ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.845A>G (p.Asp282Gly) (rs587779978)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212593 SCV000149453 uncertain significance not provided 2018-06-29 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.845A>G at the cDNA level, p.Asp282Gly (D282G) at the protein level, and results in the change of an Aspartic Acid to a Glycine (GAT>GGT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH2 Asp282Gly was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the Connector domain (Lutzen 2008, Kansikas 2011). Protein-based in silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. In addition, multiple splicing models predict that this variant may activate a cryptic splice donor site. However, in the absence of RNA or functional studies, the actual effect of this variant is unknown. Based on currently available information, it is unclear whether MSH2 Asp282Gly is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000115544 SCV000183939 uncertain significance Hereditary cancer-predisposing syndrome 2019-09-12 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000472973 SCV000548201 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-12-04 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with glycine at codon 282 of the MSH2 protein (p.Asp282Gly). The aspartic acid residue is highly conserved and there is a moderate physicochemical difference between aspartic acid and glycine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a MSH2-related disease. ClinVar contains an entry for this variant (Variation ID: 127654). 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: "Probably Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Counsyl RCV000663090 SCV000786185 uncertain significance Lynch syndrome I 2018-03-13 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001193849 SCV001362996 uncertain significance not specified 2019-07-23 criteria provided, single submitter clinical testing Variant summary: MSH2 c.845A>G (p.Asp282Gly) results in a non-conservative amino acid change located in the 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 4e-06 in 250534 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.845A>G in individuals affected with Hereditary Non-Polyposis Colon Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Four ClinVar submissions (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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