ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1703C>A (p.Pro568Gln) (rs869312801)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000233687 SCV000285081 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-11-20 criteria provided, single submitter clinical testing This sequence change replaces proline with glutamine at codon 568 of the PMS2 protein (p.Pro568Gln). The proline residue is weakly conserved and there is a moderate physicochemical difference between proline and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with a PMS2-related disease. ClinVar contains an entry for this variant (Variation ID: 237891). 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 glutamine 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, this variant has uncertain impact on PMS2 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx RCV000589233 SCV000569288 uncertain significance not provided 2016-06-10 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.1703C>A at the cDNA level, p.Pro568Gln (P568Q) at the protein level, and results in the change of a Proline to a Glutamine (CCA>CAA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. PMS2 Pro568Gln 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 Proline and Glutamine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. PMS2 Pro568Gln occurs at a position that is not conserved and is not located in a known functional domain (Guarné 2001, UniProt). 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 Pro568Gln is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000589233 SCV000697308 uncertain significance not provided 2017-05-22 criteria provided, single submitter clinical testing Variant summary: The PMS2 c.1703C>A (p.Pro568Gln) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant is absent in 121016 control chromosomes. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. The variant of interest has not, to our knowledge, been reported in affected individuals via publications; nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.
Ambry Genetics RCV001012785 SCV001173285 uncertain significance Hereditary cancer-predisposing syndrome 2018-05-17 criteria provided, single submitter clinical testing Insufficient evidence
Color RCV001012785 SCV001355180 uncertain significance Hereditary cancer-predisposing syndrome 2019-01-31 criteria provided, single submitter clinical testing

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