Navigating the complexity of BRCA1/BRCA2 constitutional mosaicism: a case report and literature review exploring clinical, molecular and genetic counselling approaches

Background Pathogenic/likely pathogenic variants (PV/LPV) in cancer predisposition genes, including BRCA1/BRCA2, are typically found with an allele frequency of approximately 50% in non-neoplastic tissues. Constitutional mosaicism is exceptionally rare for BRCA1/BRCA2 and poses significant challenges for diagnostic interpretation, risk stratification, clinical management and genetic counselling. Methods Following the identification of a low-level BRCA2 PV in leucocyte DNA from a woman with early-onset breast cancer, we undertook a comprehensive molecular characterisation across multiple tissues using next-generation sequencing (NGS) and complementary orthogonal techniques. Concurrently, we performed a comprehensive review of the literature on constitutional BRCA1/BRCA2 mosaicism, encompassing all cases reported to date. Results NGS analysis identified the BRCA2 PV at a variant allele fraction of 11–21% in four different cancer-free tissues and at 40% in the tumour tissue. Sanger sequencing failed to detect the variant in leucocyte DNA but confirmed its presence in the tumour. To date, only 10 cases of constitutional mosaicism involving pathogenic BRCA1/BRCA2 variants have been reported. Genetic counselling, along with appropriate surveillance and risk-reduction measures, was provided following extensive multidisciplinary discussion, consultation with experts in the field and a comprehensive review of the available literature. Conclusion This study broadens the current understanding of constitutional BRCA1/BRCA2 mosaicism by providing a detailed characterisation of a BRCA2 mosaic case and a comprehensive review of all cases reported to date. In the absence of dedicated clinical guidelines, we propose a multilevel approach integrating stepwise molecular investigation, multidisciplinary clinical assessment and individualised genetic counselling to optimise the management of these challenging cases.