The contribution of pathogenic variants in breast cancer susceptibility genes to familial breast cancer risk.

Understanding the gene-specific risks for development of breast cancer will lead to improved clinical care for those carrying germline mutations in cancer predisposition genes. We sought to detail the spectrum of mutations and refine risk estimates for known and proposed breast cancer susceptibility genes. Targeted massively-parallel sequencing was performed to identify mutations and copy number variants in 26 known or proposed breast cancer susceptibility genes in 2134 negative women with familial breast cancer (proband with breast cancer and a family history of breast or ovarian cancer) from a largely European-Caucasian multi-institutional cohort. Case-control analysis was performed comparing the frequency of internally classified mutations identified in familial breast cancer women to Exome Aggregation Consortium controls. Mutations were identified in 8.2% of familial breast cancer women, including mutations in high-risk (odds ratio > 5) (1.4%) and moderate-risk genes (2 < odds ratio < 5) (2.9%). The remaining familial breast cancer women had mutations in proposed breast cancer genes (1.7%), Lynch syndrome genes (0.5%), and six cases had two mutations (0.3%). Case-control analysis demonstrated associations with familial breast cancer for , and mutations (odds ratio > 3.0,  < 10), mutations (odds ratio = 3.2,  = 0.012), and truncating mutations (odds ratio1.6,  = 0.041). Our results demonstrate that approximately 4.7% of negative familial breast cancer women have mutations in genes statistically associated with breast cancer. We classified and as high-risk, and as moderate risk, and truncating mutations as low risk breast cancer predisposition genes. This study demonstrates that large case-control studies are needed to fully evaluate the breast cancer risks associated with mutations in moderate-risk and proposed susceptibility genes.