ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.861T>A (p.Asp287Glu) (rs139075637)

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Total submissions: 15
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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 2019-12-31 criteria provided, single submitter clinical testing
GeneDx RCV000657034 SCV000322129 uncertain significance not provided 2019-01-09 criteria provided, single submitter clinical testing This variant is denoted POLE c.861T>A at the cDNA level, p.Asp287Glu (D287E) at the protein level, and results in the change of an Aspartic Acid to a Glutamic Acid (GAT>GAA). This variant has been observed in at least three individuals with colorectal cancer as well as in individuals with other cancer types (Jansen 2016, Maxwell 2016, Buchanan 2017, Mandelker 2017). It has also been observed in three families with cutaneous malignant melanoma; however, it was found to incompletely segregate with disease in some of these families (Aoude 2015). POLE Asp287Glu was observed at an allele frequency of 0.17% (216/126,694) in individuals of European ancestry in large population cohorts (Lek 2016). This variant is located within motif I of the Exonuclease domain (Preston 2010). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether POLE Asp287Glu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
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 ( 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 COLORECTAL CANCER 2018-07-02 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America 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 Praxis fuer Humangenetik Tuebingen RCV000657034 SCV001148908 uncertain significance not provided 2019-01-01 criteria provided, single submitter clinical testing
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.

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