Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
Mol Genet Genomic Med. 2023 Feb;11(2):e2104. doi: 10.1002/mgg3.2104. Epub 2023 Jan 24.
Germline variants in the DNA mismatch repair (MMR) genes (MLH1, MSH2, MSH6, and PMS2) cause Lynch syndrome, an autosomal dominant hereditary cancer susceptibility syndrome. The risk for endometrial cancer is significantly higher in women with MSH6 pathogenic/likely pathogenic (P/LP) variants compared with that for MLH1 or MSH2 variants.
The proband was tested via a clinical testing, Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT). RT-PCR was performed using patient's blood DNA and cDNA was analyzed by DNA sequencing and a cloning approach.
We report a 56-year-old female with endometrial cancer who carries a germline variant, MSH6 c.4001G > C, located at the last nucleotide of exon 9. While the pathogenicity of this variant was previously unknown, functional studies demonstrated that this variant completely abolished normal splicing and caused exon 9 skipping, which is expected to lead to a prematurely truncated or abnormal protein.
Our results indicate that this variant likely contributes to cancer predisposition through disruption of normal splicing, and is classified as likely pathogenic.
DNA 错配修复（MMR）基因（MLH1、MSH2、MSH6 和 PMS2）中的种系变异导致林奇综合征，这是一种常染色体显性遗传性癌症易感性综合征。与 MLH1 或 MSH2 变异相比，MSH6 致病性/可能致病性（P/LP）变异的女性患子宫内膜癌的风险显著更高。
通过临床检测（纪念斯隆凯特琳综合行动癌症靶标突变分析（MSK-IMPACT））对先证者进行检测。使用患者血液 DNA 进行 RT-PCR，通过 DNA 测序和克隆方法分析 cDNA。
我们报告了一位 56 岁患有子宫内膜癌的女性，她携带一种种系变异，MSH6 c.4001G > C，位于外显子 9 的最后一个核苷酸处。虽然该变异的致病性以前未知，但功能研究表明，该变异完全消除了正常剪接并导致外显子 9 跳跃，这预计会导致过早截断或异常蛋白。
我们的结果表明，该变异可能通过破坏正常剪接导致癌症易感性，归类为可能致病性。
