ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.662T>C (p.Met221Thr)

gnomAD frequency: 0.00001  dbSNP: rs755607944
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV002260637 SCV000543968 uncertain significance not provided 2024-09-16 criteria provided, single submitter clinical testing This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 221 of the POLE protein (p.Met221Thr). This variant is present in population databases (rs755607944, gnomAD 0.0009%). 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: 405656). 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.
Ambry Genetics RCV000561884 SCV000676219 uncertain significance Hereditary cancer-predisposing syndrome 2015-06-19 criteria provided, single submitter clinical testing The p.M221T variant (also known as c.662T>C), located in coding exon 7 of the POLE gene, results from a T to C substitution at nucleotide position 662. The methionine at codon 221 is replaced by threonine, an amino acid with similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of p.M221T remains unclear.
GeneDx RCV002260637 SCV002540425 uncertain significance not provided 2024-03-14 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as a germline pathogenic or benign variant to our knowledge; This variant is associated with the following publications: (PMID: 29056344)

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