ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1933C>G (p.Gln645Glu) (rs267607982)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000115513 SCV000149422 uncertain significance not provided 2017-12-29 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.1933C>G at the cDNA level, p.Gln645Glu (Q645E) at the protein level, and results in the change of a Glutamine to a Glutamic Acid (CAA>GAA). This variant was observed in an individual with a personal or family history suggestive of Lynch syndrome (Tournier 2008). Functional analysis of this variant found no effect in a minigene splicing assay (Tournier 2008). MSH2 Gln645Glu was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Glutamine and Glutamic Acid differ in some properties, this is considered a semi-conservative amino acid substitution. MSH2 Gln645Glu is located in the ATPase domain and the region for interaction with EXO1 (Lutzen 2008, Kansikas 2011). In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether MSH2 Gln645Glu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000540956 SCV000625331 uncertain significance Hereditary nonpolyposis colon cancer 2018-10-23 criteria provided, single submitter clinical testing This sequence change replaces glutamine with glutamic acid at codon 645 of the MSH2 protein (p.Gln645Glu). The glutamine residue is highly conserved and there is a small physicochemical difference between glutamine and glutamic acid. This variant is present in population databases (rs267607982, ExAC 0.009%). This variant has been observed in an individual, several individual undergoing screening for Lynch syndrome (PMID: 18561205). ClinVar contains an entry for this variant (Variation ID: 90822). An algorithm developed specifically for the MSH2 gene suggests that this missense change is likely to be deleterious (PMID: 26333163). However, this prediction has not been confirmed by published functional studies and its clinical significance is uncertain. 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 RCV000573883 SCV000669705 uncertain significance Hereditary cancer-predisposing syndrome 2017-07-17 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Counsyl RCV000662923 SCV000785871 uncertain significance Lynch syndrome I 2017-12-20 criteria provided, single submitter clinical testing
Color RCV000573883 SCV000908319 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-06 criteria provided, single submitter clinical testing

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