ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.3377C>T (p.Ala1126Val)

gnomAD frequency: 0.00003  dbSNP: rs373707446
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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 RCV000759286 SCV000544133 uncertain significance not provided 2024-12-02 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1126 of the POLE protein (p.Ala1126Val). This variant is present in population databases (rs373707446, gnomAD 0.03%). 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: 405808). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Studies have shown that this missense change is associated with inconclusive levels of altered splicing (internal data). 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 RCV000759286 SCV000888525 uncertain significance not provided 2018-04-17 criteria provided, single submitter clinical testing
Ambry Genetics RCV003168756 SCV003896392 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.
GeneDx RCV000759286 SCV005382921 uncertain significance not provided 2024-01-19 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
GenomeConnect, ClinGen RCV000470845 SCV002029145 not provided Colorectal cancer, susceptibility to, 12 no assertion provided phenotyping only Variant interpreted as Uncertain significance and reported on 12-10-2019 by Lab or GTR ID 246260. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

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