Table 1. Summary of actionable germline aberrations in cancer predisposition genes.
Genes associated with predisposition or susceptibility to cancer included in NCCN guidelines, ACMG recommendations for reporting (Green et al, Genet. Med. 2013;15(7):565–574), currently being tested in clinical trials (see Supplementary Table 1A for details), or considered for reporting in MI_Oncoseq study.
| Gene MIM# | Gene | Cytoband | Chr coordinates (GRCh38) | Gene name | Phenotype* | NCCN guidelines | ACMG recommendation | Ongoing clinical trials** | MI_Oncoseq |
|---|---|---|---|---|---|---|---|---|---|
| 611731 | APC | 5q22.2 | 5:112707504–112846238 | Adenomatous polyposis coli | Colorectal cancer, somatic, 114500; Brain tumor-polyposis syndrome 2, AD, 175100; Hepatoblastoma, somatic, 114550; Adenomatous polyposis coli, AD, 175100; Gastric cancer, somatic, 613659; Adenoma, periampullary, somatic | X | X | X | X |
| 607585 | ATM | 11q22.3 | 11:108222483–108369101 | Ataxia-telangiectasia mutated (includes complementation groups A, C, D, and E) | Lymphoma, B-cell non-Hodgkin, somatic; Breast cancer, susceptibility to, AD, 114480; T-cell prolymphocytic leukemia, somatic; Lymphoma, mantle cell, somatic | X | X | ||
| 601215 | ATR | 3q23 | 3:142449234–142578825 | Ataxia-telangiectasia and Rad3-related (FRAP-related protein-1) | Cutaneous telangiectasia and cancer syndrome, familial, AD, 614564 | X | |||
| 601593 | BARD1 | 2q35 | 2:214725644–214809710 | BRCA1-associated RING domain 1 | Breast cancer, susceptibility to, AD, 114480 | X | |||
| 601299 | BMPR1A | 10q23.2 | 10:86755785–86927968 | Bone morphogenetic protein receptor, type IA | Polyposis, juvenile intestinal, AD, 174900; Polyposis syndrome, hereditary mixed, 2, 610069; Juvenile polyposis syndrome, infantile form, AD, 174900 | X | |||
| 113705 | BRCA1 | 17q21.31 | 17:43044294–43125482 | Breast cancer-1 gene | Pancreatic cancer, susceptibility to, 4, 614320; Breast-ovarian cancer, familial, 1, AD; Multifactorial), 604370 | X | X | X | X |
| 600185 | BRCA2 | 13q13.1 | 13:32315479–32399671 | BRCA2 gene | Breast cancer, male, susceptibility to, AD, 114480; Prostate cancer, AD, 176807; Wilms tumor, SM; AD, 194070; Pancreatic cancer 2, 613347; Medulloblastoma, AD, 155255; Glioblastoma 3, AR, 613029; Breast-ovarian cancer, familial, 2, AD, 612555 | X | X | X | |
| 605882 | BRIP1 | 17q23.2 | 17:61679185–61864119 | BRCA1-associated C-terminal helicase 1 | Breast cancer, early-onset, AD, 114480 | X | X | ||
| 192090 | CDH1 | 16q22.1 | 16:68737289–68835541 | Cadherin-1 (E-cadherin; uvomorulin) | Ovarian carcinoma, somatic, 167000; Gastric cancer, familial diffuse, with or without cleft lip and/or palate, AD, 137215; Endometrial carcinoma, somatic, 608089; Prostate cancer, susceptibility to, AD, 176807; Breast cancer, lobular, AD, 114480 | X | X | ||
| 604373 | CHEK2 | 22q12.1 | 22:28687742–28741865 | Checkpoint kinase 2, S. pombe, homolog of (RAD53, S. cerevisiae, homolog of) | Prostate cancer, familial, susceptibility to, AD, 176807; Breast cancer, susceptibility to, AD, 114480; Osteosarcoma, somatic, 259500 | X | X | X | |
| 606241 | DICER1 | 14q32.13 | 14:95086227–95158009 | Dicer, Drosophila, homolog of, 1 | Rhabdomyosarcoma, embryonal, 2, 180295; Pleuropulmonary blastoma, AD, 601200 | X | |||
| 131550 | EGFR | 7p11.2 | 7:55019031–55207337 | Epidermal growth factor receptor | Non-small cell lung cancer, susceptibility to, AR, 211980; Non-small cell lung cancer, response to tyrosine kinase inhibitor in, AR, 211980; Adenocarcinoma of lung, response to tyrosine kinase inhibitor in, AR, 211980 | X | |||
| 185535 | EPCAM | 2p21 | 2:47369147–47387027 | Epithelial cellular adhesion molecule | Colorectal cancer, hereditary nonpolyposis, type 8, 613244 | X | |||
