Klančar Gašper, Blatnik Ana, Šetrajčič Dragoš Vita, Vogrič Vesna, Stegel Vida, Blatnik Olga, Drev Primož, Gazič Barbara, Krajc Mateja, Novaković Srdjan
Department of Molecular Diagnostics, Institute of Oncology Ljubljana, SI-1000 Ljubljana, Slovenia.
Cancer Genetics Clinic, Institute of Oncology Ljubljana, SI-1000 Ljubljana, Slovenia.
Genes (Basel). 2020 Mar 18;11(3):325. doi: 10.3390/genes11030325.
The diagnostics of Lynch syndrome (LS) is focused on the detection of DNA mismatch repair (MMR) system deficiency. MMR deficiency can be detected on tumor tissue by microsatellite instability (MSI) using molecular genetic test or by loss of expression of one of the four proteins (MLH1, MSH2, MSH6, and PMS2) involved in the MMR system using immunohistochemistry (IHC) staining. According to the National Comprehensive Cancer Network (NCCN) guidelines, definitive diagnosis of LS requires the identification of the germline pathogenic variant in one of the MMR genes. In the report, we are presenting interesting novel in-frame deletion LRG_216t1:c.2236_2247delCTGCCTGATCTA p.(Leu746_Leu749del) associated with LS. The variant appears to be associated with uncommon isolated loss of PMS2 immunohistochemistry protein staining (expression) in tumor tissue instead of MLH1 and PMS2 protein loss, which is commonly seen with pathogenic variants in . The variant was classified as likely pathogenic, based on segregation analysis and molecular characterization of blood and tumor samples. According to the American College of Medical Genetics (ACMG) guidelines, the following evidence categories of PM1, PM2, PM4, and PP1 moderate have been used for classification of the novel variant. By detecting and classifying the novel variant as likely pathogenic, we confirmed the LS in this family.
林奇综合征（LS）的诊断重点在于检测DNA错配修复（MMR）系统缺陷。可通过分子遗传学检测利用微卫星不稳定性（MSI）在肿瘤组织中检测MMR缺陷，或通过免疫组织化学（IHC）染色检测MMR系统中涉及的四种蛋白质（MLH1、MSH2、MSH6和PMS2）之一的表达缺失来检测MMR缺陷。根据美国国立综合癌症网络（NCCN）指南，LS的明确诊断需要在MMR基因之一中鉴定出种系致病变异。在本报告中，我们呈现了一个与LS相关的有趣的新型框内缺失LRG_216t1:c.2236_2247delCTGCCTGATCTA p.(Leu746_Leu749del)。该变异似乎与肿瘤组织中罕见的孤立性PMS2免疫组化蛋白染色（表达）缺失相关，而非常见的MLH1和PMS2蛋白缺失，后者常见于……的致病变异。基于血液和肿瘤样本的分离分析和分子特征，该变异被分类为可能致病。根据美国医学遗传学学院（ACMG）指南，以下PM1、PM2、PM4和PP1中等证据类别已用于该新型变异的分类。通过将该新型变异检测并分类为可能致病，我们在这个家族中确诊了LS。
