ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.247A>G (p.Met83Val) (rs766196837)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000460763 SCV000548288 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-09-13 criteria provided, single submitter clinical testing This sequence change replaces methionine with valine at codon 83 of the MSH2 protein (p.Met83Val). The methionine residue is highly conserved and there is a small physicochemical difference between methionine and valine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with colorectal cancer (PMID: 28135145). ClinVar contains an entry for this variant (Variation ID: 408535). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.
GeneDx RCV000523794 SCV000618248 uncertain significance not provided 2016-11-10 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.247A>G at the cDNA level, p.Met83Val (M83V) at the protein level, and results in the change of a Methionine to a Valine (ATG>GTG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH2 Met83Val was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Methionine and Valine share similar properties, this is considered a conservative amino acid substitution. MSH2 Met83Val occurs at a position where amino acids with properties similar to Methionine are tolerated across species and is located in the mismatch binding domain (Lützen 2008, Kansikas 2011). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether MSH2 Met83Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000575381 SCV000669860 uncertain significance Hereditary cancer-predisposing syndrome 2017-05-16 criteria provided, single submitter clinical testing The p.M83V variant (also known as c.247A>G), located in coding exon 2 of the MSH2 gene, results from an A to G substitution at nucleotide position 247. The methionine at codon 83 is replaced by valine, an amino acid with highly similar properties. Although the specific phenotype of the patient(s) with this alteration was not reported, it was classified as a variant of uncertain significance by authors after it was identified in a cohort of 300 deceased patients whose samples were tested by whole genome sequencing to assess cancer predisposition genes (He KY et al. PLoS ONE, 2016 Dec;11:e0167847). This amino acid position is 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 borderline deleterious by MAPP-MMR in silico analyses (Chao EC et al. Hum. Mutat. 2008 Jun;29:852-60). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color RCV000575381 SCV000690076 uncertain significance Hereditary cancer-predisposing syndrome 2019-05-10 criteria provided, single submitter clinical testing
GeneKor MSA RCV000575381 SCV000822052 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing

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