ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.112G>T (p.Asp38Tyr) (rs730881761)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000160597 SCV000211193 uncertain significance not provided 2014-06-03 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.112G>T at the cDNA level, p.Asp38Tyr (D38Y) at the protein level, and results in the change of an Aspartic Acid to a Tyrosine (GAC>TAC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH2 Asp38Tyr was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Aspartic Acid and Tyrosine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH2 Asp38Tyr occurs at a position that is well conserved across species and is located in the mismatch binding domain (Lutzen 2008). In addition, in silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether MSH2 Asp38Tyr is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000465944 SCV000548320 uncertain significance Lynch syndrome 2016-09-05 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with tyrosine at codon 38 of the MSH2 protein (p.Asp38Tyr). The aspartic acid residue is moderately conserved and there is a large physicochemical difference between aspartic acid and tyrosine. 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: 182567). 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, this variant is a rare missense change with uncertain impact on 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 RCV000570990 SCV000669722 uncertain significance Hereditary cancer-predisposing syndrome 2019-09-28 criteria provided, single submitter clinical testing Insufficient evidence

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