Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV001011688 | SCV001172038 | uncertain significance | Hereditary cancer-predisposing syndrome | 2020-11-11 | criteria provided, single submitter | clinical testing | The p.A49T variant (also known as c.145G>A), located in coding exon 2 of the PMS2 gene, results from a G to A substitution at nucleotide position 145. The alanine at codon 49 is replaced by threonine, an amino acid with similar properties. This variant was detected in an Italian cohort of 113 non-BRCA patients with a personal and/or familial history of breast cancer, ovarian cancer, and/or pancreatic cancer (Germani A et al. J Clin Med, 2020 Sep;9:). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Invitae | RCV001340789 | SCV001534617 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2023-10-28 | criteria provided, single submitter | clinical testing | This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 49 of the PMS2 protein (p.Ala49Thr). This variant is not present in population databases (gnomAD no frequency). 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: 819275). 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. |