Submissions for variant NM_006231.4(POLE):c.557C>T (p.Ala186Val)

gnomAD frequency: 0.00001  dbSNP: rs151325267

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003478379	SCV000772630	uncertain significance	not provided	2025-01-26	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 186 of the POLE protein (p.Ala186Val). This variant is present in population databases (rs151325267, 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: 540682). 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.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV002465745	SCV002761032	uncertain significance	not specified	2025-03-04	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003162985	SCV003893719	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-10	criteria provided, single submitter	clinical testing	The p.A186V variant (also known as c.557C>T), located in coding exon 6 of the POLE gene, results from a C to T substitution at nucleotide position 557. The alanine at codon 186 is replaced by valine, an amino acid with 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003478379	SCV004219080	uncertain significance	not provided	2023-02-21	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000016 (4/251372 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in an individual with colorectal cancer (PMID: 34026601 (2021)) and in individuals with stomach adenocarcinoma (PMID: 35261896 (2021)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
GeneDx	RCV003478379	SCV005327437	uncertain significance	not provided	2023-12-01	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: 34026601)