Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women

Leila Dorling, Sara Carvalho, Jamie Allen, Anna Gonzalez-Neira, Craig Luccarini, Cecilia Wahlstrom, Karen A. Pooley, Michael T. Parsons, Cristina Fortuno, Qin Wang, Manjeet K. Bolla, Joe Dennis, Renske Keeman, M. Rosario Alonso, Nuria Alvarez, Belen Herraez, Victoria Fernandez, Rocio Nunez-Torres, Ana Osorio, Jeanette ValcichMinerva Li, Therese Torngren, Patricia A. Harrington, Caroline Baynes, Don M. Conroy, Brennan Decker, Laura Fachal, Nasim Mavaddat, Thomas Ahearn, Kristiina Aittomaki, Natalia N. Antonenkova, Norbert Arnold, Patrick Arveux, Margreet G. E. M. Ausems, Paivi Auvinen, Heiko Becher, Matthias W. Beckmann, Sabine Behrens, Marina Bermisheva, Katarzyna Bialkowska, Carl Blomqvist, Natalia V. Bogdanova, Nadja Bogdanova-Markov, Stig E. Bojesen, Bernardo Bonanni, Anne-Lise Borresen-Dale, Hiltrud Brauch, Michael Bremer, Ignacio Briceno, Thomas Bruning, Breast Cancer Association Consortium, Encarna Gomez Garcia

Research output: Contribution to journalArticleAcademicpeer-review

196 Citations (Web of Science)



Genetic testing for breast cancer susceptibility is widely used, but for many genes, evidence of an association with breast cancer is weak, underlying risk estimates are imprecise, and reliable subtype-specific risk estimates are lacking.


We used a panel of 34 putative susceptibility genes to perform sequencing on samples from 60,466 women with breast cancer and 53,461 controls. In separate analyses for protein-truncating variants and rare missense variants in these genes, we estimated odds ratios for breast cancer overall and tumor subtypes. We evaluated missense-variant associations according to domain and classification of pathogenicity.


Protein-truncating variants in 5 genes (ATM, BRCA1, BRCA2, CHEK2, and PALB2) were associated with a risk of breast cancer overall with a P value of less than 0.0001. Protein-truncating variants in 4 other genes (BARD1, RAD51C, RAD51D, and TP53) were associated with a risk of breast cancer overall with a P value of less than 0.05 and a Bayesian false-discovery probability of less than 0.05. For protein-truncating variants in 19 of the remaining 25 genes, the upper limit of the 95% confidence interval of the odds ratio for breast cancer overall was less than 2.0. For protein-truncating variants in ATM and CHEK2, odds ratios were higher for estrogen receptor (ER)-positive disease than for ER-negative disease; for protein-truncating variants in BARD1, BRCA1, BRCA2, PALB2, RAD51C, and RAD51D, odds ratios were higher for ER-negative disease than for ER-positive disease. Rare missense variants (in aggregate) in ATM, CHEK2, and TP53 were associated with a risk of breast cancer overall with a P value of less than 0.001. For BRCA1, BRCA2, and TP53, missense variants (in aggregate) that would be classified as pathogenic according to standard criteria were associated with a risk of breast cancer overall, with the risk being similar to that of protein-truncating variants.


The results of this study define the genes that are most clinically useful for inclusion on panels for the prediction of breast cancer risk, as well as provide estimates of the risks associated with protein-truncating variants, to guide genetic counseling. (Funded by European Union Horizon 2020 programs and others.)

Original languageEnglish
Pages (from-to)428-439
Number of pages12
JournalNew England Journal of Medicine
Issue number5
Publication statusPublished - 4 Feb 2021


  • BRCA1

Cite this