ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1883G>A (p.Gly628Glu) (rs879254044)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000236195 SCV000293274 uncertain significance not provided 2015-10-20 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.1883G>A at the cDNA level, p.Gly628Glu (G628E) at the protein level, and results in the change of a Glycine to a Glutamic Acid (GGA>GAA). This variant has not, to our knowledge, been published in the literature as being pathogenic or benign. MSH2 Gly628Glu was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Glycine and Glutamic Acid differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH2 Gly628Glu occurs at a position that is conserved across species and is located in the region of interaction with EXO1 and in the ATPase domain (Lutzen 2008). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether MSH2 Gly628Glu is pathogenic or benign.
Color RCV001178639 SCV001343141 uncertain significance Hereditary cancer-predisposing syndrome 2019-02-21 criteria provided, single submitter clinical testing
Invitae RCV001238758 SCV001411586 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-08-22 criteria provided, single submitter clinical testing This sequence change replaces glycine with glutamic acid at codon 628 of the MSH2 protein (p.Gly628Glu). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and glutamic acid. 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: 246005). 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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