ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.6610G>A (p.Val2204Met)

gnomAD frequency: 0.00001  dbSNP: rs1060500871
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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 RCV001731892 SCV000818076 uncertain significance not provided 2025-01-01 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 2204 of the POLE protein (p.Val2204Met). This variant is present in population databases (no rsID available, 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: 569695). 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.
GeneDx RCV001731892 SCV001982051 uncertain significance not provided 2024-01-31 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; This variant is associated with the following publications: (PMID: 19296856)
3billion, Medical Genetics RCV002250682 SCV002521223 uncertain significance Facial dysmorphism-immunodeficiency-livedo-short stature syndrome 2022-05-22 criteria provided, single submitter clinical testing The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.003%). In silico tool predictions suggest no damaging effect of the variant on gene or gene product (REVEL: 0.26; 3Cnet: 0.01). Therefore, this variant is classified as uncertain significanceaccording to the recommendation of ACMG/AMP guideline.
Ambry Genetics RCV002369855 SCV002667722 uncertain significance Hereditary cancer-predisposing syndrome 2021-08-02 criteria provided, single submitter clinical testing The p.V2204M variant (also known as c.6610G>A), located in coding exon 47 of the POLE gene, results from a G to A substitution at nucleotide position 6610. The valine at codon 2204 is replaced by methionine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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