ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.860G>C (p.Gly287Ala) (rs587782567)

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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 RCV000131790 SCV000186839 uncertain significance Hereditary cancer-predisposing syndrome 2013-04-25 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Color RCV000131790 SCV000292202 uncertain significance Hereditary cancer-predisposing syndrome 2019-06-06 criteria provided, single submitter clinical testing
GeneDx RCV000588299 SCV000617060 uncertain significance not provided 2018-05-24 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.860G>C at the cDNA level, p.Gly287Ala (G287A) at the protein level, and results in the change of a Glycine to an Alanine (GGA>GCA). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. MSH2 Gly287Ala was not observed at a significant frequency in large population cohorts (Lek 2016). This variant is located within the connector domain (Lutzen 2008, Kansikas 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether MSH2 Gly287Ala is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000855651 SCV000696291 uncertain significance not specified 2019-02-08 criteria provided, single submitter clinical testing Variant summary: MSH2 c.860G>C (p.Gly287Ala) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, connector domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 246026 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.860G>C in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Four ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae RCV000688511 SCV000816127 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-10-21 criteria provided, single submitter clinical testing This sequence change replaces glycine with alanine at codon 287 of the MSH2 protein (p.Gly287Ala). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and alanine. This variant is present in population databases (rs587782567, ExAC 0.02%). This variant has not been reported in the literature in individuals with MSH2-related disease. ClinVar contains an entry for this variant (Variation ID: 142587). 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: "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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