Criteria of the German Consortium for Hereditary Breast and Ovarian Cancer for the Classification of Germline Sequence Variants in Risk Genes for Hereditary Breast and Ovarian Cancer

Abstract

More than ten years ago, the German Consortium for Hereditary Breast and Ovarian Cancer (GC-HBOC) set up a panel of experts (VUS Task Force) which was tasked with reviewing the classifications of genetic variants reported by individual centres of the GC-HBOC to the central database in Leipzig and reclassifying them, where necessary, based on the most recent data. When it evaluates variants, the VUS Task Force must arrive at a consensus. The resulting classifications are recorded in a central database where they serve as a basis for ensuring the consistent evaluation of previously known and newly identified variants in the different centres of the GC-HBOC. The standardised VUS evaluation by the VUS Task Force is a key element of the recall system which has also been set up by the GC-HBOC. The system will be used to pass on information to families monitored and managed by GC-HBOC centres in the event that previously classified variants are reclassified based on new information. The evaluation algorithm of the VUS Task Force was compiled using internationally established assessment methods (IARC, ACMG, ENIGMA) and is presented here together with the underlying evaluation criteria used to arrive at the classification decision using a flow chart. In addition, the characteristics and special features of specific individual risk genes associated with breast and/or ovarian cancer are discussed in separate subsections. The URLs of relevant databases have also been included together with extensive literature references to provide additional information and cover the scope and dynamism of the current state of knowledge on the evaluation of genetic variants. In future, if criteria are updated based on new information, the update will be published on the website of the GC-HBOC (https://www.konsortium-familiaerer-brustkrebs.de/).

Key words

hereditary breast/ovarian cancer - classification of genetic variants - risk genes

• References/Literatur

• 1 Couch FJ, Shimelis H, Hu C. et al. Associations Between Cancer Predisposition Testing Panel Genes and Breast Cancer. JAMA Oncol 2017; 3: 1190-1196 doi:10.1001/jamaoncol.2017.0424
• 2 Hauke J, Horvath J, Gross E. et al. Gene panel testing of 5589 BRCA1/2-negative index patients with breast cancer in a routine diagnostic setting: results of the German Consortium for Hereditary Breast and Ovarian Cancer. Cancer Med 2018; 7: 1349-1358 doi:10.1002/cam4.1376
• 3 Richards S, Aziz N, Bale S. et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015; 17: 405-424 doi:10.1038/gim.2015.30
• 4 Plon SE, Eccles DM, Easton D. et al. Sequence variant classification and reporting: recommendations for improving the interpretation of cancer susceptibility genetic test results. Hum Mutat 2008; 29: 1282-1291 doi:10.1002/humu.20880
• 5 Moghadasi S, Meeks HD, Vreeswijk MP. et al. The BRCA1 c. 5096G>A p.Arg1699Gln (R1699Q) intermediate risk variant: breast and ovarian cancer risk estimation and recommendations for clinical management from the ENIGMA consortium. J Med Genet 2018; 55: 15-20 doi:10.1136/jmedgenet-2017-104560
• 6 Shimelis H, Mesman RLS, Von Nicolai C. et al. BRCA2 Hypomorphic Missense Variants Confer Moderate Risks of Breast Cancer. Cancer Res 2017; 77: 2789-2799 doi:10.1158/0008-5472.can-16-2568
