ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.185G>C (p.Gly62Ala) (rs879254195)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000236172 SCV000293772 uncertain significance not provided 2015-12-30 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.185G>C at the cDNA level, p.Gly62Ala (G62A) at the protein level, and results in the change of a Glycine to an Alanine (GGG>GCG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH2 Gly62Ala 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 Glycine and Alanine share similar properties, this is considered a conservative amino acid substitution. MSH2 Gly62Ala occurs at a position where amino acids with properties similar to Glycine are tolerated across species and is located in the mismatch binding domain (Lützen 2008). 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 Gly62Ala is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000630120 SCV000751076 uncertain significance Hereditary nonpolyposis colon cancer 2017-09-19 criteria provided, single submitter clinical testing This sequence change replaces glycine with alanine at codon 62 of the MSH2 protein (p.Gly62Ala). The glycine residue is moderately conserved and there is a small physicochemical difference between glycine and alanine. 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: 246289). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The alanine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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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