Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000217200 | SCV000279487 | uncertain significance | not provided | 2017-02-01 | criteria provided, single submitter | clinical testing | This variant is denoted PMS2 c.2011A>G at the cDNA level, p.Thr671Ala (T671A) at the protein level, and results in the change of a Threonine to an Alanine (ACG>GCG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. PMS2 Thr671Ala was not observed in approximately 6,100 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Threonine and Alanine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. PMS2 Thr671Ala occurs at a position that is not conserved and is located in the MLH1 interaction domain (Kondo 2001). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether PMS2 Thr671Ala is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. |
| Invitae | RCV001054379 | SCV001218690 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2023-07-25 | 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. 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. ClinVar contains an entry for this variant (Variation ID: 234561). 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 671 of the PMS2 protein (p.Thr671Ala). |
| Ambry Genetics | RCV002415911 | SCV002724310 | uncertain significance | Hereditary cancer-predisposing syndrome | 2021-09-03 | criteria provided, single submitter | clinical testing | The p.T671A variant (also known as c.2011A>G), located in coding exon 12 of the PMS2 gene, results from an A to G substitution at nucleotide position 2011. The threonine at codon 671 is replaced by alanine, an amino acid with similar properties. This amino acid position is not well 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. |