Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000571121 | SCV000670847 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-05-31 | criteria provided, single submitter | clinical testing | The p.A759S variant (also known as c.2275G>T), located in coding exon 13 of the PMS2 gene, results from a G to T substitution at nucleotide position 2275. The alanine at codon 759 is replaced by serine, an amino acid with similar properties. However, this change occurs in the last base pair of coding exon 13 and may have some effect on normal mRNA splicing. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will not have any significant effect on splicing. This amino acid position is highly conserved in available vertebrate species. In addition, as a missense substitution this is predicted to be inconclusive by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Gene |
RCV001775893 | SCV002014003 | uncertain significance | not provided | 2019-05-24 | criteria provided, single submitter | clinical testing | Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; In-silico analysis, which includes splice predictors and evolutionary conservation, is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown. |
| Invitae | RCV002528156 | SCV003453229 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2023-12-10 | criteria provided, single submitter | clinical testing | This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 759 of the PMS2 protein (p.Ala759Ser). This variant also falls at the last nucleotide of exon 13, which is part of the consensus splice site for this exon. The frequency data for this variant in the population databases (gnomAD) is considered unreliable due to the presence of homologous sequence, such as pseudogenes or paralogs, in the genome. 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: 484314). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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. |