ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.742A>G (p.Lys248Glu) (rs587779178)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000235646 SCV000292935 uncertain significance not provided 2017-12-26 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.742A>G at the cDNA level, p.Lys248Glu (K248E) at the protein level, and results in the change of a Lysine to a Glutamic Acid (AAA>GAA). This variant has not, to our knowledge, been reported in affected individuals as pathogenic or benign. MSH2 Lys248Glu was not observed at a significant frequency in large population cohorts (Lek 2016). MSH2 Lys248Glu is located in the connector domain (L?tzen 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 Lys248Glu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000491084 SCV000580531 uncertain significance Hereditary cancer-predisposing syndrome 2020-08-26 criteria provided, single submitter clinical testing <span style="font-family:arial,sans-serif; font-size:9pt">The <span style="font-family:arial,sans-serif">p.K248E variant (also known as c.742A>G), located in coding exon 4 of the <span style="font-family:arial,sans-serif">MSH2 gene, results from an A to G substitution at nucleotide position 742. The lysine at codon 248 is replaced by glutamic acid, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV000630103 SCV000751059 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-12-20 criteria provided, single submitter clinical testing This sequence change replaces lysine with glutamic acid at codon 248 of the MSH2 protein (p.Lys248Glu). The lysine residue is moderately conserved and there is a small physicochemical difference between lysine and glutamic acid. This variant is present in population databases (rs587779178, ExAC 0.006%). This variant has been reported in the InSiGHT locus-specific database (PMID: 24362816). ClinVar contains an entry for this variant (Variation ID: 91194). 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 tolerated, and an algorithm developed specifically for the MSH2 gene suggests that this missense change is likely to be tolerated (PMID: 18383312). However, these predictions have not been confirmed by published functional studies and the clinical significance of this variant 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.

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