Submissions for variant NM_000251.3(MSH2):c.1658A>G (p.Asn553Ser)

dbSNP: rs2104185998

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001544966	SCV001764198	uncertain significance	not provided	2021-03-08	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Color Diagnostics, LLC DBA Color Health	RCV001806235	SCV002053555	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-01	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with serine at codon 553 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 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.
Invitae	RCV001859363	SCV002255840	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2021-08-28	criteria provided, single submitter	clinical testing	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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MSH2 protein function. ClinVar contains an entry for this variant (Variation ID: 1186020). This variant has not been reported in the literature in individuals affected with MSH2-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces asparagine with serine at codon 553 of the MSH2 protein (p.Asn553Ser). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and serine.
Ambry Genetics	RCV001806235	SCV002707112	likely benign	Hereditary cancer-predisposing syndrome	2023-01-23	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	RCV004008923	SCV004834026	uncertain significance	Lynch syndrome	2023-03-07	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with serine at codon 553 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 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.