Case Report: A combination of CHEK2 and high polygenic risk score leads to early-onset male breast cancer
Abstract
Male breast cancer (MBC) is a rare disease, accounting for about 1% of all breast cancer cases worldwide. Compared to female breast cancer (FBC), MBC shows a higher prevalence of hormone receptor positivity and distinct germline predispositions, most frequently pathogenic variants in BRCA2 and CHEK2. The contribution of mismatch repair (MMR) genes such as MSH6 to MBC risk remains, however, unclear. In addition, polygenic risk scores (PRS) have emerged as promising tools for breast cancer risk prediction but are not yet used in routine care. We report the case of a 42-year-old man diagnosed with invasive carcinoma of no special type, strongly estrogen receptor-positive, HER2-negative, and with a family history of breast and prostate cancer. Genetic testing revealed a pathogenic CHEK2 nonsense variant (p.Trp411*), a likely pathogenic MSH6 frameshift variant, and a breast cancer PRS in the 99th percentile. Tumor sequencing confirmed both germline variants but showed microsatellite stability and no loss of heterozygosity, arguing against a causal role of MSH6. This case illustrates how PRS, in combination with moderate-risk variants, like those in CHEK2, may drive early-onset MBC and highlights the need to incorporate polygenic models into risk assessment and counseling.
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