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

Maria Zanti, Denise G. O’Mahony, Michael T. Parsons, Leila Dorling, Joe Dennis, Nicholas J. Boddicker, Wenan Chen, Chunling Hu, Marc Naven, Kristia Yiangou, Thomas U. Ahearn, Christine B. Ambrosone, Irene L. Andrulis, Antonis C. Antoniou, Paul L. Auer, Caroline Baynes, Clara Bodelon, Natalia V. Bogdanova, Stig E. Bojesen, Manjeet K. Bolla, Kristen D. Brantley, Nicola J. Camp, Archie Campbell, Jose E. Castelao, Melissa H. Cessna, Jenny Chang-Claude, Fei Chen, Georgia Chenevix-Trench, Don M. Conroy, Kamila Czene, Arcangela Nicolo, Susan M. Domchek, Thilo Dörk, Alison M. Dunning, A. Heather Eliassen, D. Gareth Evans, Peter A. Fasching, Jonine D. Figueroa, Henrik Flyger, Manuela Gago-Dominguez, Montserrat García-Closas, Gord Glendon, Anna González-Neira, Felix Grassmann, Andreas Hadjisavvas, Christopher A. Haiman, Ute Hamann, Steven N. Hart, Mikael B. A. Hartman, Weang-Kee Ho, James M. Hodge, Reiner Hoppe, Sacha J. Howell, Anna Jakubowska, Elza K. Khusnutdinova, Yon-Dschun Ko, Peter Kraft, Vessela N. Kristensen, James V. Lacey, Jingmei Li, Geok Hoon Lim, Sara Lindström, Artitaya Lophatananon, Craig Luccarini, Arto Mannermaa, Maria Elena Martinez, Dimitrios Mavroudis, Roger L. Milne, Kenneth Muir, Katherine L. Nathanson, Rocio Nuñez-Torres, Nadia Obi, Janet E. Olson, Julie R. Palmer, Mihalis I. Panayiotidis, Alpa V. Patel, Paul D. P. Pharoah, Eric C. Polley, Muhammad U. Rashid, Kathryn J. Ruddy, Emmanouil Saloustros, Elinor J. Sawyer, Marjanka K. Schmidt, Melissa C. Southey, Veronique Kiak-Mien Tan, Soo Hwang Teo, Lauren R. Teras, Diana Torres, Amy Trentham-Dietz, Thérèse Truong, Celine M. Vachon, Qin Wang, Jeffrey N. Weitzel, Siddhartha Yadav, Song Yao, Gary R. Zirpoli, Melissa S. Cline, Peter Devilee, Sean V. Tavtigian, David E. Goldgar, Fergus J. Couch, Douglas F. Easton, Amanda B. Spurdle and Kyriaki Michailidou ()
Additional contact information
Maria Zanti: The Cyprus Institute of Neurology & Genetics
Denise G. O’Mahony: The Cyprus Institute of Neurology & Genetics
Michael T. Parsons: QIMR Berghofer Medical Research Institute
Leila Dorling: University of Cambridge
Joe Dennis: University of Cambridge
Nicholas J. Boddicker: Mayo Clinic
Wenan Chen: Mayo Clinic
Chunling Hu: Mayo Clinic
Marc Naven: University of Cambridge
Kristia Yiangou: The Cyprus Institute of Neurology & Genetics
Thomas U. Ahearn: Department of Health and Human Services
Christine B. Ambrosone: Roswell Park Comprehensive Cancer Institute
Irene L. Andrulis: Toronto
Antonis C. Antoniou: University of Cambridge
Paul L. Auer: Medical College of Wisconsin
Caroline Baynes: University of Cambridge
Clara Bodelon: American Cancer Society
Natalia V. Bogdanova: Hannover Medical School
Stig E. Bojesen: Copenhagen University Hospital
Manjeet K. Bolla: University of Cambridge
Kristen D. Brantley: Dana-Farber Cancer Institute
Nicola J. Camp: University of Utah
Archie Campbell: The University of Edinburgh
Jose E. Castelao: SERGAS
Melissa H. Cessna: Intermountain Health
Jenny Chang-Claude: German Cancer Research Center (DKFZ)
Fei Chen: University of Southern California Norris Comprehensive Cancer Center
Georgia Chenevix-Trench: QIMR Berghofer Medical Research Institute
Don M. Conroy: University of Cambridge
Kamila Czene: Karolinska Institutet
Arcangela Nicolo: IRCCS San Raffaele Scientific Institute
Susan M. Domchek: University of Pennsylvania
Thilo Dörk: Hannover Medical School
Alison M. Dunning: University of Cambridge
