Total submissions: 6
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000166845 | SCV000217659 | likely benign | Hereditary cancer-predisposing syndrome | 2018-09-11 | criteria provided, single submitter | clinical testing | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. |
| Invitae | RCV000474121 | SCV000552017 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2024-01-26 | criteria provided, single submitter | clinical testing | This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 482 of the PMS2 protein (p.Ser482Gly). This variant is present in population databases (rs786203510, gnomAD 0.003%). 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: 187150). 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 |
RCV000522983 | SCV000616826 | uncertain significance | not provided | 2018-08-22 | criteria provided, single submitter | clinical testing | This variant is denoted PMS2 c.1444A>G at the cDNA level, p.Ser482Gly (S482G) at the protein level, and results in the change of a Serine to a Glycine (AGT>GGT). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. Although this variant was observed in large population cohorts, data in this region of PMS2 are not considered reliable due to high pseudogene homology (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 Ser482Gly is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. |
| Color Diagnostics, |
RCV000166845 | SCV000911127 | likely benign | Hereditary cancer-predisposing syndrome | 2017-04-11 | criteria provided, single submitter | clinical testing | |
| Quest Diagnostics Nichols Institute San Juan Capistrano | RCV000522983 | SCV001469854 | uncertain significance | not provided | 2019-11-24 | criteria provided, single submitter | clinical testing | |
| All of Us Research Program, |
RCV003995538 | SCV004844212 | likely benign | Lynch syndrome | 2024-01-11 | criteria provided, single submitter | clinical testing |