Submissions for variant NM_000251.3(MSH2):c.1408G>A (p.Val470Ile)

dbSNP: rs1391167729

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000557805	SCV000625263	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2022-08-08	criteria provided, single submitter	clinical testing	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. 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. Experimental studies have shown that this missense change does not substantially affect MSH2 function (PMID: 33357406). ClinVar contains an entry for this variant (Variation ID: 455491). This variant has not been reported in the literature in individuals affected with MSH2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 470 of the MSH2 protein (p.Val470Ile).
Color Diagnostics, LLC DBA Color Health	RCV000580051	SCV000684936	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-01	criteria provided, single submitter	clinical testing	This missense variant replaces valine with isoleucine at codon 470 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). 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	RCV000580051	SCV002699214	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-29	criteria provided, single submitter	clinical testing	The p.V470I variant (also known as c.1408G>A), located in coding exon 9 of the MSH2 gene, results from a G to A substitution at nucleotide position 1408. The valine at codon 470 is replaced by isoleucine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
All of Us Research Program, National Institutes of Health	RCV004003734	SCV004833297	uncertain significance	Lynch syndrome	2023-06-28	criteria provided, single submitter	clinical testing	This missense variant replaces valine with isoleucine at codon 470 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). 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.