ClinVar Miner

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

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Total submissions: 5
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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 ( 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.

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