CHEK2 Germline Variants and Their Clinical Implications: Experience from a Turkish Hereditary Cancer Cohort

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CHEK2 is a moderate-penetrance tumor suppressor gene primarily linked to hereditary breast cancer, yet growing evidence implicates it in a wider tumor spectrum. Data from underrepresented populations, such as Türkiye, remains limited. We retrospectively analyzed 895 individuals referred for hereditary cancer evaluation between 2019 and 2025 who underwent multigene panel testing. Germline CHEK2 variants were identified using the Hereditary Cancer Solution Kit (Sophia Genetics) and classified per ACMG guidelines. Clinical, tumor, and histopathological data were reviewed. Twenty-four carriers (83.3% female) were detected: 45.8% harbored pathogenic, 41.6% likely pathogenic, and 12.5% variant of uncertain significance. Breast cancer was the most frequent (66.6%), followed by bladder cancer (8.3%), with isolated cases of ovarian, cervical, lung, papillary thyroid cancers, parathyroid adenoma, and thymoma. Missense variants predominated (75%), clustering in the FHA (66.6%) and kinase (33.4%) domains. Recurrent c.470T > C and c.1427C > T variants comprised 41.6% of all cases. Our findings highlight variant- and sex-specific patterns and underscore the relevance of population-based data in refining cancer risk assessment and management of CHEK2 carriers.