Nature communications · 2025

Analysis of more than 400,000 women provides case-control evidence for BRCA1 and BRCA2 variant classification.

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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, De Nicolo Arcangela, 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

Аннотация

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. As an initiative of the Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) Analytical Working Group we analyze germline sequencing data of BRCA1 and BRCA2 from 96,691 female breast cancer cases and 302,116 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 observe 11,207 BRCA1 and BRCA2 variants, with 6909 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 likelihood ratio (ccLR) evidence is highly consistent with ClinVar assertions for (likely) benign or pathogenic variants; exhibiting 99.1% sensitivity and 95.3% specificity for BRCA1 and 93.3% sensitivity and 86.6% specificity for BRCA2. This approach provides case-control evidence for 787 unclassified variants; these include 579 with strong or moderate benign evidence and 10 with strong pathogenic evidence for which ccLR evidence is sufficient to alter clinical classification.

Предметные рубрики MeSH

Humans Female Case-Control Studies BRCA2 Protein Breast Neoplasms BRCA1 Protein Genetic Predisposition to Disease Genetic Testing Germ-Line Mutation Middle Aged

Analysis of more than 400,000 women provides case-control evidence for BRCA1 and BRCA2 variant classification.

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Аннотация

Предметные рубрики MeSH