ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.4523G>A (p.Arg1508His)

gnomAD frequency: 0.00170  dbSNP: rs142508245
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Total submissions: 21
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000988934 SCV000289389 likely benign Colorectal cancer, susceptibility to, 12 2021-12-18 criteria provided, single submitter clinical testing
GeneDx RCV000590106 SCV000293174 likely benign not provided 2020-12-09 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 25801821, 29458332, 30171174, 29320758)
Laboratory for Molecular Medicine,Mass General Brigham Personalized Medicine RCV000236616 SCV000540088 likely benign not specified 2016-10-31 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant is not present in HGMD and has not been reported in affected individuals. It is classified in ClinVar with 1 star as Likely Benign by Invitae and VUS by GeneDx. It is present in ExAC with a frequency of 0.27% (high frequency for disease incidence and gene contribution). 2 mammals have a Histidine at this position.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000236616 SCV000602048 uncertain significance not specified 2017-03-25 criteria provided, single submitter clinical testing
Ambry Genetics RCV000566255 SCV000671258 uncertain significance Hereditary cancer-predisposing syndrome 2015-06-24 criteria provided, single submitter clinical testing The p.R1508H variant (also known as c.4523G>A), located in coding exon 35 of the POLE gene, results from a G to A substitution at nucleotide position 4523. The arginine at codon 1508 is replaced by histidine, an amino acid with highly similar properties. This variant was previously reported in the SNPDatabase as rs142508245. Based on data from the NHLBI Exome Sequencing Project (ESP), the A allele has an overall frequency of approximately 0.18% (23/13006) total alleles studied, having been observed in 0.25% (11/4406) African American alleles and 0.14% (12/8600) European American alleles. To date, this alteration has been detected with an allele frequency of approximately 0.156% (greater than 25000 alleles tested) in our clinical cohort.This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis.Since supporting evidence is limited at this time, the clinical significance of this alterationremains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000590106 SCV000698668 benign not provided 2017-06-23 criteria provided, single submitter clinical testing Variant summary: The POLE c.4523G>A (p.Arg1508His) variant involves the alteration of a conserved nucleotide. 2/4 in silico tools predict a benign outcome for this variant. This variant was found in 128/120124 control chromosomes at a frequency of 0.0010656, which is approximately 75 times the estimated maximal expected allele frequency of a pathogenic POLE variant (0.0000142), suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely benign. An internal LCA sample reports the variant to co-occur with two pathogenic MUTYH variants, c.1187G>A and c.536A>G. Taken together, this variant is classified as benign.
PreventionGenetics,PreventionGenetics RCV000590106 SCV000806784 uncertain significance not provided 2017-06-20 criteria provided, single submitter clinical testing
Mendelics RCV000709254 SCV000838685 uncertain significance Familial colorectal cancer 2018-07-02 criteria provided, single submitter clinical testing
Mendelics RCV000988934 SCV001138867 uncertain significance Colorectal cancer, susceptibility to, 12 2019-05-28 criteria provided, single submitter clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden RCV000988934 SCV002009575 uncertain significance Colorectal cancer, susceptibility to, 12 2021-11-03 criteria provided, single submitter clinical testing
Baylor Genetics RCV001788091 SCV002030281 uncertain significance Facial dysmorphism-immunodeficiency-livedo-short stature syndrome 2021-04-29 criteria provided, single submitter clinical testing This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Genetic Services Laboratory,University of Chicago RCV000236616 SCV002066968 likely benign not specified 2021-09-21 criteria provided, single submitter clinical testing
Sema4,Sema4 RCV000566255 SCV002536854 benign Hereditary cancer-predisposing syndrome 2020-11-17 criteria provided, single submitter curation
True Health Diagnostics RCV000566255 SCV000805301 uncertain significance Hereditary cancer-predisposing syndrome 2018-03-15 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001357004 SCV001552325 likely benign Carcinoma of colon no assertion criteria provided clinical testing The POLE p.Arg1508His variant was not identified in the literature. The variant was identified in dbSNP (ID: rs142508245) as "With other allele ", ClinVar (classified as benign by Integrated Genetics/Laboratory Corporation of America; as likely benign by Invitae, Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine; as uncertain significance by GeneDx, Ambry Genetics and Quest Diagnostics Nichols Institute San Juan Capistrano), Clinvitae, Cosmic (1x stomach), MutDB, or LOVD 3.0 (3x likely benign). The variant was identified in control databases in 309 of 272998 chromosomes at a frequency of 0.001 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 54 of 23804 chromosomes (freq: 0.002), Other in 9 of 6386 chromosomes (freq: 0.001), Latino in 34 of 34334 chromosomes (freq: 0.001), European in 200 of 123186 chromosomes (freq: 0.002), Ashkenazi Jewish in 6 of 10012 chromosomes (freq: 0.001), Finnish in 5 of 25736 chromosomes (freq: 0.0002), and South Asian in 1 of 30718 chromosomes (freq: 0.00003); it was not observed in the East Asian population. The p.Arg1508 residue is conserved in mammals but not in more distantly related organisms however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000590106 SCV001809102 likely benign not provided no assertion criteria provided clinical testing
Clinical Genetics Laboratory, Department of Pathology,Netherlands Cancer Institute RCV000590106 SCV001906246 likely benign not provided no assertion criteria provided clinical testing
Clinical Genetics, Academic Medical Center RCV000590106 SCV001918533 likely benign not provided no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000590106 SCV001964326 likely benign not provided no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000590106 SCV001978137 likely benign not provided no assertion criteria provided clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV000236616 SCV002550090 uncertain significance not specified 2022-05-24 no assertion criteria provided clinical testing

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