ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.3583G>A (p.Val1195Ile)

gnomAD frequency: 0.00001  dbSNP: rs773503806
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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 RCV003541363 SCV001542100 uncertain significance not provided 2024-09-15 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 1195 of the POLE protein (p.Val1195Ile). This variant is present in population databases (rs773503806, 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: 1043678). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The isoleucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.
Sema4, Sema4 RCV002258214 SCV002536817 uncertain significance Hereditary cancer-predisposing syndrome 2021-05-10 criteria provided, single submitter curation
Ambry Genetics RCV002258214 SCV003589983 uncertain significance Hereditary cancer-predisposing syndrome 2024-03-09 criteria provided, single submitter clinical testing The p.V1195I variant (also known as c.3583G>A) is located in coding exon 30 of the POLE gene. The valine at codon 1195 is replaced by isoleucine, an amino acid with highly similar properties. This change occurs in the first base pair of coding exon 30. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this alteration remains unclear.
GeneDx RCV003541363 SCV005332835 uncertain significance not provided 2023-12-07 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

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