• 7 Walker LC, Whiley PJ, Houdayer C. et al. Evaluation of a 5-tier scheme proposed for classification of sequence variants using bioinformatic and splicing assay data: inter-reviewer variability and promotion of minimum reporting guidelines. Hum Mutat 2013; 34: 1424-1431 doi:10.1002/humu.22388
• 8 Whiley PJ, de la Hoya M, Thomassen M. et al. Comparison of mRNA splicing assay protocols across multiple laboratories: recommendations for best practice in standardized clinical testing. Clin Chem 2014; 60: 341-352 doi:10.1373/clinchem.2013.210658
• 9 Fackenthal JD, Yoshimatsu T, Zhang B. et al. Naturally occurring BRCA2 alternative mRNA splicing events in clinically relevant samples. J Med Genet 2016; 53: 548-558 doi:10.1136/jmedgenet-2015-103570
• 10 Colombo M, Blok MJ, Whiley P. et al. Comprehensive annotation of splice junctions supports pervasive alternative splicing at the BRCA1 locus: a report from the ENIGMA consortium. Hum Mol Genet 2014; 23: 3666-3680 doi:10.1093/hmg/ddu075
• 11 de la Hoya M, Soukarieh O, Lopez-Perolio I. et al. Combined genetic and splicing analysis of BRCA1 c.[594-2A>C; 641A>G] highlights the relevance of naturally occurring in-frame transcripts for developing disease gene variant classification algorithms. Hum Mol Genet 2016; 25: 2256-2268 doi:10.1093/hmg/ddw094
• 12 Li L, Biswas K, Habib LA. et al. Functional redundancy of exon 12 of BRCA2 revealed by a comprehensive analysis of the c.6853A>G (p. I2285 V) variant. Hum Mutat 2009; 30: 1543-1550 doi:10.1002/humu.21101
• 13 Goldgar DE, Easton DF, Deffenbaugh AM. et al. Integrated evaluation of DNA sequence variants of unknown clinical significance: application to BRCA1 and BRCA2. Am J Hum Genet 2004; 75: 535-544 doi:10.1086/424388
• 14 Houdayer C, Caux-Moncoutier V, Krieger S. et al. Guidelines for splicing analysis in molecular diagnosis derived from a set of 327 combined in silico/in vitro studies on BRCA1 and BRCA2 variants. Hum Mutat 2012; 33: 1228-1238 doi:10.1002/humu.22101
• 15 Findlay GM, Boyle EA, Hause RJ. et al. Saturation editing of genomic regions by multiplex homology-directed repair. Nature 2014; 513: 120-123 doi:10.1038/nature13695
• 16 Starita LM, Young DL, Islam M. et al. Massively Parallel Functional Analysis of BRCA1 RING Domain Variants. Genetics 2015; 200: 413-422 doi:10.1534/genetics.115.175802
• 17 Meeks HD, Song H, Michailidou K. et al. BRCA2 Polymorphic Stop Codon K3326X and the Risk of Breast, Prostate, and Ovarian Cancers. J Natl Cancer Inst 2016; 108: pii:djv315 doi:10.1093/jnci/djv315
• 18 Hayes F, Cayanan C, Barilla D. et al. Functional assay for BRCA1: mutagenesis of the COOH-terminal region reveals critical residues for transcription activation. Cancer Res 2000; 60: 2411-2418
• 19 Kuznetsov SG, Liu P, Sharan SK. Mouse embryonic stem cell-based functional assay to evaluate mutations in BRCA2. Nat Med 2008; 14: 875-881 doi:10.1038/nm.1719
• 20 Goldgar DE, Healey S, Dowty JG. et al. Rare variants in the ATM gene and risk of breast cancer. Breast Cancer Res 2011; 13: R73 doi:10.1186/bcr2919
• 21 Maxwell KN, Hart SN, Vijai J. et al. Evaluation of ACMG-Guideline-Based Variant Classification of Cancer Susceptibility and Non-Cancer-Associated Genes in Families Affected by Breast Cancer. Am J Hum Genet 2016; 98: 801-817 doi:10.1016/j.ajhg.2016.02.024