| 607139 | FANCA | 16q24.3 | 16:89737550–89816657 | Fanconi anemia, complementation group A | Fanconi anemia, complementation group A, AR, 227650 | X | X | ||
| 136850 | FH | 1q43 | 1:241497556–241519784 | Fumarate Hydratase | Leiomyomatosis and renal cell cancer, AD, 150800 | X | X | X | |
| 610290 | GALNT12 | 9q22.33 | 9:98807698–98850080 | UDP-N-acetyl-alpha-D-galactosamine:polypeptide N-acetylgalactosaminyltransferase 12 | Colorectal cancer, susceptibility to, 1, 608812 | X | |||
| 604607 | HOXB13 | 17q21.32 | 17:48724762–48728748 | Homeobox B13 | Breast cancer, 114480; Prostate cancer, 610997 | X | |||
| 613733 | MEN1 | 11q13.1 | 11:64803513–64811293 | Menin | Adrenal adenoma, somatic; Parathyroid adenoma, somatic; Multiple endocrine neoplasia 1, AD, 131100; Lipoma, somatic; Carcinoid tumor of lung; Angiofibroma, somatic | X | |||
| 164860 | MET | 7q31.2 | 7:116672358–116798385 | Oncogene MET | Renal cell carcinoma, papillary, 1, familial and somatic, 605074; Hepatocellular carcinoma, childhood type, somatic, 114550 | X | |||
| 120436 | MLH1 | 3p22.2 | 3:36993349–37050845 | mutL, E. coli, homolog of, 1 | Colorectal cancer, hereditary nonpolyposis, type 2, 609310; Mismatch repair cancer syndrome, AR, 276300 | X | X | X | X |
| 600814 | MRE11A | 11q21 | 11:94415569–94512700 | Meiotic recombination 11, S. cerevisiae, homolog A of | Ataxia-telangiectasia-like disorder, AR, 604391 | X | X | X | |
| 609309 | MSH2 | 2p21-p16 | 2:47403066–47634500 | mutS, E. coli, homolog of, 2 | Mismatch repair cancer syndrome, AR, 276300; Colorectal cancer, hereditary nonpolyposis, type 1, AD, 120435 | X | X | X | |
| 600678 | MSH6 | 2p16.3 | 2:47783081–47806952 | MutS, E. coli, homolog of, 6 | Endometrial cancer, familial, 608089; Colorectal cancer, hereditary nonpolyposis, type 5, AD, 614350; Mismatch repair cancer syndrome, AR, 276300 | X | X | X | |
| 604933 | MUTYH | 1p34.1 | 1:45329241–45340924 | MutY, E. coli, homolog of | Adenomas, multiple colorectal, 608456; Gastric cancer, somatic, 613659; Colorectal adenomatous polyposis, AR, with pilomatricomas, SM, 132600 | X | X | X | |
| 602667 | NBN | 8q21.3 | 8:89933335–89984732 | Nibrin | Nijmegen breakage syndrome, AR, 251260; Leukemia, acute lymphoblastic, 613065; Aplastic anemia, 609135 | X | X | ||
| 607379 | NF2 | 22q12.2 | 22:29603555–29698599 | Merlin | Neurofibromatosis, type 2, AD, 101000; Meningioma, NF2-related, somatic, 607174; Schwannomatosis, AD, 162091 | X | X | ||
| 191315 | NTRK1 | 1q23.1 | 1:156815749–156881849 | Neurotrophic tyrosine kinase, receptor, type 1 | Medullary thyroid carcinoma, familial, AD, 155240 | X | |||
| 610355 | PALB2 | 16p12.2 | 16:23603161–23641356 | Partner and localizer of BRCA2 | Pancreatic cancer, susceptibility to, 3, 613348; Breast cancer, susceptibility to, AD, 114480; Fanconi anemia, complementation group N, 610832 | X | X | ||
| 600259 | PMS2 | 7p22.1 | 7:5970924–6009105 | Postmeiotic segregation increased, S. cerevisiae, 2, homolog of | Mismatch repair cancer syndrome, AR, 276300; Colorectal cancer, hereditary nonpolyposis, type 4, 614337 | X | X | X | |
| 601728 | PTEN | 10q23.31 | 10:87863437–87971929 | Phosphatase and tensin homolog (mutated in multiple advanced cancers 1) | Glioma susceptibility 2, 613028; Endometrial carcinoma, somatic, 608089; Squamous cell carcinoma, head and neck, somatic, 275355; PTEN hamartoma tumor syndrome; Prostate cancer, somatic, 176807; Malignant melanoma, somatic, 155600; Meningioma, AD, 607174 | X | X | X | |
| 604040 | RAD50 | 5q31.1 | 5:132556923–132644620 | RAD50, S. cerevisiae, homolog of | Nijmegen breakage syndrome-like disorder, 613078 | X | |||
