Submissions for variant NM_000251.3(MSH2):c.1378A>G (p.Met460Val)

gnomAD frequency: 0.00001  dbSNP: rs575905950

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000225970	SCV000284108	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000573569	SCV000662241	benign	Hereditary cancer-predisposing syndrome	2022-04-11	criteria provided, single submitter	clinical testing	This alteration is classified as 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	RCV000573569	SCV000684933	likely benign	Hereditary cancer-predisposing syndrome	2022-12-13	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000985795	SCV001134337	likely benign	not provided	2023-08-23	criteria provided, single submitter	clinical testing
GeneDx	RCV000985795	SCV001770277	likely benign	not provided	2019-03-28	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 30441849)
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003150132	SCV003838302	uncertain significance	Breast and/or ovarian cancer	2022-02-01	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV003338475	SCV004048087	uncertain significance	Lynch syndrome 1		criteria provided, single submitter	clinical testing	The missense variant c.1378A>G (p.Met460Val) in MSH2 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant has been reported to the ClinVar database with conflicting interpretations of pathogenicity. This variant is present in the gnomAD database with a frequency of 0.008%. The amino acid Met at position 460 is changed to a Val changing protein sequence and it might alter its composition and physico-chemical properties. There is a small physicochemical difference between methionine and valine, which is not likely to impact secondary protein structure as these residues share similar properties. The p.M460V missense variant is predicted to be damaging by both SIFT and PolyPhen2. The amino acid change p.Met460Val in MSH2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance
All of Us Research Program, National Institutes of Health	RCV003998755	SCV004833208	likely benign	Lynch syndrome	2023-11-30	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with valine at codon 460 of the MSH2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with ovarian cancer (PMID: 30441849). This variant has been identified in 20/250266 chromosomes (19/30482 South Asian chromosomes) in the general population by the Genome Aggregation Database (gnomAD). The elevated variant allele frequency in the general population indicates that this variant may not be disease-causing. However, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.