ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.409G>C (p.Gly137Arg) (rs587781795)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130057 SCV000184884 likely benign Hereditary cancer-predisposing syndrome 2019-12-09 criteria provided, single submitter clinical testing Other strong data supporting benign classification
Invitae RCV000196356 SCV000254423 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2020-10-28 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 137 of the MSH2 protein (p.Gly137Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs587781795, ExAC 0.001%). This variant has not been reported in the literature in individuals with MSH2-related disease. ClinVar contains an entry for this variant (Variation ID: 141500). 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: Benign; Align-GVGD: Class C0). 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.
GeneDx RCV000679311 SCV000292616 uncertain significance not provided 2021-05-10 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function Has not been previously published as pathogenic or benign to our knowledge
Genetic Services Laboratory, University of Chicago RCV000202282 SCV000595834 uncertain significance not specified 2017-03-22 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000202282 SCV000601477 uncertain significance not specified 2017-04-10 criteria provided, single submitter clinical testing
Color Health, Inc RCV000130057 SCV000690108 uncertain significance Hereditary cancer-predisposing syndrome 2020-01-15 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000679311 SCV000806041 uncertain significance not provided 2017-07-06 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000202282 SCV000257189 uncertain significance not specified no assertion criteria provided research
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001355466 SCV001550359 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The MSH2 p.Gly137Arg variant was not identified in the literature nor was it identified in the Gene Insight-COGR, Cosmic, MutDB, UMD-LSDB, Zhejiang University Database, Mismatch Repair Genes Variant Database, or Insight Hereditary Tumors databases. The variant was identified in dbSNP (ID: rs587781795 as "With other allele") and ClinVar (1x as likely benign by Ambry Genetics and 6x as uncertain significance by GeneDx, Color Genomics, Invitae, and three other clinical laboratories). The variant was identified in control databases in 6 of 277190 chromosomes (1 homozygous) at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in European population in 6 of 126680 chromosomes (freq: 0.00005), while the variant was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.Gly137 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. 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 uncertain significance.

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