Analysis of more than 400,000 women provides case-control evidence for BRCA1 and BRCA2 variant classification
Authors: Zanti Maria , O’Mahony Denise G. , Parsons Michael T. , Dorling Leila , Dennis Joe , Boddicker Nicholas J. , Chen Wenan , Hu Chunling , Naven Marc , Yiangou Kristia , Ahearn Thomas U. , Ambrosone Christine B. , Andrulis Irene L. , Antoniou Antonis C. , Auer Paul L. , Baynes Caroline , Bodelon Clara , Bogdanova Natalia V. , Bojesen Stig E. , Bolla Manjeet K. , Brantley Kristen D. , Camp Nicola J. , Campbell Archie , Castelao Jose E. , Cessna Melissa H. , Chang-Claude Jenny , Chen Fei , Chenevix-Trench Georgia ,   NBCS Collaborators, Conroy Don M. , Czene Kamila , Nicolo Arcangela De , Domchek Susan M. , Dörk Thilo , Dunning Alison M. , Eliassen A. Heather , Evans D. Gareth , Fasching Peter A. , Figueroa Jonine D. , Flyger Henrik , Gago-Dominguez Manuela , García-Closas Montserrat , Glendon Gord , González-Neira Anna , Grassmann Felix , Hadjisavvas Andreas , Haiman Christopher A. , Hamann Ute , Hart Steven N. , Hartman Mikael B.A. , Ho Weang-Kee , Hodge James M. , Hoppe Reiner , Howell Sacha J. ,   kConFab Investigators, Jakubowska Anna , Khusnutdinova Elza K. , Ko Yon-Dschun , Kraft Peter , Kristensen Vessela N. , Lacey James V. , Li Jingmei , Lim Geok Hoon , Lindström Sara , Lophatananon Artitaya , Luccarini Craig , Mannermaa Arto , Martinez Maria Elena , Mavroudis Dimitrios , Milne Roger L. , Muir Kenneth , Nathanson Katherine L. , Nuñez-Torres Rocio , Obi Nadia , Olson Janet E. , Palmer Julie R. , Panayiotidis Mihalis I. , Patel Alpa V. , Pharoah Paul D.P. , Polley Eric C. , Rashid Muhammad U. , Ruddy Kathryn J. , Saloustros Emmanouil , Sawyer Elinor J. , Schmidt Marjanka K. , Southey Melissa C. , Tan Veronique Kiak-Mien , Teo Soo Hwang , Teras Lauren R. , Torres Diana , Trentham-Dietz Amy , Truong Thérèse , Vachon Celine M. , Wang Qin , Weitzel Jeffrey N. , Yadav Siddhartha , Yao Song , Zirpoli Gary R. , Cline Melissa S. , Devilee Peter , Tavtigian Sean V. , Goldgar David E. , Couch Fergus J. , Easton Douglas F. , Spurdle Amanda B. , Michailidou Kyriaki 
Published: September 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 ofBRCA1andBRCA2from 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 11,227BRCA1andBRCA2variants, with 6,921 being coding, covering 23.4% ofBRCA1andBRCA2VUS 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 forBRCA1and 92.2% sensitivity and 86.6% specificity forBRCA2. This approach provides case-control evidence for 785 unclassified variants, that can serve as a valuable element for clinical classification.