ClinVar Miner

Submissions for variant NM_006231.3(POLE):c.776G>A (p.Arg259His) (rs61732929)

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Total submissions: 17
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000205994 SCV000262257 benign Colorectal cancer, susceptibility to, 12 2020-12-07 criteria provided, single submitter clinical testing
Counsyl RCV000205994 SCV000489134 likely benign Colorectal cancer, susceptibility to, 12 2016-08-23 criteria provided, single submitter clinical testing
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000442441 SCV000510795 likely benign not provided 2017-01-06 criteria provided, single submitter clinical testing Converted during submission to Likely benign.
GeneDx RCV000442441 SCV000518415 likely benign not provided 2021-06-09 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 24525744, 22573403, 24480973, 29458332)
Genetic Services Laboratory, University of Chicago RCV000442749 SCV000596497 benign not specified 2019-04-20 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000442749 SCV000602099 likely benign not specified 2017-05-31 criteria provided, single submitter clinical testing
Ambry Genetics RCV000568305 SCV000671221 likely benign Hereditary cancer-predisposing syndrome 2015-06-19 criteria provided, single submitter clinical testing In silico models in agreement (benign);Subpopulation frequency in support of benign classification
PreventionGenetics,PreventionGenetics RCV000442749 SCV000806854 benign not specified 2017-01-30 criteria provided, single submitter clinical testing
Mendelics RCV000205994 SCV001138901 likely benign Colorectal cancer, susceptibility to, 12 2019-05-28 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000442441 SCV001148910 likely benign not provided 2020-02-01 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001284792 SCV001470815 likely benign none provided 2020-02-20 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000442749 SCV001478663 benign not specified 2021-01-30 criteria provided, single submitter clinical testing Variant summary: POLE c.776G>A (p.Arg259His) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0052 in 251450 control chromosomes in the gnomAD database, including 8 homozygotes. The observed variant frequency is approximately 367 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. To our knowledge, no occurrence of c.776G>A in individuals affected with POLE associated Colorectal Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Twelve clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.
True Health Diagnostics RCV000568305 SCV000788194 likely benign Hereditary cancer-predisposing syndrome 2017-11-17 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001358195 SCV001553868 likely benign Carcinoma of colon no assertion criteria provided clinical testing The POLE p.Arg259His variant was identified in 1 of 104 proband chromosomes (frequency: 0.01) from individuals or families with colon cancer (Kane 2014). The variant was identified in dbSNP (ID: rs61732929) as With other allele, ClinVar (1x as benign by Invitae; 5x as likely benign by Counsyl, GeneDx, Ambry Genetics, Children’s Mercy Hospital, and Quest Diagnostics Nichols Institute San Juan Capistrano; and 1x as uncertain significance by University of Chicago), Cosmic, and MutDB. The variant was identified in control databases in 1459 of 277200 chromosomes (8 homozygous) at a frequency of 0.005, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was seen in the following populations: African in 55 of 24024 chromosomes (freq: 0.002), Other in 24 of 6466 chromosomes (freq: 0.004), Latino in 81 of 34418 chromosomes (freq: 0.002), European Non-Finnish in 1184 of 126702 chromosomes (freq: 0.01), East Asian in 10 of 18868 chromosomes (freq: 0.0005), Finnish in 89 of 25790 chromosomes (freq: 0.003), and South Asian in 16 of 30780 chromosomes (freq: 0.0005), while the variant was not observed in the Ashkenazi Jewish population. The p.Arg259 residue is conserved in mammals but not in more distantly related organisms; however, 4 of 5 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 RCV000442441 SCV001808703 likely benign not provided no assertion criteria provided clinical testing
Clinical Genetics,Academic Medical Center RCV000442441 SCV001922942 likely benign not provided no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000442441 SCV001926813 likely benign not provided no assertion criteria provided clinical testing

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