Analysis of more than 400,000 women provides case-control evidence for BRCA1 and BRCA2 variant classification.
Maria ZantiDenise G O'MahonyMichael T ParsonsLeila DorlingJoe G DennisNicholas J BoddickerWenan ChenChunling HuMarc NavenKristia YiangouThomas U AhearnChristine B AmbrosoneIrene L AndrulisAntonis C AntoniouPaul L AuerCaroline BaynesClara BodelonNatalia V BogdanovaStig E BojesenManjeet K BollaKristen D BrantleyNicola J CampArchie CampbellJose E CastelaoMelissa H CessnaJenny Chang-ClaudeFei ChenGeorgia Chenevix-Trenchnull nullDon M ConroyKamila CzeneArcangela De NicoloSusan M DomchekThilo DörkAlison M DunningA Heather EliassenD Gareth EvansPeter A FaschingJonine D FigueroaHenrik FlygerManuela Gago-DominguezMontserrat Garcia-ClosasGord GlendonAnna González-NeiraFelix GrassmannAndreas HadjisavvasChristopher A HaimanUte HamannSteven N HartMikael B A HartmanWeang-Kee HoJames M HodgeReiner HoppeSacha J Howellnull nullAnna JakubowskaElza K KhusnutdinovaYon-Dschun KoPeter KraftVessela N KristensenJames V LaceyJingmei LiGeok Hoon LimSara LindströmArtitaya LophatananonCraig LuccariniArto MannermaaMaria Elena MartinezDimitrios MavroudisRoger L MilneKenneth MuirKatherine L NathansonRocio Nuñez-TorresNadia ObiJanet E OlsonJulie R PalmerMihalis I PanayiotidisAlpa V PatelPaul David Peter PharoahEric C PolleyMuhammad U RashidKathryn J RuddyEmmanouil SaloustrosElinor J SawyerMarjanka K SchmidtMelissa C SoutheyVeronique Kiak-Mien TanSoo Hwang TeoLauren R TerasDiana TorresAmy Trentham-DietzThérèse TruongCeline M VachonQin WangJeffrey N WeitzelSiddhartha YadavSong YaoGary R ZirpoliMelissa S ClinePeter DevileeSean V TavtigianDavid E GoldgarFergus J CouchDouglas F EastonAmanda B SpurdleKyriaki MichailidouPublished in: medRxiv : the preprint server for health sciences (2024)
Clinical genetic testing identifies variants causal for hereditary cancer, information that is used for risk assessment and clinical management. Unfortunately, some variants identified are of uncertain clinical significance (VUS), complicating patient management. Case-control data is one evidence type used to classify VUS, and previous findings indicate that case-control likelihood ratios (LRs) outperform odds ratios for variant classification. As an initiative of the Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) Analytical Working Group we analyzed germline sequencing data of BRCA1 and BRCA2 from 96,691 female breast cancer cases and 303,925 unaffected controls from three studies: the BRIDGES study of the Breast Cancer Association Consortium, the Cancer Risk Estimates Related to Susceptibility consortium, and the UK Biobank. We observed 11,227 BRCA1 and BRCA2 variants, with 6,921 being coding, covering 23.4% of BRCA1 and BRCA2 VUS in ClinVar and 19.2% of ClinVar curated (likely) benign or pathogenic variants. Case-control LR evidence was highly consistent with ClinVar assertions for (likely) benign or pathogenic variants; exhibiting 99.1% sensitivity and 95.4% specificity for BRCA1 and 92.2% sensitivity and 86.6% specificity for BRCA2 . This approach provides case-control evidence for 785 unclassified variants, that can serve as a valuable element for clinical classification.