ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.562G>C (p.Glu188Gln) (rs1064795622)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000479837 SCV000571604 uncertain significance not provided 2016-09-06 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.562G>C at the cDNA level, p.Glu188Gln (E188Q) at the protein level, and results in the change of a Glutamic Acid to a Glutamine (GAG>CAG). This variant was observed in at least one individual with a colon tumor that was microsatellite stable with MSH2 protein present on immunohistochemistry (Thompson 2013). MSH2 Glu188Gln was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Glutamic Acid and Glutamine differ in some properties, this is considered a semi-conservative amino acid substitution. MSH2 Glu188Gln occurs at a position that is conserved across species and is located in the connector domain (Lützen 2008). 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 Glu188Gln is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000580018 SCV000685099 uncertain significance Hereditary cancer-predisposing syndrome 2019-06-28 criteria provided, single submitter clinical testing
Invitae RCV000701289 SCV000830082 uncertain significance Hereditary nonpolyposis colon cancer 2018-05-07 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with glutamine at codon 188 of the MSH2 protein (p.Glu188Gln). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with colorectal cancer (PMID: 22949387). ClinVar contains an entry for this variant (Variation ID: 422198). 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 and their 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 RCV000580018 SCV001186340 uncertain significance Hereditary cancer-predisposing syndrome 2019-04-13 criteria provided, single submitter clinical testing Insufficient evidence

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