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

gnomAD frequency: 0.00122  dbSNP: rs139075637

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000657034	SCV000262049	likely benign	not provided	2024-02-01	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	RCV000657034	SCV000602102	benign	not provided	2023-01-31	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	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
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.
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	RCV003491962	SCV001138900	likely benign	Hereditary cancer	2024-01-23	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000657034	SCV001148908	likely benign	not provided	2024-02-01	criteria provided, single submitter	clinical testing	POLE: BS1
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000657034	SCV002009565	uncertain significance	not provided	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
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000255185	SCV002550199	uncertain significance	not specified	2024-07-31	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000206840	SCV004018507	uncertain significance	Colorectal cancer, susceptibility to, 12	2023-04-19	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
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
PreventionGenetics, part of Exact Sciences	RCV004529001	SCV000806858	likely benign	POLE-related disorder	2024-08-02	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
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.
GenomeConnect - Invitae Patient Insights Network	RCV000206840	SCV004228522	not provided	Colorectal cancer, susceptibility to, 12		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 12-21-2015 by Lab Ambry. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.