ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.2105T>A (p.Val702Glu) (rs587779137)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000491379 SCV000580649 uncertain significance Hereditary cancer-predisposing syndrome 2018-11-21 criteria provided, single submitter clinical testing The p.V702E variant (also known as c.2105T>A), located in coding exon 13 of the MSH2 gene, results from a T to A substitution at nucleotide position 2105. The valine at codon 702 is replaced by glutamic acid, an amino acid with dissimilar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. In addition, this alteration is predicted to be deleterious by MAPP-MMR in silico analyses (Chao E et al. Hum Mutat. 2008 Jun;29(6):852-60). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Health, Inc RCV000491379 SCV001345491 likely pathogenic Hereditary cancer-predisposing syndrome 2020-09-25 criteria provided, single submitter clinical testing This missense variant replaces valine with glutamic acid at codon 702 of the MSH2 protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. A functional study in Msh2-mutant mouse embryonic cells showed this variant to be defective in a DNA mismatched repair and microsatellite instability assays and additional ancillary assays (PMID: 23690608). This variant has been reported in two individuals affected with Lynch syndrome associated cancers (Color internal data and ClinVar variation ID: 428567), and an unaffected individual who underwent endometrial cancer panel testing (PMID: 29345684). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Invitae RCV001215708 SCV001387467 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-04-22 criteria provided, single submitter clinical testing This sequence change replaces valine with glutamic acid at codon 702 of the MSH2 protein (p.Val702Glu). The valine residue is moderately conserved and there is a moderate physicochemical difference between valine and glutamic acid. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MSH2-related conditions. ClinVar contains an entry for this variant (Variation ID: 428567). This variant has been reported to affect MSH2 protein function (PMID: 23690608). 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.

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