Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000130112 | SCV000184942 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-01-05 | criteria provided, single submitter | clinical testing | The p.V475E variant (also known as c.1424T>A), located in coding exon 11 of the PMS2 gene, results from a T to A substitution at nucleotide position 1424. The valine at codon 475 is replaced by glutamic acid, an amino acid with dissimilar properties. A functional study demonstrated that this alteration was expressed at a level similar to that of the wild type, with proficient mRNA and protein expression and viability in response to DNA-damaging treatments (Arora S et al. Cancer Biol Ther, 2017 Jul;18:519-533). 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. |
| Gene |
RCV000482982 | SCV000565405 | uncertain significance | not provided | 2014-09-02 | criteria provided, single submitter | clinical testing | This variant is denoted PMS2 c.1424T>A at the cDNA level, p.Val475Glu (V475E) at the protein level, and results in the change of a Valine to a Glutamic Acid (GTG>GAG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. PMS2 Val475Glu was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Valine and Glutamic Acid differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. PMS2 Val475Glu occurs at a position that is variable across species and is not located in a known functional domain. In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether PMS2 Val475Glu is pathogenic or benign. We consider it to be a variant of uncertain significance. |
| Invitae | RCV001059940 | SCV001224595 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2023-10-16 | criteria provided, single submitter | clinical testing | This sequence change replaces valine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 475 of the PMS2 protein (p.Val475Glu). 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: 141541). 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. 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. |