Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Color Diagnostics, |
RCV000775367 | SCV000909675 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-06-21 | criteria provided, single submitter | clinical testing | This missense variant replaces glycine with glutamic acid at codon 219 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 1/251490 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. |
Ambry Genetics | RCV000775367 | SCV001187602 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-12-27 | criteria provided, single submitter | clinical testing | The p.G219E variant (also known as c.656G>A), located in coding exon 6 of the PMS2 gene, results from a G to A substitution at nucleotide position 656. The glycine at codon 219 is replaced by glutamic acid, an amino acid with similar 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. |
Invitae | RCV001245088 | SCV001418353 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2023-02-02 | criteria provided, single submitter | clinical testing | 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 630211). This variant has not been reported in the literature in individuals affected with PMS2-related conditions. This variant is present in population databases (rs749431015, gnomAD 0.004%). This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 219 of the PMS2 protein (p.Gly219Glu). |