ClinVar Miner

Submissions for variant NM_006231.3(POLE):c.3904C>T (p.Leu1302Phe) (rs1555223949)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000549169 SCV000653249 uncertain significance Colorectal cancer, susceptibility to, 12 2017-03-29 criteria provided, single submitter clinical testing This sequence change replaces leucine with phenylalanine at codon 1302 of the POLE protein (p.Leu1302Phe). The leucine residue is weakly conserved and there is a small physicochemical difference between leucine and phenylalanine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a POLE-related disease. 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: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance.
University of Washington Department of Laboratory Medicine, University of Washington RCV000549169 SCV000788234 likely benign Colorectal cancer, susceptibility to, 12 2018-04-01 criteria provided, single submitter research The POLE variant designated as NM_006231.3:c.3904C>T (p.Leu1302Phe) is classified as likely benign. This variant has not been reported in ExAC (exac.broadinstitute.org). This variant is weakly conserved and it is not located in the exonuclease domain in which pathogenic mutations have been reported (Bellido et al, 2016). Additionally, in one observed family, this variant was inherited from an individual who is over 70 years old and who has had regular colonoscopies without colon polyps or colon cancer. Several other relatives of this individual are also over 70 years old and report no colon polyps or colon cancer, providing further evidence against pathogenicity. 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 entirely 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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