In-silico analysis of Thr767Ile pathogenic variant in the MSH6 gene in family with endometrial cancer

Abstract Objective To examine the mechanism of pathogenity of Thr767Ile variant on MSH6 protein. Study design We describe a family diagnosed with endometrial cancer in two generations associated with variant in the MSH6 gene (p. Thr767Ile / c. 2300C>T) (rs587781462). MSH6 c. 2300C>T was associated with autosomal-dominant pattern of inheritance. MSH6 c. 2300C>T has pathogenic status in ClinVar and LOVD3 databases but it has never been described in context of hereditary endometrial cancer. We utilized a number of in-silico bioinformatic approaches using MSH6 protein sequence and structural information to assess influence of Thr767Ile on MSH6 properties. Results MSH6 Thr767 is highly conservative amino acid among various kingdoms of organisms. Thr767Ile was predicted deleterious and likely decreases affinity of MSH2-MSH6 complex to DNA but not affect interaction between MSH2 and MSH6. Conclusions To the best of our knowledge, this is the first description of MSH6 T767I pathogenic variant that could be associated with a hereditary endometrial cancer. Bioinformatic analyses showed that T767I substitution most likely affects the MSH6 most important role, which is a DNA binding.