ClinVar Genomic variation as it relates to human health

The variant has been reported as a variant of uncertain significance based on immunohistochemical analysis of colorectal tumor samples from Lynch syndrome patients in the published literature (PMID 20459533 (2010)). This variant was also identified in an individual with Muir–Torre syndrome or in individuals undergoing multigene cancer panel testing (PMID: 24603434 (2014), 28514183 (2017)). Furthermore, this variant was found to segregate with MSH2-related cancers in one family tested internally. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as likely pathogenic.

This missense variant replaces leucine with proline at codon 687 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). This variant impacts MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (PMID: 33357406). This variant has been reported in multiple individuals affected with Lynch syndrome-associated clinical phenotypes (PMID: 20459533, 31391288; Communication with an external laboratory). Multiple clinical laboratories reference internal data stating that this variant segregates with MSH2-related disease in unrelated families (ClinVar SCV000548193.8, SCV000212848.6, SCV002047290.1) 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 Likely Pathogenic.

For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 90873). This missense change has been observed in individuals with clinical features of Lynch syndrome (PMID: 20459533; Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 687 of the MSH2 protein (p.Leu687Pro).

This variant is considered likely pathogenic. This variant is strongly associated with more severe personal and family histories of cancer, typical for individuals with pathogenic variants in this gene [PMID: 27363726]. This variant is expected to disrupt protein structure [Myriad internal data].

The p.L687P pathogenic mutation (also known as c.2060T>C), located in coding exon 13 of the MSH2 gene, results from a T to C substitution at nucleotide position 2060. The leucine at codon 687 is replaced by proline, an amino acid with very few similar properties. In a cohort of patients from the UK, this alteration was reported in a patient suspected of having Lynch syndrome (Barrow E et al. Histopathology, 2010 Feb;56:331-44). In another study aimed at describing the characteristics of individuals with Lynch syndrome, this alteration was reported in two probands from a cohort undergoing multigene panel testing (Espenschied CR et al. J. Clin. Oncol., 2017 Aug;35:2568-2575). In a massively parallel cell-based functional assay testing susceptibility to a DNA damaging agent, 6-thioguanine (6-TG), this variant was reported to be functionally deleterious (Jia X et al. Am J Hum Genet, 2021 Jan;108:163-175). This alteration has been identified in multiple unrelated families meeting Amsterdam criteria for Lynch syndrome, one of which had co-segregation with disease in five family members (Ambry internal data). This alteration has also been identified in several probands whose Lynch syndrome-associated tumors demonstrated loss of MSH2 and/or MSH6 expression on immunohistochemistry (Ambry internal data). Based on an internal structural assessment using published crystal structures, this alteration results in destabilization of ATPase domain (Ambry internal data; Warren JJ et al. Mol. Cell, 2007 May;26:579-92). 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.

Variant summary: MSH2 c.2060T>C (p.Leu687Pro) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, C-terminal domain (IPR000432) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251468 control chromosomes (gnomAD). c.2060T>C has been reported in the literature in individuals affected with Lynch Syndrome-associated cancer (e.g. Barrow_2010, Espenschied_2017, Li_2020). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function in a massively parallel screen in human cells, finding that the variant results in a deleterious effect on mismatch repair function (Jia_2021). The following publications have been ascertained in the context of this evaluation (PMID: 20459533, 22290698, 28514183, 33357406, 31391288). ClinVar contains an entry for this variant (Variation ID: 90873). Based on the evidence outlined above, the variant was classified as pathogenic.

This variant is denoted MSH2 c.2060T>C at the cDNA level, p.Leu687Pro (L687P) at the protein level, and results in the change of a Leucine to a Proline (CTC>CCC). This variant was observed in two tumors of the large intestine; however, it was not determined whether these variants were somatic or germline (COSMIC). MSH2 Leu687Pro was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Leucine and Proline differ in some properties, this is considered a semi-conservative amino acid substitution. MSH2 Leu687Pro occurs at a position that is highly conserved across species and is located in the ATPase domain (Lutzen 2008). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether MSH2 Leu687Pro is pathogenic or benign. We consider it to be a variant of uncertain significance.