• 22 Teraoka SN, Malone KE, Doody DR. et al. Increased frequency of ATM mutations in breast carcinoma patients with early onset disease and positive family history. Cancer 2001; 92: 479-487
• 23 Fernet M, Moullan N, Lauge A. et al. Cellular responses to ionising radiation of AT heterozygotes: differences between missense and truncating mutation carriers. Br J Cancer 2004; 90: 866-873 doi:10.1038/sj.bjc.6601549
• 24 Dörk T, Bendix-Waltes R, Wegner RD. et al. Slow progression of ataxia-telangiectasia with double missense and in frame splice mutations. Am J Med Genet A 2004; 126A: 272-277 doi:10.1002/ajmg.a.20601
• 25 Lavin MF, Scott S, Gueven N. et al. Functional consequences of sequence alterations in the ATM gene. DNA Repair (Amst) 2004; 3: 1197-1205 doi:10.1016/j.dnarep.2004.03.011
• 26 Renwick A, Thompson D, Seal S. et al. ATM mutations that cause ataxia-telangiectasia are breast cancer susceptibility alleles. Nat Genet 2006; 38: 873-875 doi:10.1038/ng1837
• 27 Tavtigian SV, Oefner PJ, Babikyan D. et al. Rare, evolutionarily unlikely missense substitutions in ATM confer increased risk of breast cancer. Am J Hum Genet 2009; 85: 427-446 doi:10.1016/j.ajhg.2009.08.018
• 28 Keimling M, Volcic M, Csernok A. et al. Functional characterization connects individual patient mutations in ataxia telangiectasia mutated (ATM) with dysfunction of specific DNA double-strand break-repair signaling pathways. FASEB J 2011; 25: 3849-3860 doi:10.1096/fj.11-185546
• 29 Gilad S, Chessa L, Khosravi R. et al. Genotype-phenotype relationships in ataxia-telangiectasia and variants. Am J Hum Genet 1998; 62: 551-561 doi:10.1086/301755
• 30 Fernandes N, Sun Y, Chen S. et al. DNA damage-induced association of ATM with its target proteins requires a protein interaction domain in the N terminus of ATM. J Biol Chem 2005; 280: 15158-15164 doi:10.1074/jbc.M412065200
• 31 Young DB, Jonnalagadda J, Gatei M. et al. Identification of domains of ataxia-telangiectasia mutated required for nuclear localization and chromatin association. J Biol Chem 2005; 280: 27587-27594 doi:10.1074/jbc.M411689200
• 32 Mitui M, Nahas SA, Du LT. et al. Functional and computational assessment of missense variants in the ataxia-telangiectasia mutated (ATM) gene: mutations with increased cancer risk. Hum Mutat 2009; 30: 12-21 doi:10.1002/humu.20805
• 33 Tavtigian SV, Oefner PJ, Babikyan D. et al. Rare, evolutionarily unlikely missense substitutions in ATM confer increased risk of breast cancer. Am J Hum Genet 2009; 85: 427-446 doi:10.1016/j.ajhg.2009.08.018
• 34 Barone G, Groom A, Reiman A. et al. Modeling ATM mutant proteins from missense changes confirms retained kinase activity. Hum Mutat 2009; 30: 1222-1230 doi:10.1002/humu.21034
• 35 Southey MC, Goldgar DE, Winqvist R. et al. PALB2, CHEK2 and ATM rare variants and cancer risk: data from COGS. J Med Genet 2016; 53: 800-811 doi:10.1136/jmedgenet-2016-103839
• 36 Khanna KK, Keating KE, Kozlov S. et al. ATM associates with and phosphorylates p 53: mapping the region of interaction. Nat Genet 1998; 20: 398-400 doi:10.1038/3882
• 37 Gatei M, Scott SP, Filippovitch I. et al. Role for ATM in DNA damage-induced phosphorylation of BRCA1. Cancer Res 2000; 60: 3299-3304
• 38 Girard E, Eon-Marchais S, Olaso R. et al. Familial breast cancer and DNA repair genes: Insights into known and novel susceptibility genes from the GENESIS study, and implications for multigene panel testing. Int J Cancer 2018; DOI: 10.1002/ijc.31921.
