ClinVar Miner

Submissions for variant NM_006231.3(POLE):c.4370G>T (p.Gly1457Val) (rs776534749)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000462104 SCV000544000 uncertain significance Colorectal cancer, susceptibility to, 12 2019-12-13 criteria provided, single submitter clinical testing This sequence change replaces glycine with valine at codon 1457 of the POLE protein (p.Gly1457Val). The glycine residue is moderately conserved and there is a moderate physicochemical difference between glycine and valine. This variant is present in population databases (rs776534749, 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: 405685). 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 RCV000486681 SCV000569428 uncertain significance not provided 2018-08-24 criteria provided, single submitter clinical testing This variant is denoted POLE c.4370G>T at the cDNA level, p.Gly1457Val (G1457V) at the protein level, and results in the change of a Glycine to a Valine (GGC>GTC). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. POLE Gly1457Val was observed at an allele frequency of 0.07% (23/33,582) in individuals of Latino 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 that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether POLE Gly1457Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000563246 SCV000671372 uncertain significance Hereditary cancer-predisposing syndrome 2015-06-24 criteria provided, single submitter clinical testing Rarity in general population databases (dbsnp, esp, 1000 genomes);In silico models in agreement (benign);Insufficient or conflicting evidence
Integrated Genetics/Laboratory Corporation of America RCV000781763 SCV000920067 likely benign not specified 2017-09-12 criteria provided, single submitter clinical testing Variant summary: The POLE c.4370G>T (p.Gly1457Val) variant involves the alteration of a conserved nucleotide and 3/5 in silico tools predict a benign outcome for this variant. However, these predictions have yet to be functionally assessed. This variant was found in 31/246270 control chromosomes, predominantly observed in the Latino subpopulation at a frequency of 0.000685 (23/33582). This frequency is about 48 times the estimated maximal expected allele frequency of a pathogenic POLE variant (0.0000142), suggesting this is likely a benign polymorphism found primarily in the populations of Latino origin. Multiple clinical diagnostic laboratories classified this variant as uncertain significance, prior to incorporation of gnomAD data. The variant of interest has not, to our knowledge, been reported in affected individuals via publications. Taken together, this variant is classified as likely benign.

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