ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.47A>C (p.Glu16Ala) (rs745771647)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000484013 SCV000570223 uncertain significance not provided 2017-03-24 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.47A>C at the cDNA level, p.Glu16Ala (E16A) at the protein level, and results in the change of a Glutamic Acid to an Alanine (GAG>GCG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH2 Glu16Ala was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Glutamic Acid and Alanine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH2 Glu16Ala occurs at a position that is conserved across species and is located within the mismatch binding domain (Lützen 2008, Kansikas 2011). 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 Glu16Ala is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000540608 SCV000625430 uncertain significance Hereditary nonpolyposis colon cancer 2017-06-20 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with alanine at codon 16 of the MSH2 protein (p.Glu16Ala). The glutamic acid residue is moderately conserved and there is a moderate physicochemical difference between glutamic acid 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 an MSH2-related disease. ClinVar contains an entry for this variant (Variation ID: 421121). 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 disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, this variant has uncertain impact on MSH2 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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