Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000166141 | SCV000216913 | uncertain significance | Hereditary cancer-predisposing syndrome | 2014-09-24 | criteria provided, single submitter | clinical testing | The p.D64G variant (also known as c.191A>G) is located in coding exon 3 of the PMS2 gene. This alteration results from a A to G substitution at nucleotide position 191. The aspartic acid at codon 64 is replaced by glycine, an amino acid with some similar properties. This variant was not reported in population-based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP) and 1000 Genomes Project. To date, this alteration has been detected with an allele frequency of approximately 0.004% (greater than 23,000 alleles tested) in our clinical cohort. Based on protein sequence alignment, this amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of p.D64G remains unclear. |
| Invitae | RCV001313587 | SCV001504088 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2024-01-15 | criteria provided, single submitter | clinical testing | This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 64 of the PMS2 protein (p.Asp64Gly). 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: 186531). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on 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. |