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; Arcangela De Nicolo; Kyriaki Michailidou; 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; 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

doi:10.1038/s41467-025-59979-6

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, Arcangela De Nicolo, Kyriaki Michailidou (Corresponding Author), 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 BogdanovaStig 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, 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

Institute of Oncology and Molecular Genetics

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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.

Original language	English
Article number	4852
Pages (from-to)	1-18
Number of pages	18
Journal	Nature Communications
Volume	16
Issue number	1
DOIs	https://doi.org/10.1038/s41467-025-59979-6
Publication status	Published - Dec 2025

Keywords*

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

Field of Science*

3.1 Basic medicine
3.2 Clinical medicine

Publication Type*

1.1. Scientific article indexed in Web of Science and/or Scopus database

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41467-025-59979-6Licence: CC BY-NC-ND

Analysis of more than 400000 womenFinal published version, 2.76 MBLicence: CC BY-NC-ND

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Zanti, M., O'Mahony, D. G., Parsons, M. T., De Nicolo, A., Michailidou, K., Dorling, L., Dennis, J., Boddicker, N. J., Chen, W., Hu, C., Naven, M., Yiangou, K., Ahearn, T. U., Ambrosone, C. B., Andrulis, I. L., Antoniou, A. C., Auer, P. L., Baynes, C., Bodelon, C., ... Ho, W.-K. (2025). Analysis of more than 400,000 women provides case-control evidence for BRCA1 and BRCA2 variant classification. Nature Communications, 16(1), 1-18. Article 4852. https://doi.org/10.1038/s41467-025-59979-6

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

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.",

keywords = "Humans, Female, Case-Control Studies, BRCA2 Protein/genetics, Breast Neoplasms/genetics, BRCA1 Protein/genetics, Genetic Predisposition to Disease, Genetic Testing, Germ-Line Mutation, Middle Aged",

author = "Maria Zanti and O'Mahony, {Denise G} and Parsons, {Michael T} and {De Nicolo}, Arcangela and Kyriaki Michailidou and Leila Dorling and Joe Dennis and Boddicker, {Nicholas J} and Wenan Chen and Chunling Hu and Marc Naven and Kristia Yiangou and Ahearn, {Thomas U} and Ambrosone, {Christine B} and Andrulis, {Irene L} and Antoniou, {Antonis C} and Auer, {Paul L} and Caroline Baynes and Clara Bodelon and Bogdanova, {Natalia V} and Bojesen, {Stig E} and Bolla, {Manjeet K} and Brantley, {Kristen D} and Camp, {Nicola J} and Archie Campbell and Castelao, {Jose E} and Cessna, {Melissa H} and Jenny Chang-Claude and Fei Chen and Georgia Chenevix-Trench and Conroy, {Don M} and Kamila Czene and Domchek, {Susan M} and Thilo D{\"o}rk and Dunning, {Alison M} and Eliassen, {A Heather} and Evans, {D Gareth} and Fasching, {Peter A} and Figueroa, {Jonine D} and Henrik Flyger and Manuela Gago-Dominguez and Montserrat Garc{\'i}a-Closas and Gord Glendon and Anna Gonz{\'a}lez-Neira and Felix Grassmann and Andreas Hadjisavvas and Haiman, {Christopher A} and Ute Hamann and Hart, {Steven N} and Hartman, {Mikael B A} and Weang-Kee Ho",

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month = dec,

doi = "10.1038/s41467-025-59979-6",

language = "English",

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pages = "1--18",

journal = "Nature Communications",

issn = "2041-1723",

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Zanti, M, O'Mahony, DG, Parsons, MT, De Nicolo, A, Michailidou, K, 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, Conroy, DM, Czene, K, Domchek, SM, Dörk, T, Dunning, AM, Eliassen, AH, Evans, DG, Fasching, PA, 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, MBA & Ho, W-K 2025, 'Analysis of more than 400,000 women provides case-control evidence for BRCA1 and BRCA2 variant classification', Nature Communications, vol. 16, no. 1, 4852, pp. 1-18. https://doi.org/10.1038/s41467-025-59979-6

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T1 - Analysis of more than 400,000 women provides case-control evidence for BRCA1 and BRCA2 variant classification

AU - Zanti, Maria

AU - O'Mahony, Denise G

AU - Parsons, Michael T

AU - De Nicolo, Arcangela

AU - Michailidou, Kyriaki

AU - Dorling, Leila

AU - Dennis, Joe

AU - Boddicker, Nicholas J

AU - Chen, Wenan

AU - Hu, Chunling

AU - Naven, Marc

AU - Yiangou, Kristia

AU - Ahearn, Thomas U

AU - Ambrosone, Christine B

AU - Andrulis, Irene L

AU - Antoniou, Antonis C

AU - Auer, Paul L

AU - Baynes, Caroline

AU - Bodelon, Clara

AU - Bogdanova, Natalia V

AU - Bojesen, Stig E

AU - Bolla, Manjeet K

AU - Brantley, Kristen D

AU - Camp, Nicola J

AU - Campbell, Archie

AU - Castelao, Jose E

AU - Cessna, Melissa H

AU - Chang-Claude, Jenny

AU - Chen, Fei

AU - Chenevix-Trench, Georgia

AU - Conroy, Don M

AU - Czene, Kamila

AU - Domchek, Susan M

AU - Dörk, Thilo

AU - Dunning, Alison M

AU - Eliassen, A Heather

AU - Evans, D Gareth

AU - Fasching, Peter A

AU - Figueroa, Jonine D

AU - Flyger, Henrik

AU - Gago-Dominguez, Manuela

AU - García-Closas, Montserrat

AU - Glendon, Gord

AU - González-Neira, Anna

AU - Grassmann, Felix

AU - Hadjisavvas, Andreas

AU - Haiman, Christopher A

AU - Hamann, Ute

AU - Hart, Steven N

AU - Hartman, Mikael B A

AU - Ho, Weang-Kee

PY - 2025/12

Y1 - 2025/12

N2 - 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.

AB - 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.

KW - Humans

KW - Female

KW - Case-Control Studies

KW - BRCA2 Protein/genetics

KW - Breast Neoplasms/genetics

KW - BRCA1 Protein/genetics

KW - Genetic Predisposition to Disease

KW - Genetic Testing

KW - Germ-Line Mutation

KW - Middle Aged

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U2 - 10.1038/s41467-025-59979-6

DO - 10.1038/s41467-025-59979-6

M3 - Article

C2 - 40413188

SN - 2041-1723

VL - 16

SP - 1

EP - 18

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 4852

ER -

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

Abstract

Keywords*

Field of Science*

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UN SDGs

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