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

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Wilcox, Naomi 
Dumont, Martine 
González-Neira, Anna 
Carvalho, Sara 
Joly Beauparlant, Charles 


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 26,368 female cases and 217,673 female controls. Burden tests were performed for protein-truncating and rare missense variants in 15,616 and 18,601 genes, respectively. Associations between protein-truncating variants and breast cancer were identified for the following six genes at exome-wide significance (P < 2.5 × 10-6): the five known susceptibility genes ATM, BRCA1, BRCA2, CHEK2 and PALB2, together with MAP3K1. Associations were also observed for LZTR1, ATR and BARD1 with P < 1 × 10-4. Associations between predicted deleterious rare missense or protein-truncating variants and breast cancer were additionally identified for CDKN2A at exome-wide significance. The overall contribution of coding variants in genes beyond the previously known genes is estimated to be small.



Female, Humans, Exome Sequencing, Exome, Mutation, Missense, Neoplasms

Journal Title

Nat Genet

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Springer Science and Business Media LLC
European Commission Horizon 2020 (H2020) Societal Challenges (634935)
European Commission Horizon 2020 (H2020) Societal Challenges (633784)
Medical Research Council (MC_UU_12015/2)
Wellcome Trust (203477/Z/16/Z)
MRC (MC_UU_00006/2)