High frequency of pathogenic non-founder germline mutations in BRCA1 and BRCA2 in families with breast and ovarian cancer in a founder population

BACKGROUND: Pathogenic BRCA1 founder mutations (c.4035delA, c.5266dupC) contribute to 3.77% of all consecutive primary breast cancers and 9.9% of all consecutive primary ovarian cancers. Identifying germline pathogenic gene variants in patients with primary breast and ovarian cancer could significantly impact the medical management of patients. The aim of the study was to evaluate the rate of pathogenic mutations in the 26 breast and ovarian cancer susceptibility genes in patients who meet the criteria for BRCA1/2 testing and to compare the accuracy of different selection criteria for second-line testing in a founder population. METHODS: Fifteen female probands and 1 male proband that met National Comprehensive Cancer Network (NCCN) criteria for BRCA1/2 testing were included in the study and underwent 26-gene panel testing. Fourteen probands had breast cancer, one proband had ovarian cancer, and one proband had both breast and ovarian cancer. In a 26-gene panel, the following breast and/or ovarian cancer susceptibility genes were included: ATM, BARD1, BLM, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, EPCAM, FAM175A, MEN1, MLH1, MRE11A, MSH2, MSH6, MUTYH, NBN, PALB2, PMS2, PTEN, RAD50, RAD51C, RAD51D, STK11, TP53, and XRCC2. All patients previously tested negative for BRCA1 founder mutations. RESULTS: In 44% (7 out of 16) of tested probands, pathogenic mutations were identified. Six probands carried pathogenic mutations in BRCA1, and one proband carried pathogenic mutations in BRCA2. In patients, a variant of uncertain significance was found in BRCA2, RAD50, MRE11A and CDH1. The Manchester scoring system showed a high accuracy (87.5%), high sensitivity (85.7%) and high specificity (88.9%) for the prediction of pathogenic non-founder BRCA1/2 mutations. CONCLUSION: A relatively high incidence of pathogenic non-founder BRCA1/2 mutations was observed in a founder population. The Manchester scoring system predicted the probability of non-founder pathogenic mutations with high accuracy.