Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000630104 | SCV000751060 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2017-10-27 | criteria provided, single submitter | clinical testing | This variant has not been reported in the literature in individuals with PMS2-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces cysteine with tyrosine at codon 276 of the PMS2 protein (p.Cys276Tyr). The cysteine residue is moderately conserved and there is a large physicochemical difference between cysteine and tyrosine. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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. |
| ARUP Laboratories, |
RCV001000746 | SCV001157794 | uncertain significance | not specified | 2018-08-12 | criteria provided, single submitter | clinical testing | The PMS2 c.827G>A; p.Cys276Tyr variant, to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 525797). This variant is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. The cysteine at codon 276 is moderately conserved but computational analyses (SIFT: Damaging, PolyPhen-2: Benign) predict conflicting effects of this variant on protein structure/function. Due to limited information, the clinical significance of the p.Cys276Tyr variant is uncertain at this time. |
| Ambry Genetics | RCV002431854 | SCV002681458 | uncertain significance | Hereditary cancer-predisposing syndrome | 2017-10-18 | criteria provided, single submitter | clinical testing | The p.C276Y variant (also known as c.827G>A), located in coding exon 8 of the PMS2 gene, results from a G to A substitution at nucleotide position 827. The cysteine at codon 276 is replaced by tyrosine, an amino acid with highly dissimilar 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. |