ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.5633G>A (p.Arg1878His)

gnomAD frequency: 0.00001  dbSNP: rs374022997
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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 RCV000235904 SCV000289433 uncertain significance not provided 2024-12-21 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 1878 of the POLE protein (p.Arg1878His). This variant is present in population databases (rs374022997, gnomAD 0.01%). This missense change has been observed in individual(s) with ovarian cancer (PMID: 30093976). ClinVar contains an entry for this variant (Variation ID: 240569). 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 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.
GeneDx RCV000235904 SCV000294052 uncertain significance not provided 2023-10-30 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in an individual with ovarian cancer (PMID: 30093976); This variant is associated with the following publications: (PMID: 30093976)
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000235904 SCV000889771 uncertain significance not provided 2017-11-27 criteria provided, single submitter clinical testing
Laboratory of Medical Genetics Unit, Bambino Gesù Children's Hospital RCV004776280 SCV005382023 uncertain significance Pediatric high-grade glioma criteria provided, single submitter research
Ambry Genetics RCV004943813 SCV005481530 uncertain significance Hereditary cancer-predisposing syndrome 2024-07-30 criteria provided, single submitter clinical testing The p.R1878H variant (also known as c.5633G>A), located in coding exon 41 of the POLE gene, results from a G to A substitution at nucleotide position 5633. The arginine at codon 1878 is replaced by histidine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.
Fulgent Genetics, Fulgent Genetics RCV005008198 SCV005633679 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 2024-06-21 criteria provided, single submitter clinical testing

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