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Abstract
Approximately 10 % of breast cancer (BC) incidence is attributed to inherited germ-line mutations in tumor suppressor genes, and about a half of all hereditary BC cases remain unexplained by known genetic determinants. Whole exome sequencing (WES) offers great promise for the identification of novel hereditary cancer genes, however the interpretation of disease-causing significance for newly identified variants presents a challenge. Here we present the results of WES analysis of 32 hereditary BC patients with unknown causative mutations. In total, 52070 germ-line genetic variants were identified. We designed a special selection algorithm, which uses a sequence of filtering steps for highlighting probably pathogenic mutations. The pipeline is capable to compute minor allele frequencies (MAF) based on public databases; to estimate the potential pathogenicity of mutation according to CADD-database; to summarize the data regarding the gene functions, its pattern of expression and protein interactions networks. As a result we assembled the list of 245 potentially deleterious germ-line mutations probably associated with increased risk of BC. Some of these variants were validated in a case-control study. For example, homozygous missense substitution BRCA1 p.Gln356Arg was detected in 0.9 % of consecutive BC cases; it was associated with 7-fold increased BC risk (95 % CI: 0.83 - 54.83). This finding supports the existence of recessive inheritance of breast cancer predisposition.
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