ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.16G>C (p.Gly6Arg)

gnomAD frequency: 0.00293  dbSNP: rs202220778
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 22
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics,Children's Hospital of Philadelphia RCV000202795 SCV000258038 likely benign not specified 2015-07-22 criteria provided, single submitter clinical testing
CSER _CC_NCGL, University of Washington RCV000210904 SCV000264609 likely benign Colorectal cancer 2015-11-01 criteria provided, single submitter research
Invitae RCV000233156 SCV000289265 benign Colorectal cancer, susceptibility to, 12 2021-12-17 criteria provided, single submitter clinical testing
Counsyl RCV000233156 SCV000488841 likely benign Colorectal cancer, susceptibility to, 12 2016-07-06 criteria provided, single submitter clinical testing
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000432993 SCV000511481 uncertain significance not provided 2016-11-10 criteria provided, single submitter clinical testing Converted during submission to Uncertain significance.
GeneDx RCV000202795 SCV000518043 likely benign not specified 2017-12-07 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000202795 SCV000601985 likely benign not specified 2017-04-17 criteria provided, single submitter clinical testing
Ambry Genetics RCV000568177 SCV000671367 benign Hereditary cancer-predisposing syndrome 2019-11-06 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other data supporting benign classification;Other strong data supporting benign classification
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000202795 SCV000698662 benign not specified 2019-08-05 criteria provided, single submitter clinical testing Variant summary: POLE c.16G>C (p.Gly6Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0027 in 110214 control chromosomes, predominantly at a frequency of 0.0045 within the Non-Finnish European subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 317 fold of the estimated maximal expected allele frequency for a pathogenic variant in POLE causing Colorectal Cancer phenotype (1.4e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.16G>C has been reported in the literature in individuals affected with Colorectal Cancer (ex Kothari_2016). These report(s) do not provide unequivocal conclusions about association of the variant with Colorectal Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Nine of these ten have classified the variant as benign (n=3)/likely benign (n=6). Based on the evidence outlined above, the variant was re-evaluated as benign.
PreventionGenetics,PreventionGenetics RCV000432993 SCV000806726 likely benign not provided 2017-02-20 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000432993 SCV000889712 benign not provided 2018-04-17 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV000432993 SCV001148917 likely benign not provided 2022-09-01 criteria provided, single submitter clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden RCV000233156 SCV002009605 uncertain significance Colorectal cancer, susceptibility to, 12 2021-11-03 criteria provided, single submitter clinical testing
Genetic Services Laboratory,University of Chicago RCV000202795 SCV002071627 likely benign not specified 2021-10-15 criteria provided, single submitter clinical testing
Sema4,Sema4 RCV000568177 SCV002536763 benign Hereditary cancer-predisposing syndrome 2020-07-31 criteria provided, single submitter curation
True Health Diagnostics RCV000568177 SCV000788161 likely benign Hereditary cancer-predisposing syndrome 2017-12-01 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001355562 SCV001550484 benign Carcinoma of colon no assertion criteria provided clinical testing The POLE p.Gly6Arg variant was not identified in the literature nor was it identified in the MutDB database. The variant was identified in the following databases: dbSNP (ID: rs202220778) as “With other allele”, ClinVar and Clinvitae (9x as benign by Invitae and Ambry Genetics, as likely benign by Children's Hospital of Philadelphia, University of Washington Medical Center, Counsyl, GeneDx, Quest Diagnostics, Integrated Genetics, and as uncertain significance by Center for Pediatric Genomic Medicine). The variant was identified in control databases in 353 of 136976 chromosomes (2 homozygous) at a frequency of 0.0025 increasing the likelihood this could be a low frequency variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the African in 13 of 11652 chromosomes (freq: 0.0011), “Other” in 11 of 3924 chromosomes (freq: 0.003), Latino in 51 of 21270 chromosomes (freq: 0.002), European Non-Finnish in 220 of 52786 chromosomes (freq: 0.004), Ashkenazi Jewish in 44 of 7670 chromosomes (freq: 0.006), European Finnish in 10 of 11688 chromosomes (freq: 0.00085), and South Asian in 4 of 19714 chromosomes (freq: 0.000203). While the variant was not observed in the East Asian, populations. The p.Gly6Arg residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, 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 this variant meets our laboratory's criteria to be classified as benign.
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) RCV000432993 SCV001799699 likely benign not provided no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000432993 SCV001807904 likely benign not provided no assertion criteria provided clinical testing
Clinical Genetics, Academic Medical Center RCV000432993 SCV001917162 likely benign not provided no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000432993 SCV001971563 likely benign not provided no assertion criteria provided clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV000202795 SCV002550233 likely benign not specified 2022-01-18 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.