Case report: a rare BRCA1 de novo variant in a female with breast cancer

Breast cancer is the most common cancer among women worldwide. While lifestyle factors contribute to rising incidence, 5–14% of cases result from pathogenic variants in core susceptibility genes such as BRCA1, which also increases ovarian cancer risk and, in men, prostate cancer risk. BRCA1 variants are typically autosomal dominant, making family history a key criterion for genetic testing under guidelines like HBOC or NCCN. Although usually inherited, de novo BRCA1 pathogenic variants occur rarely; only twelve cases have been reported. We present a young woman with breast cancer without a significant family history, and a pathogenic de novo BRCA1 variant. We report a 37-year-old woman with HER2-positive, ER/PR-positive invasive breast cancer without relevant family history. After imaging-confirmed T1cN0M0 disease, she received neoadjuvant Her2-targeted chemotherapy, breast-conserving surgery, postneoadjuvant trastuzumab emtansine, radiotherapy, and ongoing endocrine therapy. Genetic testing by Next Generation Sequencing revealed a BRCA1 frameshift variant (NM_007294.4:c.1335_1336del, p.(Arg446Serfs*9)) which was classified as pathogenic per ENIGMA/ACMG guidelines. Absent from population databases and previously reported in cancer cases, it disrupts protein function. Cascade testing showed neither parent carried the variant; microsatellite analysis confirmed parentage, indicating a de novo pathogenic variant. A rare de novo BRCA1 variant was identified in a young breast cancer patient. Such variants are likely underdiagnosed due to historical testing limitations and reliance on family history. This case highlights the importance of genetic testing and inclusion in hereditary cancer prevention programs, even without a family history.