Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000569527 | SCV000663536 | likely benign | Hereditary cancer-predisposing syndrome | 2018-08-22 | criteria provided, single submitter | clinical testing | This alteration is classified as likely benign based on a combination of the following: 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 | RCV000629904 | SCV000750860 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2023-11-04 | criteria provided, single submitter | clinical testing | This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 539 of the PMS2 protein (p.Ala539Val). This variant is present in population databases (rs138222146, gnomAD 0.004%). 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: 480353). 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. |
| Color Diagnostics, |
RCV000569527 | SCV000909652 | likely benign | Hereditary cancer-predisposing syndrome | 2017-05-07 | criteria provided, single submitter | clinical testing | |
| Gene |
RCV001755926 | SCV002007736 | uncertain significance | not provided | 2022-09-05 | criteria provided, single submitter | clinical testing | Not observed at significant frequency in large population cohorts (gnomAD); 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 |
| ARUP Laboratories, |
RCV001755926 | SCV004563527 | uncertain significance | not provided | 2023-11-11 | criteria provided, single submitter | clinical testing | The PMS2 c.1616C>T p.Ala539Val variant (rs138222146), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 480353). This variant is found in the general population with an overall allele frequency of 0.001% (3/282154 alleles) in the Genome Aggregation Database. Computational analyses predict that this variant is neutral (REVEL: 0.139). Due to limited information, the clinical significance of this variant is uncertain at this time. |