ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.2606C>A (p.Ala869Glu) (rs730881772)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000759828 SCV000211222 uncertain significance not provided 2018-07-02 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.2606C>A at the cDNA level, p.Ala869Glu (A869E) at the protein level, and results in the change of an Alanine to a Glutamic Acid (GCA>GAA). This variant has been reported in one individual with renal cancer (Yehia 2018). MSH2 Ala869Glu was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in within the helix-turn-helix domain (Lutzen 2008, Kansikas 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether MSH2 Ala869Glu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000203841 SCV000262339 uncertain significance Hereditary nonpolyposis colon cancer 2018-12-28 criteria provided, single submitter clinical testing This sequence change replaces alanine with glutamic acid at codon 869 of the MSH2 protein (p.Ala869Glu). The alanine residue is moderately conserved and there is a moderate physicochemical difference between alanine and glutamic acid. This variant is present in population databases (rs730881772, ExAC 0.001%). This variant has been reported in an individual with gastric cancer in the Universal Mutation Database (PMID: 23729658). ClinVar contains an entry for this variant (Variation ID: 182587). 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. In summary, this variant is a rare missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000565478 SCV000664849 uncertain significance Hereditary cancer-predisposing syndrome 2016-04-06 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Mendelics RCV000708846 SCV000837858 uncertain significance Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000759828 SCV000889430 uncertain significance not provided 2017-09-27 criteria provided, single submitter clinical testing

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