A. Heather Eliassen: Brigham and Women’s Hospital and Harvard Medical School
D. Gareth Evans: Manchester Academic Health Science Centre
Peter A. Fasching: University Hospital Erlangen
Jonine D. Figueroa: Department of Health and Human Services
Henrik Flyger: Copenhagen University Hospital
Manuela Gago-Dominguez: SERGAS
Montserrat García-Closas: Department of Health and Human Services
Gord Glendon: Toronto
Anna González-Neira: Spanish National Cancer Research Centre (CNIO)
Felix Grassmann: Health and Medical University
Andreas Hadjisavvas: The Cyprus Institute of Neurology & Genetics
Christopher A. Haiman: University of Southern California Norris Comprehensive Cancer Center
Ute Hamann: German Cancer Research Center (DKFZ)
Steven N. Hart: Mayo Clinic
Mikael B. A. Hartman: National University of Singapore and National University Health System
Weang-Kee Ho: Cancer Research Malaysia
James M. Hodge: American Cancer Society
Reiner Hoppe: Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology
Sacha J. Howell: University of Manchester
Anna Jakubowska: Pomeranian Medical University
Elza K. Khusnutdinova: Ufa Federal Research Centre of the Russian Academy of Sciences
Yon-Dschun Ko: Johanniter Krankenhaus
Peter Kraft: National Cancer Institute
Vessela N. Kristensen: University of Oslo
James V. Lacey: City of Hope
Jingmei Li: Technology and Research (A*STAR)
Geok Hoon Lim: KK Women’s and Children’s Hospital
Sara Lindström: University of Washington
Artitaya Lophatananon: The University of Manchester
Craig Luccarini: University of Cambridge
Arto Mannermaa: University of Eastern Finland
Maria Elena Martinez: University of California San Diego
Dimitrios Mavroudis: University Hospital of Heraklion
Roger L. Milne: Melbourne
Kenneth Muir: The University of Manchester
Katherine L. Nathanson: University of Pennsylvania
Rocio Nuñez-Torres: Spanish National Cancer Research Centre (CNIO)
Nadia Obi: University Medical Center Hamburg-Eppendorf
Janet E. Olson: Mayo Clinic
Julie R. Palmer: Boston University
Mihalis I. Panayiotidis: The Cyprus Institute of Neurology & Genetics
Alpa V. Patel: American Cancer Society
Paul D. P. Pharoah: Cedars-Sinai Medical Center
Eric C. Polley: University of Chicago
Muhammad U. Rashid: German Cancer Research Center (DKFZ)
Kathryn J. Ruddy: Mayo Clinic
Emmanouil Saloustros: University of Thessaly
Elinor J. Sawyer: King’s College London
Marjanka K. Schmidt: The Netherlands Cancer Institute
Melissa C. Southey: Melbourne
Veronique Kiak-Mien Tan: Duke-NUS Medical School
Soo Hwang Teo: Cancer Research Malaysia
Lauren R. Teras: American Cancer Society
Diana Torres: German Cancer Research Center (DKFZ)
Amy Trentham-Dietz: University of Wisconsin-Madison
Thérèse Truong: UVSQ
Celine M. Vachon: Mayo Clinic
Qin Wang: University of Cambridge
Jeffrey N. Weitzel: University of Kansas Cancer Center
Siddhartha Yadav: Mayo Clinic
Song Yao: Roswell Park Comprehensive Cancer Institute
Gary R. Zirpoli: Boston University
Melissa S. Cline: UC Santa Cruz Genomics Institute
Peter Devilee: Leiden University Medical Center
Sean V. Tavtigian: University of Utah School of Medicine
David E. Goldgar: University of Utah School of Medicine
Fergus J. Couch: Mayo Clinic
Douglas F. Easton: University of Cambridge
Amanda B. Spurdle: QIMR Berghofer Medical Research Institute
Kyriaki Michailidou: The Cyprus Institute of Neurology & Genetics

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-59979-6

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