Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000561445 | SCV000670828 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-01-30 | criteria provided, single submitter | clinical testing | The p.D97N variant (also known as c.289G>A), located in coding exon 4 of the PMS2 gene, results from a G to A substitution at nucleotide position 289. The aspartic acid at codon 97 is replaced by asparagine, an amino acid with highly similar properties. This amino acid position is highly 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 | RCV000694292 | SCV000822729 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2023-11-12 | criteria provided, single submitter | clinical testing | This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 97 of the PMS2 protein (p.Asp97Asn). This variant is present in population databases (no rsID available, gnomAD 0.009%). 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: 484301). 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%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003155237 | SCV003845099 | uncertain significance | not specified | 2023-02-21 | criteria provided, single submitter | clinical testing | |
| Color Diagnostics, |
RCV000561445 | SCV004359694 | uncertain significance | Hereditary cancer-predisposing syndrome | 2024-01-04 | criteria provided, single submitter | clinical testing | This missense variant replaces aspartic acid with asparagine at codon 97 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). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with PMS2-related disorders in the literature. This variant has been identified in 2/271042 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. |