ClinVar Miner

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

dbSNP: rs876659030
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Total submissions: 6
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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 2023-03-21 criteria provided, single submitter clinical testing The p.P794R variant (also known as c.2381C>G), located in coding exon 14 of the PMS2 gene, results from a C to G substitution at nucleotide position 2381. The proline at codon 794 is replaced by arginine, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
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 2024-01-16 criteria provided, single submitter clinical testing This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 794 of the PMS2 protein (p.Pro794Arg). The frequency data for this variant in the population databases (gnomAD) 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 affected with PMS2-related conditions. ClinVar contains an entry for this variant (Variation ID: 231217). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PMS2 protein function with a positive predictive value of 80%. 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.
Baylor Genetics RCV003469025 SCV004207842 uncertain significance Lynch syndrome 4 2023-05-12 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000222455 SCV004218985 uncertain significance not provided 2023-08-30 criteria provided, single submitter clinical testing In the published literature, this variant has been reported in individuals with PMS2 related conditions. The frequency of this variant in the general population, 0.000033 (1/30372 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Color Diagnostics, LLC DBA Color Health RCV000222159 SCV004358998 uncertain significance Hereditary cancer-predisposing syndrome 2023-03-28 criteria provided, single submitter clinical testing This missense variant replaces proline with arginine at codon 794 of the PMS2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with PMS2-related disorders in the literature. This variant has been identified in 1/247460 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

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