Exome sequencing identifies novel susceptibility genes and defines the contribution of coding variants to breast cancer risk

Linkage and candidate gene studies have identified several breast cancer susceptibility genes, but the overall contribution of coding variation to breast cancer is unclear. To evaluate the role of rare coding variants more comprehensively, we performed a meta-analysis across three large whole-exome sequencing datasets, containing 16,498 cases and 182,142 controls. Burden tests were performed for protein-truncating and rare missense variants in 16,562 and 18,681 genes respectively. Associations between protein-truncating variants and breast cancer were identified for 7 genes at exome-wide significance ( P <2.5×10-6): the five known susceptibility genes BRCA1, BRCA2, CHEK2, PALB2 and ATM , together with novel associations for ATRIP and MAP3K1 . Predicted deleterious rare missense or protein-truncating variants were additionally associated at P <2.5×10-6 for SAMHD1 . The overall contribution of coding variants in genes beyond the previously known genes is estimated to be small. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement The work was funded by grants from: Genome Canada Genome Quebec Canadian Institutes of Health Research European Union Horizon 2020 Research and Innovation Programme Wellcome Trust ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: A list of ethics committees is provided as a separate supplementary table. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes Data from UK Biobank are available through application to UK Biobank. Data from the Breast Cancer Association Consortium (BCAC) used in the present study are available upon reasonable request through the BCAC Data Access Co-ordinating Committee.