Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000166217 | SCV000216996 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-11-16 | criteria provided, single submitter | clinical testing | The p.Y645C variant (also known as c.1934A>G), located in coding exon 11 of the PMS2 gene, results from an A to G substitution at nucleotide position 1934. The tyrosine at codon 645 is replaced by cysteine, an amino acid with highly dissimilar properties. 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 | RCV000206570 | SCV000260714 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2023-09-20 | criteria provided, single submitter | clinical testing | This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 645 of the PMS2 protein (p.Tyr645Cys). 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: 186598). 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. |
| Color Diagnostics, |
RCV000166217 | SCV000909644 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-11-01 | criteria provided, single submitter | clinical testing | This missense variant replaces tyrosine with cysteine at codon 645 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 hereditary cancer 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. |
| Baylor Genetics | RCV003462202 | SCV004205363 | uncertain significance | Lynch syndrome 4 | 2023-10-20 | criteria provided, single submitter | clinical testing |