Total submissions: 7
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000233687 | SCV000285081 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2024-01-29 | criteria provided, single submitter | clinical testing | This sequence change replaces proline, which is neutral and non-polar, with glutamine, which is neutral and polar, at codon 568 of the PMS2 protein (p.Pro568Gln). This variant is present in population databases (no rsID available, gnomAD 0.02%). 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: 237891). 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. |
| Gene |
RCV000589233 | SCV000569288 | uncertain significance | not provided | 2023-08-29 | criteria provided, single submitter | clinical testing | In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000589233 | SCV000697308 | uncertain significance | not provided | 2017-05-22 | criteria provided, single submitter | clinical testing | Variant summary: The PMS2 c.1703C>A (p.Pro568Gln) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant is absent in 121016 control chromosomes. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. The variant of interest has not, to our knowledge, been reported in affected individuals via publications; nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available. |
| Ambry Genetics | RCV001012785 | SCV001173285 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-07-14 | criteria provided, single submitter | clinical testing | The p.P568Q variant (also known as c.1703C>A), located in coding exon 11 of the PMS2 gene, results from a C to A substitution at nucleotide position 1703. The proline at codon 568 is replaced by glutamine, 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. |
| Color Diagnostics, |
RCV001012785 | SCV001355180 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-10-18 | criteria provided, single submitter | clinical testing | This missense variant replaces proline with glutamine at codon 568 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 been identified in 2/31402 chromosomes 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. |
| Quest Diagnostics Nichols Institute San Juan Capistrano | RCV000589233 | SCV002774702 | uncertain significance | not provided | 2021-08-27 | criteria provided, single submitter | clinical testing | |
| Baylor Genetics | RCV003469149 | SCV004205444 | uncertain significance | Lynch syndrome 4 | 2023-09-15 | criteria provided, single submitter | clinical testing |