ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.2090C>G (p.Pro697Arg)

dbSNP: rs36120395
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 18
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000988952 SCV000289287 likely benign Colorectal cancer, susceptibility to, 12 2021-12-18 criteria provided, single submitter clinical testing
GeneDx RCV000657066 SCV000293173 likely benign not provided 2021-03-29 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 28717660, 28873162, 27244218, 31780696)
Laboratory for Molecular Medicine,Mass General Brigham Personalized Medicine RCV000235798 SCV000540090 uncertain significance not specified 2016-10-13 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: Variant not in HGMD, conflicting classifications in ClinVar. MaxMAF = 0.13%. AA not conserved but Arg not in any species.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000235798 SCV000601995 uncertain significance not specified 2017-01-20 criteria provided, single submitter clinical testing
Ambry Genetics RCV000565117 SCV000671278 uncertain significance Hereditary cancer-predisposing syndrome 2015-05-15 criteria provided, single submitter clinical testing There is insufficient or conflicting evidence for classification of this alteration.
PreventionGenetics,PreventionGenetics RCV000657066 SCV000806739 likely benign not provided 2017-05-04 criteria provided, single submitter clinical testing
Mendelics RCV000709270 SCV000838701 uncertain significance Familial colorectal cancer 2018-07-02 criteria provided, single submitter clinical testing
Mendelics RCV000988952 SCV001138893 uncertain significance Colorectal cancer, susceptibility to, 12 2019-05-28 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000235798 SCV001370689 likely benign not specified 2020-05-26 criteria provided, single submitter clinical testing Variant summary: POLE c.2090C>G (p.Pro697Arg) results in a non-conservative amino acid change located in the DNA-directed DNA polymerase, family B, multifunctional domain (IPR006134) of 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 0.00091 in 249370 control chromosomes in the gnomAD database, including 1 homozygotes. The observed variant frequency is approximately 64 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 benign. c.2090C>G has been reported in the literature in sequencing studies of individuals affected with colorectal cancer, and breast cancer (example, Bonache_2018, Kothari_2016). These report(s) do not provide unequivocal conclusions about association of the variant with Colorectal Cancer. At-least one co-occurrence with another pathogenic variant has been observed at our laboratory ( BRCA2 c.4271delC , p.Ser1424LeufsX24), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign, n=2; VUS, n=7). Based on the evidence outlined above, the variant was classified as likely benign.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000657066 SCV002048173 likely benign not provided 2020-10-20 criteria provided, single submitter clinical testing
Genetic Services Laboratory,University of Chicago RCV000235798 SCV002071550 uncertain significance not specified 2021-09-22 criteria provided, single submitter clinical testing DNA sequence analysis of the POLE gene demonstrated a sequence change, c.2090C>G, in exon 19 that results in an amino acid change, p.Pro697Arg. This sequence change has been described in the gnomAD database with a frequency of 0.15% in the European sub-population (dbSNP rs36120395). The p.Pro697Arg change has been identified in two BRCA1/BRCA2-negative individuals with a personal history of breast cancer (PMID: 31780696). The p.Pro697Arg change affects a highly conserved amino acid residue located in a domain of the POLE protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Pro697Arg substitution. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Pro697Arg change remains unknown at this time.
Sema4,Sema4 RCV000565117 SCV002536774 likely benign Hereditary cancer-predisposing syndrome 2021-07-03 criteria provided, single submitter curation
True Health Diagnostics RCV000565117 SCV000788165 uncertain significance Hereditary cancer-predisposing syndrome 2017-11-30 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000657066 SCV001553477 uncertain significance not provided no assertion criteria provided clinical testing The POLE p.Pro697Arg variant was identified in 1 of 72 proband chromosomes (frequency: 0.01) from individuals or families with personal or familial history of cancer (Cabanillas 2017). The variant was also identified in dbSNP (ID: rs36120395) as "With Uncertain significance allele", ClinVar (classified as likely benign by Invitae and PreventionGenetics; as uncertain significance by GeneDx, Ambry Genetics and four other submitters). The variant was identified in control databases in 257 of 275186 chromosomes (1 homozygous) at a frequency of 0.0009 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 10 of 23976 chromosomes (freq: 0.0004), Other in 8 of 6408 chromosomes (freq: 0.001), Latino in 39 of 34078 chromosomes (freq: 0.001), European in 190 of 125844 chromosomes (freq: 0.002), Finnish in 8 of 25670 chromosomes (freq: 0.0003), and South Asian in 2 of 30444 chromosomes (freq: 0.00007), while the variant was not observed in the Ashkenazi Jewish, and East Asian, populations. The p.Pro697 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) 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. This variant is classified as a variant of uncertain significance.
Clinical Genetics, Academic Medical Center RCV000657066 SCV001917041 likely benign not provided no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000657066 SCV001926416 likely benign not provided no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000657066 SCV001970029 likely benign not provided no assertion criteria provided clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV000235798 SCV002550162 uncertain significance not specified 2022-05-24 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.