ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.4337_4338dup (p.Val1447fs) (rs758487568)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV001022314 SCV001184033 uncertain significance Hereditary cancer-predisposing syndrome 2019-06-07 criteria provided, single submitter clinical testing The c.4337_4338dupTG variant, located in coding exon 34 of the POLE gene, results from a duplication of TG at nucleotide position 4337, causing a translational frameshift with a predicted alternate stop codon (p.V1447Wfs*7). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. However, loss of function via haploinsufficiency in POLE has not been clearly established as a mechanism of disease. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV001047275 SCV001211219 uncertain significance Colorectal cancer, susceptibility to, 12 2020-07-25 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Val1447Trpfs*7) in the POLE gene. It is expected to result in an absent or disrupted protein product. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with POLE-related disease. Missense variants that disrupt the 3'-5' exonuclease (proof-reading) activity of the POLE protein, while not abolishing its polymerase enzyme activity, are associated with an increased risk for colonic adenomatous polyps and colon cancer (PMID: 23263490, 23447401). Loss-of-function truncating variants, which result in an absent or severely disrupted POLE protein, are therefore unlikely to be associated with disease. Without further clinical and genetic evidence, however, this variant has been classified as a Variant of Uncertain Significance.
CeGaT Praxis fuer Humangenetik Tuebingen RCV001092701 SCV001249334 pathogenic not provided 2018-10-01 criteria provided, single submitter clinical testing
New York Genome Center RCV001263397 SCV001441440 likely pathogenic Short stature 2019-05-24 criteria provided, single submitter clinical testing

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