Case Report: BARD1 p.Val507Met in two relatives with ER-positive breast cancer: cascade testing and exploratory longitudinal cfDNA dynamics

We report two maternally related women with ER-positive breast cancer carrying the germline BARD1 NM_000465.4:c.1519G>A (p.Val507Met) variant. This constitutional variant is currently classified as benign/likely benign and is not presented as causally related to the observed cancers. The study integrated longitudinal clinical follow-up, germline and tumor molecular analyses, targeted family evaluation of 21 biologically related relatives, including genetic testing in 19 relatives, and serial plasma cfDNA monitoring. Longitudinal cfDNA changes were observed during follow-up in both patients; however, these exploratory observations were not interpreted as establishing a quantitative relationship between cfDNA concentration and disease stage or tumor burden. The proband showed rising cfDNA levels during the documented course of metastatic progression, without a variant-specific circulating signal, whereas in the second relative a p.Val507Met-specific signal was detected only in the final available plasma sample before mammographic detection and histopathological confirmation of breast cancer. Because the variant is constitutional, this signal could not establish the presence of tumor-derived ctDNA. These observations generate the hypothesis that sustained increases from individual baseline cfDNA levels may provide a complementary signal prompting earlier clinical assessment or imaging in individuals undergoing longitudinal breast surveillance, particularly in resource-limited settings.