Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000797877 | SCV000937462 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2024-01-17 | criteria provided, single submitter | clinical testing | This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 36 of the PMS2 protein (p.Ser36Arg). This variant is present in population databases (no rsID available, gnomAD 0.01%). 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: 644040). 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. |
| Ambry Genetics | RCV001017239 | SCV001178287 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-10-21 | criteria provided, single submitter | clinical testing | The p.S36R variant (also known as c.108C>A), located in coding exon 2 of the PMS2 gene, results from a C to A substitution at nucleotide position 108. The serine at codon 36 is replaced by arginine, an amino acid with dissimilar properties. A functional study demonstrated that this alteration was expressed at a level similar to that of the wild type, with proficient mRNA and protein expression and viability in response to DNA-damaging agents (Arora S et al. Cancer Biol Ther, 2017 Jul;18:519-533). This amino acid position is not 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 this alteration remains unclear. |
| Color Diagnostics, |
RCV001017239 | SCV001355292 | uncertain significance | Hereditary cancer-predisposing syndrome | 2020-04-09 | criteria provided, single submitter | clinical testing | This missense variant replaces serine with arginine at codon 36 of the PMS2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has shown that this variant does not impact protein expression or cell viability in the presence of DNA-damaging agents (PMID: 28494185). This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 2/245788 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. |