Total submissions: 6
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000217395 | SCV000280002 | uncertain significance | not provided | 2018-08-29 | criteria provided, single submitter | clinical testing | This variant is denoted PMS2 c.1430C>A at the cDNA level, p.Ser477Tyr (S477Y) at the protein level, and results in the change of a Serine to a Tyrosine (TCC>TAC). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. PMS2 Ser477Tyr was not observed in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether PMS2 Ser477Tyr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. |
| Invitae | RCV000472890 | SCV000551940 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2023-12-10 | criteria provided, single submitter | clinical testing | This sequence change replaces serine, which is neutral and polar, with tyrosine, which is neutral and polar, at codon 477 of the PMS2 protein (p.Ser477Tyr). 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: 234914). 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. |
| Ambry Genetics | RCV000563463 | SCV000670817 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-01-10 | criteria provided, single submitter | clinical testing | The p.S477Y variant (also known as c.1430C>A), located in coding exon 11 of the PMS2 gene, results from a C to A substitution at nucleotide position 1430. The serine at codon 477 is replaced by tyrosine, an amino acid with dissimilar properties. This variant has been reported in 1/1120 pediatric cancer patients who underwent whole genome sequencing and/or whole-exome sequencing; this patient was diagnosed with high-grade glioma (Zhang J et al. N Engl J Med, 2015 Dec;373:2336-2346). 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, |
RCV000563463 | SCV000686126 | uncertain significance | Hereditary cancer-predisposing syndrome | 2019-01-24 | criteria provided, single submitter | clinical testing | |
| St. |
RCV003153517 | SCV003842959 | uncertain significance | Lynch syndrome 4 | 2022-01-03 | criteria provided, single submitter | clinical testing | The PMS2 c.1430C>A (p.Ser477Tyr) missense change is absent in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge these predictions have not been confirmed by functional assays. This variant has been reported in heterozygosity in an individual with high-grade glioma (PMID: 26580448). To our knowledge, this variant has not been reported in individuals with Lynch syndrome or constitutional mismatch repair deficiency. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. |
| All of Us Research Program, |
RCV003998648 | SCV004844220 | uncertain significance | Lynch syndrome | 2023-04-03 | criteria provided, single submitter | clinical testing |