Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000478508 | SCV000569912 | uncertain significance | not provided | 2016-04-09 | criteria provided, single submitter | clinical testing | This variant is denoted PMS2 c.1204C>G at the cDNA level, p.Gln402Glu (Q402E) at the protein level, and results in the change of a Glutamine to a Glutamic Acid (CAA>GAA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. PMS2 Gln402Glu was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Glutamine and Glutamic Acid differ in some properties, this is considered a semi-conservative amino acid substitution. PMS2 Gln402Glu occurs at a position that is not conserved and is not located in a known functional domain (Fukui 2011). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether PMS2 Gln402Glu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. |
Ambry Genetics | RCV000562801 | SCV000674242 | uncertain significance | Hereditary cancer-predisposing syndrome | 2018-12-31 | criteria provided, single submitter | clinical testing | The p.Q402E variant (also known as c.1204C>G), located in coding exon 11 of the PMS2 gene, results from a C to G substitution at nucleotide position 1204. The glutamine at codon 402 is replaced by glutamic acid, an amino acid with highly similar properties.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. |
Invitae | RCV000630066 | SCV000751022 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2023-06-19 | criteria provided, single submitter | clinical testing | 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. 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. ClinVar contains an entry for this variant (Variation ID: 420890). This variant has not been reported in the literature in individuals affected with PMS2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamine, which is neutral and polar, with glutamic acid, which is acidic and polar, at codon 402 of the PMS2 protein (p.Gln402Glu). |