Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000575954 | SCV000663497 | uncertain significance | Hereditary cancer-predisposing syndrome | 2021-11-04 | criteria provided, single submitter | clinical testing | The p.P299L variant (also known as c.896C>T), located in coding exon 8 of the PMS2 gene, results from a C to T substitution at nucleotide position 896. The proline at codon 299 is replaced by leucine, an amino acid with similar properties. This alteration was detected in a study of 1,165 individuals with a history of colorectal cancer or colon polyps as well as 590 controls (Gordon AS et al. Am J Hum Genet, 2019 09;105:526-533). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Laboratory for Molecular Medicine, |
RCV000604101 | SCV000731464 | uncertain significance | not specified | 2017-04-21 | criteria provided, single submitter | clinical testing | The p.Pro299Leu variant in PMS2 has not been previously reported in individuals with Lynch Syndrome and was absent from large population studies. Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p .Pro299Leu variant is uncertain. |
| Color Diagnostics, |
RCV000575954 | SCV000913144 | uncertain significance | Hereditary cancer-predisposing syndrome | 2018-12-20 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV001071529 | SCV001236837 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2023-11-25 | criteria provided, single submitter | clinical testing | This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 299 of the PMS2 protein (p.Pro299Leu). 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: 480325). 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 |
RCV001775885 | SCV002013784 | uncertain significance | not provided | 2019-10-23 | criteria provided, single submitter | clinical testing | Not observed in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge |