ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1225G>C (p.Gly409Arg) (rs864622553)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000206547 SCV000261097 uncertain significance Hereditary nonpolyposis colon cancer 2018-11-19 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 409 of the PMS2 protein (p.Gly409Arg). The glycine residue is weakly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a PMS2-related disease. ClinVar contains an entry for this variant (Variation ID: 220502). 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 arginine 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. In summary, this variant is a rare missense change that is not predicted to affect 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.
Ambry Genetics RCV000217628 SCV000273556 likely benign Hereditary cancer-predisposing syndrome 2016-07-18 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Other strong data supporting benign classification,In silico models in agreement (benign)
GeneDx RCV000519330 SCV000616824 uncertain significance not provided 2017-11-03 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.1225G>C at the cDNA level, p.Gly409Arg (G409R) at the protein level, and results in the change of a Glycine to an Arginine (GGA>CGA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. PMS2 Gly409Arg was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Glycine and Arginine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. PMS2 Gly409Arg occurs at a position that is not conserved and is not located in a known functional domain. In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether PMS2 Gly409Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000217628 SCV000909657 likely benign Hereditary cancer-predisposing syndrome 2017-02-21 criteria provided, single submitter clinical testing

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