Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000219439 | SCV000274066 | uncertain significance | Hereditary cancer-predisposing syndrome | 2015-03-09 | criteria provided, single submitter | clinical testing | The p.R813G variant (also known as c.2437C>G), located in coding exon 14 of the PMS2 gene, results from a C to G substitution at nucleotide position 2437. The arginine at codon 813 is replaced by glycine, an amino acid with dissimilar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 5135 samples (10270 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.002% (greater than 40000 alleles tested) in our clinical cohort. 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 p.R813G remains unclear. |
| Genetic Services Laboratory, |
RCV000500295 | SCV000596465 | uncertain significance | not specified | 2016-06-23 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV000558531 | SCV000625616 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2023-04-14 | criteria provided, single submitter | clinical testing | ClinVar contains an entry for this variant (Variation ID: 230493). This variant has not been reported in the literature in individuals affected with PMS2-related conditions. 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 sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 813 of the PMS2 protein (p.Arg813Gly). 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. 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. |