ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.1916G>A (p.Arg639His)

dbSNP: rs754616313
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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 RCV002469264 SCV000823750 uncertain significance not provided 2024-04-24 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 639 of the POLE protein (p.Arg639His). This variant is present in population databases (rs754616313, gnomAD 0.01%). 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: 573563). 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.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV002268254 SCV002550167 uncertain significance not specified 2024-07-31 criteria provided, single submitter clinical testing
Ambry Genetics RCV002406596 SCV002721386 uncertain significance Hereditary cancer-predisposing syndrome 2024-06-08 criteria provided, single submitter clinical testing The p.R639H variant (also known as c.1916G>A), located in coding exon 17 of the POLE gene, results from a G to A substitution at nucleotide position 1916. The arginine at codon 639 is replaced by histidine, an amino acid with highly similar properties. This amino acid position is conserved. 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 RCV002469264 SCV002765204 uncertain significance not provided 2022-12-08 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 pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 29056344)
Fulgent Genetics, Fulgent Genetics RCV005010698 SCV005633752 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 2024-04-07 criteria provided, single submitter clinical testing

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