ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.5608C>T (p.Arg1870Cys)

gnomAD frequency: 0.00001  dbSNP: rs138231414
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000679652 SCV000653386 uncertain significance not provided 2024-06-28 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 1870 of the POLE protein (p.Arg1870Cys). This variant is present in population databases (rs138231414, gnomAD 0.004%). 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: 473750). 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 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.
PreventionGenetics, part of Exact Sciences RCV000679652 SCV000806812 uncertain significance not provided 2017-08-30 criteria provided, single submitter clinical testing
GeneDx RCV000679652 SCV001996624 uncertain significance not provided 2019-11-04 criteria provided, single submitter clinical testing In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as a pathogenic or benign germline variant to our knowledge; This variant is associated with the following publications: (PMID: 29056344, 31034466)
Ambry Genetics RCV002350373 SCV002648895 uncertain significance Hereditary cancer-predisposing syndrome 2021-07-28 criteria provided, single submitter clinical testing The p.R1870C variant (also known as c.5608C>T), located in coding exon 41 of the POLE gene, results from a C to T substitution at nucleotide position 5608. The arginine at codon 1870 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is conserved. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics RCV005004236 SCV005633680 uncertain significance Colorectal cancer, susceptibility to, 12; Facial dysmorphism-immunodeficiency-livedo-short stature syndrome; Intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency 2024-01-02 criteria provided, single submitter clinical testing
University of Washington Department of Laboratory Medicine, University of Washington RCV000546541 SCV001446375 likely benign Colorectal cancer, susceptibility to, 12 2019-03-01 no assertion criteria provided research

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