Identifying women at high risk for breast cancer can trigger a personal program of annual mammograms and magnetic resonance imaging scans for early detection, prophylactic surgery, or chemoprevention to reduce the risk of cancer. Yet, current strategies to identify high-risk mutations based on sequencing panels of genes have significant false-positive and false-negative results, suggesting the need for alternative approaches. Flow-variant assays (FVAs) that assess the effects of mutations in the double-strand break (DSB) repair genetic pathway in lymphoblastoid cells in response to treatment with radiomimetic agents were assessed for sensitivity, specificity, and accuracy both alone and as part of a logistic regression classification score. In turn, these assays were validated in circulating B cells and applied to individuals with personal and/or family history of breast and/or ovarian cancer. A three-FVA classification score based on logistic regression had 95% accuracy. Individuals from a breast cancer–positive cohort with affected family members had high-risk FVA classification scores. Application of a classification score based on multiple FVAs could represent an alternative to panel sequencing for identifying women at high risk for cancer. Genet Med advance online publication 16 March 2017