Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000567269 | SCV000670749 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-07-20 | criteria provided, single submitter | clinical testing | The p.T576I variant (also known as c.1727C>T), located in coding exon 11 of the PMS2 gene, results from a C to T substitution at nucleotide position 1727. The threonine at codon 576 is replaced by isoleucine, an amino acid with similar properties. This amino acid position is poorly 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. |
| Color Diagnostics, |
RCV000567269 | SCV000910477 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-04-26 | criteria provided, single submitter | clinical testing | This missense variant replaces threonine with isoleucine at codon 576 of the PMS2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, 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 not been identified 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. |
| Invitae | RCV001045950 | SCV001209827 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2023-10-30 | criteria provided, single submitter | clinical testing | This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 576 of the PMS2 protein (p.Thr576Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with ovarian cancer (PMID: 31992580). ClinVar contains an entry for this variant (Variation ID: 484250). 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 with a negative 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. |