• 39 Catucci I, Radice P, Milne RL. et al. The PALB2 p.Leu939Trp mutation is not associated with breast cancer risk. Breast Cancer Res 2016; 18: 111 doi:10.1186/s13058-016-0762-9
• 40 Antoniou AC, Casadei S, Heikkinen T. et al. Breast-cancer risk in families with mutations in PALB2. N Engl J Med 2014; 371: 497-506 doi:10.1056/NEJMoa1400382
• 41 Antoniou AC, Foulkes WD, Tischkowitz M. Breast-cancer risk in families with mutations in PALB2. N Engl J Med 2014; 371: 1651-1652 doi:10.1056/NEJMc1410673
• 42 Antoniou AC, Foulkes WD, Tischkowitz M. Breast cancer risk in women with PALB2 mutations in different populations. Lancet Oncol 2015; 16: e375-e376 doi:10.1016/s1470-2045(15)00002-9
• 43 Southey MC, Teo ZL, Dowty JG. et al. A PALB2 mutation associated with high risk of breast cancer. Breast Cancer Res 2010; 12: R109 doi:10.1186/bcr2796
• 44 Tischkowitz M, Capanu M, Sabbaghian N. et al. Rare germline mutations in PALB2 and breast cancer risk: a population-based study. Hum Mutat 2012; 33: 674-680 doi:10.1002/humu.22022
• 45 Tischkowitz M, Sabbaghian N, Hamel N. et al. Contribution of the PALB2 c.2323C>T [p. Q775X] founder mutation in well-defined breast and/or ovarian cancer families and unselected ovarian cancer cases of French Canadian descent. BMC Med Genet 2013; 14: 5 doi:10.1186/1471-2350-14-5
• 46 Obermeier K, Sachsenweger J, Friedl TW. et al. Heterozygous PALB2 c.1592delT mutation channels DNA double-strand break repair into error-prone pathways in breast cancer patients. Oncogene 2016; 35: 3796-3806 doi:10.1038/onc.2015.448
• 47 Hayakawa T, Zhang F, Hayakawa N. et al. MRG15 binds directly to PALB2 and stimulates homology-directed repair of chromosomal breaks. J Cell Sci 2010; 123: 1124-1130 doi:10.1242/jcs.060178
• 48 Sy SM, Huen MS, Chen J. MRG15 is a novel PALB2-interacting factor involved in homologous recombination. J Biol Chem 2009; 284: 21127-21131 doi:10.1074/jbc.C109.023937
• 49 Zhang F, Ma J, Wu J. et al. PALB2 links BRCA1 and BRCA2 in the DNA-damage response. Curr Biol 2009; 19: 524-529 doi:10.1016/j.cub.2009.02.018
• 50 Foo TK, Tischkowitz M, Simhadri S. et al. Compromised BRCA1-PALB2 interaction is associated with breast cancer risk. Oncogene 2017; 36: 4161-4170 doi:10.1038/onc.2017.46
• 51 Buisson R, Dion-Cote AM, Coulombe Y. et al. Cooperation of breast cancer proteins PALB2 and piccolo BRCA2 in stimulating homologous recombination. Nat Struct Mol Biol 2010; 17: 1247-1254 doi:10.1038/nsmb.1915
• 52 Dray E, Etchin J, Wiese C. et al. Enhancement of RAD51 recombinase activity by the tumor suppressor PALB2. Nat Struct Mol Biol 2010; 17: 1255-1259 doi:10.1038/nsmb.1916
• 53 Bleuyard JY, Buisson R, Masson JY. et al. ChAM, a novel motif that mediates PALB2 intrinsic chromatin binding and facilitates DNA repair. EMBO Rep 2012; 13: 135-141 doi:10.1038/embor.2011.243
• 54 Park JY, Singh TR, Nassar N. et al. Breast cancer-associated missense mutants of the PALB2 WD40 domain, which directly binds RAD51C, RAD51 and BRCA2, disrupt DNA repair. Oncogene 2014; 33: 4803-4812 doi:10.1038/onc.2013.421
