ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.5237A>T (p.Asn1746Ile)

dbSNP: rs377461656
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000235361 SCV000289418 uncertain significance not provided 2025-01-12 criteria provided, single submitter clinical testing This sequence change replaces asparagine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 1746 of the POLE protein (p.Asn1746Ile). This variant is present in population databases (no rsID available, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with POLE-related conditions. ClinVar contains an entry for this variant (Variation ID: 240554). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt POLE protein function with a negative predictive value of 80%. 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 RCV000235361 SCV000293662 uncertain significance not provided 2024-02-27 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 27720647)
Ambry Genetics RCV000572415 SCV000676221 uncertain significance Hereditary cancer-predisposing syndrome 2016-04-28 criteria provided, single submitter clinical testing There is insufficient or conflicting evidence for classification of this alteration.

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