Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000699782 | SCV000828508 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2021-01-11 | 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. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus 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 (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but 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 disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces serine with asparagine at codon 8 of the PMS2 protein (p.Ser8Asn). The serine residue is weakly conserved and there is a small physicochemical difference between serine and asparagine. This variant also falls at the last nucleotide of exon 1 of the PMS2 coding sequence, which is part of the consensus splice site for this exon. |
| Color Diagnostics, |
RCV001187935 | SCV001354877 | uncertain significance | Hereditary cancer-predisposing syndrome | 2019-05-31 | criteria provided, single submitter | clinical testing | |
| Ambry Genetics | RCV001187935 | SCV002732026 | uncertain significance | Hereditary cancer-predisposing syndrome | 2017-09-19 | criteria provided, single submitter | clinical testing | The c.23G>A variant (also known as p.S8N), located in coding exon 1 of the PMS2 gene, results from a G to A substitution at nucleotide position 23. The amino acid change results in serine to asparagine at codon 8, an amino acid with highly similar properties. However, this change occurs in the last base pair of coding exon 1, which makes it likely to have some effect on normal mRNA splicing. This amino acid position is highly 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 this alteration remains unclear. |