ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.2102A>C (p.Glu701Ala) (rs876659187)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000221209 SCV000275349 uncertain significance Hereditary cancer-predisposing syndrome 2015-03-31 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000479697 SCV000570196 uncertain significance not provided 2017-11-22 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.2102A>C at the cDNA level, p.Glu701Ala (E701A) at the protein level, and results in the change of a Glutamic Acid to an Alanine (GAA>GCA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH2 Glu701Ala was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Glutamic Acid and Alanine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH2 Glu701Ala is located in the ATPase domain (L?tzen 2008). In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Based on currently available evidence, it is unclear whether MSH2 Glu701Ala is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000553991 SCV000625346 uncertain significance Hereditary nonpolyposis colon cancer 2017-04-26 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with alanine at codon 701 of the MSH2 protein (p.Glu701Ala). The glutamic acid residue is moderately conserved and there is a moderate physicochemical difference between glutamic acid and alanine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a MSH2-related disease. ClinVar contains an entry for this variant (Variation ID: 231482). 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: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a rare missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance.
Color RCV000221209 SCV000904855 uncertain significance Hereditary cancer-predisposing syndrome 2018-05-28 criteria provided, single submitter clinical testing

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