Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000483071 | SCV000566759 | uncertain significance | not provided | 2015-05-29 | criteria provided, single submitter | clinical testing | This variant is denoted PMS2 c.41C>T at the cDNA level, p.Ala14Val (A14V) at the protein level, and results in the change of an Alanine to a Valine (GCC>GTC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. PMS2 Ala14Val 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 Alanine and Valine share similar properties, this is considered a conservative amino acid substitution. PMS2 Ala14Val occurs at a position that is not conserved and is located in the ATPase domain (Fukui 2011). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether PMS2 Ala14Val is pathogenic or benign. We consider it to be a variant of uncertain significance. |
| Invitae | RCV001035359 | SCV001198684 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2019-11-28 | 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The valine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with PMS2-related conditions. ClinVar contains an entry for this variant (Variation ID: 419149). This variant is not present in population databases (ExAC no frequency). This sequence change replaces alanine with valine at codon 14 of the PMS2 protein (p.Ala14Val). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and valine. |
| Ambry Genetics | RCV002329144 | SCV002627291 | uncertain significance | Hereditary cancer-predisposing syndrome | 2019-02-21 | criteria provided, single submitter | clinical testing | The p.A14V variant (also known as c.41C>T), located in coding exon 2 of the PMS2 gene, results from a C to T substitution at nucleotide position 41. The alanine at codon 14 is replaced by valine, an amino acid with similar properties. This amino acid position is well 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. |