Submissions for variant NM_000535.7(PMS2):c.2396G>A (p.Arg799Gln)

gnomAD frequency: 0.00001  dbSNP: rs587780055

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212873	SCV000149595	uncertain significance	not provided	2018-06-05	criteria provided, single submitter	clinical testing	This variant is denoted PMS2 c.2396G>A at the cDNA level, p.Arg799Gln (R799Q) at the protein level, and results in the change of an Arginine to a Glutamine (CGG>CAG). 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 in 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 Arg799Gln is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000115686	SCV000186301	uncertain significance	Hereditary cancer-predisposing syndrome	2022-05-23	criteria provided, single submitter	clinical testing	The p.R799Q variant (also known as c.2396G>A), located in coding exon 14 of the PMS2 gene, results from a G to A substitution at nucleotide position 2396. The arginine at codon 799 is replaced by glutamine, an amino acid with highly similar properties. This variant was identified once in a cohort of 3,579 African males diagnosed with prostate cancer who underwent multi-gene panel testing of 19 DNA repair and cancer predisposition genes (Matejcic M et al. JCO Precis Oncol, 2020 Jan;4:32-43). 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.
Invitae	RCV000466896	SCV000552019	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-10-31	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 799 of the PMS2 protein (p.Arg799Gln). 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: 127782). 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%. 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.
Baylor Genetics	RCV003467054	SCV004207850	uncertain significance	Lynch syndrome 4	2023-05-08	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000212873	SCV004218987	uncertain significance	not provided	2023-06-12	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in individuals with breast cancer (PMID: 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/PMS2), 35449176 (2022), 36200007 (2022)). A functional study reported this variant did not have a damaging effect on protein function (PMID: 35189042 (2022)). The frequency of this variant in the general population, 0.000098 (4/40920 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	RCV000115686	SCV004358994	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-16	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 799 of the PMS2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has shown the mutant protein to exhibit normal expression and mismatch repair activity (PMID: 35189042). This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 8/235626 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.