Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000128875 | SCV000172732 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-04-04 | criteria provided, single submitter | clinical testing | The p.D792N variant (also known as c.2374G>A), located in coding exon 14 of the PMS2 gene, results from a G to A substitution at nucleotide position 2374. The aspartic acid at codon 792 is replaced by asparagine, an amino acid with highly similar properties. In one study, this variant was expressed at level similar to that of the wild type, but showed reduced function in response to certain DNA-damaging agents (Arora S et al. Cancer Biol. Ther., 2017 Jul;18:519-533). This alteration was identified in an individual with a clinical suspicion of Hereditary Breast and Ovarian Cancer Syndrome (da Costa E Silva Carvalho S et al. BMC Med Genomics, 2020 02;13:21). This variant was also identified in a cohort of 3,579 African males diagnosed with prostate cancer who underwent multi-gene panel testing of 19 DNA repair and cancer predisposition genes (Matejcic M et al. JCO Precis Oncol, 2020 Jan;4:32-43). 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 | RCV000560365 | SCV000625612 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2023-05-02 | criteria provided, single submitter | clinical testing | 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. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on PMS2 function (PMID: 28494185). 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. ClinVar contains an entry for this variant (Variation ID: 140758). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 32039725). 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 aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 792 of the PMS2 protein (p.Asp792Asn). |
| Gene |
RCV001567177 | SCV001790820 | uncertain significance | not provided | 2022-11-15 | criteria provided, single submitter | clinical testing | Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with a personal or family history of breast cancer, ovarian cancer, and/or diffuse gastric cancer (da Costa E Silva Carvalho et al., 2020); Published functional studies are inconclusive: lack of impact on mRNA or MLH1 protein expression, slight decrease in ability to reduce basal cellular viability apoptosis, and deficient response to DNA damaging agents (Arora et al, 2017); This variant is associated with the following publications: (PMID: 32039725, Fukui2011[Chapter], 28494185) |