ClinVar Miner

Submissions for variant NM_006231.3(POLE):c.664C>T (p.Arg222Cys) (rs767503360)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000706790 SCV000835860 uncertain significance Colorectal cancer, susceptibility to, 12 2019-12-08 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 222 of the POLE protein (p.Arg222Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs767503360, ExAC 0.003%). This variant has not been reported in the literature in individuals with POLE-related conditions. ClinVar contains an entry for this variant (Variation ID: 582662). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.
University of Washington Department of Laboratory Medicine, University of Washington RCV000706790 SCV000886453 likely benign Colorectal cancer, susceptibility to, 12 2018-05-29 criteria provided, single submitter research The POLE variant designated as NM_006231.3:c.664C>T (p.Arg222Cys) is classified as likely benign. This variant is not in the POLE exonuclease domain and is unlikely to cause increased cancer risk, as only POLE variants that alter exonuclease activity have been documented to be associated with colon cancer risk. In one observed family, this variant was not identified in a family member over 70 years old who has been documented to be free of colon polyps on colonoscopy. The allele does not segregate with gastrointestinal cancer in one observed family. Bayesian analysis integrating all of this data (Tavtigian et al, 2018, PMID: 29300386) gives about 3% probability of pathogenicity, which is consistent with a classification of likely benign. This variant is not predicted to alter POLE function or modify cancer risk. A modest (less than 2-fold) increase in cancer risk due to this variant cannot be excluded. This analysis was performed in conjunction with the family studies project as part of the University of Washington Find My Variant Study.

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