ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1706A>G (p.Glu569Gly) (rs786201077)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000162561 SCV000212972 uncertain significance Hereditary cancer-predisposing syndrome 2017-04-11 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Clinical Genomics Lab,St. Jude Children's Research Hospital RCV000761166 SCV000891082 uncertain significance Papillary thyroid carcinoma 2017-04-26 no assertion criteria provided clinical testing
Counsyl RCV000663034 SCV000786070 uncertain significance Lynch syndrome I 2018-02-15 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000585899 SCV000696224 uncertain significance not provided 2016-12-09 criteria provided, single submitter clinical testing Variant summary: The MSH2 c.1706A>G (p.Glu569Gly) variant located in the DNA mismatch repair protein MutS, core domain (via InterPro) causes a missense change involving a conserved nucleotide, which 2/4 in silico tools (SNPs&GO not captured due to low reliability index) predict a benign outcome, although these predictions have yet to be functionally assessed. The variant of interest was not observed in controls (ExAC, 1000 Gs, or ESP), nor has it been, to our knowledge, reported in affected individuals via publications. However, multiple clinical diagnostic laboratories cite the variant as "uncertain significance." Therefore, until additional information becomes available (ie, clinical and functional studies), the variant of interest has been classified as a "Variant of Uncertain Significance (VUS)."
Invitae RCV000168102 SCV000218758 uncertain significance Hereditary nonpolyposis colon cancer 2018-10-25 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with glycine at codon 569 of the MSH2 protein (p.Glu569Gly). The glutamic acid residue is moderately conserved and there is a moderate physicochemical difference between glutamic acid and glycine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an affected individual in the Universal Mutation Database (PMID: 22144684). ClinVar contains an entry for this variant (Variation ID: 183783). 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, 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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