 23261 No No 2 No No No No Yes No Yes KIAA0833 CANT1 124583 ENST00000302345 NM_001159772 ENST00000302345 NM_001159772 Yes No 2 Yes No No No No No Yes SCAN-1, SHAPY CARS1 833 No No 2 No No No No Yes No Yes CARS +CCN6 8838 ENST00000368666 NM_198239.1 ENST00000368666 NM_198239.1 Yes Yes 2 Yes No No No Yes No No WISP-3, WISP3 CD28 940 ENST00000324106 NM_006139.3 ENST00000324106 NM_006139.3 Yes No 2 Yes No Yes No No No No -CD70 970 No No 2 No No No Yes Yes No No CD27L, CD27LG, TNFSF7 CDH11 1009 ENST00000268603 NM_001797 ENST00000268603 NM_001797 Yes No 2 Yes No No No No No Yes CAD11 CDX2 1045 No No 2 No No No No Yes No Yes CDX3 CEP43 11116 No No 2 No No No No Yes No Yes FGFR1OP, FOP @@ -654,7 +663,8 @@ CREB3L1 90993 No No 2 No No No No Yes No Yes OASIS CREB3L2 64764 No No 2 No No No No Yes No Yes BBF2H7, TCAG_1951439 CTR9 9646 ENST00000361367 NM_014633.4 ENST00000361367 NM_014633.4 No Yes 2 Yes Yes No No No No No KIAA0155, SH2BP1, p150TSP CUL4A 8451 ENST00000375440 NM_001008895 ENST00000375440 NM_001008895 Yes No 2 Yes No No Yes No No No -CYP19A1 1588 ENST00000260433 NM_000103.3 ENST00000396402 NM_000103.3 Yes No 2 Yes Yes No No No No No ARO, ARO1, CPV1, CYAR, CYP19, P-450AROM, aromatase +CYP19A1 1588 ENST00000260433 NM_000103.3 ENST00000396402 NM_000103.4 Yes No 2 Yes Yes No No No No No ARO, ARO1, CPV1, CYAR, CYP19, P-450AROM, aromatase +DDB2 1643 ENST00000256996 NM_000107 ENST00000256996 NM_000107 No Yes 2 Yes No No No No No Yes DDBB, FLJ34321, UV-DDB2, XPE DDX10 1662 No No 2 No No No No Yes No Yes Dbp4, HRH-J8 DDX5 1655 ENST00000225792 NM_004396 ENST00000225792 NM_004396 Yes No 2 Yes No No No No No Yes G17P1, HLR1, p68 DDX6 1656 No No 2 No No No No Yes No Yes HLR2, Rck/p54 @@ -662,7 +672,7 @@ ECT2L 345930 ENST00000367682 NM_001077706.2 ENST00000367682 NM_001077706.2 No Ye EGR1 1958 ENST00000239938 NM_001964.2 ENST00000239938 NM_001964.2 No Yes 2 Yes No Yes No No No No AT225, G0S30, KROX-24, NGFI-A, TIS8, ZIF-268 EIF3E 3646 ENST00000220849 NM_001568 ENST00000220849 NM_001568 No No 2 Yes No No No No No Yes EIF3S6, INT6, eIF3-p48 ELK4 2005 ENST00000357992 NM_001973 ENST00000357992 NM_001973 Yes No 2 Yes No No No No No Yes -ELN 2006 ENST00000252034 NM_001278915 ENST00000252034 NM_001278915 Yes No 2 Yes No No No Yes No No SVAS, WBS, WS +ELN 2006 ENST00000252034 NM_001278915 ENST00000252034 NM_000501 Yes No 2 Yes No No No Yes No No SVAS, WBS, WS EML4 27436 No No 2 No No No No Yes No Yes C2orf2, ELP120, ROPP120 EP400 57634 ENST00000389561 NM_015409.3 ENST00000389561 NM_015409.3 No Yes 2 Yes No Yes No No No No CAGH32, DKFZP434I225, KIAA1498, KIAA1818, P400, TNRC12 EPHB4 2050 ENST00000358173 NM_004444 ENST00000358173 NM_004444 Yes No 2 Yes No No Yes No No No HTK, Tyro11 @@ -673,7 +683,7 @@ ESCO2 157570 ENST00000305188 NM_001017420.2 ENST00000305188 NM_001017420.2 No Ye ETAA1 54465 ENST00000272342 NM_019002.3 ENST00000272342 NM_019002.3 No Yes 2 Yes Yes No No No No No ETAA16 ETS1 2113 ENST00000319397 NM_005238 ENST00000319397 NM_005238 Yes Yes 2 Yes No No No Yes No No ETS-1, EWSR2, FLJ10768 EXT1 2131 ENST00000378204 NM_000127 ENST00000378204 NM_000127 No Yes 2 Yes No No No No No Yes LGCR, LGS, ttv -EZHIP 340602 ENST00000342995 NM_203407.2 ENST00000342995 NM_203407.2 Yes No 2 Yes Yes No No No No No CATACOMB, CXorf67 +EZHIP 340602 ENST00000342995 NM_203407.2 ENST00000342995 NM_203407.3 Yes No 2 Yes Yes No No No No No CATACOMB, CXorf67 EZR 7430 No No 2 No No No Yes No No Yes VIL2 FCGR2B 2213 No No 2 No No No No Yes No Yes CD32, CD32B, FCG2, FCGR2 FCRL4 83417 No No 2 No No No No Yes No Yes CD307d, FCRH4, IGFP2, IRTA1 @@ -690,11 +700,12 @@ GAS7 8522 No No 2 No No No No Yes No Yes KIAA0394, MGC1348 GATA4 2626 ENST00000335135 NM_002052 ENST00000335135 NM_002052 No Yes 2 Yes No No Yes No No No GATA6 2627 ENST00000269216 NM_005257 ENST00000269216 NM_005257 Yes No 2 Yes No No Yes No No No GID4 79018 No No 2 No No No Yes Yes No No C17orf39, VID24 +GPC3 2719 ENST00000370818 NM_004484 ENST00000370818 NM_004484 Yes No 2 Yes No No No No No Yes DGSX, OCI-5, SDYS, SGB, SGBS, SGBS1 GPHN 10243 No No 2 No No No No Yes No Yes KIAA1385 GRM3 2913 ENST00000361669 NM_000840 ENST00000361669 NM_000840 No No 2 Yes No No Yes No No No GPRC1C, MGLUR3, mGlu3 GTF2I 2969 ENST00000324896 NM_032999.3 ENST00000573035 NM_032999.3 Yes No 2 Yes No Yes No No No No BAP-135, BTKAP1, DIWS, IB291, TFII-I, WBSCR6 H1-5 3009 ENST00000331442 NM_005322.2 ENST00000331442 NM_005322.2 No Yes 2 Yes No Yes No No No No H1F5, H1b, H1s-3, HIST1H1B -H2BC8 8339 ENST00000244601 NM_003518 ENST00000541790 NM_003518 No No 2 Yes No Yes No No No No H2B.1A, H2B/a, H2BFA, HIST1H2BG +H2BC8 8339 ENST00000244601 NM_003518 ENST00000541790 NM_003518.3 No No 2 Yes No Yes No No No No H2B.1A, H2B/a, H2BFA, HIST1H2BG H4C9 8294 No No 2 No No No No Yes No Yes H4/m, H4FM, HIST1H4I HERPUD1 9709 No No 2 No No No No Yes No Yes HERP, KIAA0025, Mif1, SUP HEY1 23462 No No 2 No No No No Yes No Yes CHF-2, CHF2, HERP2, HESR-1, HESR1, HRT-1, bHLHb31 @@ -702,7 +713,6 @@ HIP1 3092 No No 2 No No No No Yes No Yes HIRA 7290 ENST00000263208 NM_003325 ENST00000263208 NM_003325 No Yes 2 Yes No Yes No No No No DGCR1, TUP1, TUPLE1 HLA-C 3107 ENST00000376228 NM_002117.5 ENST00000376228 NM_002117.5 No Yes 2 Yes Yes No No No No No D6S204, HLA-JY3, PSORS1 HLF 3131 No No 2 No No No No Yes No Yes MGC33822 -HOXA11 3207 No No 2 No No No No Yes No Yes HOX1, HOX1I HOXA13 3209 No No 2 No No No No Yes No Yes HOX1J HOXA9 3205 No No 2 No No No No Yes No Yes HOX1G HOXC11 3227 No No 2 No No No No Yes No Yes HOX3H @@ -724,8 +734,9 @@ KDSR 2531 No No 2 No No No No Yes No Yes DHSR, FVT1, SDR35C1 KEL 3792 ENST00000355265 NM_000420 ENST00000355265 NM_000420 Yes No 2 Yes No No Yes No No No CD238, ECE3 KIF5B 3799 No No 2 No No No No Yes No Yes KNS, KNS1 KLF5 688 ENST00000377687 NM_001730.4 ENST00000377687 NM_001730.4 Yes No 2 Yes Yes No No No No No BTEB2, IKLF -KSR2 283455 ENST00000339824 ENST00000339824 Yes No 2 Yes No Yes No No No No FLJ25965 +KSR2 283455 ENST00000339824 ENST00000339824 NM_173598.6 Yes No 2 Yes No Yes No No No No FLJ25965 LASP1 3927 No No 2 No No No No Yes No Yes Lasp-1, MLN50 +LMNA 4000 ENST00000368300 NM_170707 ENST00000368300 NM_170707 Yes No 2 Yes No No No No No Yes CMD1A, HGPS, LGMD1B, LMN1, LMNL1, PRO1 LPP 4026 No No 2 No No No No Yes No Yes LTB 4050 ENST00000376117 NM_002341.1 ENST00000376117 NM_002341.1 Yes Yes 2 Yes No Yes No No No No TNFC, TNFSF3 LTK 4058 ENST00000263800 NM_002344 ENST00000263800 NM_002344 Yes No 2 Yes No No Yes No No No TYK1 @@ -738,13 +749,13 @@ MGAM 8972 ENST00000549489 NM_004668.2 ENST00000549489 NM_004668.2 Yes No 2 Yes N MKI67 4288 ENST00000368654 NM_002417 ENST00000368654 NM_002417 Yes No 2 Yes No No No Yes No No MIB-1, PPP1R105 MLF1 4291 No No 2 No No No No Yes No Yes MLLT6 4302 No No 2 No No No No Yes No Yes AF17, FLJ23480 -MN1 4330 No No 2 No No No No Yes No Yes MGCR, MGCR1, MGCR1-PEN MOB3B 79817 ENST00000262244 NM_024761.4 ENST00000262244 NM_024761.4 No Yes 2 Yes No Yes No No No No C9orf35, FLJ13204, MOB1D, MOBKL2B MPEG1 219972 ENST00000361050 NM_001039396.1 ENST00000361050 NM_001039396.1 No No 2 Yes No Yes No No No No MPG1 MRTFA 57591 No No 2 No No No No Yes No Yes BSAC, KIAA1438, MKL, MKL1, MRTF-A MSN 4478 No No 2 No No No No Yes No Yes MUC1 4582 No No 2 No No No No Yes No Yes ADMCKD, ADMCKD1, CD227, MCD, MCKD, MCKD1, PEM, PUM MYH9 4627 No No 2 No No No No Yes No Yes DFNA17, EPSTS, FTNS, MHA, NMHC-II-A, NMMHCA +MYO5A 4644 ENST00000399231 NM_000259 ENST00000399231 NM_000259 Yes No 2 Yes No No No No No Yes MYH12, MYO5, MYR12 NADK 65220 ENST00000341426 NM_001198993.1 ENST00000341426 NM_001198993.1 Yes No 2 Yes Yes No No No No No FLJ13052 NCOA2 10499 No No 2 No No No No Yes No Yes KAT13C, NCoA-2, TIF2, bHLHe75 NDRG1 10397 No No 2 No No No No Yes No Yes CAP43, NDR1, RTP, TDD5 @@ -765,12 +776,12 @@ PICALM 8301 No No 2 No No No No Yes No Yes CLTH PIGA 5277 ENST00000333590 NM_002641.3 ENST00000333590 NM_002641.3 No Yes 2 Yes No Yes No No No No GPI3 PIK3C2B 5287 ENST00000367187 NM_002646 ENST00000367187 NM_002646 Yes No 2 Yes No No Yes No No No C2-PI3K, PI3K-C2beta PLAG1 5324 No No 2 No No No No Yes No Yes ZNF912 -PML 5371 No No 2 No No No No Yes No Yes MYL, RNF71, TRIM19 POU2AF1 5450 No No 2 No No No No Yes No Yes BOB1, OBF1 PPP2R2A 5520 ENST00000380737 NM_002717.3 ENST00000380737 NM_002717.3 No Yes 2 Yes No No Yes No No No B55A, B55alpha, PR52A, PR55A, PR55alpha +PRCC 5546 ENST00000271526 NM_005973 ENST00000271526 NM_005973 Yes No 2 Yes No No No No No Yes RCCP1 PRDM16 63976 No No 2 No No No No Yes No Yes KIAA1675, KMT8F, MEL1, MGC166915, PFM13 PRKACA 5566 ENST00000308677 NM_002730.3 ENST00000308677 NM_002730.3 Yes No 2 Yes No No No No No Yes PKACa -PRKDC 5591 ENST00000314191 NM_006904 NM_006904 Yes Yes 2 Yes No No No Yes No No DNA-PKC, DNA-PKcs, DNAPK, DNAPKc, DNPK1, HYRC, HYRC1, XRCC7, p350, p460 +PRKDC 5591 ENST00000314191 NM_006904.6 ENST00000314191 NM_006904.7 Yes Yes 2 Yes No No No Yes No No DNA-PKC, DNA-PKcs, DNAPK, DNAPKc, DNPK1, HYRC, HYRC1, XRCC7, p350, p460 PRRX1 5396 No No 2 No No No No Yes No Yes PHOX1, PMX1 PSIP1 11168 No No 2 No No No No Yes No Yes DFS70, LEDGF, PSIP2 PTPN1 5770 ENST00000371621 NM_001278618.1 ENST00000371621 NM_001278618.1 Yes Yes 2 Yes No Yes No No No No PTP1B @@ -804,6 +815,7 @@ SETDB2 83852 ENST00000354234 NM_031915.2 ENST00000317257 NM_031915.2 No Yes 2 Ye SH3GL1 6455 No No 2 No No No No Yes No Yes CNSA1, EEN, MGC111371, SH3D2B, SH3P8 SLC34A2 10568 No No 2 No No No Yes No No Yes NAPI-3B SLFN11 91607 ENST00000308377 NM_001104587.1 ENST00000308377 NM_001104587.1 No Yes 2 Yes Yes No No No No No FLJ34922 +SMARCA1 6594 ENST00000371122 NM_003069 ENST00000371122 NM_003069 Yes Yes 2 Yes No No No Yes No No ISWI, NURF140, SNF2L, SNF2L1, SNF2LB, SWI, hSNF2L SMARCA2 6595 ENST00000349721 NM_001289396.1 ENST00000349721 NM_001289396.1 No Yes 2 Yes Yes No No No No No BAF190, BRM, SNF2, SNF2L2, SNF2LA, SWI2, Sth1p, hBRM, hSNF2a SMG1 23049 ENST00000446231 NM_015092.4 ENST00000446231 NM_015092.4 No Yes 2 Yes No Yes No No No No KIAA0421, LIP SOCS3 9021 ENST00000330871 NM_003955.4 ENST00000330871 NM_003955.4 No Yes 2 Yes No No No Yes No No CIS3, Cish3, SOCS-3, SSI-3 @@ -816,12 +828,11 @@ SSX2 6757 No No 2 No No No No Yes No Yes CT5.2a, HD21, HOM-MEL-40, MGC119055 SSX4 6759 No No 2 No No No No Yes No Yes CT5.4 STAG1 10274 ENST00000383202 NM_005862.2 ENST00000383202 NM_005862.2 No Yes 2 Yes No Yes No No No No SA-1, SA1, SCC3A STAT4 6775 ENST00000358470 NM_001243835 ENST00000358470 NM_001243835 Yes No 2 Yes No No No Yes No No -TAF1 6872 ENST00000373790 NM_138923 NM_138923 Yes No 2 Yes No No No Yes No No BA2R, CCG1, CCGS, DYT3, DYT3/TAF1, KAT4, NSCL2, TAFII250 +TAF1 6872 ENST00000423759 NM_001286074.1 ENST00000423759 NM_004606.5 Yes No 2 Yes No No No Yes No No BA2R, CCG1, CCGS, DYT3, DYT3/TAF1, KAT4, NSCL2, TAFII250 TAF15 8148 No No 2 No No No No Yes No Yes Npl3, RBP56, TAF2N, hTAFII68 TAL2 6887 No No 2 No No No No Yes No Yes bHLHa19 TET3 200424 ENST00000409262 NM_144993 ENST00000409262 NM_144993 No Yes 2 Yes No Yes No No No No MGC22014, hCG_40738 TFG 10342 No No 2 No No No No Yes No Yes FLJ36137, SPG57, TF6 -TNFRSF17 608 No No 2 No No No No Yes No Yes BCM, BCMA, CD269, TNFRSF13A TPM3 7170 No No 2 No No No No Yes No Yes NEM1, TRK TPM4 7171 No No 2 No No No No Yes No Yes TRA 6955 Yes No 2 Yes No No No No No Yes TCRA, TRA@ @@ -832,10 +843,11 @@ TRIM24 8805 No No 2 No No No No Yes No Yes RNF82, TIF1, TIF1A, Tif1a, hTIF1 TRIM27 5987 ENST00000377199 NM_006510 ENST00000377199 NM_006510 Yes No 2 Yes No No No No No Yes RFP, RNF76 TRIP11 9321 No No 2 No No No No Yes No Yes CEV14, GMAP-210, GMAP210, Trip230 TRIP13 9319 ENST00000166345 NM_004237.3 ENST00000166345 NM_004237.3 Yes Yes 2 Yes Yes No No No No No 16E1BP -USP6 9098 No No 2 No No No No Yes No Yes HRP1, TRE17, TRESMCR, Tre-2, Tre2 VAV1 7409 ENST00000602142 NM_005428.3 ENST00000602142 NM_005428.3 Yes No 2 Yes No Yes No No No No VAV VAV2 7410 ENST00000371850 NM_001134398.1 ENST00000371850 NM_001134398.1 Yes No 2 Yes No Yes No No No No WIF1 11197 ENST00000286574 NM_007191.4 ENST00000286574 NM_007191.4 No Yes 2 Yes No No No No No Yes +WRN 7486 ENST00000298139 NM_000553 ENST00000298139 NM_000553 No Yes 2 Yes No No No No No Yes RECQ3, RECQL2 +XPA 7507 ENST00000375128 NM_000380 ENST00000375128 NM_000380 No Yes 2 Yes No No No No No Yes XP1, XPAC XPC 7508 ENST00000285021 NM_004628 ENST00000285021 NM_004628 No Yes 2 Yes No No No No No Yes RAD4, XPCC ZBTB16 7704 No No 2 No No No No Yes No Yes PLZF, ZNF145 ZBTB7A 51341 ENST00000322357 NM_015898 ENST00000322357 NM_015898 Yes Yes 2 Yes No Yes No No No No DKFZp547O146, FBI-1, LRF, ZBTB7, ZNF857A, pokemon @@ -845,16 +857,20 @@ ZNF384 171017 No No 2 No No No No Yes No Yes CAGH1A, CIZ, NMP4, TNRC1 ZNF521 25925 No No 2 No No No No Yes No Yes EHZF, Evi3 ZNF703 80139 No No 2 No No No Yes Yes No No FLJ14299, NLZ1, ZEPPO1, ZNF503L, Zpo1 ZNRF3 84133 ENST00000544604 NM_001206998.1 ENST00000544604 NM_001206998.1 No Yes 2 Yes Yes No No No No No BK747E2.3, FLJ22057, KIAA1133, RNF203 +ABCB1 5243 ENST00000265724 NM_000927.4 ENST00000622132 NM_001348946.2 Yes No 1 Yes No No No No No No ABC20, CD243, CLCS, GP170, MDR1, P-gp, PGY1, p-170 ACSL3 2181 No No 1 No No No No No No Yes FACL3, PRO2194 ACSL6 23305 No No 1 No No No No Yes No No FACL6, KIAA0837, LACS5 ACTB 60 No No 1 No No No No Yes No No -ACVR2A 92 No No 1 No No No No No No Yes ACTRII, ACVR2 -ADGRA2 25960 No No 1 No No No No Yes No No DKFZp434C211, DKFZp434J0911, FLJ14390, GPR124, KIAA1531, TEM5 +ADARB2 105 ENST00000381312 NM_018702.3 ENST00000381312 NM_018702.4 Yes No 1 Yes No No No No No No ADAR3, RED2, hRED2 +ADGRG4 139378 ENST00000394143 NM_153834.3 ENST00000394143 NM_153834.4 No No 1 Yes No No No No No No GPR112, PGR17, RP1-299I16 ADHFE1 137872 ENST00000396623 NM_144650 ENST00000396623 NM_144650 Yes No 1 Yes No No No No No No FLJ32430 AFF3 3899 No No 1 No No No No No No Yes LAF4, MLLT2-like +AGGF1 55109 ENST00000312916 NM_018046.4 ENST00000312916 NM_018046.5 Yes No 1 Yes No No No No No No FLJ10283, GPATC7, GPATCH7, HSU84971, VG5Q +AIP 9049 ENST00000279146 NM_003977.2 ENST00000279146 NM_003977.4 Yes Yes 1 Yes No No No No No No ARA9, FKBP16, FKBP37, XAP2 AJUBA 84962 ENST00000262713 NM_032876.5 ENST00000262713 NM_032876.5 No Yes 1 Yes No No No No No No JUB, MGC15563 ALDH1L2 160428 ENST00000258494 NM_001034173 ENST00000258494 NM_001034173 Yes No 1 Yes No No No No No No FLJ38508, mtFDH ALDH2 217 ENST00000261733 NM_000690 ENST00000261733 NM_000690 No Yes 1 Yes No No No No No No +ANKRD26 22852 ENST00000376087 NM_001256053 ENST00000376087 NM_001256053 Yes No 1 Yes No No No No No No KIAA1074, THC2 APH1A 51107 No No 1 No No No No Yes No No APH-1A, CGI-78 APOBEC3B 9582 No No 1 No No No No No No Yes FLJ21201, PHRBNL ASMTL 8623 No No 1 No No No No Yes No No @@ -866,11 +882,10 @@ BAALC 79870 ENST00000297574 null ENST00000297574 null Yes No 1 Yes No No No No N BAX 581 No No 1 No No No No No No Yes BCL2L4 BCL9L 283149 No No 1 No No No No No No Yes B9L, Bcl9-2, DLNB11 BTLA 151888 No No 1 No No No No Yes No No BTLA1, CD272 -BUB1B 701 No No 1 No No No No No No Yes BUBR1, Bub1A, MAD3L, SSK1 +CASR 846 ENST00000490131 NM_000388.3 ENST00000639785 NM_000388.4 Yes Yes 1 Yes No No No No No No FHH, GPRC2A, HHC, HHC1, NSHPT CBLB 868 No No 1 No No No No No No Yes Cbl-b, RNF56 CBLC 23624 No No 1 No No No No No No Yes CBL-3, CBL-SL, RNF57 CCDC6 8030 No No 1 No No No No No No Yes D10S170, H4, TPC, TST1 -CCN6 8838 No No 1 No No No No Yes No No WISP-3, WISP3 CCNB1IP1 57820 No No 1 No No No No No No Yes C14orf18, HEI10 CCNB3 85417 ENST00000276014 NM_033031.2 ENST00000276014 NM_033031.2 Yes No 1 Yes No No No No No No CCT6B 10693 No No 1 No No No No Yes No No Cctz2, TSA303 @@ -878,6 +893,7 @@ CD19 930 ENST00000324662 NM_001770 ENST00000538922 NM_001770 Yes No 1 Yes No No CD36 948 No No 1 No No No No Yes No No GP3B, GP4, GPIV, SCARB3 CDH2 1000 ENST00000269141 NM_001792 ENST00000269141 NM_001792 Yes No 1 Yes No No No No No No CD325, CDHN, NCAD CDH4 1002 ENST00000360469 NM_001794 ENST00000614565 NM_001794 Yes No 1 Yes No No No No No No +CDKN1C 1028 ENST00000440480 NM_001122630.2 ENST00000440480 NM_001122630.2 No Yes 1 Yes No No No No No No BWCR, BWS, P57 CHCHD7 79145 No No 1 No No No No No No Yes COX23, MGC2217 CHIC2 26511 No No 1 No No No No Yes No No BTL CHN1 1123 No No 1 No No No No Yes No No ARHGAP2, CHN, DURS2, n-chimerin @@ -892,13 +908,13 @@ CPS1 1373 No No 1 No No No No Yes No No CRTC1 23373 No No 1 No No No No No No Yes FLJ14027, KIAA0616, MECT1, TORC1 CRTC3 64784 No No 1 No No No No No No Yes FLJ21868 CSF1 1435 No No 1 No No No No Yes No No M-CSF, MCSF, MGC31930 +CTDNEP1 23399 ENST00000318988 NM_015343.4 ENST00000574322 NM_001143775.2 No Yes 1 Yes No No No No No No DULLARD, HSA011916, NET56 CYP17A1 1586 No No 1 No No No Yes No No No CPT7, CYP17, P450C17, S17AH DAZAP1 26528 ENST00000233078 NM_018959.3 ENST00000233078 NM_018959.3 No No 1 Yes No No No No No No MGC19907 DCTN1 1639 No No 1 No No No No No No Yes -DDB2 1643 No No 1 No No No No No No Yes DDBB, FLJ34321, UV-DDB2, XPE DDR1 780 No No 1 No No No Yes No No No CAK, CD167, EDDR1, NEP, NTRK4, PTK3A, RTK6 DDX4 54514 ENST00000505374 NM_024415.2 ENST00000505374 NM_024415.2 Yes No 1 Yes No No No No No No VASA -DDX41 51428 ENST00000507955 NM_016222.2 ENST00000330503 NM_016222.2 No Yes 1 Yes No No No No No No ABS, MGC8828 +DDX41 51428 ENST00000507955 NM_016222.2 ENST00000330503 NM_016222.4 No Yes 1 Yes No No No No No No ABS, MGC8828 DKK1 22943 ENST00000373970 NM_012242.2 ENST00000373970 NM_012242.2 No No 1 Yes No No No No No No DKK-1, SK DKK2 27123 ENST00000285311 NM_014421.2 ENST00000285311 NM_014421.2 No No 1 Yes No No No No No No DKK3 27122 ENST00000326932 NM_001018057.1 ENST00000326932 NM_001018057.1 No No 1 Yes No No No No No No REIC @@ -907,34 +923,47 @@ DPYD 1806 ENST00000370192 NM_000110 ENST00000370192 NM_000110 No No 1 Yes No No DUSP2 1844 No No 1 No No No No Yes No No PAC-1 DUSP9 1852 No No 1 No No No No Yes No No MKP-4, MKP4 ECSIT 51295 ENST00000270517 NM_016581 ENST00000270517 NM_016581 Yes No 1 Yes No No No No No No SITPEC +EGR2 1959 ENST00000242480 NM_001136177.1 ENST00000242480 NM_000399.5 No Yes 1 Yes No No No No No No KROX20 EIF2B1 1967 ENST00000424014 NM_001414 ENST00000424014 NM_001414 No Yes 1 Yes No No No No No No EIF-2B, EIF-2Balpha, EIF2B, EIF2BA +ELL2 22936 ENST00000237853 NM_012081.5 ENST00000237853 NM_012081.6 Yes Yes 1 Yes No No No No No No MRCCAT1 ELP2 55250 No No 1 No No No No Yes No No FLJ10879, STATIP1, StIP +ERCC1 2067 ENST00000300853 NM_001983 ENST00000300853 NM_001983 No Yes 1 Yes No No No No No No RAD10 EXOSC6 118460 No No 1 No No No No Yes No No EAP4, MTR3, Mtr3p, hMtr3p, p11 EXT2 2132 No No 1 No No No No No No Yes SOTV FAF1 11124 No No 1 No No No No Yes No No CGI-03, HFAF1s, UBXD12, UBXN3A, hFAF1 +FANCI 55215 ENST00000310775 NM_001113378.1 ENST00000310775 NM_001113378.2 No No 1 Yes No No No No No No FLJ10719, KIAA1794 FANCM 57697 ENST00000267430 NM_020937 ENST00000267430 NM_020937 No Yes 1 Yes No No No No No No FAAP250, KIAA1596 FAT4 79633 No No 1 No No No No No No Yes CDHF14, CDHR11, FAT-J FBXO31 79791 No No 1 No No No No Yes No No FBXW2 26190 ENST00000608872 NM_012164 ENST00000608872 NM_012164 No No 1 Yes No No No No No No FBW2, Fwd2, Md6 +FGF1 2246 ENST00000337706 NM_000800 ENST00000337706 NM_000800 Yes No 1 Yes No No No No No No AFGF, ECGF, ECGF-beta, ECGFA, ECGFB, FGF-alpha, FGFA, GLIO703, HBGF1 FGF12 2257 No No 1 No No No Yes No No No FGF12B, FHF1 +FGF2 2247 ENST00000608478 ENST00000644866 NM_001361665.2 Yes No 1 Yes No No No No No No FGFB +FGF5 2250 ENST00000312465 NM_004464 ENST00000312465 NM_004464 Yes No 1 Yes No No No No No No +FGF7 2252 ENST00000267843 NM_002009 ENST00000267843 NM_002009 Yes No 1 Yes No No No No No No KGF +FGF8 2253 ENST00000344255 NM_033164 ENST00000344255 NM_033164 Yes No 1 Yes No No No No No No AIGF +FGF9 2254 ENST00000382353 NM_002010 ENST00000382353 NM_002010 Yes No 1 Yes No No No No No No FIP1L1 81608 No No 1 No No No No No No Yes DKFZp586K0717, FIP1 FLYWCH1 84256 No No 1 No No No No Yes No No DKFZp761A132 FNBP1 23048 No No 1 No No No No Yes No No FBP17, KIAA0554 FOLH1 2346 ENST00000256999 NM_004476 ENST00000256999 NM_004476 Yes No 1 Yes No No No No No No FOLH, GCPII, NAALAD1, NAALAdase, PSM, PSMA +FOLR1 2348 ENST00000312293 NM_000802 ENST00000312293 NM_000802 Yes No 1 Yes No No No No No No FOLR, FRα FOXN4 121643 ENST00000299162 NM_213596 ENST00000299162 NM_213596 Yes No 1 Yes No No No No No No FSTL1 11167 ENST00000295633 NM_007085 ENST00000295633 NM_007085 Yes No 1 Yes No No No No No No FRP, FSL1, OCC-1, OCC1, tsc36 FZR1 51343 ENST00000395095 NM_001136198 ENST00000395095 NM_001136198 Yes Yes 1 Yes No No No No No No CDC20C, FZR, FZR2, HCDH, HCDH1, KIAA1242 GADD45B 4616 No No 1 No No No No Yes No No DKFZP566B133, GADD45BETA, MYD118 +GEN1 348654 ENST00000381254 NM_001130009.1 ENST00000381254 NM_001130009.3 No No 1 Yes No No No No No No FLJ40869, Gen GMPS 8833 No No 1 No No No No Yes No No GATD7 GOLGA5 9950 No No 1 No No No No No No Yes GOLIM5, golgin-84, ret-II, rfg5 GOPC 57120 No No 1 No No No No No No Yes CAL, GOPC1, PIST, dJ94G16.2 -GPC3 2719 No No 1 No No No No No No Yes DGSX, OCI-5, SDYS, SGB, SGBS, SGBS1 +GRB7 2886 ENST00000309156 NM_001030002 ENST00000309156 NM_001030002 Yes No 1 Yes No No No No No No GTSE1 51512 No No 1 No No No No Yes No No B99, GTSE-1 H3C15 333932 ENST00000403683 NM_001005464.2 ENST00000403683 NM_001005464.2 No No 1 Yes No No No No No No H3/n, H3/o, HIST2H3A -H3P6 440926 ENST00000316450 null ENST00000369387 null No No 1 Yes No No No No No No H3F3AP4 -H4C6 8361 ENST00000244537 No No 1 Yes No No No No No No H4/c, H4FC, HIST1H4F +H3P6 440926 ENST00000316450 null ENST00000369387 No No 1 Yes No No No No No No H3F3AP4 +H4C6 8361 ENST00000244537 NM_003540 No No 1 Yes No No No No No No H4/c, H4FC, HIST1H4F HDAC2 3066 ENST00000519065 NM_001527.3 ENST00000519065 NM_001527.3 Yes No 1 Yes No No No No No No KDAC2, YAF1 -HNF1B 6928 ENST00000225893 NM_001165923 ENST00000617811 NM_001165923 No No 1 Yes No No No No No No HNF1beta, LFB3, MODY5, TCF2, VHNF1 +HFE 3077 ENST00000357618 NM_000410 ENST00000357618 NM_000410 Yes No 1 Yes No No No No No No HFE1 +HNF1B 6928 ENST00000225893 NM_001165923 ENST00000617811 NM_000458 No No 1 Yes No No No No No No HNF1beta, LFB3, MODY5, TCF2, VHNF1 HNRNPA2B1 3181 No No 1 No No No No No No Yes HNRPA2B1 HOOK3 84376 No No 1 No No No No No No Yes HOXA3 3200 No No 1 No No No No Yes No No HOX1E @@ -968,14 +997,15 @@ LARP4B 23185 ENST00000316157 NM_015155.2 ENST00000316157 NM_015155.2 No No 1 Yes LCP1 3936 No No 1 No No No No Yes No No CP64, L-PLASTIN, LC64P, PLS2 LGR5 8549 ENST00000266674 NM_003667 ENST00000266674 NM_003667 Yes No 1 Yes No No No No No No FEX, GPR49, GPR67, HG38 LIFR 3977 No No 1 No No No No No No Yes CD118 -LMNA 4000 No No 1 No No No No No No Yes CMD1A, HGPS, LGMD1B, LMN1, LMNL1, PRO1 LRIG3 121227 No No 1 No No No No No No Yes FLJ90440, KIAA3016 LRP5 4041 ENST00000294304 NM_001291902.1 ENST00000294304 NM_001291902.1 Yes Yes 1 Yes No No No No No No BMND1, EVR1, EVR4, LR3, LRP7, OPPG, OPS, OPTA1, VBCH2 LRP6 4040 ENST00000261349 NM_002336.2 ENST00000261349 NM_002336.2 Yes No 1 Yes No No No No No No ADCAD2 LRRK2 120892 No No 1 No No No No Yes No No DKFZp434H2111, FLJ45829, PARK8, RIPK7, ROCO2 MAGED1 9500 No No 1 No No No No Yes No No DLXIN-1, NRAGE -MAL2 114569 ENST00000276681 NM_052886.2 ENST00000614891 NM_052886.2 No Yes 1 Yes No No No No No No +MAGI2 9863 ENST00000354212 NM_012301.3 ENST00000354212 NM_012301.4 No Yes 1 Yes No No No No No No ACVRIP1, MAGI-2 +MAL2 114569 ENST00000276681 NM_052886.2 ENST00000614891 NM_052886.3 No Yes 1 Yes No No No No No No MAML2 84441 No No 1 No No No No No No Yes KIAA1819, MAM3 +MAP3K21 84451 ENST00000366624 NM_032435 ENST00000366624 NM_032435 Yes No 1 Yes No No No No No No KIAA1804, MLK4 MAP3K6 9064 No No 1 No No No No Yes No No ASK2, MAPKKK6, MEKK6 MAP4K4 9448 ENST00000347699 NM_001242559 ENST00000347699 NM_001242559 Yes No 1 Yes No No No No No No FLH21957, HGK, NIK MBD4 8930 ENST00000249910 NM_003925 ENST00000249910 NM_003925 No Yes 1 Yes No No No No No No @@ -990,9 +1020,9 @@ MLLT11 10962 No No 1 No No No No No No Yes AF1Q MNX1 3110 No No 1 No No No No Yes No No HB9, HLXB9, HOXHB9, SCRA1 MS4A1 931 ENST00000345732 NM_021950 ENST00000345732 NM_021950 No No 1 Yes No No No No No No B1, Bp35, CD20, FMC7 MTCP1 4515 No No 1 No No No No No No Yes P13MTCP1, TCL1C, p8MTCP1 +MTHFD2 10797 ENST00000394053 NM_006636 ENST00000394053 NM_006636 Yes No 1 Yes No No No No No No MYBL1 4603 ENST00000522677 NM_001080416 ENST00000522677 NM_001080416 Yes No 1 Yes No No No No No No A-myb, AMYB MYO18A 399687 No No 1 No No No No Yes No No KIAA0216, MysPDZ -MYO5A 4644 No No 1 No No No No No No Yes MYH12, MYO5, MYR12 NAB2 4665 No No 1 No No No No No No Yes MADER NACA 4666 No No 1 No No No No Yes No No NACA1 NBEAP1 606 No No 1 No No No No Yes No No BCL8, BCL8A @@ -1001,8 +1031,10 @@ NCOA4 8031 No No 1 No No No No No No Yes ARA70, DKFZp762E1112, ELE1, PTC3, R NFATC2 4773 No No 1 No No No No No No Yes NF-ATP, NFAT1, NFATp NFIB 4781 No No 1 No No No No No No Yes NFI-RED, NFIB2, NFIB3 NFKBIE 4794 No No 1 No No No No No No Yes IKBE +NHERF1 9368 ENST00000262613 NM_004252 ENST00000262613 NM_004252 Yes Yes 1 Yes No No No No No No EBP50, NHERF, SLC9A3R1 NOD1 10392 No No 1 No No No No Yes No No CARD4, CLR7.1, NLRC1 NONO 4841 No No 1 No No No No No No Yes NMT55, NRB54, P54, P54NRB, PPP1R114 +NQO1 1728 ENST00000320623 NM_000903 ENST00000320623 NM_000903 Yes No 1 Yes No No No No No No DHQU, DIA4, NMOR1, QR1 NUTM2A 728118 No No 1 No No No No Yes No No FAM22A NUTM2B 729262 No No 1 No No No No No No Yes FAM22B, bA119F19.1 NUTM2D 728130 No No 1 No No No No No No Yes FAM22D @@ -1025,13 +1057,14 @@ PHLPP1 23239 ENST00000262719 NM_194449 ENST00000262719 NM_194449 No Yes 1 Yes No PHLPP2 23035 ENST00000568954 NM_015020 ENST00000568954 NM_015020 No Yes 1 Yes No No No No No No KIAA0931, PHLPPL, PPM3B POLG 5428 ENST00000268124 NM_001126131 ENST00000268124 NM_001126131 No No 1 Yes No No No No No No POLG1, POLGA POLQ 10721 No No 1 No No No No No No Yes +POU2F2 5452 ENST00000526816 NM_001207025 ENST00000526816 NM_001207025 Yes No 1 Yes No No No No No No OTF2 POU3F2 5454 ENST00000328345 NM_005604 ENST00000328345 NM_005604 Yes No 1 Yes No No No No No No BRN2, OCT7, OTF7, POUF3 POU3F4 5456 ENST00000373200 NM_000307 ENST00000644024 NM_000307 Yes No 1 Yes No No No No No No BRN4, DFN3, DFNX2, OTF9 POU5F1 5460 No No 1 No No No No No No Yes MGC22487, OTF3, Oct4 PPFIBP1 8496 No No 1 No No No No No No Yes SGT2, hSGT2, hSgt2p PPP1CB 5500 No No 1 No No No No Yes No No MP, PP-1B, PP1B, PP1beta, PP1c, PPP1beta -PRCC 5546 No No 1 No No No No No No Yes RCCP1 PRF1 5551 No No 1 No No No No No No Yes HPLH2, PFP +PRKCB 5579 ENST00000303531 NM_002738.6 ENST00000643927 NM_002738.7 Yes Yes 1 Yes No No No No No No PKCB, PKCβ, PRKCB1, PRKCB2 PRPF8 10594 ENST00000304992 NM_006445 ENST00000304992 NM_006445 No Yes 1 Yes No No No No No No PRPC8, Prp8, RP13, SNRNP220, hPrp8 PRSS1 5644 ENST00000311737 NM_002769.4 ENST00000311737 NM_002769.4 No No 1 Yes No No No No No No TRY1 PRSS8 5652 No No 1 No No No No Yes No No @@ -1048,15 +1081,19 @@ RAD17 5884 ENST00000380774 NM_133339 ENST00000380774 NM_133339 No Yes 1 Yes No N RALGDS 5900 No No 1 No No No No Yes No No RGDS, RGF, RalGEF RASGEF1A 221002 No No 1 No No No No Yes No No CG4853, FLJ37817 REV3L 5980 ENST00000358835 NM_002912 ENST00000358835 NM_002912 Yes No 1 Yes No No No No No No POLZ, REV3 +RIOK2 55781 ENST00000283109 NM_018343.2 ENST00000283109 NM_018343.3 Yes No 1 Yes No No No No No No FLJ11159 RMI2 116028 No No 1 No No No No No No Yes BLAP18, C16orf75, MGC24665 RNASEH2A 10535 ENST00000221486 NM_006397 ENST00000221486 NM_006397 Yes No 1 Yes No No No No No No RNASEHI, RNHIA, RNHL RNASEH2B 79621 ENST00000336617 NM_024570 ENST00000336617 NM_024570 No Yes 1 Yes No No No No No No AGS2, DLEU8, FLJ11712 RNF217-AS1 7955 No No 1 No No No No Yes No No STL RPL10 6134 No No 1 No No No No No No Yes DXS648, DXS648E, FLJ23544, L10, QM +RPS15 6209 ENST00000592588 NM_001018 ENST00000593052 NM_001308226 Yes No 1 Yes No No No No No No MGC111130, S15 RSPO3 84870 No No 1 No No No No No No Yes FLJ14440, THSD2 RUNX2 860 No No 1 No No No No Yes No No AML3, CBFA1, CCD, CCD1, PEBP2A1, PEBP2aA1 S1PR2 9294 No No 1 No No No No Yes No No AGR16, DFNB68, EDG5, Gpcr13, H218 SALL4 57167 No No 1 No No No No No No Yes ZNF797, dJ1112F19.1 +SAMD9 54809 ENST00000379958 NM_017654.3 ENST00000379958 NM_017654.4 No No 1 Yes No No No No No No C7orf5, FLJ20073, KIAA2004 +SAMD9L 219285 ENST00000318238 NM_152703.2 ENST00000318238 NM_152703.5 No No 1 Yes No No No No No No C7orf6, FLJ39885, KIAA2005 SBDS 51119 No No 1 No No No No No No Yes CGI-97, FLJ10917, SDO1, SWDS SEC31A 22872 No No 1 No No No No Yes No No ABP125, ABP130, KIAA0905, SEC31L1 SEPTIN5 5413 No No 1 No No No No Yes No No HCDCREL-1, PNUTL1, SEPT5 @@ -1071,14 +1108,14 @@ SFRP4 6424 No No 1 No No No No No No Yes FRP-4, FRPHE, FRZB-2, frpHE SIX1 6495 No No 1 No No No No No No Yes DFNA23 SLC1A2 6506 No No 1 No No No No Yes No No EAAT2, GLT-1 SLC45A3 85414 No No 1 No No No No No No Yes IPCA-2, IPCA-6, IPCA-8, PCANAP2, PCANAP6, PCANAP8, prostein -SLC9A3R1 9368 ENST00000262613 NM_004252 ENST00000262613 NM_004252 Yes Yes 1 Yes No No No No No No EBP50, NHERF, NHERF1 SLIT2 9353 ENST00000504154 