Submissions for variant NM_000251.3(MSH2):c.323G>T (p.Gly108Val)

dbSNP: rs1183145967

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000572927	SCV000662218	likely benign	Hereditary cancer-predisposing syndrome	2023-03-16	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.
Color Diagnostics, LLC DBA Color Health	RCV000572927	SCV000904303	uncertain significance	Hereditary cancer-predisposing syndrome	2020-06-09	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with valine at codon 108 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 hereditary cancer 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.
GeneDx	RCV001575414	SCV001802403	uncertain significance	not provided	2019-05-03	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge
Invitae	RCV001858103	SCV002178919	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2021-09-30	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. 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 expected to disrupt MSH2 protein function. ClinVar contains an entry for this variant (Variation ID: 479788). 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 glycine with valine at codon 108 of the MSH2 protein (p.Gly108Val). The glycine residue is moderately conserved and there is a moderate physicochemical difference between glycine and valine.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV003320690	SCV004025223	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003459289	SCV004196855	uncertain significance	Lynch syndrome 1	2023-05-05	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004000847	SCV004827759	uncertain significance	Lynch syndrome	2023-05-31	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with valine at codon 108 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 hereditary cancer 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.