• 55 Oliver AW, Swift S, Lord CJ. et al. Structural basis for recruitment of BRCA2 by PALB2. EMBO Rep 2009; 10: 990-996 doi:10.1038/embor.2009.126
• 56 Zhang F, Fan Q, Ren K. et al. PALB2 functionally connects the breast cancer susceptibility proteins BRCA1 and BRCA2. Mol Cancer Res 2009; 7: 1110-1118 doi:10.1158/1541-7786.mcr-09-0123
• 57 Caleca L, Catucci I, Figlioli G. et al. Two Missense Variants Detected in Breast Cancer Probands Preventing BRCA2-PALB2 Protein Interaction. Front Oncol 2018; 8: 480 doi:10.3389/fonc.2018.00480
• 58 Hellebrand H, Sutter C, Honisch E. et al. Germline mutations in the PALB2 gene are population specific and occur with low frequencies in familial breast cancer. Hum Mutat 2011; 32: E2176-E2188 doi:10.1002/humu.21478
• 59 Sodha N, Williams R, Mangion J. et al. Screening hCHK2 for mutations. Science 2000; 289: 359
• 60 Cybulski C, Gorski B, Huzarski T. et al. CHEK2 is a multiorgan cancer susceptibility gene. Am J Hum Genet 2004; 75: 1131-1135 doi:10.1086/426403
• 61 Cai Z, Chehab NH, Pavletich NP. Structure and activation mechanism of the CHK2 DNA damage checkpoint kinase. Mol Cell 2009; 35: 818-829 doi:10.1016/j.molcel.2009.09.007
• 62 Roeb W, Higgins J, King MC. Response to DNA damage of CHEK2 missense mutations in familial breast cancer. Hum Mol Genet 2012; 21: 2738-2744 doi:10.1093/hmg/dds101
• 63 Ow GS, Ivshina AV, Fuentes G. et al. Identification of two poorly prognosed ovarian carcinoma subtypes associated with CHEK2 germ-line mutation and non-CHEK2 somatic mutation gene signatures. Cell Cycle 2014; 13: 2262-2280 doi:10.4161/cc.29271
• 64 Muranen TA, Blomqvist C, Dork T. et al. Patient survival and tumor characteristics associated with CHEK2:p. I157T – findings from the Breast Cancer Association Consortium. Breast Cancer Res 2016; 18: 98 doi:10.1186/s13058-016-0758-5
• 65 Dong X, Wang L, Taniguchi K. et al. Mutations in CHEK2 associated with prostate cancer risk. Am J Hum Genet 2003; 72: 270-280 doi:10.1086/346094
• 66 Ahn J, Prives C. Checkpoint kinase 2 (Chk2) monomers or dimers phosphorylate Cdc25C after DNA damage regardless of threonine 68 phosphorylation. J Biol Chem 2002; 277: 48418-48426 doi:10.1074/jbc.M208321200
• 67 Ahn J, Urist M, Prives C. The Chk2 protein kinase. DNA Repair (Amst) 2004; 3: 1039-1047 doi:10.1016/j.dnarep.2004.03.033
• 68 Schwarz JK, Lovly CM, Piwnica-Worms H. Regulation of the Chk2 protein kinase by oligomerization-mediated cis- and trans-phosphorylation. Mol Cancer Res 2003; 1: 598-609
• 69 Han FF, Guo CL, Liu LH. The effect of CHEK2 variant I157T on cancer susceptibility: evidence from a meta-analysis. DNA Cell Biol 2013; 32: 329-335 doi:10.1089/dna.2013.1970
• 70 Kleibl Z, Havranek O, Novotny J. et al. Analysis of CHEK2 FHA domain in Czech patients with sporadic breast cancer revealed distinct rare genetic alterations. Breast Cancer Res Treat 2008; 112: 159-164 doi:10.1007/s10549-007-9838-7
• 71 Bak A, Janiszewska H, Junkiert-Czarnecka A. et al. A risk of breast cancer in women – carriers of constitutional CHEK2 gene mutations, originating from the North – Central Poland. Hered Cancer Clin Pract 2014; 12: 10 doi:10.1186/1897-4287-12-10
