ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.2276G>A (p.Arg759His)

gnomAD frequency: 0.00003  dbSNP: rs746774432
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 7
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000235473 SCV000289295 uncertain significance not provided 2025-01-17 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 759 of the POLE protein (p.Arg759His). This variant is present in population databases (rs746774432, gnomAD 0.006%). 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: 240431). 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 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.
GeneDx RCV000235473 SCV000294063 uncertain significance not provided 2024-02-02 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 breast cancer, as well as an individual with features of tuberous sclerosis complex who also harbored a truncating variant in TSC2 (PMID: 28202063, 34344650); This variant is associated with the following publications: (PMID: 25305755, 27499911, Androsova2023[poster], 20951805, 34344650, 28202063)
Counsyl RCV000227534 SCV000785939 uncertain significance Colorectal cancer, susceptibility to, 12 2018-01-17 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV000763809 SCV000894726 uncertain significance Colorectal cancer, susceptibility to, 12; Facial dysmorphism-immunodeficiency-livedo-short stature syndrome 2018-10-31 criteria provided, single submitter clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV003321566 SCV004027348 uncertain significance not specified 2025-03-04 criteria provided, single submitter clinical testing
Ambry Genetics RCV000664289 SCV005481524 uncertain significance Hereditary cancer-predisposing syndrome 2024-10-17 criteria provided, single submitter clinical testing The p.R759H variant (also known as c.2276G>A), located in coding exon 20 of the POLE gene, results from a G to A substitution at nucleotide position 2276. The arginine at codon 759 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.
True Health Diagnostics RCV000664289 SCV000788167 uncertain significance Hereditary cancer-predisposing syndrome 2017-09-13 no assertion criteria provided clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.