ClinVar

Description

The p.P696L pathogenic mutation (also known as c.2087C>T), located in coding exon 13 of the MSH2 gene, results from a C to T substitution at nucleotide position 2087. The proline at codon 696 is replaced by leucine, an amino acid with similar properties. This mutation was reported in a Taiwanese individual whose family history met Amsterdam II criteria for Lynch syndrome and tumor displayed loss of MSH2 protein expression by immunohistochemistry as well as high microsatellite instability (MSI-H) (Tang R et al. Clin. Genet., 2009 Apr;75:334-45; Kamiza AB et al. PLoS One, 2015 Jun;10:e0130018). This variant was also reported to segregate in two affected individuals of a French family (Parc Y et al. J. Med. Genet., 2003 Mar;40:208-13) and has been identified in individuals either meeting Amsterdam criteria or whose tumors demonstrate absent staining of MSH2 and MSH6 by IHC (Ambry internal data). In two different functional studies, this alteration showed reduced MSH2 protein expression and deficient mismatch repair activity compared to wild type (Houlleberghs H et al. Proc. Natl. Acad. Sci. U.S.A., 2016 Apr;113:4128-33; Tricarico R et al. Hum. Mutat. 2017 Jan;38:64-77) and also demonstrated reduced MSH2 and MSH6 protein interaction in a yeast two-hybrid assay (Zhang X et al. Oncol Lett. 2018 May;15(5):6275-82) In an in vitro complementation assay, this variant was determined to be functionally deficient (Drost M et al. Genet Med, 2019 07;21:1486-1496). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.