• 72 Kato S, Han SY, Liu W. et al. Understanding the function-structure and function-mutation relationships of p 53 tumor suppressor protein by high-resolution missense mutation analysis. Proc Natl Acad Sci U S A 2003; 100: 8424-8429 doi:10.1073/pnas.1431692100
• 73 Mathe E, Olivier M, Kato S. et al. Predicting the transactivation activity of p 53 missense mutants using a four-body potential score derived from Delaunay tessellations. Hum Mutat 2006; 27: 163-172 doi:10.1002/humu.20284
• 74 Soussi T, Kato S, Levy PP. et al. Reassessment of the TP53 mutation database in human disease by data mining with a library of TP53 missense mutations. Hum Mutat 2005; 25: 6-17 doi:10.1002/humu.20114
• 75 Leroy B, Fournier JL, Ishioka C. et al. The TP53 website: an integrative resource centre for the TP53 mutation database and TP53 mutant analysis. Nucleic Acids Res 2013; 41: D962-D969 doi:10.1093/nar/gks1033
• 76 Monti P, Ciribilli Y, Jordan J. et al. Transcriptional functionality of germ line p 53 mutants influences cancer phenotype. Clin Cancer Res 2007; 13: 3789-3795 doi:10.1158/1078-0432.ccr-06-2545
• 77 Monti P, Perfumo C, Bisio A. et al. Dominant-negative features of mutant TP53 in germline carriers have limited impact on cancer outcomes. Mol Cancer Res 2011; 9: 271-279 doi:10.1158/1541-7786.mcr-10-0496
• 78 Saha T, Kar RK, Sa G. Structural and sequential context of p 53: A review of experimental and theoretical evidence. Prog Biophys Mol Biol 2015; 117: 250-263 doi:10.1016/j.pbiomolbio.2014.12.002
• 79 Buchhop S, Gibson MK, Wang XW. et al. Interaction of p 53 with the human Rad51 protein. Nucleic Acids Res 1997; 25: 3868-3874
• 80 Liang SH, Clarke MF. The nuclear import of p 53 is determined by the presence of a basic domain and its relative position to the nuclear localization signal. Oncogene 1999; 18: 2163-2166 doi:10.1038/sj.onc.1202350
• 81 Shaulsky G, Goldfinger N, Ben-Zeʼev A. et al. Nuclear accumulation of p 53 protein is mediated by several nuclear localization signals and plays a role in tumorigenesis. Mol Cell Biol 1990; 10: 6565-6577
• 82 Linke SP, Sengupta S, Khabie N. et al. p 53 interacts with hRAD51 and hRAD54, and directly modulates homologous recombination. Cancer Res 2003; 63: 2596-2605
• 83 Pittman DL, Weinberg LR, Schimenti JC. Identification, characterization, and genetic mapping of Rad51 d, a new mouse and human RAD51/RecA-related gene. Genomics 1998; 49: 103-111 doi:10.1006/geno.1998.5226
• 84 Cartwright R, Dunn AM, Simpson PJ. et al. Isolation of novel human and mouse genes of the recA/RAD51 recombination-repair gene family. Nucleic Acids Res 1998; 26: 1653-1659
• 85 Rivera B, Di Iorio M, Frankum J. et al. Functionally Null RAD51D Missense Mutation Associates Strongly with Ovarian Carcinoma. Cancer Res 2017; 77: 4517-4529 doi:10.1158/0008-5472.Can-17-0190
• 86 Kim YM, Choi BS. Structural and functional characterization of the N-terminal domain of human Rad51D. Int J Biochem Cell Biol 2011; 43: 416-422 doi:10.1016/j.biocel.2010.11.014
