ClinVar Genomic variation as it relates to human health

Multifactorial likelihood analysis posterior probability >0.99

The p.L187P pathogenic mutation (also known as c.560T>C), located in coding exon 3 of the MSH2 gene, results from a T to C substitution at nucleotide position 560. The leucine at codon 187 is replaced by proline, an amino acid with similar properties. This mutation has been reported in families meeting Bethesda or Amsterdam criteria and segregated with disease in one family with Muire-Torre phenotype (Mangold E et al. Int. J. Cancer 2005 Sep;116:692-702; Ollila S et al. Int. J. Oncol. 2006 Jan;28:149-53). Published structural analysis suggests that this alteration (L187P) structurally destabalizes the MSH2 protein resulting in reduced binding to MSH3 and MSH6 (Nielsen SV et al. PLoS Genet., 2017 Apr;13:e1006739). In addition, functional assays have shown that the L187P protein is MMR deficient (Ollila S et al. Int. J. Oncol. 2006 Jan;28:149-53; Ollila S et al. Gastroenterology 2006 Nov;131:1408-17; Martinez SL et al. Proc. Natl. Acad. Sci. U.S.A. 2010 Mar;107:5070-5). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

This missense variant replaces leucine with proline at codon 187 of the MSH2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant has deficient DNA repair and tolerance to DNA damaging agents (PMID: 17101317, 20176959, 28422960, 30998989, 33357406). This variant has been reported in individuals affected with Lynch syndrome (PMID: 15849733, 17101317, 17192056). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.

This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 187 of the MSH2 protein (p.Leu187Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Lynch syndrome (PMID: 15849733, 16327991, 17101317, 18951462). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 91134). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 33357406) indicates that this missense variant is expected to disrupt MSH2 function. Experimental studies have shown that this missense change affects MSH2 function (PMID: 16327991, 17101317, 18951462, 28422960). For these reasons, this variant has been classified as Pathogenic.

The p.Leu187Pro has been previously has been previously reported by our laboratory in one family with Lynch related tumors and was demonstrated to segregate in three affected individuals and to result in MSH2 immuno-deficiency. In addition, this variant was shown to result in a loss of MSH2 expression by immunohistochemistry and was found to be completely deficient by in vitro MMR activity (Ollila_2006, Ollila_2008, Martinez_2009). One study also classified this variant as deleterious using the multivariate analysis of protein polymorphisms (MAPP)-mismatch repair (MMR) assay (Chao_2008), and a three-step functional analysis model compiling information from the literature has also implicated this as a clinically significant alteration (Kansikas_2010). Another variant at the same amino acid position (p.Leu187Arg) has been documented in the literature in a proband who was MSI +ve and had both colorectal and breast carcinoma (Peel_2000), increasing the likelihood that the p.Leu187Pro variant may have clinical significance. Based on the above information this variant is classified as PATHOGENIC.