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Background and Objectives: Checkpoint kinase 2 ( CHEK2 ) is a tumor suppressor gene involved in DNA repair and cell cycle regulation. Pathogenic or likely pathogenic (P/LP) variants in CHEK2 are associated with increased cancer risk. Conversely, recent large cohort studies have identified certain variants that, despite being classified as P/LP by in silico analysis, are considered low risk. Thus, the genotype-phenotype correlations of CHEK2 require a better understanding. In this study, we aimed to characterize germline CHEK2 variants from a group of individuals who applied to cancer genetic clinics in the Marmara Region of Türkiye. We also aimed to assess the phenotypic impacts of these variants by using a new score of statistically significant in silico predictors (SSIPs). Methods: We analyzed 1707 individuals with high risk cancer predisposition, focusing on germline CHEK2 variants, using SSIP scores and population-specific data. Results: CHEK2 variants appeared in approximately 8% of cases. The SSIP scores indicated that the missense mutation, p.Arg117Gly, significantly impairs DNA repair. Almost half of the variants had higher allele frequencies than the variants listed in the Genome Aggregation Database (gnomAD), and three variants had significantly higher frequencies compared to the variants listed on the Turkish Variome database (p.Thr476Met, p.Arg137Gln, c.592+3A>T), emphasizing the importance of population-specific data. Conclusions: This comprehensive analysis of CHEK2 variants in the Turkish population provides crucial insights for cancer geneticists and oncologists. Our findings will help to enhance the evaluation and management of cancer predisposition associated with CHEK2 in Türkiye and other regions that have significant Turkish populations.