• 87 Gruver AM, Miller KA, Rajesh C. et al. The ATPase motif in RAD51D is required for resistance to DNA interstrand crosslinking agents and interaction with RAD51C. Mutagenesis 2005; 20: 433-440 doi:10.1093/mutage/gei059
• 88 Gutierrez-Enriquez S, Bonache S, de Garibay GR. et al. About 1% of the breast and ovarian Spanish families testing negative for BRCA1 and BRCA2 are carriers of RAD51D pathogenic variants. Int J Cancer 2014; 134: 2088-2097 doi:10.1002/ijc.28540
• 89 Janatova M, Soukupova J, Stribrna J. et al. Mutation Analysis of the RAD51C and RAD51D Genes in High-Risk Ovarian Cancer Patients and Families from the Czech Republic. PLoS One 2015; 10: e0127711 doi:10.1371/journal.pone.0127711
• 90 Thompson ER, Rowley SM, Sawyer S. et al. Analysis of RAD51D in ovarian cancer patients and families with a history of ovarian or breast cancer. PLoS One 2013; 8: e54772 doi:10.1371/journal.pone.0054772
• 91 Miller KA, Sawicka D, Barsky D. et al. Domain mapping of the Rad51 paralog protein complexes. Nucleic Acids Res 2004; 32: 169-178 doi:10.1093/nar/gkg925
• 92 Loveday C, Turnbull C, Ramsay E. et al. Germline mutations in RAD51D confer susceptibility to ovarian cancer. Nat Genet 2011; 43: 879-882 doi:10.1038/ng.893
• 93 Wiese C, Hinz JM, Tebbs RS. et al. Disparate requirements for the Walker A and B ATPase motifs of human RAD51D in homologous recombination. Nucleic Acids Res 2006; 34: 2833-2843 doi:10.1093/nar/gkl366
• 94 Song H, Dicks E, Ramus SJ. et al. Contribution of Germline Mutations in the RAD51B, RAD51C, and RAD51D Genes to Ovarian Cancer in the Population. J Clin Oncol 2015; 33: 2901-2907 doi:10.1200/jco.2015.61.2408
• 95 Meindl A, Hellebrand H, Wiek C. et al. Germline mutations in breast and ovarian cancer pedigrees establish RAD51C as a human cancer susceptibility gene. Nat Genet 2010; 42: 410-414 doi:10.1038/ng.569
• 96 Vaz F, Hanenberg H, Schuster B. et al. Mutation of the RAD51C gene in a Fanconi anemia-like disorder. Nat Genet 2010; 42: 406-409 doi:10.1038/ng.570
• 97 Clague J, Wilhoite G, Adamson A. et al. RAD51C germline mutations in breast and ovarian cancer cases from high-risk families. PLoS One 2011; 6: e25632 doi:10.1371/journal.pone.0025632
• 98 Osorio A, Endt D, Fernandez F. et al. Predominance of pathogenic missense variants in the RAD51C gene occurring in breast and ovarian cancer families. Hum Mol Genet 2012; 21: 2889-2898 doi:10.1093/hmg/dds115
• 99 French CA, Tambini CE, Thacker J. Identification of functional domains in the RAD51L2 (RAD51C) protein and its requirement for gene conversion. J Biol Chem 2003; 278: 45445-45450 doi:10.1074/jbc.M308621200
• 100 Jonson L, Ahlborn LB, Steffensen AY. et al. Identification of six pathogenic RAD51C mutations via mutational screening of 1228 Danish individuals with increased risk of hereditary breast and/or ovarian cancer. Breast Cancer Res Treat 2016; 155: 215-222 doi:10.1007/s10549-015-3674-y
• 101 Schnurbein G, Hauke J, Wappenschmidt B. et al. RAD51C deletion screening identifies a recurrent gross deletion in breast cancer and ovarian cancer families. Breast Cancer Res 2013; 15: R120 doi:10.1186/bcr3589
