ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1979A>G (p.Asp660Gly) (rs1085308057)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000490598 SCV000579291 likely pathogenic Lynch syndrome 2019-06-21 reviewed by expert panel curation Multifactorial likelihood analysis posterior probability 0.95-0.99
Ambry Genetics RCV000491547 SCV000580406 likely pathogenic Hereditary cancer-predisposing syndrome 2019-04-08 criteria provided, single submitter clinical testing Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Moderate segregation with disease (at least 3 informative meioses) for rare diseases.;In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Rarity in general population databases (dbsnp, esp, 1000 genomes)
Color RCV000491547 SCV000910479 uncertain significance Hereditary cancer-predisposing syndrome 2018-12-23 criteria provided, single submitter clinical testing
Invitae RCV001039917 SCV001203467 uncertain significance Hereditary nonpolyposis colon cancer 2019-05-14 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with glycine at codon 660 of the MSH2 protein (p.Asp660Gly). The aspartic acid residue is moderately conserved and there is a moderate physicochemical difference between aspartic acid and glycine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with clinical features of Lynch syndrome (PMID: 14635101, 20587412). ClinVar contains an entry for this variant (Variation ID: 427603). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glycine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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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