Total submissions: 4
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Ambry Genetics | RCV000165432 | SCV000216161 | uncertain significance | Hereditary cancer-predisposing syndrome | 2021-12-10 | criteria provided, single submitter | clinical testing | The p.G108R variant (also known as c.322G>C), located in coding exon 4 of the PMS2 gene, results from a G to C substitution at nucleotide position 322. The glycine at codon 108 is replaced by arginine, an amino acid with dissimilar properties. This alteration was detected in an individual diagnosed with colon cancer at age 49, whose tumor demonstrated high microsatellite instability and presence of MLH1, MSH2, MSH2, and PMS2 proteins on immunohistochemistry (Greene C et al. Anticancer Res., 2017 07;37:3679-3684). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
Gene |
RCV000213333 | SCV000279715 | uncertain significance | not provided | 2016-08-29 | criteria provided, single submitter | clinical testing | This variant is denoted PMS2 c.322G>C at the cDNA level, p.Gly108Arg (G108R) at the protein level, and results in the change of a Glycine to an Arginine (GGG>CGG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. PMS2 Gly108Arg was not observed in approximately 3,700 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Glycine and Arginine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. PMS2 Gly108Arg occurs at a position that is conserved across species and is located in the ATPase domain (Guarne 2001, Fukui 2011). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether PMS2 Gly108Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. |
Color Diagnostics, |
RCV000165432 | SCV000686192 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-11-09 | criteria provided, single submitter | clinical testing | This missense variant replaces glycine with arginine at codon 108 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with colorectal cancer that demonstrated high microsatellite instability, though all mismatch repair proteins were reported intact via immunohistochemistry (PMID: 28668860). This variant has been identified in 2/236460 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. |
Invitae | RCV000685491 | SCV000812974 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2024-01-20 | 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 108 of the PMS2 protein (p.Gly108Arg). This variant is present in population databases (rs750866397, gnomAD 0.002%). This missense change has been observed in individual(s) with colorectal cancer (PMID: 28668860). ClinVar contains an entry for this variant (Variation ID: 185927). 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%. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (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. |