ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.2043A>T (p.Gln681His) (rs730881763)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000160599 SCV000211195 uncertain significance not provided 2017-09-06 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.2043A>T at the cDNA level, p.Gln681His (Q681H) at the protein level, and results in the change of a Glutamine to a Histidine (CAA>CAT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH2 Gln681His was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Glutamine and Histidine differ in some properties, this is considered a semi-conservative amino acid substitution. MSH2 Gln681His occurs at a position that is conserved across species and is located in the ATPase 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 Gln681His is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000219973 SCV000278669 uncertain significance Hereditary cancer-predisposing syndrome 2015-09-28 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 RCV000219973 SCV000685003 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-15 criteria provided, single submitter clinical testing
Invitae RCV000813805 SCV000954181 uncertain significance Hereditary nonpolyposis colon cancer 2018-12-27 criteria provided, single submitter clinical testing This sequence change replaces glutamine with histidine at codon 681 of the MSH2 protein (p.Gln681His). The glutamine residue is highly conserved and there is a small physicochemical difference between glutamine and histidine. 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 conditions. ClinVar contains an entry for this variant (Variation ID: 182569). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). 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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