ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.1051G>A (p.Val351Ile)

gnomAD frequency: 0.00001  dbSNP: rs759414746
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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 RCV000766804 SCV000289236 uncertain significance not provided 2025-01-26 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 351 of the POLE protein (p.Val351Ile). This variant is present in population databases (rs759414746, gnomAD 0.006%). 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: 240373). 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000455630 SCV000540095 uncertain significance not specified 2016-10-26 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant has not been reported in affected individuals. It is classified in ClinVar with 1 star as VUS by Invitae. It is present in ExAC at a MaxMAF of 0.01%. AA is not conserved - Ile is present in 23 species, including 17 mammals.
GeneDx RCV000766804 SCV000571215 uncertain significance not provided 2023-07-26 criteria provided, single submitter clinical testing Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 20951805, 29618732)
Ambry Genetics RCV000565960 SCV000671404 likely benign Hereditary cancer-predisposing syndrome 2018-10-02 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000766804 SCV001134673 uncertain significance not provided 2019-03-12 criteria provided, single submitter clinical testing

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