ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.2381C>G (p.Pro794Arg) (rs876659030)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000222159 SCV000274994 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-27 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
GeneDx RCV000222455 SCV000279892 uncertain significance not provided 2018-09-20 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.2381C>G at the cDNA level, p.Pro794Arg (P794R) at the protein level, and results in the change of a Proline to an Arginine (CCT>CGT). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. Although this variant was observed in large population cohorts, data in this region of PMS2 are not considered reliable due to high pseudogene homology (Lek 2016). This variant is located within the endonuclease domain (Fukui 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether PMS2 Pro794Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000532159 SCV000625613 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2018-09-23 criteria provided, single submitter clinical testing This sequence change replaces proline with arginine at codon 794 of the PMS2 protein (p.Pro794Arg). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and arginine. The frequency data for this variant in the population databases (ExAC) is considered unreliable due to the presence of homologous sequence, such as pseudogenes or paralogs, in the genome. This variant has not been reported in the literature in individuals with PMS2-related disease. ClinVar contains an entry for this variant (Variation ID: 231217). 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 disruptive, but 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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