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 inCHEK2are 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 ofCHEK2require a better understanding. In this study, we aimed to characterize germlineCHEK2variants 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 germlineCHEK2variants, using SSIP scores and population-specific data.Results:CHEK2variants 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 ofCHEK2variants 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 withCHEK2in Türkiye and other regions that have significant Turkish populations.
背景与目的：检查点激酶2（CHEK2）是一种参与DNA修复和细胞周期调控的抑癌基因。CHEK2的致病性或可能致病性（P/LP）变异与癌症风险增加相关。然而，近期大规模队列研究发现，某些经计算机分析归类为P/LP的变异实际上风险较低。因此，需要更深入地理解CHEK2的基因型-表型相关性。本研究旨在对土耳其马尔马拉地区癌症遗传门诊就诊人群的种系CHEK2变异进行特征分析，并运用基于统计学显著性的计算机预测因子（SSIPs）新评分系统评估这些变异的表型影响。 方法：我们分析了1707名具有高癌症遗传易感性的个体，重点关注其种系CHEK2变异，结合SSIP评分和人群特异性数据进行分析。 结果：约8%的病例检出CHEK2变异。SSIP评分显示错义突变p.Arg117Gly显著损害DNA修复功能。近半数变异在人群中的等位基因频率高于基因组聚合数据库（gnomAD）收录的变异，其中三个变异（p.Thr476Met、p.Arg137Gln、c.592+3A>T）在土耳其变异组数据库中的频率显著更高，凸显了人群特异性数据的重要性。 结论：本次对土耳其人群CHEK2变异的全面分析为癌症遗传学家和肿瘤学家提供了重要参考。研究结果将有助于完善土耳其及土耳其裔聚居地区与CHEK2相关癌症易感性的评估和管理策略。
肿瘤(癌症)患者之家