Four novel BRCA variants found in Chinese hereditary breast cancer patients by next-generation sequencing

Breast cancer is the most frequent cancer among women worldwide. Patients carrying mutations in breast cancer susceptibility genes like BRCA1 and BRCA2 (BRCA1/2) account for 5-10% of all breast cancer patients. Therefore, screening for susceptibility genes may reduce the incidence of breast cancer and improve prognosis. To provide evidence for mutation interpretation and targeted drug use in breast cancer patients, gene mutations were screened in 78 women diagnosed with sporadic breast cancer using a next-generation sequencing panel, confirmed by Sanger sequencing. Then the pathogenicity of the identified novel variants was explored using in vitro experiments including western blotting, co-immunoprecipitation and cell-migration assays. Four novel variants (BRCA2 L1390W, BRCA2 Glu432fs, BRCA1 P706L, and BRCA1 Cys882fs) were identified. BRCA2 Glu432fs decreased the expression of BRCA2 protein, enhanced cell migration and invasion ability, and prevented the protein from interacting with RAD51, resulting in a defect in the homologous recombination pathway. The identification of these novel BRCA variants and the confirmation of their pathogenicity have enriched the genetic database of breast cancer, especially in the Chinese population. Moreover, the variants are the genetic risk factors for hereditary breast cancer. Therefore, BRCA variant detection and genetic counseling for breast cancer patients are meaningful and important.