ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1444A>G (p.Ser482Gly) (rs786203510)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000166845 SCV000217659 likely benign Hereditary cancer-predisposing syndrome 2017-01-24 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Co-occurence with a mutation in another gene that clearly explains a proband's phenotype,In silico models in agreement (benign)
Color RCV000166845 SCV000911127 likely benign Hereditary cancer-predisposing syndrome 2017-04-11 criteria provided, single submitter clinical testing
GeneDx RCV000522983 SCV000616826 uncertain significance not provided 2018-08-22 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.1444A>G at the cDNA level, p.Ser482Gly (S482G) at the protein level, and results in the change of a Serine to a Glycine (AGT>GGT). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. Although this variant was observed in large population cohorts, data in this region of PMS2 are not considered reliable due to high pseudogene homology (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether PMS2 Ser482Gly is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000474121 SCV000552017 uncertain significance Hereditary nonpolyposis colon cancer 2018-12-29 criteria provided, single submitter clinical testing This sequence change replaces serine with glycine at codon 482 of the PMS2 protein (p.Ser482Gly). The serine residue is weakly conserved and there is a small physicochemical difference between serine and glycine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with PMS2-related disease. ClinVar contains an entry for this variant (Variation ID: 187150). 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. 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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