Submissions for variant NM_000251.3(MSH2):c.1474A>T (p.Met492Leu)

dbSNP: rs774419666

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000236460	SCV000294053	uncertain significance	not provided	2016-03-07	criteria provided, single submitter	clinical testing	This variant is denoted MSH2 c.1474A>T at the cDNA level, p.Met492Leu (M492L) at the protein level, and results in the change of a Methionine to a Leucine (ATG>TTG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH2 Met492Leu was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Methionine and Leucine share similar properties, this is considered a conservative amino acid substitution. MSH2 Met492Leu occurs at a position that is conserved across species and is located in a region of interaction with MSH6 and MSH3, within the clamp domain (Lutzen 2008). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether MSH2 Met492Leu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae	RCV001047851	SCV001211833	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-07-22	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 492 of the MSH2 protein (p.Met492Leu). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 33357406) indicates that this missense variant is not expected to disrupt MSH2 function. ClinVar contains an entry for this variant (Variation ID: 246481). This variant has not been reported in the literature in individuals affected with MSH2-related conditions. This variant is present in population databases (rs774419666, gnomAD 0.0009%).
Ambry Genetics	RCV003165662	SCV003870543	likely benign	Hereditary cancer-predisposing syndrome	2023-01-18	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
All of Us Research Program, National Institutes of Health	RCV003998929	SCV004833419	uncertain significance	Lynch syndrome	2023-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with leucine at codon 492 of the MSH2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). This variant does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold <= -1.32, PMID: 33357406). To our knowledge, this variant has not been reported in individuals affected with MSH2-related disorders in the literature. This variant has been identified in 1/251318 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.