Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000545520 | SCV000625599 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2021-12-20 | criteria provided, single submitter | clinical testing | This missense change has been observed in individual(s) with clinical features of PMS2-related conditions (Invitae). 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 expected to disrupt PMS2 protein function. ClinVar contains an entry for this variant (Variation ID: 455692). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 74 of the PMS2 protein (p.Gly74Arg). |
| University of Washington Department of Laboratory Medicine, |
RCV000758691 | SCV000887464 | uncertain significance | Lynch syndrome | 2018-05-01 | criteria provided, single submitter | clinical testing | PMS2 NM_000535.5:c.220G>A has a 60.9% probability of pathogenicity based on combining prior probability from public data with a likelihood ratio of 1.56 to 1, generated from evidence of seeing this as a somatic mutation in a tumor without loss of heterozygosity at the PMS2 locus. See Shirts et al 2018, PMID 29887214. |
| Ambry Genetics | RCV001014799 | SCV001175557 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2023-11-13 | criteria provided, single submitter | clinical testing | The p.G74R variant (also known as c.220G>A), located in coding exon 3 of the PMS2 gene, results from a G to A substitution at nucleotide position 220. The glycine at codon 74 is replaced by arginine, an amino acid with dissimilar properties. This alteration was identified in an individual diagnosed with early-onset colorectal cancer whose family history met Amsterdam I criteria for Lynch syndrome (Ambry internal data). Another alteration with a different nucleotide change but the same amino acid change, c.220G>C (p.G74R), has been reported as likely pathogenic due to it being identified in individuals whose colorectal tumors displayed high microsatellite instability (MSI-H) with either absent or weak PMS2 staining on immunohistochemistry (IHC) and an internal structural assessment determined p.G74R causes significant structural destabilization of the ATPase domain (Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |