ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.4008C>G (p.Ile1336Met)

gnomAD frequency: 0.00001  dbSNP: rs780795309
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV003768938 SCV001200200 uncertain significance not provided 2024-09-22 criteria provided, single submitter clinical testing This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 1336 of the POLE protein (p.Ile1336Met). This variant is present in population databases (rs780795309, gnomAD 0.01%). 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: 835836). 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 disruptive. 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.
Ambry Genetics RCV002372750 SCV002624533 uncertain significance Hereditary cancer-predisposing syndrome 2024-02-23 criteria provided, single submitter clinical testing The p.I1336M variant (also known as c.4008C>G), located in coding exon 32 of the POLE gene, results from a C to G substitution at nucleotide position 4008. The isoleucine at codon 1336 is replaced by methionine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Breakthrough Genomics, Breakthrough Genomics RCV003768938 SCV005192063 uncertain significance not provided criteria provided, single submitter not provided
GeneDx RCV003768938 SCV005889133 uncertain significance not provided 2024-09-16 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge

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