Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000217832 | SCV000279567 | uncertain significance | not provided | 2022-08-31 | criteria provided, single submitter | clinical testing | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 18619468, Fukui2011[Chapter]) |
| Invitae | RCV001062651 | SCV001227466 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2024-01-17 | criteria provided, single submitter | clinical testing | This sequence change replaces cysteine, which is neutral and slightly polar, with phenylalanine, which is neutral and non-polar, at codon 812 of the PMS2 protein (p.Cys812Phe). 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 missense change has been observed in individuals with clinical features of Lynch syndrome (Invitae). ClinVar contains an entry for this variant (Variation ID: 234608). 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. |
| Ambry Genetics | RCV002450645 | SCV002736689 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-08-10 | criteria provided, single submitter | clinical testing | The p.C812F variant (also known as c.2435G>T), located in coding exon 14 of the PMS2 gene, results from a G to T substitution at nucleotide position 2435. The cysteine at codon 812 is replaced by phenylalanine, an amino acid with highly 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. |