文章：

一种整合临床、种系、体细胞及计算机模拟分析的方法，用于评估在两个无关林奇综合征家族中发现的新型PMS2基因变异

An Integrated Clinical, Germline, Somatic, and In Silico Approach to Assess a Novel PMS2 Gene Variant Identified in Two Unrelated Lynch Syndrome Families

原文发布日期：11 July 2025

DOI: 10.3390/cancers17142308

类型: Article

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英文摘要：

Background:Lynch syndrome (LS) is an autosomal dominant disease caused by germline pathogenic variants in one of the DNA mismatch repair (MMR) genes (MLH1,MSH2,MSH6, andPMS2) or theEPCAMgene. LS patients harboring genetic variants in one of the MMR genes display a heterogeneous phenotype in terms of cancer penetrance (lifetime cancer risk) and expressivity (malignancies in gastrointestinal or other specific organs).Methods: DNA samples from the index cases of Family 1 and Family 2 were analyzed using a next-generation sequencing (NGS) multigene panel comprising 25 genes involved in major hereditary cancer predisposition syndromes. This NGS analysis revealed a variant of uncertain significance (VUS) in thePMS2gene (NM_000535.7: c.184G>A; p.Gly62Arg) of both index cases, which was validated by Sanger sequencing. The structural and functional impact of this VUS was evaluated in silico using twelve different prediction tools and by immunohistochemical analysis of MMR proteins.Results:Based on the personal and family history of the two families, tumor pathology, and protein in silico analysis, the novelPMS2gene variant described in this study may be associated with hereditary LS. Considering the low penetrance ofPMS2gene variants in LS-associated tumors and the intrafamilial variability of the associated clinical phenotypes, the multidisciplinary approach proposed in this study could significantly support the evaluation of suspected LS cases carrying PMS2 variants.

摘要翻译： 

背景：林奇综合征（LS）是一种由DNA错配修复（MMR）基因（MLH1、MSH2、MSH6和PMS2）或EPCAM基因的种系致病性变异引起的常染色体显性遗传病。携带MMR基因变异的LS患者在癌症外显率（终生患癌风险）和表现度（胃肠道或其他特定器官恶性肿瘤）方面表现出异质性表型。 方法：采用包含25个与主要遗传性癌症易感综合征相关基因的新一代测序（NGS）多基因组合，对家族1和家族2先证者的DNA样本进行分析。NGS检测发现两个先证者的PMS2基因（NM_000535.7: c.184G>A; p.Gly62Arg）均存在意义未明变异（VUS），该结果经Sanger测序验证。通过十二种不同预测工具进行计算机模拟分析，并结合MMR蛋白的免疫组化检测，评估了该VUS的结构与功能影响。 结果：基于两个家族的个人及家族病史、肿瘤病理学特征以及蛋白质计算机模拟分析，本研究中描述的新型PMS2基因变异可能与遗传性LS相关。考虑到PMS2基因变异在LS相关肿瘤中的低外显率及其相关临床表型的家族内变异性，本研究提出的多学科联合分析方法可为携带PMS2变异的疑似LS病例评估提供重要支持。

原文链接：

An Integrated Clinical, Germline, Somatic, and In Silico Approach to Assess a Novel PMS2 Gene Variant Identified in Two Unrelated Lynch Syndrome Families