ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1465G>A (p.Glu489Lys) (rs876658187)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000222532 SCV000273108 uncertain significance Hereditary cancer-predisposing syndrome 2018-01-05 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000236848 SCV000292828 uncertain significance not provided 2018-11-21 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.1465G>A at the cDNA level, p.Glu489Lys (E489K) at the protein level, and results in the change of a Glutamic Acid to a Lysine (GAA>AAA). This variant has been observed in an unaffected control (Pritchard 2018). MSH2 Glu489Lys was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located within the clamp domain and the region of interaction with MSH6 and MSH3 (Guerrette 1998, 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 Glu489Lys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000473755 SCV000548258 uncertain significance Hereditary nonpolyposis colon cancer 2018-10-17 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 489 of the MSH2 protein (p.Glu489Lys). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual with astrocytoma and colorectal cancer in the Leiden Open-source Variation Database (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 229775). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a rare missense change with uncertain impact on protein function. While it is absent from the population and reported in affected individuals, the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Counsyl RCV000663243 SCV000786452 uncertain significance Lynch syndrome I 2018-05-03 criteria provided, single submitter clinical testing
Color RCV000222532 SCV000903703 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-17 criteria provided, single submitter clinical testing

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