ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1345C>G (p.Gln449Glu) (rs876661256)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000222807 SCV000279912 uncertain significance not provided 2016-02-19 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.1345C>G at the cDNA level, p.Gln449Glu (Q449E) at the protein level, and results in the change of a Glutamine to a Glutamic Acid (CAG>GAG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. PMS2 Gln449Glu 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 Glutamine and Glutamic Acid differ in some properties, this is considered a semi-conservative amino acid substitution. PMS2 Gln449Glu occurs at a position that is not conserved and is not located in a known functional domain (Fukui 2011, 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 Gln449Glu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000469559 SCV000551925 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-04-03 criteria provided, single submitter clinical testing This sequence change replaces glutamine with glutamic acid at codon 449 of the PMS2 protein (p.Gln449Glu). The glutamine residue is moderately conserved and there is a small physicochemical difference between glutamine and glutamic acid. 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: 234851). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but 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 RCV000575480 SCV000670836 uncertain significance Hereditary cancer-predisposing syndrome 2018-04-20 criteria provided, single submitter clinical testing Insufficient evidence

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