Submissions for variant NM_000251.3(MSH2):c.871C>G (p.Leu291Val)

dbSNP: rs878853827

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000229699	SCV000284192	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2025-01-26	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 291 of the MSH2 protein (p.Leu291Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with ovarian cancer (PMID: 30093976). ClinVar contains an entry for this variant (Variation ID: 237413). Invitae Evidence Modeling incorporating data from in vitro experimental studies (PMID: 33357406) indicates that this missense variant is not expected to disrupt MSH2 function with a negative predictive value of 95%. 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.
GeneDx	RCV000480117	SCV000566177	uncertain significance	not provided	2015-04-06	criteria provided, single submitter	clinical testing	This variant is denoted MSH2 c.871C>G at the cDNA level, p.Leu291Val (L291V) at the protein level, and results in the change of a Leucine to a Valine (CTG>GTG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH2 Leu291Val 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 Valine share similar properties, this is considered a conservative amino acid substitution. MSH2 Leu291Val occurs at a position that is conserved across species and is located within the Connector Domain (Lutzen 2008). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether MSH2 Leu291Val is pathogenic or benign. We consider it to be a variant of uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV001183554	SCV001349331	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-24	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with valine at codon 291 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 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 not been identified 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.
Ambry Genetics	RCV001183554	SCV002682289	likely benign	Hereditary cancer-predisposing syndrome	2022-05-24	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.