NM_004787 ENST00000504154 NM_004787 No No 1 Yes No No No No No No SLIL3, Slit-2 -SMARCA1 6594 No No 1 No No No No Yes No No ISWI, NURF140, SNF2L, SNF2L1, SNF2LB, SWI, hSNF2L +SLIT3 6586 ENST00000519560 NM_003062 ENST00000519560 NM_003062 No Yes 1 Yes No No No No No No MEGF5, SLIL2, Slit-3, slit2 SNCAIP 9627 No No 1 No No No Yes No No No SYPH1 SND1 27044 No No 1 No No No No No No Yes TDRD11, p100 SNX29 92017 No No 1 No No No No Yes No No FLJ12363, RUNDC2A SOCS2 8835 No No 1 No No No No Yes No No CIS2, Cish2, SOCS-2, SSI-2, SSI2, STATI2 SQSTM1 8878 ENST00000389805 NM_003900 ENST00000389805 NM_003900 Yes No 1 Yes No No No No No No A170, OSIL, PDB3, p62B +SRP72 6731 ENST00000342756 NM_006947 ENST00000642900 NM_006947 Yes No 1 Yes No No No No No No SS18L1 26039 No No 1 No No No No No No Yes CREST, KIAA0693 STAT1 6772 ENST00000361099 NM_007315.3 ENST00000361099 NM_007315.3 No No 1 Yes No No No No No No ISGF-3, STAT91 STAT2 6773 ENST00000314128 NM_005419.3 ENST00000314128 NM_005419.3 No No 1 Yes No No No No No No STAT113 @@ -1105,6 +1142,7 @@ TMSB4XP8 7117 No No 1 No No No No Yes No No TMSL3 TNFRSF11A 8792 No No 1 No No No No Yes No No CD265, FEO, LOH18CR1, PDB2, RANK TNFSF13 8741 ENST00000338784 NM_003808 ENST00000338784 NM_003808 Yes No 1 Yes No No No No No No APRIL, CD256 TONSL 4796 ENST00000409379 NM_013432 ENST00000409379 NM_013432 No No 1 Yes No No No No No No IKBR, NFKBIL2 +TOP2A 7153 ENST00000423485 NM_001067 ENST00000423485 NM_001067 Yes No 1 Yes No No No No No No TOP2 TPR 7175 No No 1 No No No No No No Yes TRIB3 57761 ENST00000217233 NM_001301188 ENST00000217233 NM_001301188 Yes No 1 Yes No No No No No No C20orf97, dJ1103G7.3 TRIM33 51592 No No 1 No No No No No No Yes FLJ11429, KIAA1113, PTC7, RFG7, TF1G, TIF1G, TIF1GAMMA, TIFGAMMA @@ -1112,13 +1150,15 @@ TRRAP 8295 No No 1 No No No No No No Yes PAF400, TR-AP, Tra1 TTL 150465 No No 1 No No No No Yes No No MGC46235 TUSC3 7991 No No 1 No No No No Yes No No MGC13453, MRT22, MRT7, MagT2, N33, OST3A, SLC58A2 TYRO3 7301 No No 1 No No No Yes No No No Brt, Dtk, Etk-2, RSE, Rek, Sky, Tif +UBA1 7317 ENST00000335972 NM_003334.3 ENST00000335972 NM_003334.4 Yes No 1 Yes No No No No No No A1S9T, CFAP124, GXP1, POC20, UBE1, UBE1X UBE2A 7319 ENST00000371558 NM_003336 ENST00000371558 NM_003336 Yes No 1 Yes No No No No No No HHR6A, HR6A, RAD6A, UBC2 +UBTF 7343 ENST00000302904 ENST00000436088 NM_014233.4 Yes No 1 Yes No No No No No No NOR-90, UBF, UBF1, UBF2 +UCHL1 7345 ENST00000284440 NM_004181 ENST00000284440 NM_004181 Yes No 1 Yes No No No No No No PARK5, PGP9.5, Uch-L1 +USP1 7398 ENST00000339950 NM_003368.4 ENST00000339950 NM_003368.5 Yes No 1 Yes No No No No No No WAS 7454 No No 1 No No No No No No Yes IMD2, THC, WASP, WASPA WDCP 80304 No No 1 No No No No No No Yes C2orf44, FLJ21945, MMAP WDR90 197335 No No 1 No No No No Yes No No C16orf15, C16orf16, C16orf17, C16orf18, C16orf19, FLJ36483, KIAA1924, POC16 -WRN 7486 No No 1 No No No No No No Yes RECQ3, RECQL2 WWP1 11059 ENST00000265428 NM_007013.3 ENST00000265428 NM_007013.3 Yes No 1 Yes No No No No No No AIP5, DKFZP434D2111 -XPA 7507 No No 1 No No No No No No Yes XP1, XPAC XRCC1 7515 ENST00000262887 NM_006297 ENST00000262887 NM_006297 No Yes 1 Yes No No No No No No RCC YPEL5 51646 No No 1 No No No No Yes No No CGI-127 YWHAE 7531 No No 1 No No No No No No Yes FLJ45465 @@ -1128,5 +1168,6 @@ ZBTB20 26137 ENST00000474710 NM_001164342.2 ENST00000474710 NM_001164342.2 Yes Y ZFP36L1 677 ENST00000336440 NM_001244698.1 ENST00000336440 NM_001244698.1 No Yes 1 Yes No No No No No No Berg36, RNF162B, TIS11B, cMG1 ZFP36L2 678 ENST00000282388 NM_006887.4 ENST00000282388 NM_006887.4 No Yes 1 Yes No No No No No No ERF2, RNF162C, TIS11D ZNF24 7572 No No 1 No No No No Yes No No KOX17, ZNF191, ZSCAN3, Zfp191 +ZNF292 23036 ENST00000369577 NM_015021.1 ENST00000369577 NM_015021.3 No Yes 1 Yes No No No No No No KIAA0530, ZFP292, Zn-15, Zn-16, bA393I2.3 ZNF331 55422 No No 1 No No No No No No Yes RITA, ZNF361, ZNF463 ZNF750 79755 ENST00000269394 NM_024702.2 ENST00000269394 NM_024702.2 No Yes 1 Yes No No No No No No FLJ13841, Zfp750 diff --git a/data/common_input/oncokb_cancer_genes_list_from_API.json b/data/common_input/oncokb_cancer_genes_list_from_API.json index 4511866..73fae41 100644 --- a/data/common_input/oncokb_cancer_genes_list_from_API.json +++ b/data/common_input/oncokb_cancer_genes_list_from_API.json @@ -19,8 +19,8 @@ "c-ABL", "ABL" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "AKT1", @@ -38,14 +38,14 @@ "vogelstein": true, "sangerCGC": true, "geneAliases": [ - "RAC-alpha", - "AKT", "RAC", "PRKBA", - "PKB" + "PKB", + "RAC-alpha", + "AKT" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "ALK", @@ -65,8 +65,8 @@ "geneAliases": [ "CD246" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "AMER1", @@ -84,13 +84,13 @@ "vogelstein": true, "sangerCGC": true, "geneAliases": [ + "FAM123B", "RP11-403E24.2", "FLJ39827", - "FAM123B", "WTX" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "APC", @@ -111,8 +111,8 @@ "PPP1R46", "DP2.5" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "AR", @@ -132,13 +132,13 @@ "geneAliases": [ "NR3C4", "DHTR", - "AIS", "SBMA", "SMAX1", + "AIS", "HUMARA" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "ARID1A", @@ -164,8 +164,8 @@ "SMARCF1", "P270" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "ASXL1", @@ -185,8 +185,8 @@ "geneAliases": [ "KIAA0978" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "ATM", @@ -211,8 +211,8 @@ "TELO1", "ATA" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "ATRX", @@ -233,11 +233,11 @@ "JMS", "MRX52", "XH2", - "XNP", - "RAD54" + "RAD54", + "XNP" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "AXIN1", @@ -257,8 +257,8 @@ "geneAliases": [ "PPP1R49" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "BAP1", @@ -276,12 +276,12 @@ "vogelstein": true, "sangerCGC": true, "geneAliases": [ - "UCHL2", "hucep-6", + "UCHL2", "KIAA0272" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "BCL2", @@ -302,8 +302,8 @@ "Bcl-2", "PPP1R50" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "BCOR", @@ -324,8 +324,8 @@ "FLJ20285", "KIAA1575" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "BRAF", @@ -345,8 +345,8 @@ "geneAliases": [ "BRAF1" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "BRCA1", @@ -368,8 +368,8 @@ "PPP1R53", "FANCS" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "BRCA2", @@ -387,12 +387,12 @@ "vogelstein": true, "sangerCGC": true, "geneAliases": [ - "FAD1", "FANCD1", - "XRCC11" + "XRCC11", + "FAD1" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "CARD11", @@ -410,11 +410,11 @@ "vogelstein": true, "sangerCGC": true, "geneAliases": [ - "BIMP3", - "CARMA1" + "CARMA1", + "BIMP3" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "CBL", @@ -436,8 +436,8 @@ "CBL2", "c-Cbl" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "CDC73", @@ -461,8 +461,8 @@ "FIHP", "HRPT1" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "CDH1", @@ -484,8 +484,8 @@ "CD324", "UVO" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "CDKN2A", @@ -515,8 +515,8 @@ "CDKN2", "MLM" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "CEBPA", @@ -537,8 +537,8 @@ "C/EBP-alpha", "CEBP" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "CIC", @@ -558,8 +558,8 @@ "geneAliases": [ "KIAA0306" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "CREBBP", @@ -578,11 +578,11 @@ "sangerCGC": true, "geneAliases": [ "RTS", - "RSTS", - "KAT3A" + "KAT3A", + "RSTS" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "CTNNB1", @@ -604,8 +604,8 @@ "CTNNB", "armadillo" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "DAXX", @@ -625,8 +625,8 @@ "geneAliases": [ "DAP6" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "DNMT3A", @@ -644,8 +644,8 @@ "vogelstein": true, "sangerCGC": true, "geneAliases": [], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "EGFR", @@ -663,12 +663,12 @@ "vogelstein": true, "sangerCGC": true, "geneAliases": [ - "ERBB", "ERBB1", - "ERRP" + "ERRP", + "ERBB" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "EP300", @@ -689,8 +689,8 @@ "p300", "KAT3B" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "ERBB2", @@ -713,8 +713,8 @@ "HER2", "HER-2" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "EZH2", @@ -732,12 +732,12 @@ "vogelstein": true, "sangerCGC": true, "geneAliases": [ - "KMT6A", "ENX-1", - "KMT6" + "KMT6", + "KMT6A" ], - "tsg": true, - "oncogene": true + "oncogene": true, + "tsg": true }, { "hugoSymbol": "FBXW7", @@ -764,8 +764,8 @@ "FLJ11071", "CDC4" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "FGFR2", @@ -794,8 +794,8 @@ "CD332", "CFD1" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "FGFR3", @@ -814,12 +814,12 @@ "sangerCGC": true, "geneAliases": [ "JTK4", - "CD333", "ACH", - "CEK2" + "CEK2", + "CD333" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "FLT3", @@ -841,8 +841,8 @@ "FLK2", "CD135" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "FOXL2", @@ -863,8 +863,8 @@ "BPES1", "BPES" ], - "tsg": true, - "oncogene": true + "oncogene": true, + "tsg": true }, { "hugoSymbol": "GATA3", @@ -884,8 +884,8 @@ "geneAliases": [ "HDR" ], - "tsg": true, - "oncogene": true + "oncogene": true, + "tsg": true }, { "hugoSymbol": "GNA11", @@ -903,13 +903,13 @@ "vogelstein": true, "sangerCGC": true, "geneAliases": [ + "FBH2", "FHH2", "FBH", - "FBH2", "HHC2" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "GNAQ", @@ -930,8 +930,8 @@ "G-ALPHA-q", "GAQ" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "GNAS", @@ -957,8 +957,8 @@ "SCG6", "GNASXL" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "HNF1A", @@ -981,8 +981,8 @@ "TCF1", "MODY3" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "HRAS", @@ -1002,8 +1002,8 @@ "geneAliases": [ "HRAS1" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "IDH1", @@ -1021,8 +1021,8 @@ "vogelstein": true, "sangerCGC": true, "geneAliases": [], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "IDH2", @@ -1040,8 +1040,8 @@ "vogelstein": true, "sangerCGC": true, "geneAliases": [], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "JAK1", @@ -1063,8 +1063,8 @@ "JAK1B", "JAK1A" ], - "tsg": true, - "oncogene": true + "oncogene": true, + "tsg": true }, { "hugoSymbol": "JAK2", @@ -1084,8 +1084,8 @@ "geneAliases": [ "JTK10" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "JAK3", @@ -1103,14 +1103,14 @@ "vogelstein": true, "sangerCGC": true, "geneAliases": [ + "JAK3_HUMAN", + "L-JAK", "JAKL", "LJAK", - "JAK-3", - "JAK3_HUMAN", - "L-JAK" + "JAK-3" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "KDM5C", @@ -1128,14 +1128,14 @@ "vogelstein": true, "sangerCGC": true, "geneAliases": [ - "SMCX", - "DXS1272E", "JARID1C", "MRX13", + "SMCX", + "DXS1272E", "XE169" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "KDM6A", @@ -1155,8 +1155,8 @@ "geneAliases": [ "UTX" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "KIT", @@ -1174,13 +1174,13 @@ "vogelstein": true, "sangerCGC": true, "geneAliases": [ + "PBT", "CD117", "C-Kit", - "SCFR", - "PBT" + "SCFR" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "KMT2D", @@ -1199,12 +1199,12 @@ "sangerCGC": true, "geneAliases": [ "MLL2", - "CAGL114", "TNRC21", - "ALR" + "ALR", + "CAGL114" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "KRAS", @@ -1226,8 +1226,8 @@ "K-Ras4B", "KRAS1" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "MAP2K1", @@ -1249,8 +1249,8 @@ "MEK1", "MAPKK1" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "MAP3K1", @@ -1269,11 +1269,11 @@ "sangerCGC": true, "geneAliases": [ "MEKK1", - "MEKK", - "MAPKKK1" + "MAPKKK1", + "MEKK" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "MED12", @@ -1301,8 +1301,8 @@ "KIAA0192", "FGS1" ], - "tsg": true, - "oncogene": true + "oncogene": true, + "tsg": true }, { "hugoSymbol": "MEN1", @@ -1320,8 +1320,8 @@ "vogelstein": true, "sangerCGC": true, "geneAliases": [], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "MET", @@ -1339,12 +1339,12 @@ "vogelstein": true, "sangerCGC": true, "geneAliases": [ - "DFNB97", + "RCCP2", "HGFR", - "RCCP2" + "DFNB97" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "MLH1", @@ -1363,12 +1363,12 @@ "sangerCGC": true, "geneAliases": [ "HNPCC", - "FCC2", "HNPCC2", + "FCC2", "COCA2" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "MPL", @@ -1390,8 +1390,8 @@ "TPOR", "THPOR" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "MSH2", @@ -1412,8 +1412,8 @@ "COCA1", "HNPCC1" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "MSH6", @@ -1433,8 +1433,8 @@ "geneAliases": [ "GTBP" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "MYD88", @@ -1452,8 +1452,8 @@ "vogelstein": true, "sangerCGC": true, "geneAliases": [], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "NF1", @@ -1471,8 +1471,8 @@ "vogelstein": true, "sangerCGC": true, "geneAliases": [], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "NF2", @@ -1490,14 +1490,14 @@ "vogelstein": true, "sangerCGC": true, "geneAliases": [ + "merlin", "SCH", "BANF", "merlin-1", - "merlin", "ACN" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "NFE2L2", @@ -1515,8 +1515,8 @@ "vogelstein": true, "sangerCGC": true, "geneAliases": [], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "NOTCH1", @@ -1536,8 +1536,8 @@ "geneAliases": [ "TAN1" ], - "tsg": true, - "oncogene": true + "oncogene": true, + "tsg": true }, { "hugoSymbol": "NOTCH2", @@ -1555,8 +1555,8 @@ "vogelstein": true, "sangerCGC": true, "geneAliases": [], - "tsg": true, - "oncogene": true + "oncogene": true, + "tsg": true }, { "hugoSymbol": "NPM1", @@ -1574,11 +1574,11 @@ "vogelstein": true, "sangerCGC": true, "geneAliases": [ - "NPM", - "B23" + "B23", + "NPM" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "NRAS", @@ -1598,8 +1598,8 @@ "geneAliases": [ "N-ras" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "PAX5", @@ -1619,8 +1619,8 @@ "geneAliases": [ "BSAP" ], - "tsg": true, - "oncogene": true + "oncogene": true, + "tsg": true }, { "hugoSymbol": "PBRM1", @@ -1641,8 +1641,8 @@ "BAF180", "PB1" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "PDGFRA", @@ -1661,11 +1661,11 @@ "sangerCGC": true, "geneAliases": [ "PDGFR2", - "CD140a", - "GAS9" + "GAS9", + "CD140a" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "PIK3CA", @@ -1685,8 +1685,8 @@ "geneAliases": [ "PI3K" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "PIK3R1", @@ -1707,8 +1707,8 @@ "p85-ALPHA", "GRB1" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "PPP2R1A", @@ -1730,8 +1730,8 @@ "PR65A", "PP2AA" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "PRDM1", @@ -1749,11 +1749,11 @@ "vogelstein": true, "sangerCGC": true, "geneAliases": [ - "BLIMP1", - "PRDI-BF1" + "PRDI-BF1", + "BLIMP1" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "PTCH1", @@ -1771,12 +1771,12 @@ "vogelstein": true, "sangerCGC": true, "geneAliases": [ - "PTCH", "NBCCS", - "BCNS" + "BCNS", + "PTCH" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "PTEN", @@ -1794,13 +1794,13 @@ "vogelstein": true, "sangerCGC": true, "geneAliases": [ + "MHAM", "BZS", "PTEN1", - "MHAM", "MMAC1" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "PTPN11", @@ -1825,8 +1825,8 @@ "BPTP3", "SH-PTP2" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "RB1", @@ -1848,8 +1848,8 @@ "RB", "PPP1R130" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "RET", @@ -1875,8 +1875,8 @@ "HSCR1", "MEN2B" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "RNF43", @@ -1894,12 +1894,12 @@ "vogelstein": true, "sangerCGC": true, "geneAliases": [ - "FLJ20315", "DKFZp781H0392", - "URCC" + "URCC", + "FLJ20315" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "SETD2", @@ -1923,8 +1923,8 @@ "KMT3A", "KIAA1732" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "SF3B1", @@ -1943,13 +1943,13 @@ "sangerCGC": true, "geneAliases": [ "Prp10", - "SF3b155", - "PRPF10", "SAP155", - "Hsh155" + "Hsh155", + "SF3b155", + "PRPF10" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "SMAD2", @@ -1968,11 +1968,11 @@ "sangerCGC": true, "geneAliases": [ "MADH2", - "JV18-1", - "MADR2" + "MADR2", + "JV18-1" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "SMAD4", @@ -1990,11 +1990,11 @@ "vogelstein": true, "sangerCGC": true, "geneAliases": [ - "DPC4", - "MADH4" + "MADH4", + "DPC4" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "SMARCA4", @@ -2018,8 +2018,8 @@ "hSNF2b", "SNF2-BETA" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "SMARCB1", @@ -2047,8 +2047,8 @@ "Snr1", "Ini1" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "SMO", @@ -2069,8 +2069,8 @@ "FZD11", "SMOH" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "SOCS1", @@ -2088,14 +2088,14 @@ "vogelstein": true, "sangerCGC": true, "geneAliases": [ - "JAB", - "SOCS-1", "SSI-1", "Cish1", + "JAB", + "SOCS-1", "TIP3" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "SPOP", @@ -2113,11 +2113,11 @@ "vogelstein": true, "sangerCGC": true, "geneAliases": [ - "BTBD32", - "TEF2" + "TEF2", + "BTBD32" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "STAG2", @@ -2135,12 +2135,12 @@ "vogelstein": true, "sangerCGC": true, "geneAliases": [ + "SCC3B", "SA-2", - "SA2", - "SCC3B" + "SA2" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "STK11", @@ -2161,8 +2161,8 @@ "PJS", "LKB1" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "TET2", @@ -2180,11 +2180,11 @@ "vogelstein": true, "sangerCGC": true, "geneAliases": [ - "FLJ20032", - "KIAA1546" + "KIAA1546", + "FLJ20032" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "TNFAIP3", @@ -2205,8 +2205,8 @@ "OTUD7C", "A20" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "TP53", @@ -2227,8 +2227,8 @@ "LFS1", "p53" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "TSC1", @@ -2250,8 +2250,8 @@ "hamartin", "KIAA0243" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "U2AF1", @@ -2269,12 +2269,12 @@ "vogelstein": true, "sangerCGC": true, "geneAliases": [ - "RNU2AF1", "U2AFBP", + "RNU2AF1", "U2AF35" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "VHL", @@ -2294,8 +2294,8 @@ "geneAliases": [ "VHL1" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "WT1", @@ -2313,14 +2313,14 @@ "vogelstein": true, "sangerCGC": true, "geneAliases": [ + "GUD", + "NPHS4", "WIT-2", "WAGR", - "AWT1", - "GUD", - "NPHS4" + "AWT1" ], - "tsg": true, - "oncogene": true + "oncogene": true, + "tsg": true }, { "hugoSymbol": "AKT2", @@ -2340,8 +2340,8 @@ "geneAliases": [ "PKB\u03b2" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "ARID2", @@ -2360,12 +2360,12 @@ "sangerCGC": true, "geneAliases": [ "KIAA1557", - "FLJ30619", "DKFZp686G052", + "FLJ30619", "BAF200" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "ATR", @@ -2385,11 +2385,11 @@ "geneAliases": [ "SCKL1", "MEC1", - "FRP1", - "SCKL" + "SCKL", + "FRP1" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "B2M", @@ -2407,8 +2407,8 @@ "vogelstein": true, "sangerCGC": true, "geneAliases": [], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "BARD1", @@ -2426,8 +2426,8 @@ "vogelstein": false, "sangerCGC": true, "geneAliases": [], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "BCL6", @@ -2446,13 +2446,13 @@ "sangerCGC": true, "geneAliases": [ "BCL5", - "LAZ3", "ZNF51", "ZBTB27", - "BCL6A" + "BCL6A", + "LAZ3" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "BRD4", @@ -2474,8 +2474,8 @@ "MCAP", "HUNK1" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "BRIP1", @@ -2495,8 +2495,8 @@ "geneAliases": [ "FANCJ" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "BTK", @@ -2514,14 +2514,14 @@ "vogelstein": false, "sangerCGC": true, "geneAliases": [ - "ATK", "IMD1", - "XLA", "AGMX1", + "ATK", + "XLA", "PSCTK1" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "CALR", @@ -2541,12 +2541,12 @@ "geneAliases": [ "SSA", "cC1qR", - "FLJ26680", "CRT", + "FLJ26680", "RO" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "CASP8", @@ -2564,13 +2564,13 @@ "vogelstein": true, "sangerCGC": true, "geneAliases": [ - "MACH", - "FLICE", "MCH5", - "Casp-8" + "Casp-8", + "MACH", + "FLICE" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "CBFB", @@ -2590,8 +2590,8 @@ "geneAliases": [ "PEBP2B" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "CCND1", @@ -2610,12 +2610,12 @@ "sangerCGC": true, "geneAliases": [ "PRAD1", - "BCL1", "D11S287E", + "BCL1", "U21B31" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "CCND2", @@ -2633,8 +2633,8 @@ "vogelstein": false, "sangerCGC": true, "geneAliases": [], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "CCND3", @@ -2652,8 +2652,8 @@ "vogelstein": false, "sangerCGC": true, "geneAliases": [], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "CCNE1", @@ -2673,8 +2673,8 @@ "geneAliases": [ "CCNE" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "CD274", @@ -2699,8 +2699,8 @@ "PDL1", "B7-H" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "CD79A", @@ -2721,8 +2721,8 @@ "IGA", "MB-1" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "CD79B", @@ -2743,8 +2743,8 @@ "IGB", "B29" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "CDK12", @@ -2762,13 +2762,13 @@ "vogelstein": false, "sangerCGC": true, "geneAliases": [ + "CRK7", "CRKR", "CRKRS", - "CRK7", "KIAA0904" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "CDK4", @@ -2788,8 +2788,8 @@ "geneAliases": [ "PSK-J3" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "CDK6", @@ -2809,8 +2809,8 @@ "geneAliases": [ "PLSTIRE" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "CDKN1B", @@ -2828,11 +2828,11 @@ "vogelstein": false, "sangerCGC": true, "geneAliases": [ - "KIP1", - "P27KIP1" + "P27KIP1", + "KIP1" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "CDKN2C", @@ -2852,8 +2852,8 @@ "geneAliases": [ "INK4C" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "CHEK2", @@ -2877,8 +2877,8 @@ "PP1425", "bA444G7" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "CRLF2", @@ -2899,8 +2899,8 @@ "TSLPR", "CRL2" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "CSF1R", @@ -2919,12 +2919,12 @@ "sangerCGC": false, "geneAliases": [ "CSFR", + "C-FMS", "CD115", - "FMS", - "C-FMS" + "FMS" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "CSF3R", @@ -2942,11 +2942,11 @@ "vogelstein": false, "sangerCGC": true, "geneAliases": [ - "CD114", - "GCSFR" + "GCSFR", + "CD114" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "CTCF", @@ -2967,8 +2967,8 @@ "FAP108", "CFAP108" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "CXCR4", @@ -2995,8 +2995,8 @@ "NPYY3R", "fusin" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "DDR2", @@ -3017,8 +3017,8 @@ "NTRKR3", "TYRO10" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "ERBB3", @@ -3039,8 +3039,8 @@ "LCCS2", "HER3" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "ERBB4", @@ -3058,11 +3058,11 @@ "vogelstein": false, "sangerCGC": true, "geneAliases": [ - "HER4", - "ALS19" + "ALS19", + "HER4" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "ERG", @@ -3082,8 +3082,8 @@ "geneAliases": [ "erg-3" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "ESR1", @@ -3106,8 +3106,8 @@ "ER-alpha", "NR3A1" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "ETV6", @@ -3127,8 +3127,8 @@ "geneAliases": [ "TEL" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "FANCA", @@ -3147,12 +3147,12 @@ "sangerCGC": true, "geneAliases": [ "FANCH", - "FACA", "FA-H", - "FAA" + "FAA", + "FACA" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "FANCC", @@ -3174,8 +3174,8 @@ "FA3", "FACC" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "FGFR1", @@ -3201,8 +3201,8 @@ "KAL2", "CD331" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "FGFR4", @@ -3220,11 +3220,11 @@ "vogelstein": false, "sangerCGC": true, "geneAliases": [ - "CD334", - "JTK2" + "JTK2", + "CD334" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "FLCN", @@ -3247,8 +3247,8 @@ "MGC17998", "BHD" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "FUBP1", @@ -3268,8 +3268,8 @@ "geneAliases": [ "FUBP" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "GATA1", @@ -3288,13 +3288,13 @@ "sangerCGC": true, "geneAliases": [ "NFE1", - "GATA-1", - "NF-E1", "GF1", - "ERYF1" + "ERYF1", + "GATA-1", + "NF-E1" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "GATA2", @@ -3314,8 +3314,8 @@ "geneAliases": [ "NFE1B" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": true }, { "hugoSymbol": "H3-3A", @@ -3333,12 +3333,12 @@ "vogelstein": true, "sangerCGC": true, "geneAliases": [ - "H3F3", "H3F3A", + "H3F3", "H3.3A" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "H3C2", @@ -3357,11 +3357,11 @@ "sangerCGC": true, "geneAliases": [ "H3FL", - "HIST1H3B", - "H3/l" + "H3/l", + "HIST1H3B" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "HGF", @@ -3380,12 +3380,12 @@ "sangerCGC": true, "geneAliases": [ "F-TCF", - "HGFB", "DFNB39", - "HPTA" + "HPTA", + "HGFB" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "IKZF1", @@ -3404,14 +3404,14 @@ "sangerCGC": true, "geneAliases": [ "hIk-1", + "IKAROS", "LyF-1", "ZNFN1A1", "Hs.54452", - "IKAROS", "PPP1R92" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "IRF4", @@ -3429,11 +3429,11 @@ "vogelstein": false, "sangerCGC": true, "geneAliases": [ - "MUM1", - "LSIRF" + "LSIRF", + "MUM1" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "JUN", @@ -3454,8 +3454,8 @@ "c-Jun", "AP-1" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "KDM5A", @@ -3476,8 +3476,8 @@ "RBBP2", "JARID1A" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "KDR", @@ -3496,12 +3496,12 @@ "sangerCGC": true, "geneAliases": [ "VEGFR2", - "VEGFR", "CD309", + "VEGFR", "FLK1" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "KEAP1", @@ -3528,8 +3528,8 @@ "MGC10630", "KIAA0132" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "KMT2A", @@ -3555,8 +3555,8 @@ "CXXC7", "HRX" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "KMT2C", @@ -3574,12 +3574,12 @@ "vogelstein": true, "sangerCGC": true, "geneAliases": [ - "KIAA1506", "MLL3", + "KIAA1506", "HALR" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "MAP2K2", @@ -3600,8 +3600,8 @@ "PRKMK2", "MEK2" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "MAP2K4", @@ -3619,14 +3619,14 @@ "vogelstein": false, "sangerCGC": true, "geneAliases": [ - "JNKK1", "MKK4", "SERK1", "MEK4", - "PRKMK4" + "PRKMK4", + "JNKK1" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "MAPK1", @@ -3645,13 +3645,13 @@ "sangerCGC": true, "geneAliases": [ "PRKM1", - "MAPK2", "PRKM2", "ERK2", - "p41mapk" + "p41mapk", + "MAPK2" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "MDM2", @@ -3672,8 +3672,8 @@ "HDM2", "MGC5370" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "MDM4", @@ -3694,8 +3694,8 @@ "MDMX", "HDMX" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "MITF", @@ -3703,7 +3703,7 @@ "grch37Isoform": "ENST00000394351", "grch37RefSeq": "NM_000248.3", "grch38Isoform": "ENST00000394351", - "grch38RefSeq": "", + "grch38RefSeq": "NM_000248.4", "oncokbAnnotated": true, "occurrenceCount": 6, "mSKImpact": true, @@ -3715,11 +3715,11 @@ "geneAliases": [ "bHLHe32", "WS2A", - "MI", - "WS2" + "WS2", + "MI" ], - "tsg": true, - "oncogene": true + "oncogene": true, + "tsg": true }, { "hugoSymbol": "MTOR", @@ -3737,15 +3737,15 @@ "vogelstein": false, "sangerCGC": true, "geneAliases": [ - "FRAP", - "FLJ44809", - "RAPT1", "FRAP1", "RAFT1", - "FRAP2" + "FRAP2", + "FRAP", + "FLJ44809", + "RAPT1" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "MUTYH", @@ -3765,8 +3765,8 @@ "geneAliases": [ "MYH" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "MYC", @@ -3784,12 +3784,12 @@ "vogelstein": false, "sangerCGC": true, "geneAliases": [ - "MYCC", "c-Myc", + "MYCC", "bHLHe39" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "MYCL", @@ -3811,8 +3811,8 @@ "bHLHe38", "MYCL1" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "MYCN", @@ -3830,13 +3830,13 @@ "vogelstein": false, "sangerCGC": true, "geneAliases": [ - "N-myc", - "NMYC", "MYCNOT", - "bHLHe37" + "bHLHe37", + "N-myc", + "NMYC" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "NKX2-1", @@ -3854,13 +3854,13 @@ "vogelstein": false, "sangerCGC": true, "geneAliases": [ - "TITF1", "NKX2A", - "TTF-1", - "BCH" + "BCH", + "TITF1", + "TTF-1" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "NSD2", @@ -3882,8 +3882,8 @@ "KMT3G", "WHSC1" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "NSD3", @@ -3906,8 +3906,8 @@ "FLJ20353", "WHSC1L1" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "NTRK1", @@ -3925,11 +3925,11 @@ "vogelstein": false, "sangerCGC": true, "geneAliases": [ - "MTC", - "TRKA" + "TRKA", + "MTC" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "NTRK2", @@ -3949,8 +3949,8 @@ "geneAliases": [ "TRKB" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "NTRK3", @@ -3970,8 +3970,8 @@ "geneAliases": [ "TRKC" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "PALB2", @@ -3992,8 +3992,8 @@ "FLJ21816", "FANCN" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "PDCD1LG2", @@ -4011,15 +4011,15 @@ "vogelstein": false, "sangerCGC": true, "geneAliases": [ + "CD273", "bA574F11.2", "PD-L2", - "CD273", "B7-DC", "Btdc", "PDL2" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "PDGFRB", @@ -4037,13 +4037,13 @@ "vogelstein": false, "sangerCGC": true, "geneAliases": [ + "PDGFR1", "PDGFR", "JTK12", - "PDGFR1", "CD140b" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "PHF6", @@ -4061,14 +4061,14 @@ "vogelstein": true, "sangerCGC": true, "geneAliases": [ - "BORJ", "KIAA1823", "BFLS", - "MGC14797", - "CENP-31" + "CENP-31", + "BORJ", + "MGC14797" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "PIM1", @@ -4088,8 +4088,8 @@ "geneAliases": [ "PIM" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "PRKAR1A", @@ -4107,12 +4107,12 @@ "vogelstein": false, "sangerCGC": true, "geneAliases": [ + "CNC1", "TSE1", - "PRKAR1", - "CNC1" + "PRKAR1" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "RAD21", @@ -4134,8 +4134,8 @@ "hHR21", "KIAA0078" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "RAF1", @@ -4157,8 +4157,8 @@ "Raf-1", "CRAF" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "RARA", @@ -4178,8 +4178,8 @@ "geneAliases": [ "NR1B1" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "ROS1", @@ -4197,12 +4197,12 @@ "vogelstein": false, "sangerCGC": true, "geneAliases": [ - "c-ros-1", "MCF3", - "ROS" + "ROS", + "c-ros-1" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "RUNX1", @@ -4220,13 +4220,13 @@ "vogelstein": true, "sangerCGC": true, "geneAliases": [ + "CBFA2", "PEBP2A2", "AMLCR1", - "CBFA2", "AML1" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "SDHA", @@ -4245,11 +4245,11 @@ "sangerCGC": true, "geneAliases": [ "SDHF", - "SDH2", - "FP" + "FP", + "SDH2" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "SDHB", @@ -4267,11 +4267,11 @@ "vogelstein": false, "sangerCGC": true, "geneAliases": [ - "SDH1", - "SDH" + "SDH", + "SDH1" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "SDHC", @@ -4290,11 +4290,11 @@ "sangerCGC": true, "geneAliases": [ "CYB560", - "cybL", - "PGL3" + "PGL3", + "cybL" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "SDHD", @@ -4316,8 +4316,8 @@ "PGL1", "cybS" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "SOX2", @@ -4335,8 +4335,8 @@ "vogelstein": false, "sangerCGC": true, "geneAliases": [], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "SPEN", @@ -4355,12 +4355,12 @@ "sangerCGC": true, "geneAliases": [ "RBM15C", + "MINT", "SHARP", - "KIAA0929", - "MINT" + "KIAA0929" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "SRC", @@ -4378,12 +4378,12 @@ "vogelstein": false, "sangerCGC": true, "geneAliases": [ - "ASV", "c-src", + "ASV", "SRC1" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "SRSF2", @@ -4407,8 +4407,8 @@ "SFRS2", "SC-35" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "STAT3", @@ -4428,8 +4428,8 @@ "geneAliases": [ "APRF" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "SUFU", @@ -4451,8 +4451,8 @@ "PRO1280", "SUFUH" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "SYK", @@ -4470,8 +4470,8 @@ "vogelstein": false, "sangerCGC": true, "geneAliases": [], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "TENT5C", @@ -4492,8 +4492,8 @@ "FAM46C", "FLJ20202" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "TGFBR2", @@ -4511,12 +4511,12 @@ "vogelstein": false, "sangerCGC": true, "geneAliases": [ - "MFS2", "TBR-ii", - "TBRII" + "TBRII", + "MFS2" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "TMPRSS2", @@ -4536,8 +4536,8 @@ "geneAliases": [ "PRSS10" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "TNFRSF14", @@ -4555,14 +4555,14 @@ "vogelstein": false, "sangerCGC": true, "geneAliases": [ + "HVEM", + "CD270", "HVEA", "ATAR", - "LIGHTR", - "HVEM", - "CD270" + "LIGHTR" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "TSC2", @@ -4580,13 +4580,13 @@ "vogelstein": false, "sangerCGC": true, "geneAliases": [ - "LAM", - "tuberin", "PPP1R160", - "TSC4" + "TSC4", + "LAM", + "tuberin" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "XPO1", @@ -4605,11 +4605,11 @@ "sangerCGC": true, "geneAliases": [ "CRM-1", - "CRM1", - "emb" + "emb", + "CRM1" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "AKT3", @@ -4627,12 +4627,12 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [ - "PKBG", "RAC-gamma", - "PRKBG" + "PRKBG", + "PKBG" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "ARAF", @@ -4652,8 +4652,8 @@ "geneAliases": [ "ARAF1" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "ARID1B", @@ -4671,15 +4671,15 @@ "vogelstein": true, "sangerCGC": true, "geneAliases": [ - "ELD/OSA1", - "DAN15", "KIAA1235", "p250R", "BAF250b", - "6A3-5" + "6A3-5", + "ELD/OSA1", + "DAN15" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "AURKA", @@ -4705,8 +4705,8 @@ "STK6", "AurA" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "AURKB", @@ -4732,8 +4732,8 @@ "STK5", "IPL1" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "AXL", @@ -4751,12 +4751,12 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [ - "Tyro7", "JTK11", + "Tyro7", "UFO" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "BCL10", @@ -4779,8 +4779,8 @@ "mE10", "CLAP" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "BCORL1", @@ -4801,8 +4801,8 @@ "CXorf10", "FLJ11362" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "BCR", @@ -4827,8 +4827,8 @@ "D22S11", "BCR1" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "BIRC3", @@ -4854,8 +4854,8 @@ "hiap-1", "MALT2" ], - "tsg": false, - "oncogene": false + "oncogene": true, + "tsg": true }, { "hugoSymbol": "BLM", @@ -4877,8 +4877,8 @@ "RECQL3", "RECQ2" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "BTG1", @@ -4898,8 +4898,8 @@ "geneAliases": [ "APRO2" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "CDK8", @@ -4919,8 +4919,8 @@ "geneAliases": [ "K35" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "CDKN2B", @@ -4940,13 +4940,13 @@ "geneAliases": [ "MTS2", "P15", - "INK4B", "TP15", + "INK4B", "CDK4I", "p15INK4b" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "CHEK1", @@ -4966,8 +4966,8 @@ "geneAliases": [ "CHK1" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "CRKL", @@ -4985,8 +4985,8 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "CYLD", @@ -5004,12 +5004,12 @@ "vogelstein": true, "sangerCGC": true, "geneAliases": [ - "USPL2", "CYLD1", + "USPL2", "KIAA0849" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "DOT1L", @@ -5027,12 +5027,12 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [ - "DOT1", "KMT4", + "DOT1", "KIAA1814" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "EED", @@ -5053,8 +5053,8 @@ "WAIT-1", "HEED" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "EIF4A2", @@ -5075,8 +5075,8 @@ "DDX2B", "BM-010" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "EPHA3", @@ -5094,14 +5094,14 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [ - "TYRO4", "ETK1", - "ETK", "HEK4", + "TYRO4", + "ETK", "HEK" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "EPHB1", @@ -5122,8 +5122,8 @@ "EPHT2", "Hek6" ], - "tsg": true, - "oncogene": true + "oncogene": true, + "tsg": true }, { "hugoSymbol": "ERCC4", @@ -5144,8 +5144,8 @@ "FANCQ", "XPF" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "ETV1", @@ -5165,8 +5165,8 @@ "geneAliases": [ "ER81" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "FAS", @@ -5184,14 +5184,14 @@ "vogelstein": false, "sangerCGC": true, "geneAliases": [ - "FAS1", "APT1", "CD95", + "FAS1", "TNFRSF6", "APO-1" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "FGF19", @@ -5209,8 +5209,8 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "FGF3", @@ -5231,8 +5231,8 @@ "INT2", "HBGF-3" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "FGF4", @@ -5252,13 +5252,13 @@ "geneAliases": [ "HBGF-4", "HST-1", + "K-FGF", "HST", "HSTF1", - "KFGF", - "K-FGF" + "KFGF" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "FH", @@ -5276,8 +5276,8 @@ "vogelstein": false, "sangerCGC": true, "geneAliases": [], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "FLT1", @@ -5298,8 +5298,8 @@ "VEGFR1", "FLT" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "FLT4", @@ -5320,8 +5320,8 @@ "VEGFR3", "VEGFR-3" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "FOXO1", @@ -5343,8 +5343,8 @@ "FKH1", "FKHR" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "FOXP1", @@ -5367,8 +5367,8 @@ "hFKH1B", "QRF1" ], - "tsg": true, - "oncogene": true + "oncogene": true, + "tsg": true }, { "hugoSymbol": "GRIN2A", @@ -5389,8 +5389,8 @@ "NMDAR2A", "GluN2A" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "GSK3B", @@ -5408,8 +5408,8 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "ID3", @@ -5430,8 +5430,8 @@ "HEIR-1", "bHLHb25" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "IGF1R", @@ -5449,14 +5449,14 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [ - "IGFR", "MGC18216", - "JTK13", "IGFIR", + "IGFR", + "JTK13", "CD221" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "IKBKE", @@ -5478,8 +5478,8 @@ "IKKE", "KIAA0151" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "IL7R", @@ -5500,8 +5500,8 @@ "CD127", "IL7RA" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "INPP4B", @@ -5519,8 +5519,8 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "IRS2", @@ -5538,8 +5538,8 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "KLF4", @@ -5560,8 +5560,8 @@ "EZF", "GKLF" ], - "tsg": true, - "oncogene": true + "oncogene": true, + "tsg": true }, { "hugoSymbol": "LMO1", @@ -5579,11 +5579,11 @@ "vogelstein": false, "sangerCGC": true, "geneAliases": [ - "RHOM1", - "RBTN1" + "RBTN1", + "RHOM1" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "MALT1", @@ -5604,8 +5604,8 @@ "MLT", "PCASP1" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "MAP3K13", @@ -5626,8 +5626,8 @@ "LZK", "MEKK13" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "MCL1", @@ -5648,8 +5648,8 @@ "Mcl-1", "BCL2L3" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "MEF2B", @@ -5669,8 +5669,8 @@ "geneAliases": [ "RSRFR2" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "MRE11", @@ -5691,8 +5691,8 @@ "ATLD", "MRE11A" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "MSH3", @@ -5710,8 +5710,8 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "MSI2", @@ -5729,8 +5729,8 @@ "vogelstein": false, "sangerCGC": true, "geneAliases": [], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "NBN", @@ -5749,13 +5749,13 @@ "sangerCGC": true, "geneAliases": [ "ATV", - "AT-V2", "NBS1", + "AT-V2", "NBS", "AT-V1" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "NCOR1", @@ -5781,8 +5781,8 @@ "hCIT529I10", "MGC104216" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "NFKBIA", @@ -5802,11 +5802,11 @@ "geneAliases": [ "IkappaBalpha", "IKBA", - "MAD-3", - "NFKBI" + "NFKBI", + "MAD-3" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "NSD1", @@ -5829,8 +5829,8 @@ "STO", "ARA267" ], - "tsg": true, - "oncogene": true + "oncogene": true, + "tsg": true }, { "hugoSymbol": "NT5C2", @@ -5848,15 +5848,15 @@ "vogelstein": false, "sangerCGC": true, "geneAliases": [ + "cN-II", + "NT5B", "PNT5", "GMP", "SPG45", - "cN-II", - "SPG65", - "NT5B" + "SPG65" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "P2RY8", @@ -5876,8 +5876,8 @@ "geneAliases": [ "P2Y8" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "PDCD1", @@ -5900,8 +5900,8 @@ "hSLE1", "PD-1" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "PIK3CB", @@ -5921,8 +5921,8 @@ "geneAliases": [ "PIK3C1" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "PMS2", @@ -5940,13 +5940,13 @@ "vogelstein": false, "sangerCGC": true, "geneAliases": [ - "H_DJ0042M02.9", "PMSL2", "HNPCC4", + "H_DJ0042M02.9", "MLH4" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "POLD1", @@ -5966,8 +5966,8 @@ "geneAliases": [ "POLD" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "POLE", @@ -5987,8 +5987,8 @@ "geneAliases": [ "POLE1" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "POT1", @@ -6009,8 +6009,8 @@ "DKFZp586D211", "hPot1" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "PPARG", @@ -6029,12 +6029,12 @@ "sangerCGC": true, "geneAliases": [ "PPARG1", + "PPARG2", "PPARgamma", - "NR1C3", - "PPARG2" + "NR1C3" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "RAC1", @@ -6052,12 +6052,12 @@ "vogelstein": false, "sangerCGC": true, "geneAliases": [ - "Rac-1", "p21-Rac1", + "Rac-1", "TC-25" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "RAD50", @@ -6075,11 +6075,11 @@ "vogelstein": false, "sangerCGC": true, "geneAliases": [ - "RAD50-2", - "hRad50" + "hRad50", + "RAD50-2" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "RAD51", @@ -6098,14 +6098,14 @@ "sangerCGC": false, "geneAliases": [ "RAD51A", + "RECA", "HsRad51", "FANCR", "HsT16930", - "BRCC5", - "RECA" + "BRCC5" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "RAD51B", @@ -6128,8 +6128,8 @@ "hREC2", "RAD51L1" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "RBM10", @@ -6148,14 +6148,14 @@ "sangerCGC": true, "geneAliases": [ "GPATCH9", + "S1-1", "DXS8237E", "KIAA0122", - "S1-1", "GPATC9", "ZRANB5" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "REL", @@ -6173,12 +6173,12 @@ "vogelstein": false, "sangerCGC": true, "geneAliases": [ - "HIVEN86A", "c-Rel", + "HIVEN86A", "I-Rel" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "RHOA", @@ -6196,13 +6196,13 @@ "vogelstein": false, "sangerCGC": true, "geneAliases": [ - "RHOH12", "ARH12", "ARHA", + "RHOH12", "Rho12" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "RICTOR", @@ -6220,13 +6220,13 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [ - "PIA", "KIAA1999", "MGC39830", - "AVO3" + "AVO3", + "PIA" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "RPTOR", @@ -6244,13 +6244,13 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [ - "Mip1", "raptor", - "KOG1", - "KIAA1303" + "KIAA1303", + "Mip1", + "KOG1" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "SETBP1", @@ -6271,8 +6271,8 @@ "SEB", "KIAA0437" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "SOX9", @@ -6290,11 +6290,11 @@ "vogelstein": true, "sangerCGC": false, "geneAliases": [ - "CMD1", - "CMPD1" + "CMPD1", + "CMD1" ], - "tsg": true, - "oncogene": true + "oncogene": true, + "tsg": true }, { "hugoSymbol": "STAT5B", @@ -6312,8 +6312,8 @@ "vogelstein": false, "sangerCGC": true, "geneAliases": [], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "SUZ12", @@ -6335,8 +6335,8 @@ "JJAZ1", "KIAA0160" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "TBX3", @@ -6354,12 +6354,12 @@ "vogelstein": false, "sangerCGC": true, "geneAliases": [ + "UMS", "TBX3-ISO", - "XHL", - "UMS" + "XHL" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "TCF3", @@ -6385,8 +6385,8 @@ "bHLHb21", "VDIR" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "TERT", @@ -6404,14 +6404,14 @@ "vogelstein": false, "sangerCGC": true, "geneAliases": [ + "TRT", + "TP2", "TCS1", "EST2", - "hEST2", - "TRT", - "TP2" + "hEST2" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "TET1", @@ -6434,8 +6434,8 @@ "CXXC6", "bA119F7.1" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "TOP1", @@ -6453,8 +6453,8 @@ "vogelstein": false, "sangerCGC": true, "geneAliases": [], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "TP63", @@ -6484,8 +6484,8 @@ "p63", "p73H" ], - "tsg": true, - "oncogene": true + "oncogene": true, + "tsg": true }, { "hugoSymbol": "TRAF7", @@ -6504,12 +6504,12 @@ "sangerCGC": true, "geneAliases": [ "MGC7807", - "DKFZp586I021", "RFWD1", - "RNF119" + "RNF119", + "DKFZp586I021" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "TSHR", @@ -6529,8 +6529,8 @@ "geneAliases": [ "LGR3" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "ZRSR2", @@ -6550,11 +6550,11 @@ "geneAliases": [ "URP", "ZC3H22", - "U2AF1L2", - "U2AF1-RS2" + "U2AF1-RS2", + "U2AF1L2" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "ACVR1", @@ -6577,8 +6577,8 @@ "ALK2", "ACVR1A" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "ACVR1B", @@ -6601,8 +6601,8 @@ "ActRIB", "SKR2" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "ALOX12B", @@ -6622,8 +6622,8 @@ "geneAliases": [ "12R-LOX" ], - "tsg": true, - "oncogene": true + "oncogene": true, + "tsg": true }, { "hugoSymbol": "AXIN2", @@ -6644,8 +6644,8 @@ "MGC126582", "DKFZp781B0869" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "BCL11B", @@ -6663,13 +6663,13 @@ "vogelstein": false, "sangerCGC": true, "geneAliases": [ - "CTIP-2", "ZNF856B", - "CTIP2", - "hRIT1-alpha" + "hRIT1-alpha", + "CTIP-2", + "CTIP2" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "BCL2L1", @@ -6687,15 +6687,15 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [ - "bcl-xL", "BCLX", "bcl-xS", - "PPP1R52", "BCL2L", - "Bcl-X" + "Bcl-X", + "bcl-xL", + "PPP1R52" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "BMPR1A", @@ -6714,11 +6714,11 @@ "sangerCGC": true, "geneAliases": [ "CD292", - "ALK3", - "ACVRLK3" + "ACVRLK3", + "ALK3" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "CDKN1A", @@ -6736,15 +6736,15 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [ - "p21CIP1", "p21Cip1/Waf1", + "p21CIP1", "CDKN1", "WAF1", "CAP20", "SDI1" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "CIITA", @@ -6765,8 +6765,8 @@ "NLRA", "MHC2TA" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "CUL3", @@ -6784,8 +6784,8 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "CUX1", @@ -6814,8 +6814,8 @@ "CUTL1", "Cux/CDP" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "DDX3X", @@ -6837,8 +6837,8 @@ "DDX14", "DBX" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "DICER1", @@ -6856,14 +6856,14 @@ "vogelstein": false, "sangerCGC": true, "geneAliases": [ - "KIAA0928", "K12H4.8-LIKE", "Dicer", + "KIAA0928", "MNG1", "HERNA" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "DIS3", @@ -6882,12 +6882,12 @@ "sangerCGC": false, "geneAliases": [ "KIAA1008", + "EXOSC11", "dis3p", - "RRP44", - "EXOSC11" + "RRP44" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "DNAJB1", @@ -6910,8 +6910,8 @@ "Hsp40", "RSPH16B" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "DNMT1", @@ -6933,8 +6933,8 @@ "DNMT", "MCMT" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "DROSHA", @@ -6958,8 +6958,8 @@ "Etohi2", "RN3" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "EPAS1", @@ -6978,12 +6978,12 @@ "sangerCGC": true, "geneAliases": [ "MOP2", - "HIF2A", "PASD2", + "HIF2A", "bHLHe73" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "EPHA5", @@ -7004,8 +7004,8 @@ "CEK7", "Hek7" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "EPHA7", @@ -7025,8 +7025,8 @@ "geneAliases": [ "Hek11" ], - "tsg": true, - "oncogene": true + "oncogene": true, + "tsg": true }, { "hugoSymbol": "ERCC2", @@ -7050,8 +7050,8 @@ "XPD", "MGC126219" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "ERCC3", @@ -7072,8 +7072,8 @@ "RAD25", "XPB" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "ERCC5", @@ -7094,8 +7094,8 @@ "ERCM2", "XPGC" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "ERRFI1", @@ -7113,12 +7113,12 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [ - "GENE-33", "RALT", - "MIG-6" + "MIG-6", + "GENE-33" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "ETV4", @@ -7137,11 +7137,11 @@ "sangerCGC": true, "geneAliases": [ "E1AF", - "E1A-F", - "PEA3" + "PEA3", + "E1A-F" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "ETV5", @@ -7161,8 +7161,8 @@ "geneAliases": [ "ERM" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "EWSR1", @@ -7182,8 +7182,8 @@ "geneAliases": [ "EWS" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "FANCD2", @@ -7205,8 +7205,8 @@ "FACD", "FANCD" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "FANCG", @@ -7227,8 +7227,8 @@ "XRCC9", "FAG" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "FAT1", @@ -7250,8 +7250,8 @@ "CDHF7", "CDHR8" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "FBXO11", @@ -7272,8 +7272,8 @@ "FBX11", "UBR6" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "FOXA1", @@ -7293,8 +7293,8 @@ "geneAliases": [ "HNF3A" ], - "tsg": true, - "oncogene": true + "oncogene": true, + "tsg": true }, { "hugoSymbol": "GLI1", @@ -7314,8 +7314,8 @@ "geneAliases": [ "GLI" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "GNA13", @@ -7336,8 +7336,8 @@ "MGC46138", "G13" ], - "tsg": true, - "oncogene": true + "oncogene": true, + "tsg": true }, { "hugoSymbol": "H1-2", @@ -7356,13 +7356,13 @@ "sangerCGC": false, "geneAliases": [ "H1s-1", - "H1c", "H1F2", + "H1c", "H1.2", "HIST1H1C" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "H3-3B", @@ -7383,8 +7383,8 @@ "H3F3B", "H3.3B" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "HDAC1", @@ -7407,8 +7407,8 @@ "RPD3L1", "KDAC1" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "HLA-A", @@ -7426,8 +7426,8 @@ "vogelstein": false, "sangerCGC": true, "geneAliases": [], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "IKZF3", @@ -7448,8 +7448,8 @@ "ZNFN1A3", "Aiolos" ], - "tsg": true, - "oncogene": true + "oncogene": true, + "tsg": true }, { "hugoSymbol": "INHBA", @@ -7467,8 +7467,8 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [], - "tsg": true, - "oncogene": true + "oncogene": true, + "tsg": true }, { "hugoSymbol": "LATS1", @@ -7488,8 +7488,8 @@ "geneAliases": [ "WARTS" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "LATS2", @@ -7507,8 +7507,8 @@ "vogelstein": false, "sangerCGC": true, "geneAliases": [], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "LYN", @@ -7528,8 +7528,8 @@ "geneAliases": [ "JTK8" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "MAF", @@ -7549,8 +7549,8 @@ "geneAliases": [ "c-MAF" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "MAP3K14", @@ -7572,8 +7572,8 @@ "HS", "FTDCR1B" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "MAX", @@ -7597,8 +7597,8 @@ "bHLHd5", "bHLHd4" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "MLLT1", @@ -7620,8 +7620,8 @@ "ENL", "YEATS1" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "MST1R", @@ -7641,12 +7641,12 @@ "geneAliases": [ "RON", "PTK8", + "CDw136", "CD136", - "SEA", - "CDw136" + "SEA" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "MYB", @@ -7666,8 +7666,8 @@ "geneAliases": [ "c-myb" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "MYOD1", @@ -7689,8 +7689,8 @@ "bHLHc1", "MYF3" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "NCOR2", @@ -7708,14 +7708,14 @@ "vogelstein": false, "sangerCGC": true, "geneAliases": [ + "TNRC14", "SMRT", "SMRTE", "TRAC-1", - "CTG26", - "TNRC14" + "CTG26" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "NOTCH3", @@ -7736,8 +7736,8 @@ "CADASIL", "CASIL" ], - "tsg": true, - "oncogene": true + "oncogene": true, + "tsg": true }, { "hugoSymbol": "NUP93", @@ -7757,8 +7757,8 @@ "geneAliases": [ "KIAA0095" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "PARP1", @@ -7781,8 +7781,8 @@ "ARTD1", "ADPRT" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "PHOX2B", @@ -7803,8 +7803,8 @@ "PMX2B", "NBPhox" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "PIK3C2G", @@ -7822,8 +7822,8 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "PIK3CG", @@ -7841,8 +7841,8 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "PIK3R2", @@ -7862,8 +7862,8 @@ "geneAliases": [ "P85B" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "PLCG2", @@ -7881,8 +7881,8 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "PPM1D", @@ -7900,11 +7900,11 @@ "vogelstein": false, "sangerCGC": true, "geneAliases": [ - "Wip1", - "PP2C-DELTA" + "PP2C-DELTA", + "Wip1" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "PPP6C", @@ -7924,8 +7924,8 @@ "geneAliases": [ "PP6" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "PREX2", @@ -7949,8 +7949,8 @@ "DEPDC2", "FLJ12987" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "PRKCI", @@ -7971,8 +7971,8 @@ "DXS1179E", "PKCI" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "PRKN", @@ -7990,13 +7990,13 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [ - "AR-JP", "parkin", - "PARK2", - "PDJ" + "PDJ", + "AR-JP", + "PARK2" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "PTPRT", @@ -8017,8 +8017,8 @@ "RPTPrho", "KIAA0283" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "RAD51C", @@ -8039,8 +8039,8 @@ "RAD51L2", "FANCO" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "RAD51D", @@ -8058,13 +8058,13 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [ - "RAD51L3", "HsTRAD", "R51H3", - "Trad" + "Trad", + "RAD51L3" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "RAD52", @@ -8082,8 +8082,8 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "RAD54L", @@ -8101,12 +8101,12 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [ - "RAD54A", "hRAD54", - "hHR54" + "hHR54", + "RAD54A" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "RECQL4", @@ -8126,8 +8126,8 @@ "geneAliases": [ "RecQ4" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "RRAS2", @@ -8147,8 +8147,8 @@ "geneAliases": [ "TC21" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "RUNX1T1", @@ -8167,13 +8167,13 @@ "sangerCGC": true, "geneAliases": [ "ETO", + "AML1T1", "MTG8", "ZMYND2", - "AML1T1", "CBFA2T1" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "SDHAF2", @@ -8196,8 +8196,8 @@ "SDH5", "C11orf79" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "SGK1", @@ -8217,8 +8217,8 @@ "geneAliases": [ "SGK" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "SH2B3", @@ -8236,11 +8236,11 @@ "vogelstein": false, "sangerCGC": true, "geneAliases": [ - "LNK", - "IDDM20" + "IDDM20", + "LNK" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "SMAD3", @@ -8262,8 +8262,8 @@ "JV15-2", "HsT17436" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "STAT5A", @@ -8283,8 +8283,8 @@ "geneAliases": [ "STAT5" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "STAT6", @@ -8305,8 +8305,8 @@ "IL-4-STAT", "D12S1644" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "TBL1XR1", @@ -8330,8 +8330,8 @@ "C21", "IRA1" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "TCF7L2", @@ -8351,8 +8351,8 @@ "geneAliases": [ "TCF-4" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "TEK", @@ -8370,14 +8370,14 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [ - "VMCM", "TIE-2", "TIE2", "CD202b", + "VMCM", "VMCM1" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "TMEM127", @@ -8395,11 +8395,11 @@ "vogelstein": false, "sangerCGC": true, "geneAliases": [ - "FLJ22257", - "FLJ20507" + "FLJ20507", + "FLJ22257" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "TRAF2", @@ -8417,11 +8417,11 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [ - "RNF117", - "TRAP3" + "TRAP3", + "RNF117" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "VEGFA", @@ -8439,12 +8439,12 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [ + "VEGF", "VEGF-A", - "VPF", - "VEGF" + "VPF" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "WWTR1", @@ -8464,8 +8464,8 @@ "geneAliases": [ "DKFZp586I1419" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "XRCC2", @@ -8485,8 +8485,8 @@ "geneAliases": [ "FANCU" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "ZFHX3", @@ -8505,12 +8505,12 @@ "sangerCGC": true, "geneAliases": [ "ATBF1", + "ZNF927", "C16orf47", - "FLJ26184", - "ZNF927" + "FLJ26184" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "ABL2", @@ -8530,8 +8530,8 @@ "geneAliases": [ "ABLL" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "ABRAXAS1", @@ -8550,13 +8550,36 @@ "sangerCGC": false, "geneAliases": [ "ABRA1", + "FAM175A", "CCDC98", "ABRAXAS", - "FAM175A", "FLJ13614" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true + }, + { + "hugoSymbol": "AFDN", + "entrezGeneId": 4301, + "grch37Isoform": "ENST00000351017", + "grch37RefSeq": "", + "grch38Isoform": "ENST00000683244", + "grch38RefSeq": "NM_001386888.1", + "oncokbAnnotated": true, + "occurrenceCount": 3, + "mSKImpact": false, + "mSKHeme": false, + "foundation": false, + "foundationHeme": true, + "vogelstein": false, + "sangerCGC": true, + "geneAliases": [ + "AF-6", + "AF6", + "MLLT4" + ], + "oncogene": false, + "tsg": true }, { "hugoSymbol": "AFF4", @@ -8577,8 +8600,8 @@ "AF5Q31", "MCEF" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "AGO2", @@ -8597,13 +8620,13 @@ "sangerCGC": false, "geneAliases": [ "Q10", - "hAGO2", "LINC00980", - "EIF2C2", - "CASC7" + "CASC7", + "hAGO2", + "EIF2C2" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "ANKRD11", @@ -8624,8 +8647,32 @@ "LZ16", "T13" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true + }, + { + "hugoSymbol": "ARHGAP26", + "entrezGeneId": 23092, + "grch37Isoform": "ENST00000274498", + "grch37RefSeq": "NM_015071", + "grch38Isoform": "ENST00000274498", + "grch38RefSeq": "NM_015071", + "oncokbAnnotated": true, + "occurrenceCount": 3, + "mSKImpact": false, + "mSKHeme": false, + "foundation": false, + "foundationHeme": true, + "vogelstein": false, + "sangerCGC": true, + "geneAliases": [ + "GRAF", + "OPHN1L1", + "KIAA0621", + "OPHN1L" + ], + "oncogene": true, + "tsg": true }, { "hugoSymbol": "ARHGAP35", @@ -8650,8 +8697,8 @@ "p190ARhoGAP", "P190A" ], - "tsg": true, - "oncogene": true + "oncogene": true, + "tsg": true }, { "hugoSymbol": "ARHGEF12", @@ -8672,8 +8719,8 @@ "LARG", "KIAA0382" ], - "tsg": true, - "oncogene": true + "oncogene": true, + "tsg": true }, { "hugoSymbol": "ARID5B", @@ -8691,11 +8738,11 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [ - "MRF2", - "FLJ21150" + "FLJ21150", + "MRF2" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "ASXL2", @@ -8717,8 +8764,8 @@ "ASXH2", "FLJ10898" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "ATF1", @@ -8738,8 +8785,31 @@ "geneAliases": [ "TREB36" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false + }, + { + "hugoSymbol": "ATIC", + "entrezGeneId": 