ClinVar Genomic variation as it relates to human health

This variant is considered likely pathogenic. This variant is expected to disrupt protein structure [Myriad internal data]. Functional studies indicate this variant impacts protein function [PMID: 33357406].

This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 800 of the MSH2 protein (p.Leu800Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 24114314; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1790666). 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 with a positive predictive value of 95%. 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.

This missense variant replaces leucine with proline at codon 800 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 (internally defined LOF score threshold >= 0.88, PMID: 33357406). This variant has been reported in individuals affected with Lynch syndrome (PMID: 24114314, 31332305). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Although there is a suspicion that this variant may be associated with disease, additional functional and clinical studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

The p.L800P variant (also known as c.2399T>C), located in coding exon 14 of the MSH2 gene, results from a T to C substitution at nucleotide position 2399. The leucine at codon 800 is replaced by proline, an amino acid with similar properties. This alteration has been reported in the germline of a female diagnosed with MSH2/MSH6 deficient endometrial cancer at age 55 and fulfilling Amsterdam II criteria (Rhees J et al. Fam. Cancer, 2014 Jun;13:219-25). 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 01;108:163-175). This variant is considered to be rare based on population 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 majority of available evidence to date, this variant is likely to be pathogenic.