Submissions for variant NM_000251.3(MSH2):c.149C>T (p.Ala50Val)

dbSNP: rs876658582

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Neuberg Centre For Genomic Medicine, NCGM	RCV001823604	SCV002073172	uncertain significance	Lynch syndrome 1		criteria provided, single submitter	clinical testing	The missense variant p.A50V in MSH2 (NM_000251.3) has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.A50V variant is observed in 1/19,798 (0.0051%) alleles from individuals of Finnish background in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The p.A50V missense variant is predicted to be damaging by both SIFT and PolyPhen2. The alanine residue at codon 50 of MSH2 is conserved in all mammalian species. The nucleotide c.149 in MSH2 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance
Invitae	RCV001869818	SCV002266286	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-02-10	criteria provided, single submitter	clinical testing	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: 1339150). This variant has not been reported in the literature in individuals affected with MSH2-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 50 of the MSH2 protein (p.Ala50Val). 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.
Ambry Genetics	RCV002388685	SCV002702067	likely benign	Hereditary cancer-predisposing syndrome	2022-09-13	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	RCV004009163	SCV004832732	uncertain significance	Lynch syndrome	2023-11-30	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with valine at codon 50 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). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MSH2-related disorders in the literature. This variant has been identified in 1/231462 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.