
==== Front
medRxiv
MEDRXIV
medRxiv
Cold Spring Harbor Laboratory

10.1101/2024.09.04.24313051
preprint
1
Article
Analysis of more than 400,000 women provides case-control evidence for BRCA1 and BRCA2 variant classification
Zanti Maria http://orcid.org/0000-0002-0136-9921

O’Mahony Denise G. http://orcid.org/0000-0002-7212-0920

Parsons Michael T. http://orcid.org/0000-0003-3242-8477

Dorling Leila
Dennis Joe http://orcid.org/0000-0003-4591-1214

Boddicker Nicholas J. http://orcid.org/0000-0002-6784-2072

Chen Wenan
Hu Chunling
Naven Marc
Yiangou Kristia http://orcid.org/0009-0005-2559-9747

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 http://orcid.org/0000-0002-1878-2587

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 http://orcid.org/0000-0003-1033-2650

Glendon Gord
González-Neira Anna
Grassmann Felix
Hadjisavvas Andreas
Haiman Christopher A.
Hamann Ute
Hart Steven N. http://orcid.org/0000-0001-7714-2734

Hartman Mikael B.A.
Ho Weang-Kee
Hodge James M.
Hoppe Reiner
Howell Sacha J.
kConFab Investigators
Jakubowska Anna http://orcid.org/0000-0002-5650-0501

Khusnutdinova Elza K.
Ko Yon-Dschun
Kraft Peter
Kristensen Vessela N.
Lacey James V.
Li Jingmei http://orcid.org/0000-0001-8587-7511

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. http://orcid.org/0000-0002-1450-3552

Patel Alpa V.
Pharoah Paul D.P. http://orcid.org/0000-0001-8494-732X

Polley Eric C.
Rashid Muhammad U.
Ruddy Kathryn J.
Saloustros Emmanouil
Sawyer Elinor J.
Schmidt Marjanka K. http://orcid.org/0000-0002-2228-429X

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. http://orcid.org/0000-0001-6714-092X

Yadav Siddhartha
Yao Song
Zirpoli Gary R.
Cline Melissa S. http://orcid.org/0000-0002-0148-1956

Devilee Peter http://orcid.org/0000-0002-8023-2009

Tavtigian Sean V.
Goldgar David E.
Couch Fergus J.
Easton Douglas F.
Spurdle Amanda B.
Michailidou Kyriaki http://orcid.org/0000-0001-7065-1237

04 9 2024
2024.09.04.24313051https://creativecommons.org/licenses/by-nc-nd/4.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which allows reusers to copy and distribute the material in any medium or format in unadapted form only, for noncommercial purposes only, and only so long as attribution is given to the creator.
http://medrxiv.org/lookup/doi/10.1101/2024.09.04.24313051
nihpp-2024.09.04.24313051.pdf
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, 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.
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