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

Background: Pathogenic 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 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 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: and . All patients previously tested negative for founder mutations.

Results: In 44% (7 out of 16) of tested probands, pathogenic mutations were identified. Six probands carried pathogenic mutations in , and one proband carried pathogenic mutations in . In patients, a variant of uncertain significance was found in , and . 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 mutations.

Conclusion: A relatively was The Manchester scoring system predicted the probability of non-founder pathogenic mutations with high accuracy.