Multifocal Breast Cancer With Discordant Molecular Profiles in a Patient With NF1 and MUTYH Germline Variants: A Case...

The identification of synchronous breast cancers with inter-tumor heterogeneity presents significant diagnostic and therapeutic challenges, particularly in cases of discordant biomarker profiles. We report the case of a 66-year-old African American female with a significant family history of cancer, including two sisters diagnosed with breast cancer at ages 29 and 32. Diagnostic imaging revealed two synchronous right breast masses with similar high-grade histomorphology but discordant molecular profiles, with the larger focus being hormone receptor-negative and human epidermal growth factor receptor 2 (HER2)-positive, and the smaller focus being triple-negative. Initial germline testing identified a heterozygous variant of uncertain significance (VUS) in NF1 (c.2643G>A, p.Met881Ile). Subsequent testing with an expanded panel identified a pathogenic variant in MUTYH (c.1187G>A, p.G396D). The patient was treated with neoadjuvant chemotherapy followed by unilateral mastectomy. This case illustrates the clinical utility of evaluating all foci in multifocal high-grade disease to ensure appropriate systemic therapy and highlights the challenges of interpreting germline variants in the absence of well-described genotype-phenotype associations.