ClinVar Miner

Submissions for variant NM_006231.3(POLE):c.4055G>C (p.Gly1352Ala) (rs147088333)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000457743 SCV000543988 uncertain significance Colorectal cancer, susceptibility to, 12 2019-12-31 criteria provided, single submitter clinical testing This sequence change replaces glycine with alanine at codon 1352 of the POLE protein (p.Gly1352Ala). The glycine residue is moderately conserved and there is a small physicochemical difference between glycine and alanine. This variant is present in population databases (rs147088333, ExAC 0.03%), 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: 405675). 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 tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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 RCV000766512 SCV000569636 uncertain significance not provided 2018-12-06 criteria provided, single submitter clinical testing This variant is denoted POLE c.4055G>C at the cDNA level, p.Gly1352Ala (G1352A) at the protein level, and results in the change of a Glycine to an Alanine (GGC>GCC). This variant has been reported in at least one individual with advanced cancer (Mandelker 2017). POLE Gly1352Ala was observed at an allele frequency at 0.03% (8/25,424) 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 Gly1352Ala is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000483342 SCV000602039 uncertain significance not specified 2017-01-17 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000766512 SCV001148888 uncertain significance not provided 2018-10-01 criteria provided, single submitter clinical testing

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