Total submissions: 5
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV000630102 | SCV000751058 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2023-11-25 | criteria provided, single submitter | clinical testing | This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 805 of the PMS2 protein (p.Gln805Arg). 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: 525796). 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. |
Quest Diagnostics Nichols Institute San Juan Capistrano | RCV000985907 | SCV001134592 | uncertain significance | not provided | 2019-08-20 | criteria provided, single submitter | clinical testing | |
Ambry Genetics | RCV001015268 | SCV001176084 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-02-21 | criteria provided, single submitter | clinical testing | The p.Q805R variant (also known as c.2414A>G), located in coding exon 14 of the PMS2 gene, results from an A to G substitution at nucleotide position 2414. The glutamine at codon 805 is replaced by arginine, an amino acid with highly similar properties. This variant was identified 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. |
Prevention |
RCV003403445 | SCV004105536 | uncertain significance | PMS2-related condition | 2023-07-17 | criteria provided, single submitter | clinical testing | The PMS2 c.2414A>G variant is predicted to result in the amino acid substitution p.Gln805Arg. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. It is interpreted as uncertain significance in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/525796/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. |
Baylor Genetics | RCV003459498 | SCV004205437 | uncertain significance | Lynch syndrome 4 | 2023-09-19 | criteria provided, single submitter | clinical testing |