ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.766G>A (p.Gly256Ser) (rs587782633)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 8
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000132021 SCV000187080 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-12 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000167945 SCV000218593 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-12-02 criteria provided, single submitter clinical testing This sequence change replaces glycine with serine at codon 256 of the PMS2 protein (p.Gly256Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant is present in population databases (rs587782633, ExAC 0.009%). This variant has not been reported in the literature in individuals with a PMS2-related disease. ClinVar contains an entry for this variant (Variation ID: 142671). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, this variant has uncertain impact on PMS2 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx RCV000588881 SCV000565833 uncertain significance not provided 2018-08-14 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.766G>A at the cDNA level, p.Gly256Ser (G256S) at the protein level, and results in the change of a Glycine to a Serine (GGT>AGT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign germline variant. PMS2 Gly256Ser was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the ATPase domain (Guarne 2001). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether PMS2 Gly256Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000132021 SCV000686237 uncertain significance Hereditary cancer-predisposing syndrome 2020-03-17 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000588881 SCV000697385 uncertain significance not provided 2016-11-10 criteria provided, single submitter clinical testing Variant summary: The c.766G>A (p.Gly256Ser) in PMS2 gene is a missense change that involves a mildly conserved nucleotide and 3/4 in silico tools predict deleterious outcome. The variant of interest is located within a region that has a high homology to C-terminal domain of DNA mismatch repair proteins. The functional impact of this missense change is yet to be studied. The variant is present in the large control population dataset of ExAC at a low frequency 0.000025 (3/120532 chrs tested). This frequency does not exceed the maximal expected frequency of a pathogenic allele (0.0001) in this gene. The variant has not been reported in the affected individuals via published reports, but it was cited as VUS by reputable databases/clinical laboratories. At this time there is not sufficient undeniable evidence to classify this variant with confidence. Taken together, the variant was classified as VUS until more data becomes available.
Counsyl RCV000663252 SCV000786477 uncertain significance Hereditary nonpolyposis colorectal cancer type 4 2018-05-08 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000765961 SCV000897382 uncertain significance Turcot syndrome; Hereditary nonpolyposis colorectal cancer type 4 2018-10-31 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000588881 SCV001134614 uncertain significance not provided 2019-04-15 criteria provided, single submitter clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.