ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.4051G>A (p.Val1351Ile)

gnomAD frequency: 0.00004  dbSNP: rs138443282
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000759291 SCV000289363 uncertain significance not provided 2024-01-27 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 1351 of the POLE protein (p.Val1351Ile). This variant is present in population databases (rs138443282, gnomAD 0.04%). 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: 240499). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000759291 SCV000888531 uncertain significance not provided 2018-05-22 criteria provided, single submitter clinical testing
GeneDx RCV000759291 SCV001818336 likely benign not provided 2020-09-09 criteria provided, single submitter clinical testing Has not been previously published as pathogenic or benign to our knowledge
Ambry Genetics RCV004020825 SCV003745315 likely benign Hereditary cancer-predisposing syndrome 2024-10-17 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital RCV000226790 SCV004171492 uncertain significance Colorectal cancer, susceptibility to, 12 2023-10-18 criteria provided, single submitter clinical testing The POLE c.4051G>A (p.Val1351Ile) missense change has a maximum subpopulation frequency of 0.035% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). The in silico tool predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. To our knowledge, this variant has not been reported in the literature in individuals with POLE-related disease. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.

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