ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1354G>C (p.Gly452Arg) (rs569947936)

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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 RCV000214914 SCV000274274 uncertain significance Hereditary cancer-predisposing syndrome 2019-02-20 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000460028 SCV000552067 uncertain significance Hereditary nonpolyposis colon cancer 2018-01-25 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 452 of the PMS2 protein (p.Gly452Arg). The glycine residue is weakly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs569947936, ExAC 0.02%). This variant has been observed in an individual with colon cancer (Invitae). However, in that individual a pathogenic variant was also identified in MSH2 gene, which suggests that this c.1354G>C variant was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 230651). 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 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.
GeneDx RCV000481558 SCV000565399 uncertain significance not provided 2016-07-20 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.1354G>C at the cDNA level, p.Gly452Arg (G452R) at the protein level, and results in the change of a Glycine to an Arginine (GGT>CGT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. PMS2 Gly452Arg was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Glycine and Arginine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. PMS2 Gly452Arg 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 information, it is unclear whether PMS2 Gly452Arg is pathogenic or benign. We consider it to be a variant of uncertain significance.
Color RCV000214914 SCV000903500 uncertain significance Hereditary cancer-predisposing syndrome 2019-11-15 criteria provided, single submitter clinical testing
Mendelics RCV000987831 SCV001137300 uncertain significance Hereditary nonpolyposis colorectal cancer type 4 2019-05-28 criteria provided, single submitter clinical testing

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