A MSH6 3’UTR variant (c.*23_26dup) was found in 13 unrelated families consulted for Lynch/Muir-Torre Syndrome. This variant, which is very rare in the genomic databases, was absent in healthy controls and strongly segregated with the disease in the studied pedigrees. All tumors were defective for MSH2/MSH6/MSH3 proteins expression, but only MSH2 somatic pathogenic mutations were found in 5 of the 12 sequenced tumors. Moreover, we had no evidence of MSH6 transcript decrease in carriers, whereas MSH2 transcript was downregulated. Additional evaluations performed in representative carriers, including karyotype, arrayCGH and Linked-Reads whole genome sequencing, failed to evidence any MSH2 germline pathogenic variant. Posterior probability of pathogenicity for MSH6 c.*23_26dup was obtained from a multifactorial analysis incorporating segregation and phenotypic data and resulted >0.999, allowing to classify the variant as pathogenic (InSiGHT Class 5). Carriers shared a common haplotype involving MSH2/MSH6 loci, then a cryptic disease-associated variant, linked with MSH6 c.*23_26dup, cannot be completely excluded. Even if it is not clear whether the MSH6 variant is pathogenic per se or simply a marker of a disease-associated MSH2/MSH6 haplotype, all data collected on patients and pedigrees prompted us to manage the variant as pathogenic and to offer predictive testing within these families.

一个MSH6 3'UTR变型（C * 23_26dup）在征询林奇/缪尔-托雷综合征13个无关的家庭被发现。这种变异在基因组数据库中非常罕见，但在健康对照中不存在，并且在所研究的谱系中与疾病强烈分离。所有肿瘤都存在 MSH2/MSH6/MSH3 蛋白表达缺陷，但在 12 个测序肿瘤中的 5 个中仅发现MSH2体细胞致病突变。此外，我们没有证据表明携带者中MSH6转录物减少，而MSH2转录物被下调。在代表性携带者中进行的其他评估，包括核型、arrayCGH 和 Linked-Reads 全基因组测序，未能证明任何MSH2种系致病变异。MSH6 c.*23_26dup致病性的后验概率是从包含分离和表型数据的多因素分析中获得的，结果 >0.999，允许将该变异分类为致病性（InSiGHT 5 类）。携带者共享一个涉及MSH2 / MSH6基因座的常见单倍型，然后不能完全排除与MSH6 c.*23_26dup相关的隐匿疾病相关变异。即使尚不清楚MSH6变异本身是致病性的还是仅仅是疾病相关MSH2/MSH6的标志物 单倍型，所有收集到的关于患者和系谱的数据促使我们将变异管理为致病性，并在这些家族中提供预测性测试。