ClinVar Miner

Submissions for variant NM_006231.3(POLE):c.1583C>T (p.Thr528Met) (rs116263919)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 5
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000226009 SCV000289260 uncertain significance Colorectal cancer, susceptibility to, 12 2018-12-12 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 528 of the POLE protein (p.Thr528Met). The threonine residue is moderately conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs116263919, ExAC 0.01%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with POLE-related disease. ClinVar contains an entry for this variant (Variation ID: 240397). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
GeneDx RCV000657110 SCV000293799 uncertain significance not provided 2018-08-02 criteria provided, single submitter clinical testing This variant is denoted POLE c.1583C>T at the cDNA level, p.Thr528Met (T528M) at the protein level, and results in the change of a Threonine to a Methionine (ACG>ATG). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. POLE Thr528Met was observed at an allele frequency of 0.02% (31/126,236) in individuals of European ancestry in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether POLE Thr528Met is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000236971 SCV000601983 uncertain significance not specified 2016-11-17 criteria provided, single submitter clinical testing
Ambry Genetics RCV000563355 SCV000671275 uncertain significance Hereditary cancer-predisposing syndrome 2015-06-27 criteria provided, single submitter clinical testing Rarity in general population databases (dbsnp, esp, 1000 genomes);In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Insufficient or conflicting evidence
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000236971 SCV000966739 uncertain significance not specified 2018-12-04 criteria provided, single submitter clinical testing The p.Thr528Met variant in POLE has not been previously reported in individuals with colorectal cancer but has been identified in 0.02% (30/128702) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has also been reported as a variant of uncertain significance in ClinVar (Variation ID 24 0397). Computational prediction tools and conservation analysis suggest that thi s variant may impact the protein, though this information is not predictive enou gh to determine pathogenicity. In summary, the clinical significance of the p.Th r528Met variant is uncertain. ACMG/AMP Criteria applied: PP3.

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.