ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.881G>A (p.Arg294Gln)

gnomAD frequency: 0.00001  dbSNP: rs373239341
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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000222705 SCV000277568 uncertain significance Hereditary cancer-predisposing syndrome 2023-09-02 criteria provided, single submitter clinical testing The p.R294Q variant (also known as c.881G>A), located in coding exon 8 of the PMS2 gene, results from a G to A substitution at nucleotide position 881. The arginine at codon 294 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV000473195 SCV000551977 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2024-01-23 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 294 of the PMS2 protein (p.Arg294Gln). This variant is present in population databases (rs373239341, gnomAD 0.007%). This missense change has been observed in individual(s) with breast cancer (PMID: 34326862). ClinVar contains an entry for this variant (Variation ID: 233232). 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 not expected to disrupt PMS2 protein function with a negative predictive value of 80%. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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.
GeneDx RCV000486648 SCV000569365 uncertain significance not provided 2020-12-16 criteria provided, single submitter clinical testing In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as a pathogenic or benign germline variant to our knowledge; This variant is associated with the following publications: (PMID: 27093186)
Counsyl RCV000662988 SCV000785977 uncertain significance Lynch syndrome 4 2018-01-29 criteria provided, single submitter clinical testing
Mendelics RCV000708991 SCV000838187 uncertain significance Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000222705 SCV000903867 uncertain significance Hereditary cancer-predisposing syndrome 2023-05-04 criteria provided, single submitter clinical testing This missense variant replaces arginine with glutamine at codon 294 of the PMS2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 3/251388 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.
Mendelics RCV000662988 SCV001137312 uncertain significance Lynch syndrome 4 2019-05-28 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000486648 SCV002047138 uncertain significance not provided 2021-05-18 criteria provided, single submitter clinical testing
Myriad Genetics, Inc. RCV000662988 SCV004019830 uncertain significance Lynch syndrome 4 2023-04-04 criteria provided, single submitter clinical testing This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Baylor Genetics RCV000662988 SCV004205459 uncertain significance Lynch syndrome 4 2023-09-05 criteria provided, single submitter clinical testing

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