ClinVar Miner

Submissions for variant NM_006231.3(POLE):c.691C>T (p.Arg231Cys) (rs146592584)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000229088 SCV000289487 likely benign Colorectal cancer, susceptibility to, 12 2020-01-06 criteria provided, single submitter clinical testing
GeneDx RCV000657130 SCV000569809 uncertain significance not provided 2018-08-29 criteria provided, single submitter clinical testing This variant is denoted POLE c.691C>T at the cDNA level, p.Arg231Cys (R231C) at the protein level, and results in the change of an Arginine to a Cysteine (CGC>TGC). This variant has been reported in an individual with a personal and family history of colon cancer and in another individual with an unspecified advanced cancer (Mandelker 2017, Raskin 2017). POLE Arg231Cys was observed at an allele frequency of 0.03% (37/126,680) 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 Arg231Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
PreventionGenetics,PreventionGenetics RCV000657130 SCV000806852 uncertain significance not provided 2017-07-14 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000657130 SCV000889791 uncertain significance not provided 2019-04-05 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000478783 SCV000967515 uncertain significance not specified 2018-10-18 criteria provided, single submitter clinical testing The p.Arg231Cys variant in POLE has been reported in the literature in two indiv iduals with colorectal cancer (Raskin 2017, Mandelker 2017) and has also been re ported by other clinical laboratories in ClinVar (Variation ID: 240623). This va riant has also been identified in 37/126680 European chromosomes by gnomAD (http ://gnomad.broadinstitute.org). Computational prediction tools and conservation a nalysis suggest that the p.Arg231Cys variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, th e clinical significance of the p.Arg231Cys variant is uncertain. ACMG/AMP Criter ia applied: PP3, PS4_Supporting.

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