ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.2075G>A (p.Gly692Glu) (rs63751432)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color RCV000772137 SCV000905240 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-25 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000501019 SCV000592531 uncertain significance Lynch syndrome 2015-05-06 criteria provided, single submitter clinical testing
GeneDx RCV000255143 SCV000322613 likely pathogenic not provided 2016-06-20 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.2075G>A at the cDNA level, p.Gly692Glu (G692E) at the protein level, and results in the change of a Glycine to a Glutamic Acid (GGG>GAG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. However, a different variant at the same position, the non-conservative change MSH2 Gly692Arg, has been reported in individuals with Lynch syndrome, associated with functional defects in vitro, and classified by the International Society for Gastrointestinal Tumours Incorporated (InSiGHT) as likely pathogenic (Isidro 2000, Gammie 2007, Thompson 2013, Houlleberghs 2016). MSH2 Gly692Glu 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 Glycine and Glutamic Acid differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH2 Gly692Glu occurs at a position that is conserved across species and is located within the ATPase domain (Lützen 2008). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on the currently available evidence, we consider MSH2 Gly692Glu to be a likely pathogenic variant.
University of Washington Department of Laboratory Medicine,University of Washington RCV000501019 SCV000887417 likely pathogenic Lynch syndrome 2018-05-01 criteria provided, single submitter clinical testing MSH2 NM_000251.2:c.2075G>A has a 96.7% probability of pathogenicity based on combining prior probability from public data with a likelihood ratio of 1.56 to 1, generated from evidence of seeing this as a somatic mutation in a tumor without loss of heterozygosity at the MSH2 locus. See Shirts et al 2018, PMID 29887214.

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