Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000566590 | SCV000670777 | uncertain significance | Hereditary cancer-predisposing syndrome | 2021-10-29 | criteria provided, single submitter | clinical testing | The p.N775I variant (also known as c.2324A>T), located in coding exon 14 of the PMS2 gene, results from an A to T substitution at nucleotide position 2324. The asparagine at codon 775 is replaced by isoleucine, an amino acid with dissimilar properties. 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. |
| Invitae | RCV001350662 | SCV001545072 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2023-09-27 | criteria provided, single submitter | clinical testing | This sequence change replaces asparagine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 775 of the PMS2 protein (p.Asn775Ile). 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: 484267). 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 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. |