Exome Sequencing Identifies Breast Cancer Susceptibility Genes and Defines the Contribution of Coding Variants to Breast Cancer Risk

Introductory paragraphLinkage 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.