Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000562759 | SCV000664768 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-05-23 | criteria provided, single submitter | clinical testing | The p.G512D variant (also known as c.1535G>A), located in coding exon 11 of the PMS2 gene, results from a G to A substitution at nucleotide position 1535. The glycine at codon 512 is replaced by aspartic acid, an amino acid with 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 | RCV000706511 | SCV000835566 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2022-03-14 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 512 of the PMS2 protein (p.Gly512Asp). This variant is present in population databases (no rsID available, gnomAD 0.003%). 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: 480870). 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. 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. |
| St. |
RCV000761128 | SCV000891044 | uncertain significance | Lynch syndrome | 2020-12-01 | criteria provided, single submitter | clinical testing | The PMS2 c.1535G>A (p.Gly512Asp) missense change has a maximum subpopulation frequency of 0.0029% in gnomAD v2.1.1 (PM2_Supporting; https://gnomad.broadinstitute.org/variant/7-6026861-C-T). Seven of seven in silico tools predict a benign effect of this variant on protein function (BP4), but these predictions have not been confirmed by functional studies. To our knowledge, this variant has not been reported in individuals with Lynch syndrome or CMMRD. In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: PM2_Supporting, BP4. |