ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.861T>A (p.Asp287Glu)

gnomAD frequency: 0.00083  dbSNP: rs139075637
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Total submissions: 19
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000206840 SCV000262049 likely benign Colorectal cancer, susceptibility to, 12 2021-12-17 criteria provided, single submitter clinical testing
GeneDx RCV000657034 SCV000322129 likely benign not provided 2020-08-21 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 26648449, 30374176, 30680046, 30971823, 30414346, 29454559, 29120461, 29185122, 28873162, 27720647, 27153395, 25224212, 26251183)
Counsyl RCV000206840 SCV000488769 uncertain significance Colorectal cancer, susceptibility to, 12 2016-07-05 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000255185 SCV000602102 uncertain significance not specified 2017-02-03 criteria provided, single submitter clinical testing
University of Washington Department of Laboratory Medicine,University of Washington RCV000206840 SCV000611870 likely benign Colorectal cancer, susceptibility to, 12 2018-03-28 criteria provided, single submitter research The POLE variant designated as NM_006231.2:c.861T>A (p.Asp287Glu) is classified as likely benign. This variant has been reported at a frequency of over 1 in 400 individuals in individuals with European non-Finnish ancestry (exac.broadinstitute.org). Variants present at this population frequency are unlikely to be associated with high penetrance hereditary cancer risk. Cosegregation analysis of one observed family was performed and shows a likelihood ratio of pathogenicity of 0.98 to 1 (Thompson, et al., 2003, PMID:2900794). Bayesian analysis integrating all of this data (Tavtigian et al, 2018, PMID: 29300386) gives less than 1% probability of pathogenicity, which is consistent with a classification of likely benign. This variant is not predicted to alter POLE function or modify cancer risk. This analysis was performed in conjunction with the family studies project as part of the University of Washington Find My Variant Study.
Ambry Genetics RCV000575649 SCV000671231 likely benign Hereditary cancer-predisposing syndrome 2019-09-26 criteria provided, single submitter clinical testing No disease association in small case-control study;Other data supporting benign classification
CSER _CC_NCGL, University of Washington RCV000590895 SCV000700109 uncertain significance Colorectal cancer 2016-10-01 criteria provided, single submitter research Found in patient having exome sequencing due to suspicion for hereditary colon cancer and/or polyps. Patient is a 32 year old male with gastric cancer, bladder cancer and colon polyps. Family history of gastric cancer and colon polyps. Patient also has a pathogenic variant in CDH1. This interpretation considers GERP score and allele frequency data, in addition to published reports of the variant in the literature, available at the time of review.
PreventionGenetics,PreventionGenetics RCV000657034 SCV000806858 uncertain significance not provided 2017-03-16 criteria provided, single submitter clinical testing
Mendelics RCV000709279 SCV000838710 uncertain significance Familial colorectal cancer 2018-07-02 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000255185 SCV000920077 benign not specified 2018-12-04 criteria provided, single submitter clinical testing Variant summary: POLE c.861T>A (p.Asp287Glu) results in a conservative amino acid change located in the DNA-directed DNA polymerase, family B, exonuclease domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00083 in 277192 control chromosomes, predominantly at a frequency of 0.0017 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 120-folds higher then 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.861T>A has been reported in the literature in individuals affected with cutaneous malignant melanoma, endometrial cancer and Lynch Syndrome (Aoude_2015, Billingsley_2015, Jansen_2016, Potjer_2018). Two families published by Auode_2015 indicate the variant did not segregate with disease, along with Jansen_2016 reporting a patient with the variant of interest, who had two MLH1 pathogenic somatic variants, c.208-1G>A and c.440_447del. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eleven ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) predominantly cite the variant as uncertain significance, while two cite the variant as likely benign. Based on the evidence outlined above, the variant was classified as benign.
Mendelics RCV000206840 SCV001138900 uncertain significance Colorectal cancer, susceptibility to, 12 2019-05-28 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV000657034 SCV001148908 uncertain significance not provided 2018-11-01 criteria provided, single submitter clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden RCV000206840 SCV002009565 uncertain significance Colorectal cancer, susceptibility to, 12 2021-11-03 criteria provided, single submitter clinical testing
Genetic Services Laboratory,University of Chicago RCV000255185 SCV002071583 uncertain significance not specified 2020-04-20 criteria provided, single submitter clinical testing DNA sequence analysis of the POLE gene demonstrated a sequence change, c.861T>A, in exon 9 that results in an amino acid change, p.Asp287Glu. This sequence change has been described in the gnomAD database with a frequency of 0.18% in the European sub-population (dbSNP rs139075637). The p.Asp287Glu change has been reported in one suspected Lynch syndrome patient (PMID: 26648449) and nine melanoma patients (PMID: 30414346). This sequence change has also been reported in three families with cutaneous malignant melanoma; however, incomplete segregation with disease was observed (PMID: 26251183). The p.Asp287Glu change affects a highly conserved amino acid residue located in a domain of the POLE protein that is known to be functional. The p.Asp287Glu substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Asp287Glu change remains unknown at this time.
Sema4,Sema4 RCV000575649 SCV002536950 benign Hereditary cancer-predisposing syndrome 2021-02-04 criteria provided, single submitter curation
Knight Diagnostic Laboratories, Oregon Health and Sciences University RCV000206840 SCV000493786 uncertain significance Colorectal cancer, susceptibility to, 12 2015-08-13 no assertion criteria provided clinical testing
True Health Diagnostics RCV000575649 SCV000788195 uncertain significance Hereditary cancer-predisposing syndrome 2018-02-01 no assertion criteria provided clinical testing
GenomeConnect, ClinGen RCV000657034 SCV000840126 not provided not provided no assertion provided phenotyping only GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV000255185 SCV002550199 uncertain significance not specified 2022-07-22 no assertion criteria provided clinical testing

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