ClinVar Miner

Submissions for variant NM_006231.3(POLE):c.6068C>T (p.Thr2023Ile) (rs771628123)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000228854 SCV000289447 uncertain significance Colorectal cancer, susceptibility to, 12 2019-12-19 criteria provided, single submitter clinical testing This sequence change replaces threonine with isoleucine at codon 2023 of the POLE protein (p.Thr2023Ile). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with POLE-related disease. ClinVar contains an entry for this variant (Variation ID: 240583). 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: "Tolerated"; PolyPhen-2: "Possibly 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 RCV000679659 SCV000322487 uncertain significance not provided 2016-07-06 criteria provided, single submitter clinical testing This variant is denoted POLE c.6068C>T at the cDNA level, p.Thr2023Ile (T2023I) at the protein level, and results in the change of a Threonine to an Isoleucine (ACC>ATC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. POLE Thr2023Ile was not observed in approximately 6,500 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 Threonine and Isoleucine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. POLE Thr2023Ile occurs at a position that is conserved across species and is not located in a known functional domain (Tahirov 2009, Preston 2010). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether POLE Thr2023Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000255149 SCV000602079 uncertain significance not specified 2017-04-21 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000679659 SCV000806826 uncertain significance not provided 2017-06-27 criteria provided, single submitter clinical testing

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