ClinVar Miner

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

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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.
Color Health, Inc RCV000772137 SCV000905240 uncertain significance Hereditary cancer-predisposing syndrome 2020-01-23 criteria provided, single submitter clinical testing
Invitae RCV000803818 SCV000943704 likely pathogenic Hereditary nonpolyposis colorectal neoplasms 2019-11-29 criteria provided, single submitter clinical testing This sequence change replaces glycine with glutamic acid at codon 692 of the MSH2 protein (p.Gly692Glu). 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 been observed in individual(s) with clinical features of Lynch syndrome (Invitae). Also, this variant has been reported in individuals in the Universal Mutation Database (PMID: 10612827). ClinVar contains an entry for this variant (Variation ID: 265620). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MSH2 protein function. Variants that disrupt the p.Gly692 amino acid residue in MSH2 have been observed in individuals affected with Lynch syndrome and constitutional mismatch repair deficiency (PMID: 10523644, 28577310, 15713769, 10612836, 29212164, 28135145, 23454724). This suggests that it is a clinically significant residue, and that other variants that disrupt this residue are likely to be causative of disease. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353568 SCV000592531 uncertain significance Carcinoma of colon no assertion criteria provided clinical testing The MSH2 p.Gly692Glu variant was not identified in the literature nor was it identified in the dbSNP, NHLBI Exome Sequencing Project (Exome Variant Server), Exome Aggregation Consortium (ExAC) database, HGMD, COSMIC, “Mismatch Repair Genes Variant Database”, “MMR Gene Unclassified Variants Database”, InSiGHT Colon Cancer Gene Variant Database, “Zhejiang Colon Cancer Database”, the ClinVar database and GeneInsight VariantWire database. The variant was only identified in MutDB and UMD (1X as a likely pathogenic variant). The p.Gly692 residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the p.Gly692 variant may impact the protein. However, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and 2 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of unknown significance.

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