ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.13G>C (p.Glu5Gln) (rs372539944)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000471375 SCV000551951 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-11-26 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with glutamine at codon 5 of the PMS2 protein (p.Glu5Gln). The glutamic acid residue is weakly conserved and there is a small physicochemical difference between glutamic acid and glutamine. This variant is present in population databases (rs372539944, ExAC 0.02%). 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: 411026). 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 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 RCV000479582 SCV000566804 uncertain significance not provided 2018-11-12 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.13G>C at the cDNA level, p.Glu5Gln (E5Q) at the protein level, and results in the change of a Glutamic Acid to a Glutamine (GAG>CAG). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. PMS2 Glu5Gln was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the ATPase domain (Guarne 2001). 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 Glu5Gln is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000572234 SCV000663433 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-07 criteria provided, single submitter clinical testing Insufficient evidence
Color RCV000572234 SCV000686124 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-21 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000479582 SCV001134578 uncertain significance not provided 2019-03-15 criteria provided, single submitter clinical testing

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