ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.950T>C (p.Ile317Thr)

dbSNP: rs1060500783
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001770306 SCV000543928 uncertain significance not provided 2024-12-26 criteria provided, single submitter clinical testing This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 317 of the POLE protein (p.Ile317Thr). This variant is present in population databases (no rsID available, 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: 405617). 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 expected to disrupt POLE protein function with a positive 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 RCV000575391 SCV000674376 uncertain significance Hereditary cancer-predisposing syndrome 2023-01-17 criteria provided, single submitter clinical testing The p.I317T variant (also known as c.950T>C), located in coding exon 10 of the POLE gene, results from a T to C substitution at nucleotide position 950. The isoleucine at codon 317 is replaced by threonine, an amino acid with similar properties. This amino acid position is well 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 this alteration remains unclear.
GeneDx RCV001770306 SCV001993381 uncertain significance not provided 2019-08-09 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek 2016); Has not been previously published as pathogenic or benign to our knowledge
St. Jude Molecular Pathology, St. Jude Children's Research Hospital RCV000457449 SCV002584556 uncertain significance Colorectal cancer, susceptibility to, 12 2022-08-16 criteria provided, single submitter clinical testing The POLE c.950T>C (p.Ile317Thr) missense change has a maximum subpopulation frequency of 0.0055% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function, and to our knowledge functional studies have not been performed. To our knowledge, this variant has not been reported in individuals with POLE-associated polyposis, FILS syndrome, or IMAGE-I syndrome. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
Baylor Genetics RCV000457449 SCV004203551 uncertain significance Colorectal cancer, susceptibility to, 12 2023-07-14 criteria provided, single submitter clinical testing

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