ClinVar

Description

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Variants that disrupt the p.Leu187 amino acid residue in MSH2 have been observed in affected individuals (PMID: 18951462, 16327991, 28422960, 17101317, 26951660). This suggests that it is a clinically significant residue, and that other variants that disrupt this residue are likely to be causative of disease. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. Experimental studies have shown that this missense change impairs the mismatch repair activity of the MSH2 protein (PMID: 26951660, 19697156). This variant has been observed in several families affected with Lynch syndrome-associated cancers (PMID: 12624141, 21642682, 16395668, 19697156, 10995807). ClinVar contains an entry for this variant (Variation ID: 91135). This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with arginine at codon 187 of the MSH2 protein (p.Leu187Arg). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and arginine.