ClinVar Miner

Submissions for variant NM_006231.3(POLE):c.2932G>T (p.Glu978Ter) (rs1555225958)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000663250 SCV000786475 likely pathogenic Colorectal cancer, susceptibility to, 12 2018-05-08 criteria provided, single submitter clinical testing
Invitae RCV000663250 SCV001385287 uncertain significance Colorectal cancer, susceptibility to, 12 2019-08-22 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Glu978*) in the POLE gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with POLE-related conditions. ClinVar contains an entry for this variant (Variation ID: 548907). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.
True Health Diagnostics RCV000758173 SCV000886709 pathogenic Hereditary cancer-predisposing syndrome 2018-08-09 no assertion criteria provided clinical testing

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