ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.147C>G (p.Asp49Glu) (rs730881771)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000160616 SCV000211214 uncertain significance not provided 2017-10-18 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.147C>G at the cDNA level, p.Asp49Glu (D49E) at the protein level, and results in the change of an Aspartic Acid to a Glutamic Acid (GAC>GAG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH2 Asp49Glu was not observed in large population cohorts (Lek 2016). Since Aspartic Acid and Glutamic Acid share similar properties, this is considered a conservative amino acid substitution. MSH2 Asp49Glu occurs at a position that is conserved and is located in the mismatch binding domain (Lutzen 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 Asp49Glu is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000196255 SCV000254386 uncertain significance Hereditary nonpolyposis colon cancer 2018-12-27 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with glutamic acid at codon 49 of the MSH2 protein (p.Asp49Glu). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and glutamic acid. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a MSH2-related disease. ClinVar contains an entry for this variant (Variation ID: 182582). 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. 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.
Ambry Genetics RCV000565780 SCV000669721 uncertain significance Hereditary cancer-predisposing syndrome 2017-08-19 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Insufficient or conflicting evidence
Color RCV000565780 SCV000684940 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-03 criteria provided, single submitter clinical testing

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