Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000564836 | SCV000676191 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2023-08-23 | criteria provided, single submitter | clinical testing | The p.G74R variant (also known as c.220G>C), located in coding exon 3 of the PMS2 gene, results from a G to C substitution at nucleotide position 220. The glycine at codon 74 is replaced by arginine, an amino acid with dissimilar properties. This alteration has been identified in individuals whose colorectal tumors displayed high microsatellite instability (MSI-H) and either absent or weak PMS2 staining on immunohistochemistry (Ambry Internal Data). Based on an internal structural assessment, this alteration causes significant structural destabilization of the ATPase domain (Guarné A et al. EMBO J. 2001 Oct;20:5521-31). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. |
| Invitae | RCV000630233 | SCV000751189 | pathogenic | Hereditary nonpolyposis colorectal neoplasms | 2024-01-18 | criteria provided, single submitter | clinical testing | 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). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of Lynch syndrome and constitutional mismatch repair deficiency syndrome (Invitae). ClinVar contains an entry for this variant (Variation ID: 486943). 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 with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. |
| Gene |
RCV001545463 | SCV001764800 | likely pathogenic | not provided | 2022-10-25 | criteria provided, single submitter | clinical testing | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 11574484) |
| Baylor Genetics | RCV003465282 | SCV004205412 | likely pathogenic | Lynch syndrome 4 | 2023-10-04 | criteria provided, single submitter | clinical testing | |
| Quest Diagnostics Nichols Institute San Juan Capistrano | RCV001545463 | SCV004218980 | likely pathogenic | not provided | 2023-05-04 | criteria provided, single submitter | clinical testing | This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). The variant has been reported in individuals with Lynch syndrome associated cancers. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as likely pathogenic. |