ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.4090C>T (p.Arg1364Cys)

gnomAD frequency: 0.00002  dbSNP: rs770024304
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001836821 SCV000543932 uncertain significance not provided 2024-01-28 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1364 of the POLE protein (p.Arg1364Cys). This variant is present in population databases (rs770024304, gnomAD 0.02%). 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: 405621). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000609141 SCV000731330 uncertain significance not specified 2016-12-28 criteria provided, single submitter clinical testing The p.Arg1364Cys variant in POLE has not been previously reported in individuals with colorectal cancer, but has been identified in 1/66324 of European chromoso mes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; d bSNP rs770024304). Computational prediction tools and conservation analysis sugg est that the p.Arg1364Cys variant may impact the protein, though this informatio n is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Arg1364Cys variant is uncertain.
Baylor Genetics RCV001293922 SCV001482618 uncertain significance Facial dysmorphism-immunodeficiency-livedo-short stature syndrome 2020-11-25 criteria provided, single submitter clinical testing This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden RCV001836821 SCV002009579 uncertain significance not provided 2021-11-03 criteria provided, single submitter clinical testing
GeneDx RCV001836821 SCV002097475 uncertain significance not provided 2023-10-10 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individual(s) with breast cancer (Melloni et al., 2017); This variant is associated with the following publications: (PMID: 29056344, 28569218)

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