471, + "grch37Isoform": "ENST00000236959", + "grch37RefSeq": "NM_004044", + "grch38Isoform": "ENST00000236959", + "grch38RefSeq": "NM_004044", + "oncokbAnnotated": true, + "occurrenceCount": 3, + "mSKImpact": false, + "mSKHeme": false, + "foundation": false, + "foundationHeme": true, + "vogelstein": false, + "sangerCGC": true, + "geneAliases": [ + "IMPCHASE", + "PURH", + "AICARFT" + ], + "oncogene": true, + "tsg": false }, { "hugoSymbol": "BABAM1", @@ -8758,13 +8828,13 @@ "sangerCGC": false, "geneAliases": [ "NBA1", - "HSPC142", "C19orf62", "FLJ20571", - "MERIT40" + "MERIT40", + "HSPC142" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "BBC3", @@ -8782,11 +8852,11 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [ - "PUMA", - "JFY1" + "JFY1", + "PUMA" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "BCL2L11", @@ -8804,14 +8874,37 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [ - "BimL", "BimS", "BOD", - "BimEL", - "BIM" + "BIM", + "BimL", + "BimEL" + ], + "oncogene": false, + "tsg": true + }, + { + "hugoSymbol": "BCL2L2", + "entrezGeneId": 599, + "grch37Isoform": "ENST00000250405", + "grch37RefSeq": "NM_004050", + "grch38Isoform": "ENST00000250405", + "grch38RefSeq": "NM_004050", + "oncokbAnnotated": true, + "occurrenceCount": 3, + "mSKImpact": false, + "mSKHeme": false, + "foundation": true, + "foundationHeme": true, + "vogelstein": false, + "sangerCGC": false, + "geneAliases": [ + "BCL-W", + "PPP1R51", + "KIAA0271" ], - "tsg": true, - "oncogene": false + "oncogene": true, + "tsg": false }, { "hugoSymbol": "BCL3", @@ -8829,11 +8922,11 @@ "vogelstein": false, "sangerCGC": true, "geneAliases": [ - "D19S37", - "BCL4" + "BCL4", + "D19S37" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "BCL7A", @@ -8853,8 +8946,8 @@ "geneAliases": [ "BCL7" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "BCL9", @@ -8872,8 +8965,8 @@ "vogelstein": false, "sangerCGC": true, "geneAliases": [], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "BTG2", @@ -8896,8 +8989,8 @@ "APRO1", "TIS21" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "CARM1", @@ -8917,8 +9010,8 @@ "geneAliases": [ "PRMT4" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "CBFA2T3", @@ -8942,8 +9035,8 @@ "MTGR2", "RUNX1T3" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "CCNQ", @@ -8964,8 +9057,8 @@ "CycM", "FAM58A" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "CD22", @@ -8986,8 +9079,8 @@ "SIGLEC-2", "SIGLEC2" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "CD276", @@ -9005,12 +9098,12 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [ - "B7-H3", "B7RP-2", + "B7-H3", "B7H3" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "CD58", @@ -9030,8 +9123,31 @@ "geneAliases": [ "LFA3" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true + }, + { + "hugoSymbol": "CD70", + "entrezGeneId": 970, + "grch37Isoform": "ENST00000245903", + "grch37RefSeq": "NM_001252", + "grch38Isoform": "ENST00000245903", + "grch38RefSeq": "NM_001252", + "oncokbAnnotated": true, + "occurrenceCount": 3, + "mSKImpact": false, + "mSKHeme": false, + "foundation": true, + "foundationHeme": true, + "vogelstein": false, + "sangerCGC": false, + "geneAliases": [ + "CD27L", + "CD27LG", + "TNFSF7" + ], + "oncogene": true, + "tsg": false }, { "hugoSymbol": "CD74", @@ -9051,8 +9167,8 @@ "geneAliases": [ "DHLAG" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "CDC42", @@ -9073,8 +9189,8 @@ "G25K", "CDC42Hs" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "CENPA", @@ -9095,8 +9211,8 @@ "CenH3", "CENP-A" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "CLTCL1", @@ -9114,13 +9230,13 @@ "vogelstein": false, "sangerCGC": true, "geneAliases": [ - "CLH22", "CLTD", "CLTCL", + "CLH22", "CHC22" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "CNTRL", @@ -9128,7 +9244,7 @@ "grch37Isoform": "ENST00000238341", "grch37RefSeq": "NM_007018", "grch38Isoform": "ENST00000373855", - "grch38RefSeq": null, + "grch38RefSeq": "NM_007018.6", "oncokbAnnotated": true, "occurrenceCount": 3, "mSKImpact": false, @@ -9141,8 +9257,8 @@ "CEP110", "CEP1" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "COL1A1", @@ -9160,8 +9276,8 @@ "vogelstein": false, "sangerCGC": true, "geneAliases": [], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "COP1", @@ -9185,8 +9301,8 @@ "CFAP78", "FAP78" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": true }, { "hugoSymbol": "CSDE1", @@ -9206,8 +9322,8 @@ "geneAliases": [ "D1S155E" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "CTLA4", @@ -9225,14 +9341,14 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [ - "GSE", "CD152", - "CTLA-4", "CELIAC3", - "IDDM12" + "IDDM12", + "GSE", + "CTLA-4" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "CTNNA1", @@ -9252,8 +9368,8 @@ "geneAliases": [ "CAP102" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "CYSLTR2", @@ -9271,11 +9387,11 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [ - "CysLT(2)", - "CYSLT2R" + "CYSLT2R", + "CysLT(2)" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "DCUN1D1", @@ -9295,12 +9411,12 @@ "geneAliases": [ "DCUN1L1", "SCCRO", + "Tes3", "RP42", - "SCRO", - "Tes3" + "SCRO" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "DDIT3", @@ -9319,11 +9435,11 @@ "sangerCGC": true, "geneAliases": [ "CHOP10", - "CHOP", - "GADD153" + "GADD153", + "CHOP" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "DEK", @@ -9343,8 +9459,8 @@ "geneAliases": [ "D6S231E" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "DNM2", @@ -9363,14 +9479,14 @@ "sangerCGC": true, "geneAliases": [ "CMT2M", + "DI-CMTB", "DYN2", "CMTDI1", - "DI-CMTB", "CMTDIB", "DYNII" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "DNMT3B", @@ -9388,8 +9504,8 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "DTX1", @@ -9410,8 +9526,8 @@ "hDx-1", "RNF140" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "DUSP22", @@ -9429,13 +9545,13 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [ - "JSP1", "MKPX", "JKAP", - "VHX" + "VHX", + "JSP1" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "DUSP4", @@ -9453,12 +9569,12 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [ + "MKP-2", "HVH2", - "TYP", - "MKP-2" + "TYP" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "E2F3", @@ -9476,8 +9592,8 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "EBF1", @@ -9495,12 +9611,12 @@ "vogelstein": false, "sangerCGC": true, "geneAliases": [ + "COE1", "EBF", - "OLF1", - "COE1" + "OLF1" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "EGFL7", @@ -9520,8 +9636,8 @@ "geneAliases": [ "ZNEU1" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "EIF1AX", @@ -9540,12 +9656,12 @@ "sangerCGC": false, "geneAliases": [ "eIF-4C", - "EIF1A", "eIF-1A", + "EIF1A", "EIF4C" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "EIF4E", @@ -9563,12 +9679,12 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [ - "EIF4E1", "EIF4EL1", - "EIF4F" + "EIF4F", + "EIF4E1" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "ELF3", @@ -9586,13 +9702,13 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [ + "ERT", "ESE-1", "EPR-1", - "ESX", - "ERT" + "ESX" ], - "tsg": true, - "oncogene": true + "oncogene": true, + "tsg": true }, { "hugoSymbol": "ELF4", @@ -9612,8 +9728,8 @@ "geneAliases": [ "ELFR" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "ELL", @@ -9631,13 +9747,13 @@ "vogelstein": false, "sangerCGC": true, "geneAliases": [ - "C19orf17", - "ELL1", "PPP1R68", - "Men" + "Men", + "C19orf17", + "ELL1" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "ELOC", @@ -9657,8 +9773,8 @@ "geneAliases": [ "TCEB1" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "EMSY", @@ -9678,8 +9794,8 @@ "geneAliases": [ "C11orf30" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "EPCAM", @@ -9719,8 +9835,8 @@ "MOC31", "MH99" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "ERF", @@ -9741,8 +9857,8 @@ "PE2", "PE-2" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "ETNK1", @@ -9763,8 +9879,8 @@ "EKI", "EKI1" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "EZH1", @@ -9785,8 +9901,8 @@ "KIAA0388", "KMT6B" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "FANCE", @@ -9804,11 +9920,11 @@ "vogelstein": false, "sangerCGC": true, "geneAliases": [ - "FACE", - "FAE" + "FAE", + "FACE" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "FANCF", @@ -9826,8 +9942,8 @@ "vogelstein": false, "sangerCGC": true, "geneAliases": [], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "FANCL", @@ -9850,8 +9966,8 @@ "FAAP43", "PHF9" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "FEV", @@ -9871,8 +9987,8 @@ "geneAliases": [ "Pet-1" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "FGF10", @@ -9890,8 +10006,8 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "FGF14", @@ -9912,8 +10028,8 @@ "FHF4", "SCA27" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "FGF23", @@ -9931,8 +10047,8 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "FGF6", @@ -9950,8 +10066,8 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "FHIT", @@ -9971,8 +10087,8 @@ "geneAliases": [ "FRA3B" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "FLI1", @@ -9992,8 +10108,8 @@ "geneAliases": [ "SIC-1" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "FOXO3", @@ -10016,8 +10132,8 @@ "FOXO3A", "FOXO2" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "FUS", @@ -10037,11 +10153,11 @@ "geneAliases": [ "ALS6", "HNRNPP2", - "TLS", - "hnRNP-P2" + "hnRNP-P2", + "TLS" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "FYN", @@ -10061,8 +10177,8 @@ "geneAliases": [ "MGC45350" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "GNA12", @@ -10082,8 +10198,8 @@ "geneAliases": [ "gep" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "GNB1", @@ -10101,8 +10217,8 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "GPS2", @@ -10120,8 +10236,8 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "GREM1", @@ -10139,15 +10255,15 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [ - "HMPS", "gremlin", - "CKTSF1B1", "DAND2", "CRAC1", + "HMPS", + "CKTSF1B1", "DRM" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "H1-3", @@ -10165,14 +10281,14 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [ - "HIST1H1D", "H1s-2", - "H1d", "H1F3", + "HIST1H1D", + "H1d", "H1.3" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "H1-4", @@ -10190,14 +10306,14 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [ + "H1F4", "HIST1H1E", "H1e", - "H1F4", "H1.4", "H1s-4" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "H2AC11", @@ -10215,13 +10331,13 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [ - "HIST1H2AG", "H2A.1b", "H2A/p", + "HIST1H2AG", "H2AFP" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "H2AC16", @@ -10244,8 +10360,8 @@ "dJ193B12.9", "H2A/i" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "H2AC17", @@ -10264,12 +10380,12 @@ "sangerCGC": false, "geneAliases": [ "HIST1H2AM", - "H2A/n", "H2AFN", - "H2A.1" + "H2A.1", + "H2A/n" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "H2AC6", @@ -10287,11 +10403,11 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [ - "HIST1H2AC", - "H2AFL" + "H2AFL", + "HIST1H2AC" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "H2BC11", @@ -10313,8 +10429,8 @@ "H2B/r", "H2BFR" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "H2BC12", @@ -10332,12 +10448,12 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [ - "H2BFT", "H2BFAiii", - "HIST1H2BK" + "HIST1H2BK", + "H2BFT" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "H2BC17", @@ -10355,13 +10471,13 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [ - "H2B/n", "H2B.2", "HIST1H2BO", + "H2B/n", "H2BFN" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "H2BC4", @@ -10383,8 +10499,8 @@ "H2B/l", "HIST1H2BC" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "H2BC5", @@ -10406,8 +10522,8 @@ "H2BFB", "HIST1H2BD" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "H3-4", @@ -10426,13 +10542,13 @@ "sangerCGC": false, "geneAliases": [ "H3.4", - "H3FT", - "H3t", "H3/g", - "HIST3H3" + "HIST3H3", + "H3FT", + "H3t" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "H3-5", @@ -10450,11 +10566,11 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [ - "H3F3C", - "H3.5" + "H3.5", + "H3F3C" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "H3C1", @@ -10472,12 +10588,12 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [ - "H3/A", "HIST1H3A", - "H3FA" + "H3FA", + "H3/A" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "H3C10", @@ -10496,12 +10612,12 @@ "sangerCGC": false, "geneAliases": [ "H3FK", + "H3/k", "HIST1H3H", - "H3F1K", - "H3/k" + "H3F1K" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "H3C11", @@ -10520,12 +10636,12 @@ "sangerCGC": false, "geneAliases": [ "H3.f", - "H3FF", "H3/f", + "H3FF", "HIST1H3I" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "H3C12", @@ -10544,11 +10660,11 @@ "sangerCGC": false, "geneAliases": [ "HIST1H3J", - "H3FJ", - "H3/j" + "H3/j", + "H3FJ" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "H3C13", @@ -10568,8 +10684,8 @@ "geneAliases": [ "HIST2H3D" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "H3C14", @@ -10596,8 +10712,8 @@ "H3.2", "MGC9629" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "H3C3", @@ -10619,8 +10735,8 @@ "HIST1H3C", "H3/c" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "H3C4", @@ -10642,8 +10758,8 @@ "HIST1H3D", "H3/b" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "H3C6", @@ -10661,13 +10777,13 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [ - "H3FD", "H3/d", + "H3FD", "HIST1H3E", "H3.1" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "H3C7", @@ -10689,8 +10805,8 @@ "HIST1H3F", "H3FI" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "H3C8", @@ -10708,12 +10824,12 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [ - "H3FH", "H3/h", - "HIST1H3G" + "HIST1H3G", + "H3FH" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "HDAC4", @@ -10739,8 +10855,8 @@ "HDAC-A", "HDAC-4" ], - "tsg": true, - "oncogene": true + "oncogene": true, + "tsg": true }, { "hugoSymbol": "HDAC7", @@ -10761,8 +10877,8 @@ "HDAC7A", "DKFZP586J0917" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "HIF1A", @@ -10781,13 +10897,13 @@ "sangerCGC": true, "geneAliases": [ "PASD8", - "HIF-1alpha", "bHLHe78", - "HIF1", - "MOP1" + "MOP1", + "HIF-1alpha", + "HIF1" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "HLA-B", @@ -10807,8 +10923,8 @@ "geneAliases": [ "AS" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "HMGA1", @@ -10828,8 +10944,8 @@ "geneAliases": [ "HMGIY" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "HMGA2", @@ -10851,8 +10967,30 @@ "BABL", "LIPO" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false + }, + { + "hugoSymbol": "HOXA11", + "entrezGeneId": 3207, + "grch37Isoform": "ENST00000006015", + "grch37RefSeq": "NM_005523", + "grch38Isoform": "ENST00000006015", + "grch38RefSeq": "NM_005523", + "oncokbAnnotated": true, + "occurrenceCount": 3, + "mSKImpact": false, + "mSKHeme": false, + "foundation": false, + "foundationHeme": true, + "vogelstein": false, + "sangerCGC": true, + "geneAliases": [ + "HOX1", + "HOX1I" + ], + "oncogene": false, + "tsg": true }, { "hugoSymbol": "HOXB13", @@ -10870,8 +11008,8 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [], - "tsg": true, - "oncogene": true + "oncogene": true, + "tsg": true }, { "hugoSymbol": "HSP90AA1", @@ -10896,8 +11034,8 @@ "HSPC1", "HSPCA" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "ICOSLG", @@ -10926,8 +11064,8 @@ "B7RP-1", "ICOS-L" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "IFNGR1", @@ -10945,11 +11083,11 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [ - "IFNGR", - "CD119" + "CD119", + "IFNGR" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "IGF1", @@ -10967,13 +11105,13 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [ - "IGF", "IGF-I", "IGFI", + "IGF", "IGF1A" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "IGF2", @@ -10995,8 +11133,8 @@ "FLJ44734", "IGF-II" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "IL10", @@ -11014,12 +11152,12 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [ - "IL10A", "CSIF", + "IL10A", "IL-10" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "INHA", @@ -11037,8 +11175,8 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "INPP4A", @@ -11058,8 +11196,8 @@ "geneAliases": [ "INPP4" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "INPPL1", @@ -11079,8 +11217,8 @@ "geneAliases": [ "SHIP2" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "INSR", @@ -11100,8 +11238,8 @@ "geneAliases": [ "CD220" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "IRF1", @@ -11121,8 +11259,8 @@ "geneAliases": [ "MAR" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "IRF8", @@ -11144,8 +11282,8 @@ "IRF-8", "ICSBP" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "IRS1", @@ -11165,8 +11303,8 @@ "geneAliases": [ "HIRS-1" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "JARID2", @@ -11186,8 +11324,8 @@ "geneAliases": [ "JMJ" ], - "tsg": true, - "oncogene": true + "oncogene": true, + "tsg": true }, { "hugoSymbol": "KAT6A", @@ -11206,13 +11344,13 @@ "sangerCGC": true, "geneAliases": [ "MYST3", + "ZNF220", "RUNXBP2", "ZC2HC6A", - "ZNF220", "MOZ" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "KLHL6", @@ -11232,8 +11370,8 @@ "geneAliases": [ "FLJ00029" ], - "tsg": true, - "oncogene": true + "oncogene": true, + "tsg": true }, { "hugoSymbol": "KMT2B", @@ -11259,8 +11397,8 @@ "MLL1B", "TRX2" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "KMT5A", @@ -11280,11 +11418,11 @@ "geneAliases": [ "SET8", "PR-Set7", - "SET07", - "SETD8" + "SETD8", + "SET07" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "KNSTRN", @@ -11308,8 +11446,8 @@ "FLJ14502", "C15orf23" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "LCK", @@ -11327,8 +11465,8 @@ "vogelstein": false, "sangerCGC": true, "geneAliases": [], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "LEF1", @@ -11350,8 +11488,8 @@ "TCF1ALPHA", "TCF10" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "LMO2", @@ -11374,8 +11512,8 @@ "RHOM2", "TTG2" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "LRP1B", @@ -11396,8 +11534,8 @@ "LRPDIT", "LRP-DIT" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "LZTR1", @@ -11418,8 +11556,8 @@ "BTBD29", "LZTR-1" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "MAFB", @@ -11439,8 +11577,8 @@ "geneAliases": [ "KRML" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "MAPK3", @@ -11460,11 +11598,11 @@ "geneAliases": [ "p44erk1", "PRKM3", - "p44mapk", - "ERK1" + "ERK1", + "p44mapk" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "MAPKAP1", @@ -11486,8 +11624,8 @@ "MIP1", "SIN1" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "MDC1", @@ -11505,12 +11643,12 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [ + "Em:AB023051.5", "NFBD1", - "KIAA0170", - "Em:AB023051.5" + "KIAA0170" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "MECOM", @@ -11529,13 +11667,13 @@ "sangerCGC": true, "geneAliases": [ "MDS1", - "EVI1", - "KMT8E", "MDS1-EVI1", - "PRDM3" + "PRDM3", + "EVI1", + "KMT8E" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "MGA", @@ -11553,13 +11691,13 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [ - "MXD5", "MAD5", + "MXD5", "KIAA0518", "FLJ12634" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "MLLT10", @@ -11579,8 +11717,8 @@ "geneAliases": [ "AF10" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "MLLT3", @@ -11602,8 +11740,31 @@ "YEATS3", "AF-9" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false + }, + { + "hugoSymbol": "MN1", + "entrezGeneId": 4330, + "grch37Isoform": "ENST00000302326", + "grch37RefSeq": "NM_002430", + "grch38Isoform": "ENST00000302326", + "grch38RefSeq": "NM_002430", + "oncokbAnnotated": true, + "occurrenceCount": 3, + "mSKImpact": false, + "mSKHeme": false, + "foundation": false, + "foundationHeme": true, + "vogelstein": false, + "sangerCGC": true, + "geneAliases": [ + "MGCR1", + "MGCR1-PEN", + "MGCR" + ], + "oncogene": true, + "tsg": false }, { "hugoSymbol": "MSI1", @@ -11621,8 +11782,8 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "MST1", @@ -11641,12 +11802,12 @@ "sangerCGC": false, "geneAliases": [ "NF15S2", - "D3F15S2", "HGFL", + "D3F15S2", "DNF15S2" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "MTAP", @@ -11664,11 +11825,11 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [ - "c86fus", - "MSAP" + "MSAP", + "c86fus" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "MYH11", @@ -11689,8 +11850,8 @@ "SMHC", "SMMHC" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "NCOA3", @@ -11719,8 +11880,8 @@ "ACTR", "CAGH16" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "NCSTN", @@ -11738,11 +11899,11 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [ - "KIAA0253", - "APH2" + "APH2", + "KIAA0253" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "NEGR1", @@ -11765,8 +11926,8 @@ "MGC46680", "KILON" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "NKX3-1", @@ -11784,12 +11945,12 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [ - "NKX3.1", "NKX3A", + "NKX3.1", "BAPX2" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "NOTCH4", @@ -11809,8 +11970,8 @@ "geneAliases": [ "INT3" ], - "tsg": true, - "oncogene": true + "oncogene": true, + "tsg": true }, { "hugoSymbol": "NR4A3", @@ -11831,8 +11992,8 @@ "CSMF", "MINOR" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "NTHL1", @@ -11853,8 +12014,8 @@ "OCTS3", "NTH1" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "NUF2", @@ -11873,11 +12034,11 @@ "sangerCGC": false, "geneAliases": [ "CT106", - "NUF2R", - "CDCA1" + "CDCA1", + "NUF2R" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "NUP214", @@ -11897,11 +12058,11 @@ "geneAliases": [ "CAN", "N214", - "CAIN", - "D9S46E" + "D9S46E", + "CAIN" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "NUP98", @@ -11919,12 +12080,12 @@ "vogelstein": false, "sangerCGC": true, "geneAliases": [ - "NUP96", "Nup98-96", + "NUP96", "Nup98-Nup96" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "NUTM1", @@ -11947,8 +12108,8 @@ "C15orf55", "DKFZp434O192" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "PAK1", @@ -11966,8 +12127,8 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "PAK5", @@ -11988,8 +12149,8 @@ "PAK7", "KIAA1264" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "PAX3", @@ -12010,8 +12171,8 @@ "WS1", "HUP2" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "PAX7", @@ -12031,8 +12192,8 @@ "geneAliases": [ "Hup1" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "PCBP1", @@ -12055,8 +12216,8 @@ "hnRNP-E1", "HNRPX" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "PDGFB", @@ -12074,11 +12235,11 @@ "vogelstein": false, "sangerCGC": true, "geneAliases": [ - "SIS", - "SSV" + "SSV", + "SIS" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "PDK1", @@ -12096,8 +12257,8 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "PDPK1", @@ -12115,8 +12276,8 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "PGR", @@ -12137,8 +12298,8 @@ "PR", "NR3C3" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "PIK3C3", @@ -12158,8 +12319,8 @@ "geneAliases": [ "Vps34" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "PIK3CD", @@ -12179,8 +12340,8 @@ "geneAliases": [ "p110D" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "PIK3R3", @@ -12198,8 +12359,8 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "PLCG1", @@ -12218,13 +12379,13 @@ "sangerCGC": true, "geneAliases": [ "NCKAP3", - "PLCgamma1", "PLC-II", + "PLCgamma1", "PLC1", "PLC148" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "PLK2", @@ -12244,8 +12405,8 @@ "geneAliases": [ "SNK" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "PMAIP1", @@ -12265,8 +12426,31 @@ "geneAliases": [ "NOXA" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true + }, + { + "hugoSymbol": "PML", + "entrezGeneId": 5371, + "grch37Isoform": "ENST00000268058", + "grch37RefSeq": "NM_033238", + "grch38Isoform": "ENST00000268058", + "grch38RefSeq": "NM_033238", + "oncokbAnnotated": true, + "occurrenceCount": 3, + "mSKImpact": false, + "mSKHeme": false, + "foundation": false, + "foundationHeme": true, + "vogelstein": false, + "sangerCGC": true, + "geneAliases": [ + "MYL", + "TRIM19", + "RNF71" + ], + "oncogene": false, + "tsg": true }, { "hugoSymbol": "PMS1", @@ -12287,8 +12471,8 @@ "PMSL1", "MLH2" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "PNRC1", @@ -12306,12 +12490,12 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [ + "PRR2", "B4-2", - "PROL2", - "PRR2" + "PROL2" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "PPP4R2", @@ -12329,8 +12513,8 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "PRDM14", @@ -12348,8 +12532,8 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "PRKD1", @@ -12372,8 +12556,8 @@ "PRKCM", "PKC-mu" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "PTP4A1", @@ -12394,8 +12578,8 @@ "PRL-1", "PTPCAAX1" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "PTPN2", @@ -12418,8 +12602,8 @@ "TCELLPTP", "PTPT" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "PTPRD", @@ -12440,8 +12624,8 @@ "HPTP", "PTPD" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "PTPRS", @@ -12459,8 +12643,8 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "QKI", @@ -12480,8 +12664,8 @@ "geneAliases": [ "QK3" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "RAB35", @@ -12501,8 +12685,8 @@ "geneAliases": [ "H-ray" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "RAC2", @@ -12522,8 +12706,8 @@ "geneAliases": [ "EN-7" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "RASA1", @@ -12541,14 +12725,14 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [ + "CM-AVM", + "GAP", "p120GAP", "p120RASGAP", - "CM-AVM", - "RASA", - "GAP" + "RASA" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "RBM15", @@ -12566,11 +12750,11 @@ "vogelstein": false, "sangerCGC": true, "geneAliases": [ - "OTT", - "OTT1" + "OTT1", + "OTT" ], - "tsg": true, - "oncogene": true + "oncogene": true, + "tsg": true }, { "hugoSymbol": "RECQL", @@ -12588,11 +12772,11 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [ - "RecQL1", - "RecQ1" + "RecQ1", + "RecQL1" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "RHEB", @@ -12612,8 +12796,8 @@ "geneAliases": [ "RHEB2" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "RIT1", @@ -12637,8 +12821,8 @@ "ROC1", "MGC125865" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "RPS6KA4", @@ -12659,8 +12843,8 @@ "RSK-B", "MSK2" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "RPS6KB2", @@ -12686,8 +12870,8 @@ "S6KB", "S6K\u03b2" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "RRAGC", @@ -12705,11 +12889,11 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [ - "GTR2", - "FLJ13311" + "FLJ13311", + "GTR2" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "RRAS", @@ -12729,8 +12913,8 @@ "geneAliases": [ "R-Ras" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "RTEL1", @@ -12748,15 +12932,15 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [ - "KIAA1088", "NHL", "DKFZP434C013", + "KIAA1088", "C20orf41", "bK3184A7.3", "RTEL" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "RXRA", @@ -12776,8 +12960,8 @@ "geneAliases": [ "NR2B1" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "RYBP", @@ -12799,8 +12983,8 @@ "DEDAF", "AAP1" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "SESN1", @@ -12821,8 +13005,8 @@ "PA26", "SEST1" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "SESN2", @@ -12840,12 +13024,12 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [ - "HI95", "DKFZp761M0212", + "HI95", "SEST2" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "SESN3", @@ -12866,8 +13050,8 @@ "SEST3", "MGC29667" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "SET", @@ -12886,14 +13070,14 @@ "sangerCGC": true, "geneAliases": [ "IGAAD", - "TAF-I", "IPP2A2", - "PHAPII", "2PP2A", - "TAF-IBETA" + "TAF-IBETA", + "TAF-I", + "PHAPII" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "SETDB1", @@ -12911,14 +13095,14 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [ - "TDRD21", "KMT1E", + "TDRD21", "KIAA0067", "KG1T", "ESET" ], - "tsg": true, - "oncogene": true + "oncogene": true, + "tsg": true }, { "hugoSymbol": "SH2D1A", @@ -12944,8 +13128,8 @@ "EBVS", "XLP" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "SHOC2", @@ -12964,13 +13148,13 @@ "sangerCGC": false, "geneAliases": [ "SUR-8", + "KIAA0862", "SOC-2", "SOC2", - "KIAA0862", "SUR8" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "SHQ1", @@ -12988,11 +13172,11 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [ - "Shq1p", - "FLJ10539" + "FLJ10539", + "Shq1p" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "SLX4", @@ -13011,12 +13195,12 @@ "sangerCGC": false, "geneAliases": [ "KIAA1987", + "KIAA1784", "FANCP", - "BTBD12", - "KIAA1784" + "BTBD12" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "SMARCD1", @@ -13035,11 +13219,11 @@ "sangerCGC": false, "geneAliases": [ "BAF60A", - "CRACD1", - "Rsc6p" + "Rsc6p", + "CRACD1" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "SMARCE1", @@ -13059,8 +13243,8 @@ "geneAliases": [ "BAF57" ], - "tsg": true, - "oncogene": true + "oncogene": true, + "tsg": true }, { "hugoSymbol": "SMC1A", @@ -13084,8 +13268,8 @@ "SB1.8", "Smcb" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "SMC3", @@ -13103,14 +13287,14 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [ - "CSPG6", "SMC3L1", + "CSPG6", "HCAP", "bamacan", "BAM" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "SMYD3", @@ -13132,8 +13316,8 @@ "ZNFN3A1", "ZMYND1" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "SOS1", @@ -13153,8 +13337,8 @@ "geneAliases": [ "GINGF" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "SOX17", @@ -13172,8 +13356,8 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "SPRED1", @@ -13194,8 +13378,8 @@ "FLJ33903", "PPP1R147" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "SS18", @@ -13215,8 +13399,8 @@ "geneAliases": [ "SSXT" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "STK19", @@ -13234,11 +13418,11 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [ - "G11", - "D6S60" + "D6S60", + "G11" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "STK40", @@ -13259,8 +13443,8 @@ "MGC4796", "SgK495" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "TAL1", @@ -13281,8 +13465,8 @@ "bHLHa17", "TCL5" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "TAP1", @@ -13301,11 +13485,11 @@ "sangerCGC": false, "geneAliases": [ "ABCB2", - "D6S114E", - "RING4" + "RING4", + "D6S114E" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "TAP2", @@ -13323,12 +13507,12 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [ - "D6S217E", "ABCB3", - "RING11" + "RING11", + "D6S217E" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "TCL1A", @@ -13348,8 +13532,8 @@ "geneAliases": [ "TCL1" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "TFE3", @@ -13367,11 +13551,11 @@ "vogelstein": false, "sangerCGC": true, "geneAliases": [ - "TFEA", - "bHLHe33" + "bHLHe33", + "TFEA" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "TGFBR1", @@ -13396,8 +13580,8 @@ "TBR-i", "ALK-5" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "TLX1", @@ -13418,8 +13602,8 @@ "TCL3", "HOX11" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "TLX3", @@ -13440,8 +13624,32 @@ "HOX11L2", "RNX" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false + }, + { + "hugoSymbol": "TNFRSF17", + "entrezGeneId": 608, + "grch37Isoform": "ENST00000053243", + "grch37RefSeq": "NM_001192", + "grch38Isoform": "ENST00000053243", + "grch38RefSeq": "NM_001192", + "oncokbAnnotated": true, + "occurrenceCount": 3, + "mSKImpact": false, + "mSKHeme": false, + "foundation": false, + "foundationHeme": true, + "vogelstein": false, + "sangerCGC": true, + "geneAliases": [ + "TNFRSF13A", + "BCMA", + "CD269", + "BCM" + ], + "oncogene": true, + "tsg": false }, { "hugoSymbol": "TP53BP1", @@ -13463,8 +13671,8 @@ "53BP1", "p202" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "TRAF3", @@ -13483,13 +13691,13 @@ "sangerCGC": false, "geneAliases": [ "CD40bp", - "CAP-1", - "CRAF1", "LAP1", - "RNF118" + "RNF118", + "CAP-1", + "CRAF1" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "TRAF5", @@ -13509,8 +13717,8 @@ "geneAliases": [ "RNF84" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "TYK2", @@ -13530,8 +13738,8 @@ "geneAliases": [ "JTK1" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "U2AF2", @@ -13551,8 +13759,8 @@ "geneAliases": [ "U2AF65" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "UBR5", @@ -13573,11 +13781,11 @@ "HYD", "DD5", "EDD", - "EDD1", - "KIAA0896" + "KIAA0896", + "EDD1" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "UPF1", @@ -13597,13 +13805,38 @@ "geneAliases": [ "HUPF1", "pNORF1", + "smg-2", "KIAA0221", "RENT1", - "NORF1", - "smg-2" + "NORF1" + ], + "oncogene": false, + "tsg": false + }, + { + "hugoSymbol": "USP6", + "entrezGeneId": 9098, + "grch37Isoform": "ENST00000250066", + "grch37RefSeq": "NM_004505", + "grch38Isoform": "ENST00000250066", + "grch38RefSeq": "NM_004505", + "oncokbAnnotated": true, + "occurrenceCount": 3, + "mSKImpact": false, + "mSKHeme": false, + "foundation": false, + "foundationHeme": true, + "vogelstein": false, + "sangerCGC": true, + "geneAliases": [ + "Tre-2", + "HRP1", + "TRE17", + "TRESMCR", + "Tre2" ], - "tsg": false, - "oncogene": false + "oncogene": true, + "tsg": false }, { "hugoSymbol": "USP8", @@ -13626,8 +13859,8 @@ "SPG59", "KIAA0055" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "VTCN1", @@ -13651,8 +13884,8 @@ "B7-H4", "B7H4" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "XBP1", @@ -13672,8 +13905,8 @@ "geneAliases": [ "XBP2" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "XIAP", @@ -13691,13 +13924,13 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [ - "BIRC4", - "ILP-1", "hILP", - "API3" + "API3", + "BIRC4", + "ILP-1" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "YAP1", @@ -13717,8 +13950,8 @@ "geneAliases": [ "YAP65" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "YES1", @@ -13740,8 +13973,8 @@ "c-yes", "Yes" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "ZNF217", @@ -13761,8 +13994,8 @@ "geneAliases": [ "ZABC1" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "ABI1", @@ -13784,8 +14017,8 @@ "SSH3BP1", "ABI-1" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "ACKR3", @@ -13803,13 +14036,13 @@ "vogelstein": false, "sangerCGC": true, "geneAliases": [ + "RDC1", "CMKOR1", "GPR159", - "CXCR7", - "RDC1" + "CXCR7" ], - "tsg": true, - "oncogene": true + "oncogene": true, + "tsg": true }, { "hugoSymbol": "ACTG1", @@ -13831,31 +14064,56 @@ "ACTG", "DFNA20" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { - "hugoSymbol": "AFDN", - "entrezGeneId": 4301, - "grch37Isoform": "", - "grch37RefSeq": "", - "grch38Isoform": "", - "grch38RefSeq": "", - "oncokbAnnotated": false, + "hugoSymbol": "ACVR2A", + "entrezGeneId": 92, + "grch37Isoform": "ENST00000241416", + "grch37RefSeq": "NM_001278579", + "grch38Isoform": "ENST00000241416", + "grch38RefSeq": "NM_001278579", + "oncokbAnnotated": true, "occurrenceCount": 2, "mSKImpact": false, "mSKHeme": false, "foundation": false, - "foundationHeme": true, + "foundationHeme": false, "vogelstein": false, "sangerCGC": true, "geneAliases": [ - "AF-6", - "AF6", - "MLLT4" + "ACTRII", + "ACVR2" + ], + "oncogene": true, + "tsg": true + }, + { + "hugoSymbol": "ADGRA2", + "entrezGeneId": 25960, + "grch37Isoform": "ENST00000412232", + "grch37RefSeq": "NM_032777", + "grch38Isoform": "ENST00000412232", + "grch38RefSeq": "NM_032777", + "oncokbAnnotated": true, + "occurrenceCount": 2, + "mSKImpact": false, + "mSKHeme": false, + "foundation": false, + "foundationHeme": true, + "vogelstein": false, + "sangerCGC": false, + "geneAliases": [ + "DKFZp434C211", + "KIAA1531", + "DKFZp434J0911", + "TEM5", + "FLJ14390", + "GPR124" ], - "tsg": false, - "oncogene": false + "oncogene": true, + "tsg": false }, { "hugoSymbol": "AFF1", @@ -13878,8 +14136,8 @@ "MLLT2", "AF4" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "AGO1", @@ -13900,8 +14158,8 @@ "hAGO1", "EIF2C1" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "ALB", @@ -13919,8 +14177,8 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "APLNR", @@ -13938,13 +14196,13 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [ + "AGTRL1", "APJR", "FLJ90771", - "AGTRL1", "APJ" ], - "tsg": true, - "oncogene": true + "oncogene": true, + "tsg": true }, { "hugoSymbol": "ARFRP1", @@ -13966,32 +14224,8 @@ "Arp1", "ARP" ], - "tsg": false, - "oncogene": false - }, - { - "hugoSymbol": "ARHGAP26", - "entrezGeneId": 23092, - "grch37Isoform": "", - "grch37RefSeq": "", - "grch38Isoform": "", - "grch38RefSeq": "", - "oncokbAnnotated": false, - "occurrenceCount": 2, - "mSKImpact": false, - "mSKHeme": false, - "foundation": false, - "foundationHeme": true, - "vogelstein": false, - "sangerCGC": true, - "geneAliases": [ - "GRAF", - "OPHN1L", - "OPHN1L1", - "KIAA0621" - ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "ARHGEF28", @@ -14013,8 +14247,8 @@ "RGNEF", "RIP2" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "ARID3A", @@ -14035,8 +14269,8 @@ "DRIL1", "BRIGHT" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "ARID3B", @@ -14057,8 +14291,8 @@ "DRIL2", "BDP" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "ARID3C", @@ -14076,8 +14310,8 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "ARID4A", @@ -14098,8 +14332,8 @@ "RBBP1", "RBP-1" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "ARID4B", @@ -14122,8 +14356,8 @@ "SAP180", "BCAA" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "ARID5A", @@ -14144,8 +14378,8 @@ "MRF-1", "RP11-363D14" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "ARNT", @@ -14166,31 +14400,8 @@ "HIF-1beta", "bHLHe2" ], - "tsg": false, - "oncogene": false - }, - { - "hugoSymbol": "ATIC", - "entrezGeneId": 471, - "grch37Isoform": "", - "grch37RefSeq": "", - "grch38Isoform": "", - "grch38RefSeq": "", - "oncokbAnnotated": false, - "occurrenceCount": 2, - "mSKImpact": false, - "mSKHeme": false, - "foundation": false, - "foundationHeme": true, - "vogelstein": false, - "sangerCGC": true, - "geneAliases": [ - "IMPCHASE", - "PURH", - "AICARFT" - ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "ATP1A1", @@ -14208,8 +14419,8 @@ "vogelstein": false, "sangerCGC": true, "geneAliases": [], - "tsg": true, - "oncogene": true + "oncogene": true, + "tsg": true }, { "hugoSymbol": "ATP6AP1", @@ -14237,8 +14448,8 @@ "Ac45", "CF2" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "ATP6V1B2", @@ -14256,11 +14467,11 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [ - "HO57", - "ATP6B2" + "ATP6B2", + "HO57" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "ATXN2", @@ -14278,12 +14489,12 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [ - "TNRC13", "ATX2", + "TNRC13", "SCA2" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "ATXN7", @@ -14306,8 +14517,8 @@ "OPCA3", "SGF73" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "BACH2", @@ -14327,8 +14538,8 @@ "geneAliases": [ "BTBD25" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "BCL11A", @@ -14354,31 +14565,8 @@ "BCL11A-L", "CTIP1" ], - "tsg": false, - "oncogene": false - }, - { - "hugoSymbol": "BCL2L2", - "entrezGeneId": 599, - "grch37Isoform": "", - "grch37RefSeq": "", - "grch38Isoform": "", - "grch38RefSeq": "", - "oncokbAnnotated": false, - "occurrenceCount": 2, - "mSKImpact": false, - "mSKHeme": false, - "foundation": true, - "foundationHeme": true, - "vogelstein": false, - "sangerCGC": false, - "geneAliases": [ - "BCL-W", - "PPP1R51", - "KIAA0271" - ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "BRD3", @@ -14400,8 +14588,8 @@ "KIAA0043", "RING3L" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "BRSK1", @@ -14421,8 +14609,32 @@ "geneAliases": [ "KIAA1811" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true + }, + { + "hugoSymbol": "BUB1B", + "entrezGeneId": 701, + "grch37Isoform": "ENST00000287598", + "grch37RefSeq": "NM_001211.5", + "grch38Isoform": "ENST00000287598", + "grch38RefSeq": "NM_001211.6", + "oncokbAnnotated": true, + "occurrenceCount": 2, + "mSKImpact": false, + "mSKHeme": false, + "foundation": false, + "foundationHeme": false, + "vogelstein": false, + "sangerCGC": true, + "geneAliases": [ + "SSK1", + "MAD3L", + "BUBR1", + "Bub1A" + ], + "oncogene": true, + "tsg": false }, { "hugoSymbol": "CACNA1D", @@ -14440,14 +14652,14 @@ "vogelstein": false, "sangerCGC": true, "geneAliases": [ - "CACNL1A2", "CACN4", + "CACNL1A2", "CCHL1A2", "CACH3", "Cav1.3" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "CAD", @@ -14467,8 +14679,8 @@ "geneAliases": [ "GATD4" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "CAMTA1", @@ -14488,8 +14700,8 @@ "geneAliases": [ "KIAA0833" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "CANT1", @@ -14510,8 +14722,8 @@ "SCAN-1", "SHAPY" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "CARS1", @@ -14531,50 +14743,49 @@ "geneAliases": [ "CARS" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { - "hugoSymbol": "CD28", - "entrezGeneId": 940, - "grch37Isoform": "ENST00000324106", - "grch37RefSeq": "NM_006139.3", - "grch38Isoform": "ENST00000324106", - "grch38RefSeq": "NM_006139.3", - "oncokbAnnotated": true, + "hugoSymbol": "CCN6", + "entrezGeneId": 8838, + "grch37Isoform": "ENST00000368666", + "grch37RefSeq": "NM_198239.1", + "grch38Isoform": "ENST00000368666", + "grch38RefSeq": "NM_198239.1", + "oncokbAnnotated": true, "occurrenceCount": 2, "mSKImpact": false, - "mSKHeme": true, + "mSKHeme": false, "foundation": false, - "foundationHeme": false, + "foundationHeme": true, "vogelstein": false, "sangerCGC": false, - "geneAliases": [], - "tsg": false, - "oncogene": true + "geneAliases": [ + "WISP-3", + "WISP3" + ], + "oncogene": true, + "tsg": true }, { - "hugoSymbol": "CD70", - "entrezGeneId": 970, - "grch37Isoform": "", - "grch37RefSeq": "", - "grch38Isoform": "", - "grch38RefSeq": "", - "oncokbAnnotated": false, + "hugoSymbol": "CD28", + "entrezGeneId": 940, + "grch37Isoform": "ENST00000324106", + "grch37RefSeq": "NM_006139.3", + "grch38Isoform": "ENST00000324106", + "grch38RefSeq": "NM_006139.3", + "oncokbAnnotated": true, "occurrenceCount": 2, "mSKImpact": false, - "mSKHeme": false, - "foundation": true, - "foundationHeme": true, + "mSKHeme": true, + "foundation": false, + "foundationHeme": false, "vogelstein": false, "sangerCGC": false, - "geneAliases": [ - "CD27L", - "CD27LG", - "TNFSF7" - ], - "tsg": false, - "oncogene": false + "geneAliases": [], + "oncogene": true, + "tsg": false }, { "hugoSymbol": "CDH11", @@ -14594,8 +14805,8 @@ "geneAliases": [ "CAD11" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "CDX2", @@ -14615,8 +14826,8 @@ "geneAliases": [ "CDX3" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "CEP43", @@ -14634,11 +14845,11 @@ "vogelstein": false, "sangerCGC": true, "geneAliases": [ - "FGFR1OP", - "FOP" + "FOP", + "FGFR1OP" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "CHD2", @@ -14657,12 +14868,12 @@ "sangerCGC": false, "geneAliases": [ "DKFZp781D1727", - "DKFZp686E01200", "DKFZp547I1315", + "DKFZp686E01200", "FLJ38614" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "CHD4", @@ -14680,11 +14891,11 @@ "vogelstein": false, "sangerCGC": true, "geneAliases": [ - "Mi-2b", - "Mi2-BETA" + "Mi2-BETA", + "Mi-2b" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "CLTC", @@ -14705,8 +14916,8 @@ "CLTCL2", "Hc" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "CMTR2", @@ -14729,8 +14940,8 @@ "FLJ11171", "AFT" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "COL2A1", @@ -14752,8 +14963,8 @@ "SEDC", "AOM" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "CRBN", @@ -14771,11 +14982,11 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [ - "MRT2A", - "MRT2" + "MRT2", + "MRT2A" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "CREB1", @@ -14793,8 +15004,8 @@ "vogelstein": false, "sangerCGC": true, "geneAliases": [], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "CREB3L1", @@ -14814,8 +15025,8 @@ "geneAliases": [ "OASIS" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "CREB3L2", @@ -14836,8 +15047,8 @@ "TCAG_1951439", "BBF2H7" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "CTR9", @@ -14855,12 +15066,12 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [ - "p150TSP", "SH2BP1", - "KIAA0155" + "KIAA0155", + "p150TSP" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "CUL4A", @@ -14878,8 +15089,8 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "CYP19A1", @@ -14905,8 +15116,32 @@ "ARO", "P-450AROM" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false + }, + { + "hugoSymbol": "DDB2", + "entrezGeneId": 1643, + "grch37Isoform": "ENST00000256996", + "grch37RefSeq": "NM_000107", + "grch38Isoform": "ENST00000256996", + "grch38RefSeq": "NM_000107", + "oncokbAnnotated": true, + "occurrenceCount": 2, + "mSKImpact": false, + "mSKHeme": false, + "foundation": false, + "foundationHeme": false, + "vogelstein": false, + "sangerCGC": true, + "geneAliases": [ + "UV-DDB2", + "FLJ34321", + "XPE", + "DDBB" + ], + "oncogene": false, + "tsg": true }, { "hugoSymbol": "DDX10", @@ -14924,11 +15159,11 @@ "vogelstein": false, "sangerCGC": true, "geneAliases": [ - "HRH-J8", - "Dbp4" + "Dbp4", + "HRH-J8" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "DDX5", @@ -14950,8 +15185,8 @@ "HLR1", "p68" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "DDX6", @@ -14969,11 +15204,11 @@ "vogelstein": false, "sangerCGC": true, "geneAliases": [ - "HLR2", - "Rck/p54" + "Rck/p54", + "HLR2" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "ECT2L", @@ -14993,11 +15228,11 @@ "geneAliases": [ "C6orf91", "ARHGEF32", - "LFDH", - "FBXO49" + "FBXO49", + "LFDH" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "EGR1", @@ -15015,15 +15250,15 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [ + "NGFI-A", "G0S30", "AT225", - "NGFI-A", "ZIF-268", "TIS8", "KROX-24" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "EIF3E", @@ -15042,11 +15277,11 @@ "sangerCGC": true, "geneAliases": [ "INT6", - "eIF3-p48", - "EIF3S6" + "EIF3S6", + "eIF3-p48" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "ELK4", @@ -15064,8 +15299,8 @@ "vogelstein": false, "sangerCGC": true, "geneAliases": [], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "ELN", @@ -15083,12 +15318,12 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [ - "WS", + "SVAS", "WBS", - "SVAS" + "WS" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "EML4", @@ -15107,11 +15342,11 @@ "sangerCGC": true, "geneAliases": [ "ELP120", - "ROPP120", - "C2orf2" + "C2orf2", + "ROPP120" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "EP400", @@ -15131,13 +15366,13 @@ "geneAliases": [ "DKFZP434I225", "P400", - "KIAA1818", "TNRC12", "CAGH32", - "KIAA1498" + "KIAA1498", + "KIAA1818" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "EPHB4", @@ -15155,11 +15390,11 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [ - "HTK", - "Tyro11" + "Tyro11", + "HTK" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "EPOR", @@ -15177,8 +15412,8 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "EPS15", @@ -15196,11 +15431,11 @@ "vogelstein": false, "sangerCGC": true, "geneAliases": [ - "MLLT5", - "AF-1P" + "AF-1P", + "MLLT5" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "ERC1", @@ -15224,8 +15459,8 @@ "ELKS", "MGC12974" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "ESCO2", @@ -15243,11 +15478,11 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [ - "EFO2", - "RBS" + "RBS", + "EFO2" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "ETAA1", @@ -15267,8 +15502,8 @@ "geneAliases": [ "ETAA16" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "ETS1", @@ -15287,11 +15522,11 @@ "sangerCGC": false, "geneAliases": [ "EWSR2", - "FLJ10768", - "ETS-1" + "ETS-1", + "FLJ10768" ], - "tsg": true, - "oncogene": true + "oncogene": true, + "tsg": true }, { "hugoSymbol": "EXT1", @@ -15309,12 +15544,12 @@ "vogelstein": false, "sangerCGC": true, "geneAliases": [ + "ttv", "LGCR", - "LGS", - "ttv" + "LGS" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "EZHIP", @@ -15322,7 +15557,7 @@ "grch37Isoform": "ENST00000342995", "grch37RefSeq": "NM_203407.2", "grch38Isoform": "ENST00000342995", - "grch38RefSeq": "", + "grch38RefSeq": "NM_203407.3", "oncokbAnnotated": true, "occurrenceCount": 2, "mSKImpact": true, @@ -15335,8 +15570,8 @@ "CXorf67", "CATACOMB" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "EZR", @@ -15356,8 +15591,8 @@ "geneAliases": [ "VIL2" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "FCGR2B", @@ -15375,13 +15610,13 @@ "vogelstein": false, "sangerCGC": true, "geneAliases": [ - "FCG2", "FCGR2", + "FCG2", "CD32B", "CD32" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "FCRL4", @@ -15404,8 +15639,8 @@ "FCRH4", "IGFP2" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "FES", @@ -15425,8 +15660,8 @@ "geneAliases": [ "FPS" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "FOXF1", @@ -15447,8 +15682,8 @@ "FKHL5", "FREAC1" ], - "tsg": true, - "oncogene": true + "oncogene": true, + "tsg": true }, { "hugoSymbol": "FOXO4", @@ -15469,8 +15704,8 @@ "MLLT7", "AFX1" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "FRS2", @@ -15492,8 +15727,8 @@ "FRS2A", "SNT-1" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "FSTL3", @@ -15514,8 +15749,8 @@ "FSRP", "FLRG" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "FURIN", @@ -15537,8 +15772,8 @@ "PACE", "PCSK3" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "GAB1", @@ -15558,8 +15793,8 @@ "geneAliases": [ "DFNB26" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "GAB2", @@ -15579,8 +15814,8 @@ "geneAliases": [ "KIAA0571" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "GABRA6", @@ -15598,8 +15833,8 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "GAS7", @@ -15620,8 +15855,8 @@ "MGC1348", "KIAA0394" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "GATA4", @@ -15639,8 +15874,8 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "GATA6", @@ -15658,8 +15893,8 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "GID4", @@ -15680,8 +15915,34 @@ "C17orf39", "VID24" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false + }, + { + "hugoSymbol": "GPC3", + "entrezGeneId": 2719, + "grch37Isoform": "ENST00000370818", + "grch37RefSeq": "NM_004484", + "grch38Isoform": "ENST00000370818", + "grch38RefSeq": "NM_004484", + "oncokbAnnotated": true, + "occurrenceCount": 2, + "mSKImpact": false, + "mSKHeme": false, + "foundation": false, + "foundationHeme": false, + "vogelstein": false, + "sangerCGC": true, + "geneAliases": [ + "SGBS", + "OCI-5", + "DGSX", + "SDYS", + "SGBS1", + "SGB" + ], + "oncogene": true, + "tsg": false }, { "hugoSymbol": "GPHN", @@ -15701,8 +15962,8 @@ "geneAliases": [ "KIAA1385" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "GRM3", @@ -15724,8 +15985,8 @@ "MGLUR3", "GPRC1C" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "GTF2I", @@ -15746,12 +16007,12 @@ "WBSCR6", "DIWS", "IB291", - "BTKAP1", "BAP-135", + "BTKAP1", "TFII-I" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "H1-5", @@ -15774,8 +16035,8 @@ "HIST1H1B", "H1s-3" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "H2BC8", @@ -15793,13 +16054,13 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [ + "H2B/a", "H2B.1A", "HIST1H2BG", - "H2B/a", "H2BFA" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "H4C9", @@ -15821,8 +16082,8 @@ "HIST1H4I", "H4/m" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "HERPUD1", @@ -15840,13 +16101,13 @@ "vogelstein": false, "sangerCGC": true, "geneAliases": [ - "HERP", "Mif1", "KIAA0025", + "HERP", "SUP" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "HEY1", @@ -15872,8 +16133,8 @@ "CHF2", "bHLHb31" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "HIP1", @@ -15891,8 +16152,8 @@ "vogelstein": false, "sangerCGC": true, "geneAliases": [], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "HIRA", @@ -15911,11 +16172,11 @@ "sangerCGC": false, "geneAliases": [ "DGCR1", - "TUP1", - "TUPLE1" + "TUPLE1", + "TUP1" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "HLA-C", @@ -15937,8 +16198,8 @@ "HLA-JY3", "PSORS1" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "HLF", @@ -15958,30 +16219,8 @@ "geneAliases": [ "MGC33822" ], - "tsg": false, - "oncogene": false - }, - { - "hugoSymbol": "HOXA11", - "entrezGeneId": 3207, - "grch37Isoform": "", - "grch37RefSeq": "", - "grch38Isoform": "", - "grch38RefSeq": "", - "oncokbAnnotated": false, - "occurrenceCount": 2, - "mSKImpact": false, - "mSKHeme": false, - "foundation": false, - "foundationHeme": true, - "vogelstein": false, - "sangerCGC": true, - "geneAliases": [ - "HOX1", - "HOX1I" - ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "HOXA13", @@ -16001,8 +16240,8 @@ "geneAliases": [ "HOX1J" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "HOXA9", @@ -16022,8 +16261,8 @@ "geneAliases": [ "HOX1G" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "HOXC11", @@ -16043,8 +16282,8 @@ "geneAliases": [ "HOX3H" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "HOXC13", @@ -16062,11 +16301,11 @@ "vogelstein": false, "sangerCGC": true, "geneAliases": [ - "HOX3G", - "HOX3" + "HOX3", + "HOX3G" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "HOXD11", @@ -16086,8 +16325,8 @@ "geneAliases": [ "HOX4F" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "HOXD13", @@ -16105,11 +16344,11 @@ "vogelstein": false, "sangerCGC": true, "geneAliases": [ - "HOX4I", - "SPD" + "SPD", + "HOX4I" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "HSD3B1", @@ -16131,8 +16370,8 @@ "HSD3B", "HSDB3" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "HSP90AB1", @@ -16153,8 +16392,8 @@ "HSPC2", "HSPCB" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "IGH", @@ -16175,8 +16414,8 @@ "IGH@", "IGHDY1" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "IGK", @@ -16196,8 +16435,8 @@ "geneAliases": [ "IGK@" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "IGL", @@ -16217,8 +16456,8 @@ "geneAliases": [ "IGL@" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "IL21R", @@ -16238,8 +16477,8 @@ "geneAliases": [ "CD360" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "IL3", @@ -16259,12 +16498,12 @@ "geneAliases": [ "MCGF", "MGC79399", + "MULTI-CSF", "IL-3", - "MGC79398", - "MULTI-CSF" + "MGC79398" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "IL6ST", @@ -16282,13 +16521,13 @@ "vogelstein": false, "sangerCGC": true, "geneAliases": [ + "CD130", "GP130", "sGP130", - "CD130", "IL-6RB" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "IRF2", @@ -16306,8 +16545,8 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "ITK", @@ -16329,8 +16568,8 @@ "PSCTK2", "LYK" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "KBTBD4", @@ -16348,12 +16587,12 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [ - "HSPC252", "BKLHD4", - "FLJ10450" + "FLJ10450", + "HSPC252" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "KDSR", @@ -16371,12 +16610,12 @@ "vogelstein": false, "sangerCGC": true, "geneAliases": [ - "FVT1", "DHSR", - "SDR35C1" + "SDR35C1", + "FVT1" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "KEL", @@ -16394,11 +16633,11 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [ - "ECE3", - "CD238" + "CD238", + "ECE3" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "KIF5B", @@ -16419,8 +16658,8 @@ "KNS", "KNS1" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "KLF5", @@ -16441,8 +16680,8 @@ "BTEB2", "IKLF" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "KSR2", @@ -16450,7 +16689,7 @@ "grch37Isoform": "ENST00000339824", "grch37RefSeq": "", "grch38Isoform": "ENST00000339824", - "grch38RefSeq": "", + "grch38RefSeq": "NM_173598.6", "oncokbAnnotated": true, "occurrenceCount": 2, "mSKImpact": false, @@ -16462,8 +16701,8 @@ "geneAliases": [ "FLJ25965" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "LASP1", @@ -16484,8 +16723,34 @@ "MLN50", "Lasp-1" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false + }, + { + "hugoSymbol": "LMNA", + "entrezGeneId": 4000, + "grch37Isoform": "ENST00000368300", + "grch37RefSeq": "NM_170707", + "grch38Isoform": "ENST00000368300", + "grch38RefSeq": "NM_170707", + "oncokbAnnotated": true, + "occurrenceCount": 2, + "mSKImpact": false, + "mSKHeme": false, + "foundation": false, + "foundationHeme": false, + "vogelstein": false, + "sangerCGC": true, + "geneAliases": [ + "PRO1", + "LMNL1", + "HGPS", + "LMN1", + "CMD1A", + "LGMD1B" + ], + "oncogene": true, + "tsg": false }, { "hugoSymbol": "LPP", @@ -16503,8 +16768,8 @@ "vogelstein": false, "sangerCGC": true, "geneAliases": [], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "LTB", @@ -16525,8 +16790,8 @@ "TNFC", "TNFSF3" ], - "tsg": true, - "oncogene": true + "oncogene": true, + "tsg": true }, { "hugoSymbol": "LTK", @@ -16546,8 +16811,8 @@ "geneAliases": [ "TYK1" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "LYL1", @@ -16567,8 +16832,8 @@ "geneAliases": [ "bHLHa18" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "MAD2L2", @@ -16586,13 +16851,13 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [ - "POLZ2", "REV7", + "POLZ2", "MAD2B", "FANCV" ], - "tsg": true, - "oncogene": true + "oncogene": true, + "tsg": true }, { "hugoSymbol": "MAP3K7", @@ -16610,11 +16875,11 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [ - "TAK1", - "MEKK7" + "MEKK7", + "TAK1" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "MEF2C", @@ -16632,8 +16897,8 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [], - "tsg": true, - "oncogene": true + "oncogene": true, + "tsg": true }, { "hugoSymbol": "MERTK", @@ -16651,13 +16916,13 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [ - "mer", "RP38", "c-Eyk", - "Tyro12" + "Tyro12", + "mer" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "MGAM", @@ -16675,8 +16940,8 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "MKI67", @@ -16697,8 +16962,8 @@ "MIB-1", "PPP1R105" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "MLF1", @@ -16716,8 +16981,8 @@ "vogelstein": false, "sangerCGC": true, "geneAliases": [], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "MLLT6", @@ -16735,34 +17000,11 @@ "vogelstein": false, "sangerCGC": true, "geneAliases": [ - "FLJ23480", - "AF17" - ], - "tsg": false, - "oncogene": false - }, - { - "hugoSymbol": "MN1", - "entrezGeneId": 4330, - "grch37Isoform": "", - "grch37RefSeq": "", - "grch38Isoform": "", - "grch38RefSeq": "", - "oncokbAnnotated": false, - "occurrenceCount": 