ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.476C>T (p.Thr159Ile)

dbSNP: rs150083426
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV001763734 SCV002001134 uncertain significance not provided 2020-01-14 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge
Labcorp Genetics (formerly Invitae), Labcorp RCV001763734 SCV002172645 uncertain significance not provided 2021-09-23 criteria provided, single submitter clinical testing This sequence change replaces threonine with isoleucine at codon 159 of the POLE protein (p.Thr159Ile). The threonine residue is moderately conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with POLE-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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 RCV004945707 SCV005479026 uncertain significance Hereditary cancer-predisposing syndrome 2024-07-25 criteria provided, single submitter clinical testing The p.T159I variant (also known as c.476C>T), located in coding exon 6 of the POLE gene, results from a C to T substitution at nucleotide position 476. The threonine at codon 159 is replaced by isoleucine, an amino acid with similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.

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