Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001070803 | SCV001236074 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2023-05-10 | 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. 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 not expected to disrupt PMS2 protein function. ClinVar contains an entry for this variant (Variation ID: 863758). This variant has not been reported in the literature in individuals affected with PMS2-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 264 of the PMS2 protein (p.His264Arg). |
| Color Diagnostics, |
RCV001806017 | SCV002053046 | uncertain significance | Hereditary cancer-predisposing syndrome | 2021-03-15 | criteria provided, single submitter | clinical testing | This missense variant replaces histidine with arginine at codon 264 of the PMS2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in a pancreatic cancer case-control study in which it was detected in one unaffected individual and absent in cancer cases (PMID: 32980694). This variant has been identified in 2/281586 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. |
| Ambry Genetics | RCV001806017 | SCV003859086 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-12-19 | criteria provided, single submitter | clinical testing | The p.H264R variant (also known as c.791A>G), located in coding exon 7 of the PMS2 gene, results from an A to G substitution at nucleotide position 791. The histidine at codon 264 is replaced by arginine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Baylor Genetics | RCV003469266 | SCV004207810 | uncertain significance | Lynch syndrome 4 | 2023-06-15 | criteria provided, single submitter | clinical testing |