ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1883G>A (p.Arg628Gln) (rs587780044)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000214212 SCV000274494 likely benign Hereditary cancer-predisposing syndrome 2017-09-11 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,In silico models in agreement (benign),Structural Evidence
Color RCV000214212 SCV000911523 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-18 criteria provided, single submitter clinical testing
GeneDx RCV000115667 SCV000149576 uncertain significance not provided 2018-01-02 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.1883G>A at the cDNA level, p.Arg628Gln (R628Q) at the protein level, and results in the change of an Arginine to a Glutamine (CGA>CAA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. Although this variant was observed in large population cohorts, population data in this region of PMS2 are not considered reliable due to high pseudogene homology (Lek 2016). This variant is located in the MLH1 interaction domain and the nuclear localization sequence (Kondo 2001, Leong 2009). In-silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available information, it is unclear whether PMS2 Arg628Gln is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000559426 SCV000625563 uncertain significance Hereditary nonpolyposis colon cancer 2018-10-11 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 628 of the PMS2 protein (p.Arg628Gln). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs587780044, ExAC 0.01%). This variant has not been reported in the literature in individuals with PMS2-related disease. ClinVar contains an entry for this variant (Variation ID: 127767). 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, 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.

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