Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000130335 | SCV000185185 | uncertain significance | Hereditary cancer-predisposing syndrome | 2014-01-07 | criteria provided, single submitter | clinical testing | ​The p.T732A variant (also known as c.2194A>G) is located in coding exon 13 of the PMS2 gene. This alteration results from an A to G substitution at nucleotide position 2194. The threonine at codon 732 is replaced by alanine, an amino acid with some similar properties. This variant was not reported in population-based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP) and 1000 Genomes Project. To date, this alteration has been detected with an allele frequency of approximately 0.01% (greater than 11,000 alleles tested) in our clinical cohort (includes this individual). Based on protein sequence alignment, this amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be possibly damaging and deleterious by PolyPhen and SIFT in silico analyses, respectively. Since supporting evidence is limited at this time, the clinical significance of p.T732A remains unclear. |
| Gene |
RCV001588985 | SCV001823702 | uncertain significance | not provided | 2019-04-16 | criteria provided, single submitter | clinical testing | Not observed in large population cohorts (Lek et al., 2016) |
| Invitae | RCV001849932 | SCV002136081 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2022-02-20 | 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 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 141716). This variant has not been reported in the literature in individuals affected with PMS2-related conditions. 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 threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 732 of the PMS2 protein (p.Thr732Ala). |
| Baylor Genetics | RCV003460922 | SCV004205474 | uncertain significance | Lynch syndrome 4 | 2023-08-25 | criteria provided, single submitter | clinical testing |