ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.6494G>A (p.Arg2165His)

gnomAD frequency: 0.00550  dbSNP: rs5745068
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Total submissions: 17
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000204118 SCV000261708 benign Colorectal cancer, susceptibility to, 12 2021-12-18 criteria provided, single submitter clinical testing
Counsyl RCV000204118 SCV000488502 likely benign Colorectal cancer, susceptibility to, 12 2016-06-08 criteria provided, single submitter clinical testing
GeneDx RCV000438859 SCV000518489 benign not specified 2017-05-17 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.
Ambry Genetics RCV000492600 SCV000581376 likely benign Hereditary cancer-predisposing syndrome 2015-05-26 criteria provided, single submitter clinical testing in silico models in agreement (benign);Subpopulation frequency in support of benign classification
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000438859 SCV000602083 likely benign not specified 2017-06-09 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000438859 SCV000806838 benign not specified 2017-07-07 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000759315 SCV000888567 benign not provided 2017-08-14 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000438859 SCV000920072 benign not specified 2018-01-29 criteria provided, single submitter clinical testing Variant summary: POLE c.6494G>A (p.Arg2165His) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0057 in 269142 control chromosomes in the gnomAD database, including 10 homozygotes. The observed variant frequency is approximately 402 fold above 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. The variant c.6494G>A has been reported in the literature in individuals affected with Colorectal Cancer. These report(s) do not provide unequivocal conclusions about the association of the variant with Colorectal Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, with all laboratories classifying the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.
CeGaT Center for Human Genetics Tuebingen RCV000759315 SCV001502158 benign not provided 2022-07-01 criteria provided, single submitter clinical testing
Genetic Services Laboratory,University of Chicago RCV000438859 SCV002065115 likely benign not specified 2021-08-19 criteria provided, single submitter clinical testing
Sema4,Sema4 RCV000492600 SCV002536916 benign Hereditary cancer-predisposing syndrome 2021-05-11 criteria provided, single submitter curation
True Health Diagnostics RCV000492600 SCV000788191 likely benign Hereditary cancer-predisposing syndrome 2017-09-29 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000438859 SCV001551484 benign not specified no assertion criteria provided clinical testing The POLE p.Arg2165His variant was identified in 6 of 600 proband chromosomes (frequency: 0.01) from individuals or families with endometrial carcinoma and breast cancer (Wong 2016, Maxwell 2016). The variant was also identified in the following databases: dbSNP (ID: rs5745068) as "With other allele", ClinVar (4x likely benign, 1x benign), and Clinvitae. The variant was not identified in Cosmic or the MutDB database. The variant was identified in control databases in 1538 of 269142 chromosomes (10 homozygous) at a frequency of 0.006 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 191 of 23136 chromosomes (freq: 0.008), Other in 48 of 6318 chromosomes (freq: 0.008), Latino in 93 of 33642 chromosomes (freq: 0.003), European in 474 of 122460 chromosomes (freq: 0.004), Ashkenazi Jewish in 117 of 9978 chromosomes (freq: 0.01), East Asian in 180 of 18418 chromosomes (freq: 0.01), Finnish in 8 of 25212 chromosomes (freq: 0.0003), and South Asian in 427 of 29978 chromosomes (freq: 0.01). The p.Arg2165 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, 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.
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000438859 SCV001808704 benign not specified no assertion criteria provided clinical testing
Clinical Genetics, Academic Medical Center RCV000438859 SCV001917021 benign not specified no assertion criteria provided clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV000438859 SCV001953348 benign not specified no assertion criteria provided clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV000438859 SCV002550033 benign not specified 2021-08-27 no assertion criteria provided clinical testing

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