Germline pathogenic variants in the DNA mismatch repair (MMR) genes (Lynch syndrome) predispose to colorectal (CRC) and endometrial (EC) cancer. However, mosaic variants in the MMR genes have been rarely described. We identified a likely de novo mosaic MSH6:c.1135_1139del p.Arg379* pathogenic variant in a patient diagnosed with suspected Lynch syndrome/Lynch-like syndrome. The patient developed MSH6-deficient EC and CRC at 54 and 58 years of age, respectively, without a detectable germline MMR pathogenic variant. Multigene panel sequencing of tumor and blood-derived DNA identified an MSH6 somatic mutation (MSH6:c.1135_1139del p.Arg379*) common to both the EC and CRC, raising suspicion of mosaicism. A droplet digital polymerase chain reaction (ddPCR) assay detected the MSH6 variant at 5.34% frequency in normal colonic tissue, 3.49% in saliva and 1.64% in blood DNA, demonstrating the presence of the MSH6 variant in all three germ layers. This study highlights the utility of tumor sequencing to guide sensitive ddPCR testing to detect low-level mosaicism in the MMR genes. Further investigation of the prevalence of MMR mosaicism is needed to inform routine diagnostic approaches and genetic counselling.

DNA 错配修复 (MMR) 基因的种系致病性变异（林奇综合征）易患结直肠癌 (CRC) 和子宫内膜癌 (EC)。然而，MMR 基因中的嵌合变异体很少被描述。我们在一名诊断为疑似林奇综合征/林奇样综合征的患者中发现了可能的从头嵌合 MSH6 :c.1135_1139del p.Arg379* 致病性变异。该患者分别在 54 岁和 58 岁时患上 MSH6 缺陷型 EC 和 CRC，且未检测到种系 MMR 致病性变异。肿瘤和血液来源 DNA 的多基因组测序鉴定出EC 和 CRC 共有的MSH6体细胞突变 ( MSH6 :c.1135_1139del p.Arg379*)，引发了嵌合现象的怀疑。液滴数字聚合酶链反应 (ddPCR) 检测在正常结肠组织中检测到MSH6变体的频率为 5.34%，在唾液中为 3.49%，在血液 DNA 中为 1.64%，证明在所有三个胚层中都存在 MSH6 变体。这项研究强调了肿瘤测序在指导敏感 ddPCR 测试以检测 MMR 基因中低水平嵌合性方面的实用性。需要进一步调查 MMR 嵌合体的患病率，为常规诊断方法和遗传咨询提供信息。