2, - "mSKImpact": false, - "mSKHeme": false, - "foundation": false, - "foundationHeme": true, - "vogelstein": false, - "sangerCGC": true, - "geneAliases": [ - "MGCR", - "MGCR1", - "MGCR1-PEN" + "AF17", + "FLJ23480" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "MOB3B", @@ -16780,13 +17022,13 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [ - "C9orf35", "MOBKL2B", "MOB1D", + "C9orf35", "FLJ13204" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "MPEG1", @@ -16806,8 +17048,8 @@ "geneAliases": [ "MPG1" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "MRTFA", @@ -16827,12 +17069,12 @@ "geneAliases": [ "KIAA1438", "MRTF-A", - "BSAC", "MKL1", + "BSAC", "MKL" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "MSN", @@ -16850,8 +17092,8 @@ "vogelstein": false, "sangerCGC": true, "geneAliases": [], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "MUC1", @@ -16878,8 +17120,8 @@ "ADMCKD", "MCD" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "MYH9", @@ -16904,8 +17146,31 @@ "EPSTS", "MHA" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false + }, + { + "hugoSymbol": "MYO5A", + "entrezGeneId": 4644, + "grch37Isoform": "ENST00000399231", + "grch37RefSeq": "NM_000259", + "grch38Isoform": "ENST00000399231", + "grch38RefSeq": "NM_000259", + "oncokbAnnotated": true, + "occurrenceCount": 2, + "mSKImpact": false, + "mSKHeme": false, + "foundation": false, + "foundationHeme": false, + "vogelstein": false, + "sangerCGC": true, + "geneAliases": [ + "MYR12", + "MYO5", + "MYH12" + ], + "oncogene": true, + "tsg": false }, { "hugoSymbol": "NADK", @@ -16925,8 +17190,8 @@ "geneAliases": [ "FLJ13052" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "NCOA2", @@ -16949,8 +17214,8 @@ "KAT13C", "TIF2" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "NDRG1", @@ -16973,8 +17238,8 @@ "CAP43", "RTP" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "NFE2", @@ -16994,8 +17259,8 @@ "geneAliases": [ "NF-E2" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "NFKB2", @@ -17017,8 +17282,8 @@ "NF-kB2", "p49/p100" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "NIN", @@ -17036,8 +17301,8 @@ "vogelstein": false, "sangerCGC": true, "geneAliases": [], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "NRG1", @@ -17057,11 +17322,11 @@ "geneAliases": [ "NDF", "NRG1-IT2", - "HGL", - "GGF" + "GGF", + "HGL" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "NUMA1", @@ -17079,8 +17344,8 @@ "vogelstein": false, "sangerCGC": true, "geneAliases": [], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "PAFAH1B2", @@ -17098,8 +17363,8 @@ "vogelstein": false, "sangerCGC": true, "geneAliases": [], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "PAX8", @@ -17117,8 +17382,8 @@ "vogelstein": false, "sangerCGC": true, "geneAliases": [], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "PBX1", @@ -17136,8 +17401,8 @@ "vogelstein": false, "sangerCGC": true, "geneAliases": [], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "PCM1", @@ -17157,8 +17422,8 @@ "geneAliases": [ "PTC4" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "PDE4DIP", @@ -17181,8 +17446,8 @@ "KIAA0454", "KIAA0477" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "PDS5B", @@ -17202,12 +17467,12 @@ "geneAliases": [ "APRIN", "AS3", - "FLJ23236", "CG008", + "FLJ23236", "KIAA0979" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "PER1", @@ -17225,11 +17490,11 @@ "vogelstein": false, "sangerCGC": true, "geneAliases": [ - "PER", - "RIGUI" + "RIGUI", + "PER" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "PGBD5", @@ -17250,8 +17515,8 @@ "DKFZp761A0620", "FLJ11413" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "PICALM", @@ -17271,8 +17536,8 @@ "geneAliases": [ "CLTH" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "PIGA", @@ -17292,8 +17557,8 @@ "geneAliases": [ "GPI3" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "PIK3C2B", @@ -17314,8 +17579,8 @@ "PI3K-C2beta", "C2-PI3K" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "PLAG1", @@ -17335,31 +17600,8 @@ "geneAliases": [ "ZNF912" ], - "tsg": false, - "oncogene": false - }, - { - "hugoSymbol": "PML", - "entrezGeneId": 5371, - "grch37Isoform": "", - "grch37RefSeq": "", - "grch38Isoform": "", - "grch38RefSeq": "", - "oncokbAnnotated": false, - "occurrenceCount": 2, - "mSKImpact": false, - "mSKHeme": false, - "foundation": false, - "foundationHeme": true, - "vogelstein": false, - "sangerCGC": true, - "geneAliases": [ - "RNF71", - "MYL", - "TRIM19" - ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "POU2AF1", @@ -17377,11 +17619,11 @@ "vogelstein": false, "sangerCGC": true, "geneAliases": [ - "OBF1", - "BOB1" + "BOB1", + "OBF1" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "PPP2R2A", @@ -17405,8 +17647,29 @@ "B55alpha", "PR52A" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true + }, + { + "hugoSymbol": "PRCC", + "entrezGeneId": 5546, + "grch37Isoform": "ENST00000271526", + "grch37RefSeq": "NM_005973", + "grch38Isoform": "ENST00000271526", + "grch38RefSeq": "NM_005973", + "oncokbAnnotated": true, + "occurrenceCount": 2, + "mSKImpact": false, + "mSKHeme": false, + "foundation": false, + "foundationHeme": false, + "vogelstein": false, + "sangerCGC": true, + "geneAliases": [ + "RCCP1" + ], + "oncogene": true, + "tsg": false }, { "hugoSymbol": "PRDM16", @@ -17425,13 +17688,13 @@ "sangerCGC": true, "geneAliases": [ "PFM13", - "MEL1", "KIAA1675", "KMT8F", + "MEL1", "MGC166915" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "PRKACA", @@ -17451,16 +17714,16 @@ "geneAliases": [ "PKACa" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "PRKDC", "entrezGeneId": 5591, "grch37Isoform": "ENST00000314191", - "grch37RefSeq": "NM_006904", - "grch38Isoform": "", - "grch38RefSeq": "", + "grch37RefSeq": "NM_006904.6", + "grch38Isoform": "ENST00000314191", + "grch38RefSeq": "NM_006904.7", "oncokbAnnotated": true, "occurrenceCount": 2, "mSKImpact": false, @@ -17481,8 +17744,8 @@ "DNPK1", "HYRC1" ], - "tsg": true, - "oncogene": true + "oncogene": true, + "tsg": true }, { "hugoSymbol": "PRRX1", @@ -17500,11 +17763,11 @@ "vogelstein": false, "sangerCGC": true, "geneAliases": [ - "PHOX1", - "PMX1" + "PMX1", + "PHOX1" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "PSIP1", @@ -17526,8 +17789,8 @@ "DFS70", "PSIP2" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "PTPN1", @@ -17547,8 +17810,8 @@ "geneAliases": [ "PTP1B" ], - "tsg": true, - "oncogene": true + "oncogene": true, + "tsg": true }, { "hugoSymbol": "PTPN13", @@ -17571,8 +17834,8 @@ "PTP1E", "PTPL1" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "PTPRO", @@ -17590,14 +17853,14 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [ - "NPHS6", - "PTP-oc", "GLEPP1", "PTP-U2", - "PTPU2" + "PTPU2", + "NPHS6", + "PTP-oc" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "RABEP1", @@ -17620,8 +17883,8 @@ "RAB5EP", "RABPT5" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "RANBP2", @@ -17643,8 +17906,8 @@ "ADANE", "ANE1" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "RAP1GDS1", @@ -17664,8 +17927,8 @@ "geneAliases": [ "SmgGDS" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "RELN", @@ -17686,8 +17949,8 @@ "PRO1598", "RL" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "REST", @@ -17705,12 +17968,12 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [ - "XBR", "DFNA27", - "NRSF" + "NRSF", + "XBR" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "RHOH", @@ -17731,8 +17994,8 @@ "TTF", "ARHH" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "RNF213", @@ -17757,8 +18020,8 @@ "ALO17", "KIAA1618" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "ROBO1", @@ -17780,8 +18043,8 @@ "DUTT1", "SAX3" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "RPL22", @@ -17802,8 +18065,8 @@ "EAP", "L22" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "RPL5", @@ -17825,8 +18088,8 @@ "L5", "PPP1R135" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "RPN1", @@ -17844,8 +18107,8 @@ "vogelstein": false, "sangerCGC": true, "geneAliases": [], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "RSPO2", @@ -17865,8 +18128,8 @@ "geneAliases": [ "MGC35555" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "SAMHD1", @@ -17890,8 +18153,8 @@ "AGS5", "Mg11" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "SCG5", @@ -17909,12 +18172,12 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [ - "SGNE1", "SgV", + "SGNE1", "7B2" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "SDC4", @@ -17936,8 +18199,8 @@ "SYND4", "ryudocan" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "SERPINB3", @@ -17960,8 +18223,8 @@ "T4-A", "HsT1196" ], - "tsg": true, - "oncogene": true + "oncogene": true, + "tsg": true }, { "hugoSymbol": "SERPINB4", @@ -17980,12 +18243,12 @@ "sangerCGC": false, "geneAliases": [ "SCCA-2", - "PI11", "SCCA2", + "PI11", "LEUPIN" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "SETD1A", @@ -18004,12 +18267,12 @@ "sangerCGC": false, "geneAliases": [ "SET1A", - "Set1", "KIAA0339", - "KMT2F" + "KMT2F", + "Set1" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "SETD1B", @@ -18027,12 +18290,12 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [ - "KIAA1076", "Set1B", - "KMT2G" + "KMT2G", + "KIAA1076" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "SETD3", @@ -18053,8 +18316,8 @@ "C14orf154", "FLJ23027" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "SETD4", @@ -18072,11 +18335,11 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [ - "C21orf18", - "C21orf27" + "C21orf27", + "C21orf18" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "SETD5", @@ -18096,8 +18359,8 @@ "geneAliases": [ "FLJ10707" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "SETD6", @@ -18117,8 +18380,8 @@ "geneAliases": [ "FLJ21148" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "SETD7", @@ -18137,13 +18400,13 @@ "sangerCGC": false, "geneAliases": [ "Set9", - "SET7/9", "SET7", "KMT7", + "SET7/9", "KIAA1717" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "SETDB2", @@ -18163,11 +18426,11 @@ "geneAliases": [ "KMT1F", "CLLD8", - "CLLL8", - "C13orf4" + "C13orf4", + "CLLL8" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "SH3GL1", @@ -18186,13 +18449,13 @@ "sangerCGC": true, "geneAliases": [ "MGC111371", - "CNSA1", "SH3P8", "SH3D2B", + "CNSA1", "EEN" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "SLC34A2", @@ -18212,8 +18475,8 @@ "geneAliases": [ "NAPI-3B" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "SLFN11", @@ -18233,8 +18496,35 @@ "geneAliases": [ "FLJ34922" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true + }, + { + "hugoSymbol": "SMARCA1", + "entrezGeneId": 6594, + "grch37Isoform": "ENST00000371122", + "grch37RefSeq": "NM_003069", + "grch38Isoform": "ENST00000371122", + "grch38RefSeq": "NM_003069", + "oncokbAnnotated": true, + "occurrenceCount": 2, + "mSKImpact": false, + "mSKHeme": false, + "foundation": false, + "foundationHeme": true, + "vogelstein": false, + "sangerCGC": false, + "geneAliases": [ + "SNF2LB", + "SNF2L1", + "SNF2L", + "hSNF2L", + "NURF140", + "SWI", + "ISWI" + ], + "oncogene": true, + "tsg": true }, { "hugoSymbol": "SMARCA2", @@ -18262,8 +18552,8 @@ "hSNF2a", "BRM" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "SMG1", @@ -18281,11 +18571,11 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [ - "KIAA0421", - "LIP" + "LIP", + "KIAA0421" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "SOCS3", @@ -18303,13 +18593,13 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [ + "SSI-3", "CIS3", "SOCS-3", - "Cish3", - "SSI-3" + "Cish3" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "SOX10", @@ -18327,12 +18617,12 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [ - "WS4", "DOM", - "WS2E" + "WS2E", + "WS4" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "SP140", @@ -18353,8 +18643,8 @@ "LYSP100-A", "LYSP100-B" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "SPRTN", @@ -18377,8 +18667,8 @@ "Spartan", "DKFZP547N043" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "SRSF3", @@ -18396,11 +18686,11 @@ "vogelstein": false, "sangerCGC": true, "geneAliases": [ - "SFRS3", - "SRp20" + "SRp20", + "SFRS3" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "SSX1", @@ -18420,8 +18710,8 @@ "geneAliases": [ "CT5.1" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "SSX2", @@ -18447,8 +18737,8 @@ "HD21", "MGC3884" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "SSX4", @@ -18468,8 +18758,8 @@ "geneAliases": [ "CT5.4" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "STAG1", @@ -18488,11 +18778,11 @@ "sangerCGC": false, "geneAliases": [ "SCC3A", - "SA-1", - "SA1" + "SA1", + "SA-1" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "STAT4", @@ -18510,16 +18800,16 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "TAF1", "entrezGeneId": 6872, - "grch37Isoform": "ENST00000373790", - "grch37RefSeq": "NM_138923", - "grch38Isoform": "", - "grch38RefSeq": "", + "grch37Isoform": "ENST00000423759", + "grch37RefSeq": "NM_001286074.1", + "grch38Isoform": "ENST00000423759", + "grch38RefSeq": "NM_004606.5", "oncokbAnnotated": true, "occurrenceCount": 2, "mSKImpact": false, @@ -18538,8 +18828,8 @@ "KAT4", "DYT3/TAF1" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "TAF15", @@ -18562,8 +18852,8 @@ "Npl3", "hTAFII68" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "TAL2", @@ -18583,8 +18873,8 @@ "geneAliases": [ "bHLHa19" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "TET3", @@ -18605,8 +18895,8 @@ "MGC22014", "hCG_40738" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "TFG", @@ -18628,36 +18918,12 @@ "TF6", "SPG57" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { - "hugoSymbol": "TNFRSF17", - "entrezGeneId": 608, - "grch37Isoform": "", - "grch37RefSeq": "", - "grch38Isoform": "", - "grch38RefSeq": "", - "oncokbAnnotated": false, - "occurrenceCount": 2, - "mSKImpact": false, - "mSKHeme": false, - "foundation": false, - "foundationHeme": true, - "vogelstein": false, - "sangerCGC": true, - "geneAliases": [ - "BCMA", - "CD269", - "TNFRSF13A", - "BCM" - ], - "tsg": false, - "oncogene": false - }, - { - "hugoSymbol": "TPM3", - "entrezGeneId": 7170, + "hugoSymbol": "TPM3", + "entrezGeneId": 7170, "grch37Isoform": "", "grch37RefSeq": "", "grch38Isoform": "", @@ -18674,8 +18940,8 @@ "TRK", "NEM1" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "TPM4", @@ -18693,8 +18959,8 @@ "vogelstein": false, "sangerCGC": true, "geneAliases": [], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "TRA", @@ -18715,8 +18981,8 @@ "TCRA", "TRA@" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "TRB", @@ -18737,8 +19003,8 @@ "TCRB", "TRB@" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "TRD", @@ -18757,11 +19023,11 @@ "sangerCGC": true, "geneAliases": [ "TCRDV1", - "TRD@", - "TCRD" + "TCRD", + "TRD@" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "TRG", @@ -18782,8 +19048,8 @@ "TRG@", "TCRG" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "TRIM24", @@ -18802,13 +19068,13 @@ "sangerCGC": true, "geneAliases": [ "TIF1A", - "hTIF1", "Tif1a", - "RNF82", - "TIF1" + "TIF1", + "hTIF1", + "RNF82" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "TRIM27", @@ -18829,8 +19095,8 @@ "RNF76", "RFP" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "TRIP11", @@ -18853,8 +19119,8 @@ "Trip230", "CEV14" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "TRIP13", @@ -18874,33 +19140,8 @@ "geneAliases": [ "16E1BP" ], - "tsg": true, - "oncogene": true - }, - { - "hugoSymbol": "USP6", - "entrezGeneId": 9098, - "grch37Isoform": "", - "grch37RefSeq": "", - "grch38Isoform": "", - "grch38RefSeq": "", - "oncokbAnnotated": false, - "occurrenceCount": 2, - "mSKImpact": false, - "mSKHeme": false, - "foundation": false, - "foundationHeme": true, - "vogelstein": false, - "sangerCGC": true, - "geneAliases": [ - "Tre-2", - "HRP1", - "TRE17", - "TRESMCR", - "Tre2" - ], - "tsg": false, - "oncogene": false + "oncogene": true, + "tsg": true }, { "hugoSymbol": "VAV1", @@ -18920,8 +19161,8 @@ "geneAliases": [ "VAV" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "VAV2", @@ -18939,8 +19180,8 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "WIF1", @@ -18958,8 +19199,52 @@ "vogelstein": false, "sangerCGC": true, "geneAliases": [], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true + }, + { + "hugoSymbol": "WRN", + "entrezGeneId": 7486, + "grch37Isoform": "ENST00000298139", + "grch37RefSeq": "NM_000553", + "grch38Isoform": "ENST00000298139", + "grch38RefSeq": "NM_000553", + "oncokbAnnotated": true, + "occurrenceCount": 2, + "mSKImpact": false, + "mSKHeme": false, + "foundation": false, + "foundationHeme": false, + "vogelstein": false, + "sangerCGC": true, + "geneAliases": [ + "RECQ3", + "RECQL2" + ], + "oncogene": false, + "tsg": true + }, + { + "hugoSymbol": "XPA", + "entrezGeneId": 7507, + "grch37Isoform": "ENST00000375128", + "grch37RefSeq": "NM_000380", + "grch38Isoform": "ENST00000375128", + "grch38RefSeq": "NM_000380", + "oncokbAnnotated": true, + "occurrenceCount": 2, + "mSKImpact": false, + "mSKHeme": false, + "foundation": false, + "foundationHeme": false, + "vogelstein": false, + "sangerCGC": true, + "geneAliases": [ + "XPAC", + "XP1" + ], + "oncogene": false, + "tsg": true }, { "hugoSymbol": "XPC", @@ -18980,8 +19265,8 @@ "XPCC", "RAD4" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "ZBTB16", @@ -19002,8 +19287,8 @@ "PLZF", "ZNF145" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "ZBTB7A", @@ -19021,15 +19306,15 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [ - "FBI-1", "LRF", "ZBTB7", "pokemon", "ZNF857A", + "FBI-1", "DKFZp547O146" ], - "tsg": true, - "oncogene": true + "oncogene": true, + "tsg": true }, { "hugoSymbol": "ZMYM2", @@ -19047,12 +19332,12 @@ "vogelstein": false, "sangerCGC": true, "geneAliases": [ - "RAMP", "ZNF198", + "RAMP", "FIM" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "ZMYM3", @@ -19071,12 +19356,12 @@ "sangerCGC": false, "geneAliases": [ "DXS6673E", - "KIAA0385", "ZNF261", - "ZNF198L2" + "ZNF198L2", + "KIAA0385" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "ZNF384", @@ -19099,8 +19384,8 @@ "CIZ", "NMP4" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "ZNF521", @@ -19121,8 +19406,8 @@ "Evi3", "EHZF" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "ZNF703", @@ -19140,14 +19425,14 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [ - "ZNF503L", "NLZ1", "Zpo1", - "ZEPPO1", - "FLJ14299" + "FLJ14299", + "ZNF503L", + "ZEPPO1" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "ZNRF3", @@ -19166,12 +19451,40 @@ "sangerCGC": false, "geneAliases": [ "RNF203", - "KIAA1133", "FLJ22057", - "BK747E2.3" + "BK747E2.3", + "KIAA1133" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true + }, + { + "hugoSymbol": "ABCB1", + "entrezGeneId": 5243, + "grch37Isoform": "ENST00000265724", + "grch37RefSeq": "NM_000927.4", + "grch38Isoform": "ENST00000622132", + "grch38RefSeq": "NM_001348946.2", + "oncokbAnnotated": true, + "occurrenceCount": 1, + "mSKImpact": false, + "mSKHeme": false, + "foundation": false, + "foundationHeme": false, + "vogelstein": false, + "sangerCGC": false, + "geneAliases": [ + "MDR1", + "ABC20", + "p-170", + "P-gp", + "CLCS", + "PGY1", + "GP170", + "CD243" + ], + "oncogene": true, + "tsg": false }, { "hugoSymbol": "ACSL3", @@ -19192,8 +19505,8 @@ "FACL3", "PRO2194" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "ACSL6", @@ -19211,12 +19524,12 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [ - "LACS5", "FACL6", + "LACS5", "KIAA0837" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "ACTB", @@ -19234,56 +19547,54 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { - "hugoSymbol": "ACVR2A", - "entrezGeneId": 92, - "grch37Isoform": "", - "grch37RefSeq": "", - "grch38Isoform": "", - "grch38RefSeq": "", - "oncokbAnnotated": false, + "hugoSymbol": "ADARB2", + "entrezGeneId": 105, + "grch37Isoform": "ENST00000381312", + "grch37RefSeq": "NM_018702.3", + "grch38Isoform": "ENST00000381312", + "grch38RefSeq": "NM_018702.4", + "oncokbAnnotated": true, "occurrenceCount": 1, "mSKImpact": false, "mSKHeme": false, "foundation": false, "foundationHeme": false, "vogelstein": false, - "sangerCGC": true, + "sangerCGC": false, "geneAliases": [ - "ACTRII", - "ACVR2" + "hRED2", + "RED2", + "ADAR3" ], - "tsg": false, - "oncogene": false + "oncogene": true, + "tsg": false }, { - "hugoSymbol": "ADGRA2", - "entrezGeneId": 25960, - "grch37Isoform": "", - "grch37RefSeq": "", - "grch38Isoform": "", - "grch38RefSeq": "", - "oncokbAnnotated": false, + "hugoSymbol": "ADGRG4", + "entrezGeneId": 139378, + "grch37Isoform": "ENST00000394143", + "grch37RefSeq": "NM_153834.3", + "grch38Isoform": "ENST00000394143", + "grch38RefSeq": "NM_153834.4", + "oncokbAnnotated": true, "occurrenceCount": 1, "mSKImpact": false, "mSKHeme": false, "foundation": false, - "foundationHeme": true, + "foundationHeme": false, "vogelstein": false, "sangerCGC": false, "geneAliases": [ - "DKFZp434C211", - "KIAA1531", - "TEM5", - "FLJ14390", - "DKFZp434J0911", - "GPR124" + "PGR17", + "GPR112", + "RP1-299I16" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "ADHFE1", @@ -19303,8 +19614,8 @@ "geneAliases": [ "FLJ32430" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "AFF3", @@ -19325,8 +19636,57 @@ "LAF4", "MLLT2-like" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false + }, + { + "hugoSymbol": "AGGF1", + "entrezGeneId": 55109, + "grch37Isoform": "ENST00000312916", + "grch37RefSeq": "NM_018046.4", + "grch38Isoform": "ENST00000312916", + "grch38RefSeq": "NM_018046.5", + "oncokbAnnotated": true, + "occurrenceCount": 1, + "mSKImpact": false, + "mSKHeme": false, + "foundation": false, + "foundationHeme": false, + "vogelstein": false, + "sangerCGC": false, + "geneAliases": [ + "FLJ10283", + "VG5Q", + "HSU84971", + "GPATC7", + "GPATCH7" + ], + "oncogene": true, + "tsg": false + }, + { + "hugoSymbol": "AIP", + "entrezGeneId": 9049, + "grch37Isoform": "ENST00000279146", + "grch37RefSeq": "NM_003977.2", + "grch38Isoform": "ENST00000279146", + "grch38RefSeq": "NM_003977.4", + "oncokbAnnotated": true, + "occurrenceCount": 1, + "mSKImpact": false, + "mSKHeme": false, + "foundation": false, + "foundationHeme": false, + "vogelstein": false, + "sangerCGC": false, + "geneAliases": [ + "XAP2", + "FKBP37", + "ARA9", + "FKBP16" + ], + "oncogene": true, + "tsg": true }, { "hugoSymbol": "AJUBA", @@ -19347,8 +19707,8 @@ "MGC15563", "JUB" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "ALDH1L2", @@ -19369,8 +19729,8 @@ "mtFDH", "FLJ38508" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "ALDH2", @@ -19388,8 +19748,30 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true + }, + { + "hugoSymbol": "ANKRD26", + "entrezGeneId": 22852, + "grch37Isoform": "ENST00000376087", + "grch37RefSeq": "NM_001256053", + "grch38Isoform": "ENST00000376087", + "grch38RefSeq": "NM_001256053", + "oncokbAnnotated": true, + "occurrenceCount": 1, + "mSKImpact": false, + "mSKHeme": false, + "foundation": false, + "foundationHeme": false, + "vogelstein": false, + "sangerCGC": false, + "geneAliases": [ + "THC2", + "KIAA1074" + ], + "oncogene": true, + "tsg": false }, { "hugoSymbol": "APH1A", @@ -19410,8 +19792,8 @@ "CGI-78", "APH-1A" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "APOBEC3B", @@ -19432,8 +19814,8 @@ "PHRBNL", "FLJ21201" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "ASMTL", @@ -19451,8 +19833,8 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "ASPSCR1", @@ -19471,13 +19853,13 @@ "sangerCGC": true, "geneAliases": [ "ASPL", + "TUG", "ASPS", "UBXN9", - "UBXD9", - "TUG" + "UBXD9" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "ATG5", @@ -19495,12 +19877,12 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [ - "hAPG5", + "APG5", "APG5L", - "APG5" + "hAPG5" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "ATP2B3", @@ -19519,12 +19901,12 @@ "sangerCGC": true, "geneAliases": [ "PMCA3", - "SCAX1", "CLA2", - "CFAP39" + "CFAP39", + "SCAX1" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "ATRIP", @@ -19547,8 +19929,8 @@ "MGC26740", "MGC21482" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "BAALC", @@ -19566,8 +19948,8 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "BAX", @@ -19587,8 +19969,8 @@ "geneAliases": [ "BCL2L4" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "BCL9L", @@ -19610,8 +19992,8 @@ "B9L", "Bcl9-2" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "BTLA", @@ -19632,32 +20014,33 @@ "BTLA1", "CD272" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { - "hugoSymbol": "BUB1B", - "entrezGeneId": 701, - "grch37Isoform": "", - "grch37RefSeq": "", - "grch38Isoform": "", - "grch38RefSeq": "", - "oncokbAnnotated": false, + "hugoSymbol": "CASR", + "entrezGeneId": 846, + "grch37Isoform": "ENST00000490131", + "grch37RefSeq": "NM_000388.3", + "grch38Isoform": "ENST00000639785", + "grch38RefSeq": "NM_000388.4", + "oncokbAnnotated": true, "occurrenceCount": 1, "mSKImpact": false, "mSKHeme": false, "foundation": false, "foundationHeme": false, "vogelstein": false, - "sangerCGC": true, + "sangerCGC": false, "geneAliases": [ - "SSK1", - "MAD3L", - "BUBR1", - "Bub1A" + "HHC", + "NSHPT", + "FHH", + "GPRC2A", + "HHC1" ], - "tsg": false, - "oncogene": false + "oncogene": true, + "tsg": true }, { "hugoSymbol": "CBLB", @@ -19675,11 +20058,11 @@ "vogelstein": false, "sangerCGC": true, "geneAliases": [ - "Cbl-b", - "RNF56" + "RNF56", + "Cbl-b" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "CBLC", @@ -19697,12 +20080,12 @@ "vogelstein": false, "sangerCGC": true, "geneAliases": [ + "CBL-SL", "RNF57", - "CBL-3", - "CBL-SL" + "CBL-3" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "CCDC6", @@ -19720,35 +20103,13 @@ "vogelstein": false, "sangerCGC": true, "geneAliases": [ + "TPC", "D10S170", "TST1", - "H4", - "TPC" + "H4" ], - "tsg": false, - "oncogene": false - }, - { - "hugoSymbol": "CCN6", - "entrezGeneId": 8838, - "grch37Isoform": "", - "grch37RefSeq": "", - "grch38Isoform": "", - "grch38RefSeq": "", - "oncokbAnnotated": false, - "occurrenceCount": 1, - "mSKImpact": false, - "mSKHeme": false, - "foundation": false, - "foundationHeme": true, - "vogelstein": false, - "sangerCGC": false, - "geneAliases": [ - "WISP-3", - "WISP3" - ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "CCNB1IP1", @@ -19766,11 +20127,11 @@ "vogelstein": false, "sangerCGC": true, "geneAliases": [ - "HEI10", - "C14orf18" + "C14orf18", + "HEI10" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "CCNB3", @@ -19788,8 +20149,8 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "CCT6B", @@ -19810,8 +20171,8 @@ "Cctz2", "TSA303" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "CD19", @@ -19829,8 +20190,8 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "CD36", @@ -19848,13 +20209,13 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [ - "GP3B", - "GP4", "SCARB3", - "GPIV" + "GPIV", + "GP3B", + "GP4" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "CDH2", @@ -19873,11 +20234,11 @@ "sangerCGC": false, "geneAliases": [ "CDHN", - "NCAD", - "CD325" + "CD325", + "NCAD" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "CDH4", @@ -19895,8 +20256,31 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false + }, + { + "hugoSymbol": "CDKN1C", + "entrezGeneId": 1028, + "grch37Isoform": "ENST00000440480", + "grch37RefSeq": "NM_001122630.2", + "grch38Isoform": "ENST00000440480", + "grch38RefSeq": "NM_001122630.2", + "oncokbAnnotated": true, + "occurrenceCount": 1, + "mSKImpact": false, + "mSKHeme": false, + "foundation": false, + "foundationHeme": false, + "vogelstein": false, + "sangerCGC": false, + "geneAliases": [ + "P57", + "BWCR", + "BWS" + ], + "oncogene": false, + "tsg": true }, { "hugoSymbol": "CHCHD7", @@ -19917,8 +20301,8 @@ "MGC2217", "COX23" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "CHIC2", @@ -19938,8 +20322,8 @@ "geneAliases": [ "BTL" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "CHN1", @@ -19957,13 +20341,13 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [ - "CHN", - "ARHGAP2", "n-chimerin", - "DURS2" + "DURS2", + "CHN", + "ARHGAP2" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "CHTF8", @@ -19981,11 +20365,11 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [ - "CTF8", - "FLJ20400" + "FLJ20400", + "CTF8" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "CILK1", @@ -20008,8 +20392,8 @@ "LCK2", "KIAA0936" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "CKS1B", @@ -20029,8 +20413,8 @@ "geneAliases": [ "ckshs1" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "CLIP1", @@ -20053,8 +20437,8 @@ "CLIP-170", "RSN" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "CLP1", @@ -20075,8 +20459,8 @@ "hClp1", "HEAB" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "CNBP", @@ -20094,14 +20478,14 @@ "vogelstein": false, "sangerCGC": true, "geneAliases": [ - "DM2", "ZCCHC22", + "DM2", "CNBP1", "ZNF9", "RNF163" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "CNOT3", @@ -20119,13 +20503,13 @@ "vogelstein": false, "sangerCGC": true, "geneAliases": [ + "NOT3", "NOT3H", "KIAA0691", - "NOT3", "LENG2" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "CPS1", @@ -20143,8 +20527,8 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "CRTC1", @@ -20167,8 +20551,8 @@ "MECT1", "KIAA0616" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "CRTC3", @@ -20188,8 +20572,8 @@ "geneAliases": [ "FLJ21868" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "CSF1", @@ -20211,8 +20595,31 @@ "M-CSF", "MCSF" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false + }, + { + "hugoSymbol": "CTDNEP1", + "entrezGeneId": 23399, + "grch37Isoform": "ENST00000318988", + "grch37RefSeq": "NM_015343.4", + "grch38Isoform": "ENST00000574322", + "grch38RefSeq": "NM_001143775.2", + "oncokbAnnotated": true, + "occurrenceCount": 1, + "mSKImpact": false, + "mSKHeme": false, + "foundation": false, + "foundationHeme": false, + "vogelstein": false, + "sangerCGC": false, + "geneAliases": [ + "DULLARD", + "NET56", + "HSA011916" + ], + "oncogene": false, + "tsg": true }, { "hugoSymbol": "CYP17A1", @@ -20235,8 +20642,8 @@ "P450C17", "CPT7" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "DAZAP1", @@ -20256,8 +20663,8 @@ "geneAliases": [ "MGC19907" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "DCTN1", @@ -20275,32 +20682,8 @@ "vogelstein": false, "sangerCGC": true, "geneAliases": [], - "tsg": false, - "oncogene": false - }, - { - "hugoSymbol": "DDB2", - "entrezGeneId": 1643, - "grch37Isoform": "", - "grch37RefSeq": "", - "grch38Isoform": "", - "grch38RefSeq": "", - "oncokbAnnotated": false, - "occurrenceCount": 1, - "mSKImpact": false, - "mSKHeme": false, - "foundation": false, - "foundationHeme": false, - "vogelstein": false, - "sangerCGC": true, - "geneAliases": [ - "UV-DDB2", - "FLJ34321", - "XPE", - "DDBB" - ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "DDR1", @@ -20326,8 +20709,8 @@ "CAK", "CD167" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "DDX4", @@ -20347,8 +20730,8 @@ "geneAliases": [ "VASA" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "DDX41", @@ -20366,11 +20749,11 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [ - "MGC8828", - "ABS" + "ABS", + "MGC8828" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "DKK1", @@ -20391,8 +20774,8 @@ "SK", "DKK-1" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "DKK2", @@ -20410,8 +20793,8 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "DKK3", @@ -20431,8 +20814,8 @@ "geneAliases": [ "REIC" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "DKK4", @@ -20450,8 +20833,8 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "DPYD", @@ -20469,11 +20852,11 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [ - "DPD", - "DHPDHase" + "DHPDHase", + "DPD" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "DUSP2", @@ -20493,8 +20876,8 @@ "geneAliases": [ "PAC-1" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "DUSP9", @@ -20512,11 +20895,11 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [ - "MKP-4", - "MKP4" + "MKP4", + "MKP-4" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "ECSIT", @@ -20536,8 +20919,29 @@ "geneAliases": [ "SITPEC" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false + }, + { + "hugoSymbol": "EGR2", + "entrezGeneId": 1959, + "grch37Isoform": "ENST00000242480", + "grch37RefSeq": "NM_001136177.1", + "grch38Isoform": "ENST00000242480", + "grch38RefSeq": "NM_000399.5", + "oncokbAnnotated": true, + "occurrenceCount": 1, + "mSKImpact": false, + "mSKHeme": false, + "foundation": false, + "foundationHeme": false, + "vogelstein": false, + "sangerCGC": false, + "geneAliases": [ + "KROX20" + ], + "oncogene": false, + "tsg": true }, { "hugoSymbol": "EIF2B1", @@ -20555,13 +20959,34 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [ - "EIF-2B", "EIF-2Balpha", + "EIF-2B", "EIF2B", "EIF2BA" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true + }, + { + "hugoSymbol": "ELL2", + "entrezGeneId": 22936, + "grch37Isoform": "ENST00000237853", + "grch37RefSeq": "NM_012081.5", + "grch38Isoform": "ENST00000237853", + "grch38RefSeq": "NM_012081.6", + "oncokbAnnotated": true, + "occurrenceCount": 1, + "mSKImpact": false, + "mSKHeme": false, + "foundation": false, + "foundationHeme": false, + "vogelstein": false, + "sangerCGC": false, + "geneAliases": [ + "MRCCAT1" + ], + "oncogene": true, + "tsg": true }, { "hugoSymbol": "ELP2", @@ -20579,12 +21004,33 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [ - "FLJ10879", "STATIP1", + "FLJ10879", "StIP" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false + }, + { + "hugoSymbol": "ERCC1", + "entrezGeneId": 2067, + "grch37Isoform": "ENST00000300853", + "grch37RefSeq": "NM_001983", + "grch38Isoform": "ENST00000300853", + "grch38RefSeq": "NM_001983", + "oncokbAnnotated": true, + "occurrenceCount": 1, + "mSKImpact": false, + "mSKHeme": false, + "foundation": false, + "foundationHeme": false, + "vogelstein": false, + "sangerCGC": false, + "geneAliases": [ + "RAD10" + ], + "oncogene": false, + "tsg": true }, { "hugoSymbol": "EXOSC6", @@ -20608,8 +21054,8 @@ "Mtr3p", "MTR3" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "EXT2", @@ -20629,8 +21075,8 @@ "geneAliases": [ "SOTV" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "FAF1", @@ -20651,11 +21097,33 @@ "HFAF1s", "CGI-03", "hFAF1", - "UBXD12", - "UBXN3A" + "UBXN3A", + "UBXD12" + ], + "oncogene": false, + "tsg": false + }, + { + "hugoSymbol": "FANCI", + "entrezGeneId": 55215, + "grch37Isoform": "ENST00000310775", + "grch37RefSeq": "NM_001113378.1", + "grch38Isoform": "ENST00000310775", + "grch38RefSeq": "NM_001113378.2", + "oncokbAnnotated": true, + "occurrenceCount": 1, + "mSKImpact": false, + "mSKHeme": false, + "foundation": false, + "foundationHeme": false, + "vogelstein": false, + "sangerCGC": false, + "geneAliases": [ + "FLJ10719", + "KIAA1794" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "FANCM", @@ -20676,8 +21144,8 @@ "KIAA1596", "FAAP250" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "FAT4", @@ -20699,35 +21167,149 @@ "FAT-J", "CDHR11" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false + }, + { + "hugoSymbol": "FBXO31", + "entrezGeneId": 79791, + "grch37Isoform": "", + "grch37RefSeq": "", + "grch38Isoform": "", + "grch38RefSeq": "", + "oncokbAnnotated": false, + "occurrenceCount": 1, + "mSKImpact": false, + "mSKHeme": false, + "foundation": false, + "foundationHeme": true, + "vogelstein": false, + "sangerCGC": false, + "geneAliases": [], + "oncogene": false, + "tsg": false + }, + { + "hugoSymbol": "FBXW2", + "entrezGeneId": 26190, + "grch37Isoform": "ENST00000608872", + "grch37RefSeq": "NM_012164", + "grch38Isoform": "ENST00000608872", + "grch38RefSeq": "NM_012164", + "oncokbAnnotated": true, + "occurrenceCount": 1, + "mSKImpact": false, + "mSKHeme": false, + "foundation": false, + "foundationHeme": false, + "vogelstein": false, + "sangerCGC": false, + "geneAliases": [ + "FBW2", + "Md6", + "Fwd2" + ], + "oncogene": false, + "tsg": false + }, + { + "hugoSymbol": "FGF1", + "entrezGeneId": 2246, + "grch37Isoform": "ENST00000337706", + "grch37RefSeq": "NM_000800", + "grch38Isoform": "ENST00000337706", + "grch38RefSeq": "NM_000800", + "oncokbAnnotated": true, + "occurrenceCount": 1, + "mSKImpact": false, + "mSKHeme": false, + "foundation": false, + "foundationHeme": false, + "vogelstein": false, + "sangerCGC": false, + "geneAliases": [ + "ECGF-beta", + "FGF-alpha", + "AFGF", + "GLIO703", + "FGFA", + "ECGF", + "HBGF1", + "ECGFB", + "ECGFA" + ], + "oncogene": true, + "tsg": false + }, + { + "hugoSymbol": "FGF12", + "entrezGeneId": 2257, + "grch37Isoform": "", + "grch37RefSeq": "", + "grch38Isoform": "", + "grch38RefSeq": "", + "oncokbAnnotated": false, + "occurrenceCount": 1, + "mSKImpact": false, + "mSKHeme": false, + "foundation": true, + "foundationHeme": false, + "vogelstein": false, + "sangerCGC": false, + "geneAliases": [ + "FGF12B", + "FHF1" + ], + "oncogene": false, + "tsg": false + }, + { + "hugoSymbol": "FGF2", + "entrezGeneId": 2247, + "grch37Isoform": "ENST00000608478", + "grch37RefSeq": "", + "grch38Isoform": "ENST00000644866", + "grch38RefSeq": "NM_001361665.2", + "oncokbAnnotated": true, + "occurrenceCount": 1, + "mSKImpact": false, + "mSKHeme": false, + "foundation": false, + "foundationHeme": false, + "vogelstein": false, + "sangerCGC": false, + "geneAliases": [ + "FGFB" + ], + "oncogene": true, + "tsg": false }, { - "hugoSymbol": "FBXO31", - "entrezGeneId": 79791, - "grch37Isoform": "", - "grch37RefSeq": "", - "grch38Isoform": "", - "grch38RefSeq": "", - "oncokbAnnotated": false, + "hugoSymbol": "FGF5", + "entrezGeneId": 2250, + "grch37Isoform": "ENST00000312465", + "grch37RefSeq": "NM_004464", + "grch38Isoform": "ENST00000312465", + "grch38RefSeq": "NM_004464", + "oncokbAnnotated": true, "occurrenceCount": 1, "mSKImpact": false, "mSKHeme": false, "foundation": false, - "foundationHeme": true, + "foundationHeme": false, "vogelstein": false, "sangerCGC": false, "geneAliases": [], - "tsg": false, - "oncogene": false + "oncogene": true, + "tsg": false }, { - "hugoSymbol": "FBXW2", - "entrezGeneId": 26190, - "grch37Isoform": "ENST00000608872", - "grch37RefSeq": "NM_012164", - "grch38Isoform": "ENST00000608872", - "grch38RefSeq": "NM_012164", + "hugoSymbol": "FGF7", + "entrezGeneId": 2252, + "grch37Isoform": "ENST00000267843", + "grch37RefSeq": "NM_002009", + "grch38Isoform": "ENST00000267843", + "grch38RefSeq": "NM_002009", "oncokbAnnotated": true, "occurrenceCount": 1, "mSKImpact": false, @@ -20737,34 +21319,50 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [ - "Md6", - "Fwd2", - "FBW2" + "KGF" ], - "tsg": false, - "oncogene": false + "oncogene": true, + "tsg": false }, { - "hugoSymbol": "FGF12", - "entrezGeneId": 2257, - "grch37Isoform": "", - "grch37RefSeq": "", - "grch38Isoform": "", - "grch38RefSeq": "", - "oncokbAnnotated": false, + "hugoSymbol": "FGF8", + "entrezGeneId": 2253, + "grch37Isoform": "ENST00000344255", + "grch37RefSeq": "NM_033164", + "grch38Isoform": "ENST00000344255", + "grch38RefSeq": "NM_033164", + "oncokbAnnotated": true, "occurrenceCount": 1, "mSKImpact": false, "mSKHeme": false, - "foundation": true, + "foundation": false, "foundationHeme": false, "vogelstein": false, "sangerCGC": false, "geneAliases": [ - "FGF12B", - "FHF1" + "AIGF" ], - "tsg": false, - "oncogene": false + "oncogene": true, + "tsg": false + }, + { + "hugoSymbol": "FGF9", + "entrezGeneId": 2254, + "grch37Isoform": "ENST00000382353", + "grch37RefSeq": "NM_002010", + "grch38Isoform": "ENST00000382353", + "grch38RefSeq": "NM_002010", + "oncokbAnnotated": true, + "occurrenceCount": 1, + "mSKImpact": false, + "mSKHeme": false, + "foundation": false, + "foundationHeme": false, + "vogelstein": false, + "sangerCGC": false, + "geneAliases": [], + "oncogene": true, + "tsg": false }, { "hugoSymbol": "FIP1L1", @@ -20785,8 +21383,8 @@ "FIP1", "DKFZp586K0717" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "FLYWCH1", @@ -20806,8 +21404,8 @@ "geneAliases": [ "DKFZp761A132" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "FNBP1", @@ -20825,11 +21423,11 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [ - "KIAA0554", - "FBP17" + "FBP17", + "KIAA0554" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "FOLH1", @@ -20847,15 +21445,37 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [ - "NAALAD1", "PSMA", - "PSM", "FOLH", + "NAALAD1", + "PSM", "NAALAdase", "GCPII" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false + }, + { + "hugoSymbol": "FOLR1", + "entrezGeneId": 2348, + "grch37Isoform": "ENST00000312293", + "grch37RefSeq": "NM_000802", + "grch38Isoform": "ENST00000312293", + "grch38RefSeq": "NM_000802", + "oncokbAnnotated": true, + "occurrenceCount": 1, + "mSKImpact": false, + "mSKHeme": false, + "foundation": false, + "foundationHeme": false, + "vogelstein": false, + "sangerCGC": false, + "geneAliases": [ + "FR\u03b1", + "FOLR" + ], + "oncogene": true, + "tsg": false }, { "hugoSymbol": "FOXN4", @@ -20873,8 +21493,8 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "FSTL1", @@ -20893,13 +21513,13 @@ "sangerCGC": false, "geneAliases": [ "FSL1", - "OCC-1", "FRP", "OCC1", + "OCC-1", "tsc36" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "FZR1", @@ -20917,15 +21537,15 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [ - "KIAA1242", "CDC20C", "HCDH1", "FZR2", + "KIAA1242", "HCDH", "FZR" ], - "tsg": true, - "oncogene": true + "oncogene": true, + "tsg": true }, { "hugoSymbol": "GADD45B", @@ -20944,11 +21564,33 @@ "sangerCGC": false, "geneAliases": [ "DKFZP566B133", - "MYD118", - "GADD45BETA" + "GADD45BETA", + "MYD118" + ], + "oncogene": false, + "tsg": false + }, + { + "hugoSymbol": "GEN1", + "entrezGeneId": 348654, + "grch37Isoform": "ENST00000381254", + "grch37RefSeq": "NM_001130009.1", + "grch38Isoform": "ENST00000381254", + "grch38RefSeq": "NM_001130009.3", + "oncokbAnnotated": true, + "occurrenceCount": 1, + "mSKImpact": false, + "mSKHeme": false, + "foundation": false, + "foundationHeme": false, + "vogelstein": false, + "sangerCGC": false, + "geneAliases": [ + "Gen", + "FLJ40869" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "GMPS", @@ -20968,8 +21610,8 @@ "geneAliases": [ "GATD7" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "GOLGA5", @@ -20987,13 +21629,13 @@ "vogelstein": false, "sangerCGC": true, "geneAliases": [ - "golgin-84", "ret-II", - "GOLIM5", - "rfg5" + "rfg5", + "golgin-84", + "GOLIM5" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "GOPC", @@ -21016,34 +21658,27 @@ "PIST", "CAL" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { - "hugoSymbol": "GPC3", - "entrezGeneId": 2719, - "grch37Isoform": "", - "grch37RefSeq": "", - "grch38Isoform": "", - "grch38RefSeq": "", - "oncokbAnnotated": false, + "hugoSymbol": "GRB7", + "entrezGeneId": 2886, + "grch37Isoform": "ENST00000309156", + "grch37RefSeq": "NM_001030002", + "grch38Isoform": "ENST00000309156", + "grch38RefSeq": "NM_001030002", + "oncokbAnnotated": true, "occurrenceCount": 1, "mSKImpact": false, "mSKHeme": false, "foundation": false, "foundationHeme": false, "vogelstein": false, - "sangerCGC": true, - "geneAliases": [ - "SGBS", - "OCI-5", - "SDYS", - "SGBS1", - "DGSX", - "SGB" - ], - "tsg": false, - "oncogene": false + "sangerCGC": false, + "geneAliases": [], + "oncogene": true, + "tsg": false }, { "hugoSymbol": "GTSE1", @@ -21061,11 +21696,11 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [ - "GTSE-1", - "B99" + "B99", + "GTSE-1" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "H3C15", @@ -21083,12 +21718,12 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [ - "H3/o", "HIST2H3A", + "H3/o", "H3/n" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "H3P6", @@ -21108,8 +21743,8 @@ "geneAliases": [ "H3F3AP4" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "H4C6", @@ -21127,12 +21762,12 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [ - "H4FC", "H4/c", + "H4FC", "HIST1H4F" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "HDAC2", @@ -21150,11 +21785,32 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [ - "YAF1", - "KDAC2" + "KDAC2", + "YAF1" + ], + "oncogene": true, + "tsg": false + }, + { + "hugoSymbol": "HFE", + "entrezGeneId": 3077, + "grch37Isoform": "ENST00000357618", + "grch37RefSeq": "NM_000410", + "grch38Isoform": "ENST00000357618", + "grch38RefSeq": "NM_000410", + "oncokbAnnotated": true, + "occurrenceCount": 1, + "mSKImpact": false, + "mSKHeme": false, + "foundation": false, + "foundationHeme": false, + "vogelstein": false, + "sangerCGC": false, + "geneAliases": [ + "HFE1" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "HNF1B", @@ -21178,8 +21834,8 @@ "MODY5", "HNF1beta" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "HNRNPA2B1", @@ -21199,8 +21855,8 @@ "geneAliases": [ "HNRPA2B1" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "HOOK3", @@ -21218,8 +21874,8 @@ "vogelstein": false, "sangerCGC": true, "geneAliases": [], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "HOXA3", @@ -21239,8 +21895,8 @@ "geneAliases": [ "HOX1E" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "HSD17B2", @@ -21261,8 +21917,8 @@ "SDR9C2", "HSD17" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "HTATIP2", @@ -21282,11 +21938,11 @@ "geneAliases": [ "CC3", "FLJ26963", - "TIP30", - "SDR44U1" + "SDR44U1", + "TIP30" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "ID1", @@ -21307,8 +21963,8 @@ "dJ857M17.1.2", "bHLHb24" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "IFNAR1", @@ -21326,11 +21982,11 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [ - "IFRC", - "IFNAR" + "IFNAR", + "IFRC" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "IKBKB", @@ -21353,8 +22009,8 @@ "IKK2", "IKKB" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "IKZF2", @@ -21375,8 +22031,8 @@ "Helios", "ZNFN1A2" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "IL2", @@ -21397,8 +22053,8 @@ "TCGF", "IL-2" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "ING1", @@ -21423,8 +22079,8 @@ "p47ING1a", "p33ING1" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "INPP5D", @@ -21446,8 +22102,8 @@ "SHIP1", "SHIP" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "INTS6", @@ -21467,13 +22123,13 @@ "geneAliases": [ "DDX26", "DBI-1", - "DICE1", "DDX26A", "HDB", + "DICE1", "Notchl2" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "IQGAP1", @@ -21495,8 +22151,8 @@ "p195", "KIAA0051" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "IRS4", @@ -21517,8 +22173,8 @@ "PY160", "IRS-4" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "ITPKB", @@ -21536,11 +22192,11 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [ - "IP3KB", - "IP3-3KB" + "IP3-3KB", + "IP3KB" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "JAZF1", @@ -21558,12 +22214,12 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [ - "DKFZp761K2222", "TIP27", + "DKFZp761K2222", "ZNF802" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "KAT6B", @@ -21583,13 +22239,13 @@ "geneAliases": [ "MYST4", "Morf", + "ZC2HC6B", "querkopf", "qkf", - "MOZ2", - "ZC2HC6B" + "MOZ2" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "KAT7", @@ -21612,8 +22268,8 @@ "HBO1", "ZC2HC7" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "KCNJ5", @@ -21636,8 +22292,8 @@ "GIRK4", "LQT13" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "KDM2B", @@ -21656,13 +22312,13 @@ "sangerCGC": false, "geneAliases": [ "FBXL10", - "CXXC2", - "PCCX2", "JHDM1B", - "Fbl10" + "Fbl10", + "CXXC2", + "PCCX2" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "KDM4C", @@ -21681,12 +22337,12 @@ "sangerCGC": false, "geneAliases": [ "GASC1", + "TDRD14C", "JMJD2C", - "KIAA0780", - "TDRD14C" + "KIAA0780" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "KDM5D", @@ -21710,8 +22366,8 @@ "KIAA0234", "SMCY" ], - "tsg": true, - "oncogene": true + "oncogene": true, + "tsg": true }, { "hugoSymbol": "KLF2", @@ -21731,8 +22387,8 @@ "geneAliases": [ "LKLF" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "KLF3", @@ -21752,8 +22408,8 @@ "geneAliases": [ "BKLF" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "KLF6", @@ -21779,8 +22435,8 @@ "PAC1", "Zf9" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "KLK2", @@ -21798,8 +22454,8 @@ "vogelstein": false, "sangerCGC": true, "geneAliases": [], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "KNL1", @@ -21828,8 +22484,8 @@ "KIAA1570", "AF15Q14" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "KTN1", @@ -21850,8 +22506,8 @@ "KNT", "KIAA0004" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "LARP4B", @@ -21872,8 +22528,8 @@ "KIAA0217", "LARP5" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "LCP1", @@ -21891,13 +22547,13 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [ - "L-PLASTIN", "CP64", "LC64P", + "L-PLASTIN", "PLS2" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "LGR5", @@ -21916,12 +22572,12 @@ "sangerCGC": false, "geneAliases": [ "GPR49", - "FEX", "GPR67", - "HG38" + "HG38", + "FEX" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "LIFR", @@ -21941,34 +22597,8 @@ "geneAliases": [ "CD118" ], - "tsg": false, - "oncogene": false - }, - { - "hugoSymbol": "LMNA", - "entrezGeneId": 4000, - "grch37Isoform": "", - "grch37RefSeq": "", - "grch38Isoform": "", - "grch38RefSeq": "", - "oncokbAnnotated": false, - "occurrenceCount": 1, - "mSKImpact": false, - "mSKHeme": false, - "foundation": false, - "foundationHeme": false, - "vogelstein": false, - "sangerCGC": true, - "geneAliases": [ - "PRO1", - "LMNL1", - "HGPS", - "CMD1A", - "LMN1", - "LGMD1B" - ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "LRIG3", @@ -21989,8 +22619,8 @@ "KIAA3016", "FLJ90440" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "LRP5", @@ -22018,8 +22648,8 @@ "OPTA1", "LRP7" ], - "tsg": true, - "oncogene": true + "oncogene": true, + "tsg": true }, { "hugoSymbol": "LRP6", @@ -22039,8 +22669,8 @@ "geneAliases": [ "ADCAD2" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "LRRK2", @@ -22059,13 +22689,13 @@ "sangerCGC": false, "geneAliases": [ "RIPK7", - "PARK8", "ROCO2", "FLJ45829", + "PARK8", "DKFZp434H2111" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "MAGED1", @@ -22086,8 +22716,30 @@ "NRAGE", "DLXIN-1" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false + }, + { + "hugoSymbol": "MAGI2", + "entrezGeneId": 9863, + "grch37Isoform": "ENST00000354212", + "grch37RefSeq": "NM_012301.3", + "grch38Isoform": "ENST00000354212", + "grch38RefSeq": "NM_012301.4", + "oncokbAnnotated": true, + "occurrenceCount": 1, + "mSKImpact": false, + "mSKHeme": false, + "foundation": false, + "foundationHeme": false, + "vogelstein": false, + "sangerCGC": false, + "geneAliases": [ + "ACVRIP1", + "MAGI-2" + ], + "oncogene": false, + "tsg": true }, { "hugoSymbol": "MAL2", @@ -22105,8 +22757,8 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "MAML2", @@ -22127,8 +22779,30 @@ "KIAA1819", "MAM3" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false + }, + { + "hugoSymbol": "MAP3K21", + "entrezGeneId": 84451, + "grch37Isoform": "ENST00000366624", + "grch37RefSeq": "NM_032435", + "grch38Isoform": "ENST00000366624", + "grch38RefSeq": "NM_032435", + "oncokbAnnotated": true, + "occurrenceCount": 1, + "mSKImpact": false, + "mSKHeme": false, + "foundation": false, + "foundationHeme": false, + "vogelstein": false, + "sangerCGC": false, + "geneAliases": [ + "KIAA1804", + "MLK4" + ], + "oncogene": true, + "tsg": false }, { "hugoSymbol": "MAP3K6", @@ -22150,8 +22824,8 @@ "MEKK6", "ASK2" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "MAP4K4", @@ -22170,11 +22844,11 @@ "sangerCGC": false, "geneAliases": [ "NIK", - "HGK", - "FLH21957" + "FLH21957", + "HGK" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "MBD4", @@ -22192,8 +22866,8 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "MBD6", @@ -22213,8 +22887,8 @@ "geneAliases": [ "KIAA1887" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "MDS2", @@ -22232,8 +22906,8 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "MEF2D", @@ -22251,8 +22925,8 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "MIB1", @@ -22276,8 +22950,8 @@ "MIB", "DIP-1" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "MIDEAS", @@ -22295,13 +22969,13 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [ - "LSR68", "C14orf43", - "C14orf117", - "ELMSAN1" + "ELMSAN1", + "LSR68", + "C14orf117" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "MKNK1", @@ -22321,8 +22995,8 @@ "geneAliases": [ "MNK1" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "MLH3", @@ -22340,8 +23014,8 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "MLLT11", @@ -22361,8 +23035,8 @@ "geneAliases": [ "AF1Q" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "MNX1", @@ -22385,8 +23059,8 @@ "SCRA1", "HB9" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "MS4A1", @@ -22409,8 +23083,8 @@ "B1", "Bp35" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "MTCP1", @@ -22429,11 +23103,30 @@ "sangerCGC": true, "geneAliases": [ "TCL1C", - "p8MTCP1", - "P13MTCP1" + "P13MTCP1", + "p8MTCP1" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false + }, + { + "hugoSymbol": "MTHFD2", + "entrezGeneId": 10797, + "grch37Isoform": "ENST00000394053", + "grch37RefSeq": "NM_006636", + "grch38Isoform": "ENST00000394053", + "grch38RefSeq": "NM_006636", + "oncokbAnnotated": true, + "occurrenceCount": 1, + "mSKImpact": false, + "mSKHeme": false, + "foundation": false, + "foundationHeme": false, + "vogelstein": false, + "sangerCGC": false, + "geneAliases": [], + "oncogene": true, + "tsg": false }, { "hugoSymbol": "MYBL1", @@ -22454,8 +23147,8 @@ "A-myb", "AMYB" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "MYO18A", @@ -22473,34 +23166,11 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [ - "MysPDZ", - "KIAA0216" - ], - "tsg": false, - "oncogene": false - }, - { - "hugoSymbol": "MYO5A", - "entrezGeneId": 4644, - "grch37Isoform": "", - "grch37RefSeq": "", - "grch38Isoform": "", - "grch38RefSeq": "", - "oncokbAnnotated": false, - "occurrenceCount": 1, - "mSKImpact": false, - "mSKHeme": false, - "foundation": false, - "foundationHeme": false, - "vogelstein": false, - "sangerCGC": true, - "geneAliases": [ - "MYR12", - "MYO5", - "MYH12" + "KIAA0216", + "MysPDZ" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "NAB2", @@ -22520,8 +23190,8 @@ "geneAliases": [ "MADER" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "NACA", @@ -22541,8 +23211,8 @@ "geneAliases": [ "NACA1" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "NBEAP1", @@ -22560,11 +23230,11 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [ - "BCL8A", - "BCL8" + "BCL8", + "BCL8A" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "NCOA1", @@ -22588,8 +23258,8 @@ "F-SRC-1", "KAT13A" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "NCOA4", @@ -22613,8 +23283,8 @@ "ELE1", "DKFZp762E1112" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "NFATC2", @@ -22636,8 +23306,8 @@ "NFAT1", "NFATp" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "NFIB", @@ -22655,12 +23325,12 @@ "vogelstein": false, "sangerCGC": true, "geneAliases": [ - "NFIB2", "NFI-RED", + "NFIB2", "NFIB3" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "NFKBIE", @@ -22680,8 +23350,31 @@ "geneAliases": [ "IKBE" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false + }, + { + "hugoSymbol": "NHERF1", + "entrezGeneId": 9368, + "grch37Isoform": "ENST00000262613", + "grch37RefSeq": "NM_004252", + "grch38Isoform": "ENST00000262613", + "grch38RefSeq": "NM_004252", + "oncokbAnnotated": true, + "occurrenceCount": 1, + "mSKImpact": false, + "mSKHeme": false, + "foundation": false, + "foundationHeme": false, + "vogelstein": false, + "sangerCGC": false, + "geneAliases": [ + "SLC9A3R1", + "NHERF", + "EBP50" + ], + "oncogene": true, + "tsg": true }, { "hugoSymbol": "NOD1", @@ -22700,11 +23393,11 @@ "sangerCGC": false, "geneAliases": [ "CLR7.1", - "NLRC1", - "CARD4" + "CARD4", + "NLRC1" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "NONO", @@ -22728,8 +23421,32 @@ "P54", "PPP1R114" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false + }, + { + "hugoSymbol": "NQO1", + "entrezGeneId": 1728, + "grch37Isoform": "ENST00000320623", + "grch37RefSeq": "NM_000903", + "grch38Isoform": "ENST00000320623", + "grch38RefSeq": "NM_000903", + "oncokbAnnotated": true, + "occurrenceCount": 1, + "mSKImpact": false, + "mSKHeme": false, + "foundation": false, + "foundationHeme": false, + "vogelstein": false, + "sangerCGC": false, + "geneAliases": [ + "NMOR1", + "QR1", + "DIA4", + "DHQU" + ], + "oncogene": true, + "tsg": false }, { "hugoSymbol": "NUTM2A", @@ -22749,8 +23466,8 @@ "geneAliases": [ "FAM22A" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "NUTM2B", @@ -22771,8 +23488,8 @@ "bA119F19.1", "FAM22B" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "NUTM2D", @@ -22792,8 +23509,8 @@ "geneAliases": [ "FAM22D" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "OLIG2", @@ -22817,8 +23534,8 @@ "RACK17", "OLIGO2" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "OMD", @@ -22836,11 +23553,11 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [ - "SLRR2C", - "osteoadherin" + "osteoadherin", + "SLRR2C" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "ONECUT2", @@ -22860,8 +23577,8 @@ "geneAliases": [ "OC-2" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "PAG1", @@ -22881,8 +23598,8 @@ "geneAliases": [ "PAG" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "PAK3", @@ -22905,8 +23622,8 @@ "bPAK", "hPAK3" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "PARP2", @@ -22927,8 +23644,8 @@ "ADPRTL2", "ARTD2" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "PARP3", @@ -22946,15 +23663,15 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [ + "IRT1", + "pADPRT-3", "ARTD3", "ADPRTL3", "ADPRT3", - "hPARP-3", - "IRT1", - "pADPRT-3" + "hPARP-3" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "PASK", @@ -22976,8 +23693,8 @@ "KIAA0135", "STK37" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "PATZ1", @@ -23003,8 +23720,8 @@ "MAZR", "ZSG" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "PC", @@ -23024,8 +23741,8 @@ "geneAliases": [ "PCB" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "PCLO", @@ -23043,12 +23760,12 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [ + "KIAA0559", "DKFZp779G1236", - "ACZ", - "KIAA0559" + "ACZ" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "PCSK7", @@ -23068,11 +23785,11 @@ "geneAliases": [ "PC8", "PC7", - "LPC", - "SPC7" + "SPC7", + "LPC" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "PDCD11", @@ -23090,13 +23807,13 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [ - "KIAA0185", "NFBP", "RRP5", - "ALG-4" + "ALG-4", + "KIAA0185" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "PHF1", @@ -23114,12 +23831,12 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [ - "MTF2L2", "TDRD19C", + "MTF2L2", "PCL1" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "PHF19", @@ -23142,8 +23859,8 @@ "DKFZP727G051", "PCL3" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "PHLPP1", @@ -23162,13 +23879,13 @@ "sangerCGC": false, "geneAliases": [ "PLEKHE1", - "PHLPP", - "KIAA0606", "SCOP", - "PPM3A" + "PPM3A", + "PHLPP", + "KIAA0606" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "PHLPP2", @@ -23190,8 +23907,8 @@ "KIAA0931", "PHLPPL" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "POLG", @@ -23212,8 +23929,8 @@ "POLG1", "POLGA" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "POLQ", @@ -23231,8 +23948,29 @@ "vogelstein": false, "sangerCGC": true, "geneAliases": [], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false + }, + { + "hugoSymbol": "POU2F2", + "entrezGeneId": 5452, + "grch37Isoform": "ENST00000526816", + "grch37RefSeq": "NM_001207025", + "grch38Isoform": "ENST00000526816", + "grch38RefSeq": "NM_001207025", + "oncokbAnnotated": true, + "occurrenceCount": 1, + "mSKImpact": false, + "mSKHeme": false, + "foundation": false, + "foundationHeme": false, + "vogelstein": false, + "sangerCGC": false, + "geneAliases": [ + "OTF2" + ], + "oncogene": true, + "tsg": false }, { "hugoSymbol": "POU3F2", @@ -23255,8 +23993,8 @@ "BRN2", "POUF3" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "POU3F4", @@ -23279,8 +24017,8 @@ "DFNX2", "OTF9" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "POU5F1", @@ -23302,8 +24040,8 @@ "OTF3", "MGC22487" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "PPFIBP1", @@ -23322,11 +24060,11 @@ "sangerCGC": true, "geneAliases": [ "SGT2", - "hSgt2p", - "hSGT2" + "hSGT2", + "hSgt2p" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "PPP1CB", @@ -23351,12 +24089,12 @@ "PP1beta", "PP1c" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, - { - "hugoSymbol": "PRCC", - "entrezGeneId": 5546, + { + "hugoSymbol": "PRF1", + "entrezGeneId": 5551, "grch37Isoform": "", "grch37RefSeq": "", "grch38Isoform": "", @@ -23370,32 +24108,35 @@ "vogelstein": false, "sangerCGC": true, "geneAliases": [ - "RCCP1" + "HPLH2", + "PFP" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { - "hugoSymbol": "PRF1", - "entrezGeneId": 5551, - "grch37Isoform": "", - "grch37RefSeq": "", - "grch38Isoform": "", - "grch38RefSeq": "", - "oncokbAnnotated": false, + "hugoSymbol": "PRKCB", + "entrezGeneId": 5579, + "grch37Isoform": "ENST00000303531", + "grch37RefSeq": "NM_002738.6", + "grch38Isoform": "ENST00000643927", + "grch38RefSeq": "NM_002738.7", + "oncokbAnnotated": true, "occurrenceCount": 1, "mSKImpact": false, "mSKHeme": false, "foundation": false, "foundationHeme": false, "vogelstein": false, - "sangerCGC": true, + "sangerCGC": false, "geneAliases": [ - "HPLH2", - "PFP" + "PRKCB2", + "PRKCB1", + "PKCB", + "PKC\u03b2" ], - "tsg": false, - "oncogene": false + "oncogene": true, + "tsg": true }, { "hugoSymbol": "PRPF8", @@ -23414,13 +24155,13 @@ "sangerCGC": false, "geneAliases": [ "SNRNP220", + "RP13", "Prp8", "hPrp8", - "RP13", "PRPC8" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "PRSS1", @@ -23440,8 +24181,8 @@ "geneAliases": [ "TRY1" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "PRSS8", @@ -23459,8 +24200,8 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "PSMB2", @@ -23480,8 +24221,8 @@ "geneAliases": [ "HC7-I" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "PTK6", @@ -23501,8 +24242,8 @@ "geneAliases": [ "BRK" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "PTK7", @@ -23522,8 +24263,8 @@ "geneAliases": [ "CCK4" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "PTPN14", @@ -23543,8 +24284,8 @@ "geneAliases": [ "PEZ" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "PTPN6", @@ -23567,8 +24308,8 @@ "PTP-1C", "SHP-1" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "PTPRB", @@ -23588,8 +24329,8 @@ "geneAliases": [ "PTPB" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "PTPRC", @@ -23610,8 +24351,8 @@ "T200", "CD45" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "PTPRK", @@ -23631,8 +24372,8 @@ "geneAliases": [ "R-PTP-kappa" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "PUM1", @@ -23653,8 +24394,8 @@ "KIAA0099", "PUMH1" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "RAD17", @@ -23676,8 +24417,8 @@ "Rad24", "RAD17Sp" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "RALGDS", @@ -23696,11 +24437,11 @@ "sangerCGC": false, "geneAliases": [ "RGF", - "RalGEF", - "RGDS" + "RGDS", + "RalGEF" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "RASGEF1A", @@ -23718,11 +24459,11 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [ - "FLJ37817", - "CG4853" + "CG4853", + "FLJ37817" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "REV3L", @@ -23740,11 +24481,32 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [ - "POLZ", - "REV3" + "REV3", + "POLZ" + ], + "oncogene": true, + "tsg": false + }, + { + "hugoSymbol": "RIOK2", + "entrezGeneId": 55781, + "grch37Isoform": "ENST00000283109", + "grch37RefSeq": "NM_018343.2", + "grch38Isoform": "ENST00000283109", + "grch38RefSeq": "NM_018343.3", + "oncokbAnnotated": true, + "occurrenceCount": 1, + "mSKImpact": false, + "mSKHeme": false, + "foundation": false, + "foundationHeme": false, + "vogelstein": false, + "sangerCGC": false, + "geneAliases": [ + "FLJ11159" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "RMI2", @@ -23766,8 +24528,8 @@ "BLAP18", "C16orf75" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "RNASEH2A", @@ -23785,12 +24547,12 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [ - "RNHIA", "RNHL", - "RNASEHI" + "RNASEHI", + "RNHIA" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "RNASEH2B", @@ -23808,12 +24570,12 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [ - "FLJ11712", "DLEU8", + "FLJ11712", "AGS2" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "RNF217-AS1", @@ -23833,8 +24595,8 @@ "geneAliases": [ "STL" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "RPL10", @@ -23852,14 +24614,36 @@ "vogelstein": false, "sangerCGC": true, "geneAliases": [ - "L10", "DXS648", + "DXS648E", + "L10", "FLJ23544", - "QM", - "DXS648E" + "QM" + ], + "oncogene": false, + "tsg": false + }, + { + "hugoSymbol": "RPS15", + "entrezGeneId": 6209, + "grch37Isoform": "ENST00000592588", + "grch37RefSeq": "NM_001018", + "grch38Isoform": "ENST00000593052", + "grch38RefSeq": "NM_001308226", + "oncokbAnnotated": true, + "occurrenceCount": 1, + "mSKImpact": false, + "mSKHeme": false, + "foundation": false, + "foundationHeme": false, + "vogelstein": false, + "sangerCGC": false, + "geneAliases": [ + "S15", + "MGC111130" ], - "tsg": false, - "oncogene": false + "oncogene": true, + "tsg": false }, { "hugoSymbol": "RSPO3", @@ -23880,8 +24664,8 @@ "FLJ14440", "THSD2" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "RUNX2", @@ -23899,15 +24683,15 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [ - "CBFA1", - "PEBP2aA1", "CCD1", "CCD", - "AML3", - "PEBP2A1" + "PEBP2A1", + "CBFA1", + "PEBP2aA1", + "AML3" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "S1PR2", @@ -23927,12 +24711,12 @@ "geneAliases": [ "DFNB68", "H218", - "Gpcr13", "AGR16", + "Gpcr13", "EDG5" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "SALL4", @@ -23950,11 +24734,57 @@ "vogelstein": false, "sangerCGC": true, "geneAliases": [ - "ZNF797", - "dJ1112F19.1" + "dJ1112F19.1", + "ZNF797" + ], + "oncogene": false, + "tsg": false + }, + { + "hugoSymbol": "SAMD9", + "entrezGeneId": 54809, + "grch37Isoform": "ENST00000379958", + "grch37RefSeq": "NM_017654.3", + "grch38Isoform": "ENST00000379958", + "grch38RefSeq": "NM_017654.4", + "oncokbAnnotated": true, + "occurrenceCount": 1, + "mSKImpact": false, + "mSKHeme": false, + "foundation": false, + "foundationHeme": false, + "vogelstein": false, + "sangerCGC": false, + "geneAliases": [ + "FLJ20073", + "KIAA2004", + "C7orf5" + ], + "oncogene": false, + "tsg": false + }, + { + "hugoSymbol": "SAMD9L", + "entrezGeneId": 219285, + "grch37Isoform": "ENST00000318238", + "grch37RefSeq": "NM_152703.2", + "grch38Isoform": "ENST00000318238", + "grch38RefSeq": "NM_152703.5", + "oncokbAnnotated": true, + "occurrenceCount": 1, + "mSKImpact": false, + "mSKHeme": false, + "foundation": false, + "foundationHeme": false, + "vogelstein": false, + "sangerCGC": false, + "geneAliases": [ + "FLJ39885", + "KIAA2005", + "C7orf6" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "SBDS", @@ -23972,13 +24802,13 @@ "vogelstein": false, "sangerCGC": true, "geneAliases": [ - "CGI-97", "SWDS", "SDO1", - "FLJ10917" + "FLJ10917", + "CGI-97" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "SEC31A", @@ -23996,13 +24826,13 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [ + "ABP125", "KIAA0905", "ABP130", - "ABP125", "SEC31L1" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "SEPTIN5", @@ -24024,8 +24854,8 @@ "SEPT5", "HCDCREL-1" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "SEPTIN6", @@ -24048,8 +24878,8 @@ "MGC20339", "MGC16619" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "SEPTIN9", @@ -24075,8 +24905,8 @@ "KIAA0991", "AF17q25" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "SERP2", @@ -24097,8 +24927,8 @@ "C13orf21", "bA269C23.1" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "SF3B2", @@ -24117,12 +24947,12 @@ "sangerCGC": false, "geneAliases": [ "Cus1", - "SAP145", "SF3b145", + "SAP145", "SF3b1" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "SFPQ", @@ -24142,8 +24972,8 @@ "geneAliases": [ "PPP1R140" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "SFRP1", @@ -24161,11 +24991,11 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [ - "FRP-1", - "SARP2" + "SARP2", + "FRP-1" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "SFRP2", @@ -24183,12 +25013,12 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [ - "SDF-5", "SARP1", - "FRP-2" + "FRP-2", + "SDF-5" ], - "tsg": true, - "oncogene": true + "oncogene": true, + "tsg": true }, { "hugoSymbol": "SFRP4", @@ -24207,12 +25037,12 @@ "sangerCGC": true, "geneAliases": [ "FRPHE", - "FRZB-2", "frpHE", + "FRZB-2", "FRP-4" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "SIX1", @@ -24232,8 +25062,8 @@ "geneAliases": [ "DFNA23" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "SLC1A2", @@ -24254,8 +25084,8 @@ "EAAT2", "GLT-1" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "SLC45A3", @@ -24281,31 +25111,8 @@ "IPCA-8", "PCANAP2" ], - "tsg": false, - "oncogene": false - }, - { - "hugoSymbol": "SLC9A3R1", - "entrezGeneId": 9368, - "grch37Isoform": "ENST00000262613", - "grch37RefSeq": "NM_004252", - "grch38Isoform": "ENST00000262613", - "grch38RefSeq": "NM_004252", - "oncokbAnnotated": true, - "occurrenceCount": 1, - "mSKImpact": false, - "mSKHeme": false, - "foundation": false, - "foundationHeme": false, - "vogelstein": false, - "sangerCGC": false, - "geneAliases": [ - "EBP50", - "NHERF", - "NHERF1" - ], - "tsg": true, - "oncogene": true + "oncogene": false, + "tsg": false }, { "hugoSymbol": "SLIT2", @@ -24323,38 +25130,35 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [ - "Slit-2", - "SLIL3" + "SLIL3", + "Slit-2" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { - "hugoSymbol": "SMARCA1", - "entrezGeneId": 6594, - "grch37Isoform": "", - "grch37RefSeq": "", - "grch38Isoform": "", - "grch38RefSeq": "", - "oncokbAnnotated": false, + "hugoSymbol": "SLIT3", + "entrezGeneId": 6586, + "grch37Isoform": "ENST00000519560", + "grch37RefSeq": "NM_003062", + "grch38Isoform": "ENST00000519560", + "grch38RefSeq": "NM_003062", + "oncokbAnnotated": true, "occurrenceCount": 1, "mSKImpact": false, "mSKHeme": false, "foundation": false, - "foundationHeme": true, + "foundationHeme": false, "vogelstein": false, "sangerCGC": false, "geneAliases": [ - "SNF2LB", - "SNF2L1", - "SNF2L", - "hSNF2L", - "NURF140", - "SWI", - "ISWI" + "SLIL2", + "MEGF5", + "slit2", + "Slit-3" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "SNCAIP", @@ -24374,8 +25178,8 @@ "geneAliases": [ "SYPH1" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "SND1", @@ -24393,11 +25197,11 @@ "vogelstein": false, "sangerCGC": true, "geneAliases": [ - "TDRD11", - "p100" + "p100", + "TDRD11" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "SNX29", @@ -24415,11 +25219,11 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [ - "RUNDC2A", - "FLJ12363" + "FLJ12363", + "RUNDC2A" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "SOCS2", @@ -24437,15 +25241,15 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [ + "SSI-2", + "Cish2", "SOCS-2", "CIS2", "STATI2", - "SSI-2", - "Cish2", "SSI2" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "SQSTM1", @@ -24468,8 +25272,27 @@ "p62B", "A170" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false + }, + { + "hugoSymbol": "SRP72", + "entrezGeneId": 6731, + "grch37Isoform": "ENST00000342756", + "grch37RefSeq": "NM_006947", + "grch38Isoform": "ENST00000642900", + "grch38RefSeq": "NM_006947", + "oncokbAnnotated": true, + "occurrenceCount": 1, + "mSKImpact": false, + "mSKHeme": false, + "foundation": false, + "foundationHeme": false, + "vogelstein": false, + "sangerCGC": false, + "geneAliases": [], + "oncogene": true, + "tsg": false }, { "hugoSymbol": "SS18L1", @@ -24490,8 +25313,8 @@ "CREST", "KIAA0693" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "STAT1", @@ -24509,11 +25332,11 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [ - "STAT91", - "ISGF-3" + "ISGF-3", + "STAT91" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "STAT2", @@ -24533,8 +25356,8 @@ "geneAliases": [ "STAT113" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "STIL", @@ -24555,8 +25378,8 @@ "MCPH7", "SIL" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "STRN", @@ -24577,8 +25400,8 @@ "STRN1", "PPP2R6A" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "SZT2", @@ -24605,8 +25428,8 @@ "FLJ34502", "RP11-506B15.1" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "TCEA1", @@ -24627,11 +25450,11 @@ "TFIIS", "SII", "TF2S", - "TCEA", - "GTF2S" + "GTF2S", + "TCEA" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "TCF12", @@ -24649,14 +25472,14 @@ "vogelstein": false, "sangerCGC": true, "geneAliases": [ - "HTF4", "HEB", - "bHLHb20", "HsT17266", + "HTF4", + "bHLHb20", "p64" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "TCL1B", @@ -24676,8 +25499,8 @@ "geneAliases": [ "TML1" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "TEC", @@ -24697,8 +25520,8 @@ "geneAliases": [ "PSCTK4" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "TERC", @@ -24716,12 +25539,12 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [ + "hTR", "TRC3", - "SCARNA19", - "hTR" + "SCARNA19" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "TFEB", @@ -24742,8 +25565,8 @@ "bHLHe35", "TCFEB" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "TFPT", @@ -24765,8 +25588,8 @@ "FB1", "INO80F" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "TFRC", @@ -24788,8 +25611,8 @@ "TFR1", "p90" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "TIGAR", @@ -24809,8 +25632,8 @@ "geneAliases": [ "C12orf5" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "TIPARP", @@ -24838,8 +25661,8 @@ "PARP7", "pART14" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "TLE1", @@ -24860,8 +25683,8 @@ "GRG1", "ESG1" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "TLE2", @@ -24879,13 +25702,13 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [ - "ESG", - "ESG2", "FLJ41188", - "GRG2" + "GRG2", + "ESG", + "ESG2" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "TLE3", @@ -24904,12 +25727,12 @@ "sangerCGC": false, "geneAliases": [ "KIAA1547", + "GRG3", "ESG3", - "HsT18976", - "GRG3" + "HsT18976" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "TLE4", @@ -24930,8 +25753,8 @@ "E(spl)", "GRG4" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "TLL2", @@ -24949,8 +25772,8 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "TMEM30A", @@ -24968,12 +25791,12 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [ + "CDC50A", "C6orf67", - "FLJ10856", - "CDC50A" + "FLJ10856" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "TMSB4XP8", @@ -24993,8 +25816,8 @@ "geneAliases": [ "TMSL3" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "TNFRSF11A", @@ -25018,8 +25841,8 @@ "RANK", "CD265" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "TNFSF13", @@ -25040,8 +25863,8 @@ "CD256", "APRIL" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "TONSL", @@ -25062,8 +25885,29 @@ "IKBR", "NFKBIL2" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false + }, + { + "hugoSymbol": "TOP2A", + "entrezGeneId": 7153, + "grch37Isoform": "ENST00000423485", + "grch37RefSeq": "NM_001067", + "grch38Isoform": "ENST00000423485", + "grch38RefSeq": "NM_001067", + "oncokbAnnotated": true, + "occurrenceCount": 1, + "mSKImpact": false, + "mSKHeme": false, + "foundation": false, + "foundationHeme": false, + "vogelstein": false, + "sangerCGC": false, + "geneAliases": [ + "TOP2" + ], + "oncogene": true, + "tsg": false }, { "hugoSymbol": "TPR", @@ -25081,8 +25925,8 @@ "vogelstein": false, "sangerCGC": true, "geneAliases": [], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "TRIB3", @@ -25103,8 +25947,8 @@ "C20orf97", "dJ1103G7.3" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "TRIM33", @@ -25131,8 +25975,8 @@ "PTC7", "TF1G" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "TRRAP", @@ -25150,12 +25994,12 @@ "vogelstein": false, "sangerCGC": true, "geneAliases": [ - "Tra1", "PAF400", + "Tra1", "TR-AP" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "TTL", @@ -25175,8 +26019,8 @@ "geneAliases": [ "MGC46235" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "TUSC3", @@ -25202,8 +26046,8 @@ "OST3A", "N33" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "TYRO3", @@ -25229,8 +26073,34 @@ "Rek", "Dtk" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false + }, + { + "hugoSymbol": "UBA1", + "entrezGeneId": 7317, + "grch37Isoform": "ENST00000335972", + "grch37RefSeq": "NM_003334.3", + "grch38Isoform": "ENST00000335972", + "grch38RefSeq": "NM_003334.4", + "oncokbAnnotated": true, + "occurrenceCount": 1, + "mSKImpact": false, + "mSKHeme": false, + "foundation": false, + "foundationHeme": false, + "vogelstein": false, + "sangerCGC": false, + "geneAliases": [ + "GXP1", + "UBE1X", + "A1S9T", + "CFAP124", + "UBE1", + "POC20" + ], + "oncogene": true, + "tsg": false }, { "hugoSymbol": "UBE2A", @@ -25249,12 +26119,78 @@ "sangerCGC": false, "geneAliases": [ "RAD6A", - "UBC2", "HR6A", - "HHR6A" + "HHR6A", + "UBC2" + ], + "oncogene": true, + "tsg": false + }, + { + "hugoSymbol": "UBTF", + "entrezGeneId": 7343, + "grch37Isoform": "ENST00000302904", + "grch37RefSeq": "", + "grch38Isoform": "ENST00000436088", + "grch38RefSeq": "NM_014233.4", + "oncokbAnnotated": true, + "occurrenceCount": 1, + "mSKImpact": false, + "mSKHeme": false, + "foundation": false, + "foundationHeme": false, + "vogelstein": false, + "sangerCGC": false, + "geneAliases": [ + "UBF", + "NOR-90", + "UBF2", + "UBF1" + ], + "oncogene": true, + "tsg": false + }, + { + "hugoSymbol": "UCHL1", + "entrezGeneId": 7345, + "grch37Isoform": "ENST00000284440", + "grch37RefSeq": "NM_004181", + "grch38Isoform": "ENST00000284440", + "grch38RefSeq": "NM_004181", + "oncokbAnnotated": true, + "occurrenceCount": 1, + "mSKImpact": false, + "mSKHeme": false, + "foundation": false, + "foundationHeme": false, + "vogelstein": false, + "sangerCGC": false, + "geneAliases": [ + "PGP9.5", + "Uch-L1", + "PARK5" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false + }, + { + "hugoSymbol": "USP1", + "entrezGeneId": 7398, + "grch37Isoform": "ENST00000339950", + "grch37RefSeq": "NM_003368.4", + "grch38Isoform": "ENST00000339950", + "grch38RefSeq": "NM_003368.5", + "oncokbAnnotated": true, + "occurrenceCount": 1, + "mSKImpact": false, + "mSKHeme": false, + "foundation": false, + "foundationHeme": false, + "vogelstein": false, + "sangerCGC": false, + "geneAliases": [], + "oncogene": true, + "tsg": false }, { "hugoSymbol": "WAS", @@ -25277,8 +26213,8 @@ "THC", "WASP" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "WDCP", @@ -25297,11 +26233,11 @@ "sangerCGC": true, "geneAliases": [ "C2orf44", - "FLJ21945", - "MMAP" + "MMAP", + "FLJ21945" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "WDR90", @@ -25328,30 +26264,8 @@ "C16orf15", "KIAA1924" ], - "tsg": false, - "oncogene": false - }, - { - "hugoSymbol": "WRN", - "entrezGeneId": 7486, - "grch37Isoform": "", - "grch37RefSeq": "", - "grch38Isoform": "", - "grch38RefSeq": "", - "oncokbAnnotated": false, - "occurrenceCount": 1, - "mSKImpact": false, - "mSKHeme": false, - "foundation": false, - "foundationHeme": false, - "vogelstein": false, - "sangerCGC": true, - "geneAliases": [ - "RECQ3", - "RECQL2" - ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "WWP1", @@ -25372,30 +26286,8 @@ "DKFZP434D2111", "AIP5" ], - "tsg": false, - "oncogene": true - }, - { - "hugoSymbol": "XPA", - "entrezGeneId": 7507, - "grch37Isoform": "", - "grch37RefSeq": "", - "grch38Isoform": "", - "grch38RefSeq": "", - "oncokbAnnotated": false, - "occurrenceCount": 1, - "mSKImpact": false, - "mSKHeme": false, - "foundation": false, - "foundationHeme": false, - "vogelstein": false, - "sangerCGC": true, - "geneAliases": [ - "XP1", - "XPAC" - ], - "tsg": false, - "oncogene": false + "oncogene": true, + "tsg": false }, { "hugoSymbol": "XRCC1", @@ -25415,8 +26307,8 @@ "geneAliases": [ "RCC" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "YPEL5", @@ -25436,8 +26328,8 @@ "geneAliases": [ "CGI-127" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "YWHAE", @@ -25457,8 +26349,8 @@ "geneAliases": [ "FLJ45465" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "YY1", @@ -25480,8 +26372,8 @@ "YIN-YANG-1", "UCRBP" ], - "tsg": false, - "oncogene": true + "oncogene": true, + "tsg": false }, { "hugoSymbol": "YY1AP1", @@ -25503,8 +26395,8 @@ "YY1AP", "HCCA2" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "ZBTB20", @@ -25522,13 +26414,13 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [ + "ODA-8S", "DPZF", "DKFZp566F123", - "ODA-8S", "ZNF288" ], - "tsg": true, - "oncogene": true + "oncogene": true, + "tsg": true }, { "hugoSymbol": "ZFP36L1", @@ -25546,13 +26438,13 @@ "vogelstein": false, "sangerCGC": false, "geneAliases": [ - "cMG1", "RNF162B", "TIS11B", + "cMG1", "Berg36" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "ZFP36L2", @@ -25574,8 +26466,8 @@ "ERF2", "RNF162C" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true }, { "hugoSymbol": "ZNF24", @@ -25598,8 +26490,33 @@ "ZSCAN3", "KOX17" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false + }, + { + "hugoSymbol": "ZNF292", + "entrezGeneId": 23036, + "grch37Isoform": "ENST00000369577", + "grch37RefSeq": "NM_015021.1", + "grch38Isoform": "ENST00000369577", + "grch38RefSeq": "NM_015021.3", + "oncokbAnnotated": true, + "occurrenceCount": 1, + "mSKImpact": false, + "mSKHeme": false, + "foundation": false, + "foundationHeme": false, + "vogelstein": false, + "sangerCGC": false, + "geneAliases": [ + "KIAA0530", + "ZFP292", + "Zn-16", + "Zn-15", + "bA393I2.3" + ], + "oncogene": false, + "tsg": true }, { "hugoSymbol": "ZNF331", @@ -25621,8 +26538,8 @@ "RITA", "ZNF361" ], - "tsg": false, - "oncogene": false + "oncogene": false, + "tsg": false }, { "hugoSymbol": "ZNF750", @@ -25643,7 +26560,7 @@ "FLJ13841", "Zfp750" ], - "tsg": true, - "oncogene": false + "oncogene": false, + "tsg": true } ] diff --git a/data/grch37_ensembl92/export/annotation_version.txt b/data/grch37_ensembl92/export/annotation_version.txt index afd9bf7..7af8d57 100644 --- a/data/grch37_ensembl92/export/annotation_version.txt +++ b/data/grch37_ensembl92/export/annotation_version.txt @@ -4,6 +4,7 @@ HGNC 2023-10 mirrored hgnc The resource for approved human gene nomenclature. Ge Cancer Hotspots v2 mirrored cancer_hotspots A resource for statistically significant mutations in cancer https://www.cancerhotspots.org 3D Hotspots v2 mirrored 3d_hotspots A resource for statistically significant mutations clustering in 3d protein structures in cancer https://www.3dhotspots.org/ reVUE https://github.com/knowledgesystems/reVUE-data/blob/main/VUEs.json mirrored revue A Repository for Variants with Unexpected Effects (VUE) in Cancer https://www.cancerrevue.org/ -Mutation Assessor v3 mirrored mutation_assessor Mutation Assessor predicts the functional impact of amino-acid substitutions in proteins, such as mutations discovered in cancer or missense polymorphisms. http://mutationassessor.org/r3/ +Mutation Assessor v4 mirrored mutation_assessor Mutation Assessor predicts the functional impact of amino-acid substitutions in proteins, such as mutations discovered in cancer or missense polymorphisms. http://mutationassessor.org/r3/ My Variant Info Includes many annotation sources, see https://docs.myvariant.info/en/latest/doc/data.html external my_variant_info MyVariant.info provides simple-to-use REST web services to query/retrieve variant annotation data, aggregated from many popular data resources. https://myvariant.info ClinVar 20230722 mirrored clinvar ClinVar aggregates information about genomic variation and its relationship to human health. https://www.ncbi.nlm.nih.gov/clinvar/ +OncoKB v4.24 mirrored oncokb OncoKB™ is a precision oncology knowledge base that contains biological and clinical information about genomic alterations in cancer. https://www.oncokb.org/ diff --git a/data/grch38_ensembl92/export/annotation_version.txt b/data/grch38_ensembl92/export/annotation_version.txt index 1d418cc..af288b8 100644 --- a/data/grch38_ensembl92/export/annotation_version.txt +++ b/data/grch38_ensembl92/export/annotation_version.txt @@ -5,3 +5,4 @@ Cancer Hotspots v2 mirrored cancer_hotspots A resource for statistically signifi 3D Hotspots v2 mirrored 3d_hotspots A resource for statistically significant mutations clustering in 3d protein structures in cancer https://www.3dhotspots.org/ My Variant Info Includes many annotation sources, see https://docs.myvariant.info/en/latest/doc/data.html external my_variant_info MyVariant.info provides simple-to-use REST web services to query/retrieve variant annotation data, aggregated from many popular data resources. https://myvariant.info ClinVar 20230722 mirrored clinvar ClinVar aggregates information about genomic variation and its relationship to human health. https://www.ncbi.nlm.nih.gov/clinvar/ +OncoKB v4.24 mirrored oncokb OncoKB™ is a precision oncology knowledge base that contains biological and clinical information about genomic alterations in cancer. https://www.oncokb.org/ \ No newline at end of file diff --git a/data/grch38_ensembl95/export/annotation_version.txt b/data/grch38_ensembl95/export/annotation_version.txt index 1d418cc..af288b8 100644 --- a/data/grch38_ensembl95/export/annotation_version.txt +++ b/data/grch38_ensembl95/export/annotation_version.txt @@ -5,3 +5,4 @@ Cancer Hotspots v2 mirrored cancer_hotspots A resource for statistically signifi 3D Hotspots v2 mirrored 3d_hotspots A resource for statistically significant mutations clustering in 3d protein structures in cancer https://www.3dhotspots.org/ My Variant Info Includes many annotation sources, see https://docs.myvariant.info/en/latest/doc/data.html external my_variant_info MyVariant.info provides simple-to-use REST web services to query/retrieve variant annotation data, aggregated from many popular data resources. https://myvariant.info ClinVar 20230722 mirrored clinvar ClinVar aggregates information about genomic variation and its relationship to human health. https://www.ncbi.nlm.nih.gov/clinvar/ +OncoKB v4.24 mirrored oncokb OncoKB™ is a precision oncology knowledge base that contains biological and clinical information about genomic alterations in cancer. https://www.oncokb.org/ \ No newline at end of file diff --git a/scripts/download_oncokb_isoform_overrides.py b/scripts/download_oncokb_isoform_overrides.py index d8ee2a0..050da89 100644 --- a/scripts/download_oncokb_isoform_overrides.py +++ b/scripts/download_oncokb_isoform_overrides.py @@ -2,11 +2,11 @@ import requests import pandas as pd -def main(reference_genome): +def main(reference_genome, version): # check if genome is grch37 (hg19), drop grch38 columns if reference_genome is grch37 drop_columns_name = 'grch38' if reference_genome == 'grch37' else 'grch37' - url ='https://www.oncokb.org/api/v1/utils/allCuratedGenes?includeEvidence=false' + url ='https://www.oncokb.org/api/v1/utils/allCuratedGenes?includeEvidence=false&version=' + version oncokb_df = pd.json_normalize(requests.get(url).json()) oncokb_df.drop(list(oncokb_df.filter(regex =drop_columns_name)), axis = 1, inplace = True) @@ -30,6 +30,7 @@ def main(reference_genome): parser = argparse.ArgumentParser() parser.add_argument("reference_genome", help="grch37 or grch38") + parser.add_argument("version", help="OncoKB version"), args = parser.parse_args() - main(args.reference_genome) + main(args.reference_genome, args.version)