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

Zanti M, O’Mahony DG, Parsons MT, Dorling L, Dennis J, Boddicker NJ, Chen W, Hu C, Naven M, Yiangou K, Ahearn TU, Ambrosone CB, Andrulis IL, Antoniou AC, Auer PL, Baynes C, Bodelon C, Bogdanova NV, Bojesen SE, Bolla MK, Brantley KD, Camp NJ, Campbell A, Castelao JE, Cessna MH, Chang-Claude J, Chen F, Chenevix-Trench G, Kristensen VN, Conroy DM, Czene K, De Nicolo A, Domchek SM, Dörk T, Dunning AM, Eliassen AH, Evans DG, Fasching P, Figueroa JD, Flyger H, Gago-Dominguez M, García-Closas M, Glendon G, González-Neira A, Grassmann F, Hadjisavvas A, Haiman CA, Hamann U, Hart SN, Hartman MB, Ho WK, Hodge JM, Hoppe R, Howell SJ, Jakubowska A, Khusnutdinova EK, Ko YD, Kraft P, Lacey JV, Li J, Lim GH, Lindström S, Lophatananon A, Luccarini C, Mannermaa A, Martinez ME, Mavroudis D, Milne RL, Muir K, Nathanson KL, Nuñez-Torres R, Obi N, Olson JE, Palmer JR, Panayiotidis MI, Patel AV, Pharoah PD, Polley EC, Rashid MU, Ruddy KJ, Saloustros E, Sawyer EJ, Schmidt MK, Southey MC, Tan VKM, Teo SH, Teras LR, Torres D, Trentham-Dietz A, Truong T, Vachon CM, Wang Q, Weitzel JN, Yadav S, Yao S, Zirpoli GR, Cline MS, Devilee P, Tavtigian SV, Goldgar DE, Couch FJ, Easton DF, Spurdle AB, Michailidou K (2025)

Publication Type: Journal article

Publication year: 2025

Journal

Book Volume: 16

Article Number: 4852

Journal Issue: 1

DOI: 10.1038/s41467-025-59979-6

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.

Authors with CRIS profile

Involved external institutions

Cyprus Institute of Neurology and Genetics Cyprus (CY) QIMR Berghofer Medical Research Institute (früher: the Queensland Institute of Medical Research) Australia (AU) University of Cambridge United Kingdom (GB) American Cancer Society United States (USA) (US) Medical College of Wisconsin (MCW) United States (USA) (US) Medizinische Hochschule Hannover (MHH) / Hannover Medical School Germany (DE) Gentofte Hospital Denmark (DK) Complejo Hospitalario Universitario de Santiago de Compostela Spain (ES) Dana–Farber Cancer Institute United States (USA) (US) University of Utah United States (USA) (US) Intermountain Healthcare United States (USA) (US) University of Edinburgh United Kingdom (GB) Deutsches Krebsforschungszentrum (DKFZ) Germany (DE) Keck School of Medicine of USC United States (USA) (US) Brigham and Women's Hospital (BWH) United States (USA) (US) University of Manchester United Kingdom (GB) National Cancer Institute (NCI) United States (USA) (US) University of Oslo Norway (NO) Karolinska Institute Sweden (SE) Ospedale San Raffaele (früher: Centro San Raffaele del Monte Tabor Foundation) Italy (IT) University of Eastern Finland Finland (FI) Moores Cancer Center United States (USA) (US) University General Hospital of Heraklion Greece (GR) Cancer Council Victoria Australia (AU) Penn Medicine United States (USA) (US) Spanish National Cancer Research Centre / Centro Nacional de Investigaciones Oncológicas (CNIO) Spain (ES) Lunenfeld-Tanenbaum Research Institute Canada (CA) Universitätsklinikum Hamburg-Eppendorf (UKE) Germany (DE) Mayo Clinic United States (USA) (US) Boston University United States (USA) (US) HMU Health and Medical University Potsdam Germany (DE) Cedars-Sinai Medical Center United States (USA) (US) University of Chicago United States (USA) (US) National University of Singapore (NUS) Singapore (SG) Cancer Research Initiatives Foundation (CARIF) / Cancer Research Malaysia (CRM) Malaysia (MY) General University Hospital of Larissa Greece (GR) Dr. Margarete Fischer-Bosch-Institut für Klinische Pharmakologie Germany (DE) Pomeranian Medical University / Pomorski Uniwersytet Medyczny w Szczecinie (PMU) Poland (PL) University of Wisconsin Carbone Cancer Center United States (USA) (US) Russian Academy of Sciences / Росси́йская акаде́мия нау́к (RAS) Russian Federation (RU) Research Center in Epidemiology and Population Health / Centre de recherche en Epidémiologie et Santé des Populations (CESP) France (FR) University of Kansas (KU) United States (USA) (US) Johanniter GmbH Germany (DE) City of Hope Medical Center United States (USA) (US) Genome Institute of Singapore Singapore (SG) SingHealth Group / Singapore Health Services Singapore (SG) University of Washington United States (USA) (US) King’s College London United Kingdom (GB) Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital (NKI / NKI-AVL) Netherlands (NL) Roswell Park Cancer Institute United States (USA) (US) University of California Santa Cruz United States (USA) (US) Leiden University Medical Center Netherlands (NL) Huntsman Cancer Institute United States (USA) (US)

How to cite

APA:

Zanti, M., O’Mahony, D.G., Parsons, M.T., Dorling, L., Dennis, J., Boddicker, N.J.,... Michailidou, K. (2025). Analysis of more than 400,000 women provides case-control evidence for BRCA1 and BRCA2 variant classification. Nature Communications, 16(1). https://doi.org/10.1038/s41467-025-59979-6

MLA:

Zanti, Maria, et al. "Analysis of more than 400,000 women provides case-control evidence for BRCA1 and BRCA2 variant classification." Nature Communications 16.1 (2025).

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