| 602774 | RAD51C | 17q22 | 17:58692537–58734341 | RAD51, S. cerevisiae, homolog of, C | Breast-ovarian cancer, familial, susceptibility to, 3, 613399; Fanconi anemia, complementation group O, AR, 613390 | X | X | ||
| 602954 | RAD51D | 17q12 | 17:35099791–35119868 | RAD51, S. cerevisiae, homolog of, D | Breast-ovarian cancer, familial, susceptibility to, 4, 614291 | X | |||
| 614041 | RB1 | 13q14.2 | 13:48303746–48481889 | Retinoblastoma-1 | Small-cell cancer of the lung, somatic, 182280; Retinoblastoma, trilateral, SM; AD, 180200; Retinoblastoma, SM; AD, 180200; Osteosarcoma, somatic, 259500; Bladder cancer, somatic, 109800 | X | X | ||
| 604610 | RECQL3 | 15q26.1 | 15:90717326–90815461 | DNA helicase, RecQ-like 3 | Bloom syndrome, AR, 210900 | X | |||
| 164761 | RET | 10q11.21 | 10:43077068–43130350 | RET transforming sequence; oncogene RET | Multiple endocrine neoplasia IIB, AD, 162300; Multiple endocrine neoplasia IIA, AD, 171400; Medullary thyroid carcinoma, AD, 155240; Pheochromocytoma, AD, 171300 | X | |||
| 613019 | SDHAF2 | 11q12.2 | 11:61430124–61446766 | Succinate dehydrogenase complex assembly factor 2 | Paragangliomas 2, AD, 601650 | X | |||
| 185470 | SDHB | 1p36.13 | 1:17018721–17054169 | Succinate dehydrogenase complex, subunit B, iron sulfur (Ip) | Pheochromocytoma, AD, 171300; Paragangliomas 4, AD, 115310; Paraganglioma and gastric stromal sarcoma, 606864; Gastrointestinal stromal tumor, AD; Isolated cases, 606764 | X | |||
| 602413 | SDHC | 1q23.3 | 1:161314375–161364750 | Succinate dehydrogenase complex, subunit C, integral membrane protein, 15kD | Paragangliomas 3, AD, 605373; Paraganglioma and gastric stromal sarcoma, 606864; Gastrointestinal stromal tumor, AD; isolated cases, 606764 | X | |||
| 602690 | SDHD | 11q23.1 | 11:112086823–112095800 | Succinate dehydrogenase complex, subunit D, integral membrane protein | Carcinoid tumors, intestinal, AD, 114900; Paragangliomas 1, with or without deafness, AD, 168000; Paraganglioma and gastric stromal sarcoma, 606864; Merkel cell carcinoma, somatic; Cowden syndrome 3, 615106; Pheochromocytoma, AD, 171300 | X | |||
| 600993 | SMAD4 | 18q21.2 | 18:51030212–51085041 | Mothers against decapentaplegic, Drosophila, homolog of, 4 | Polyposis, juvenile intestinal, AD, 174900; Pancreatic cancer, somatic, 260350; Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome, AD, 175050 | X | |||
| 602216 | STK11 | 19p13.3 | 19:1205798–1228434 | Serine/threonine protein kinase-11 | Pancreatic cancer, (SM; AD; Multifactorial), 260350; Melanoma, malignant, somatic; Testicular tumor, somatic, 273300 | X | X | ||
| 191170 | TP53 | 17p13.1 | 17:7668401–7687549 | Tumor protein p53 | Glioma susceptibility 1, (SM; AD), 137800; Hepatocellular carcinoma, SM, 114550; Basal cell carcinoma 7, 614740; Colorectal cancer, AD, 114500; Pancreatic cancer, (SM; AD; Multifactorial), 260350; Choroid plexus papilloma, AD, 260500; Osteosarcoma, AR, 259500; Breast cancer, AD, 114480; Nasopharyngeal carcinoma, 607107; Adrenal cortical carcinoma, AR, 202300 | X | X | ||
| 605284 | TSC1 | 9q34.13 | 9:132891347–132945268 | Hamartin (tuberous sclerosis 1 gene) | Tuberous sclerosis-1, AD, 191100; Lymphangioleiomyomatosis, 606690 | X | |||
| 191092 | TSC2 | 16p13.3 | 16:2047803–2088719 | Tuberin (tuberous sclerosis 2 gene) | Tuberous sclerosis-2, AD, 613254; Lymphangioleiomyomatosis, somatic, 606690 | X | |||
| 608537 | VHL | 3p25.3 | 3:10141634–10153669 | VHL gene | Renal cell carcinoma, somatic, 144700; Pheochromocytoma, AD, 171300; Hemangioblastoma, cerebellar, somatic | X | |||
| 607102 | WT1 | 11p13 | 11:32387774–32435534 | Wilms tumor-1 | Mesothelioma, somatic, 156240; Wilms tumor, type 1, (SM; AD), 194070 | X |
*
AD: Autosomal dominant; AR: Autosomal recessive; SM: somatic mutation
**
See Supplementary Table 1A for details