ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.898A>G (p.Met300Val) (rs730881753)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000160578 SCV000211168 uncertain significance not provided 2016-09-14 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.898A>G at the cDNA level, p.Met300Val (M300V) 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 Met300Val 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 Met300Val occurs at a position where amino acids with properties similar to Methionine are tolerated across species and is located in the lever domain (Lutzen 2008). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether MSH2 Met300Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000203837 SCV000260886 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2017-10-09 criteria provided, single submitter clinical testing This sequence change replaces methionine with valine at codon 300 of the MSH2 protein (p.Met300Val). 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 not been reported in the literature in individuals with MSH2-related disease. ClinVar contains an entry for this variant (Variation ID: 182555). 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. 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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