• 102 Ali AM, Singh TR, Meetei AR. FANCM-FAAP24 and FANCJ: FA proteins that metabolize DNA. Mutat Res 2009; 668: 20-26 doi:10.1016/j.mrfmmm.2009.04.002
• 103 Yu X, Chini CC, He M. et al. The BRCT domain is a phospho-protein binding domain. Science 2003; 302: 639-642 doi:10.1126/science.1088753
• 104 Peng M, Litman R, Xie J. et al. The FANCJ/MutLalpha interaction is required for correction of the cross-link response in FA-J cells. EMBO J 2007; 26: 3238-3249 doi:10.1038/sj.emboj.7601754
• 105 Weber-Lassalle N, Hauke J, Ramser J. et al. BRIP1 loss-of-function mutations confer high risk for familial ovarian cancer, but not familial breast cancer. Breast Cancer Res 2018; 20: 7 doi:10.1186/s13058-018-0935-9
• 106 Castera L, Harter V, Muller E. et al. Landscape of pathogenic variations in a panel of 34 genes and cancer risk estimation from 5131 HBOC families. Genet Med 2018; DOI: 10.1038/s41436-018-0005-9.
• 107 Li J, Meeks H, Feng BJ. et al. Targeted massively parallel sequencing of a panel of putative breast cancer susceptibility genes in a large cohort of multiple-case breast and ovarian cancer families. J Med Genet 2016; 53: 34-42 doi:10.1136/jmedgenet-2015-103452
• 108 Norquist BM, Harrell MI, Brady MF. et al. Inherited Mutations in Women With Ovarian Carcinoma. JAMA Oncol 2016; 2: 482-490 doi:10.1001/jamaoncol.2015.5495
• 109 Ramus SJ, Song H, Dicks E. et al. Germline Mutations in the BRIP1, BARD1, PALB2, and NBN Genes in Women With Ovarian Cancer. J Natl Cancer Inst 2015; 107: pii:djv214 doi:10.1093/jnci/djv214
• 110 Lilyquist J, LaDuca H, Polley E. et al. Frequency of mutations in a large series of clinically ascertained ovarian cancer cases tested on multi-gene panels compared to reference controls. Gynecol Oncol 2017; 147: 375-380 doi:10.1016/j.ygyno.2017.08.030
• 111 Hansford S, Kaurah P, Li-Chang H. et al. Hereditary Diffuse Gastric Cancer Syndrome: CDH1 Mutations and Beyond. JAMA Oncol 2015; 1: 23-32 doi:10.1001/jamaoncol.2014.168
• 112 Melo S, Figueiredo J, Fernandes MS. et al. Predicting the Functional Impact of CDH1 Missense Mutations in Hereditary Diffuse Gastric Cancer. Int J Mol Sci 2017; 18: pii:E2687 doi:10.3390/ijms18122687
• 113 Oliveira C, Pinheiro H, Figueiredo J. et al. Familial gastric cancer: genetic susceptibility, pathology, and implications for management. Lancet Oncol 2015; 16: e60-e70 doi:10.1016/S1470-2045(14)71016-2
• 114 Corso G, Intra M, Trentin C. et al. CDH1 germline mutations and hereditary lobular breast cancer. Fam Cancer 2016; 15: 215-219 doi:10.1007/s10689-016-9869-5
• 115 Krempely K, Karam R. A novel de novo CDH1 germline variant aids in the classification of carboxy-terminal E-cadherin alterations predicted to escape nonsense-mediated mRNA decay. Cold Spring Harb Mol Case Stud 2018; 4: pii:a003012 doi:10.1101/mcs.a003012
• 116 Matsuoka S, Rotman G, Ogawa A. et al. Ataxia telangiectasia-mutated phosphorylates Chk2 in vivo and in vitro. Proc Natl Acad Sci U S A 2000; 97: 10389-10394 doi:10.1073/pnas.190030497