rs139075637

Positions:

chr12-132676594-A-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The ENST00000320574.10(POLE):c.861T>A(p.Asp287Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00135 in 1,614,080 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D287H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0012 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0014 ( 3 hom. )

Consequence

POLE
ENST00000320574.10 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8B:10O:2

Conservation

PhyloP100: 1.19

Variant links:

Genes affected

POLE (HGNC:9177): (DNA polymerase epsilon, catalytic subunit) This gene encodes the catalytic subunit of DNA polymerase epsilon. The enzyme is involved in DNA repair and chromosomal DNA replication. Mutations in this gene have been associated with colorectal cancer 12 and facial dysmorphism, immunodeficiency, livedo, and short stature. [provided by RefSeq, Sep 2013]

POLE links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.044186294).

BP6

Variant 12-132676594-A-T is Benign according to our data. Variant chr12-132676594-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 221000.We mark this variant Likely_benign, oryginal submissions are: {Benign=3, Uncertain_significance=6, Likely_benign=6, not_provided=2}. Variant chr12-132676594-A-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00116 (176/152294) while in subpopulation NFE AF= 0.00215 (146/68016). AF 95% confidence interval is 0.00186. There are 1 homozygotes in gnomad4. There are 85 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLE	NM_006231.4 linkuse as main transcript	c.861T>A	p.Asp287Glu	missense_variant	9/49	ENST00000320574.10	NP_006222.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLE	ENST00000320574.10 linkuse as main transcript	c.861T>A	p.Asp287Glu	missense_variant	9/49	1	NM_006231.4	ENSP00000322570	P1

Frequencies

GnomAD3 genomes

AF:

0.00116

AC:

176

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000290

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000917

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00215

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.000859

AC:

216

AN:

251450

Hom.:

AF XY:

0.000758

AC XY:

103

AN XY:

135908

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000924

Gnomad NFE exome

AF:

0.00179

Gnomad OTH exome

AF:

0.000814

GnomAD4 exome

AF:

0.00137

AC:

1999

AN:

1461786

Hom.:

Cov.:

AF XY:

0.00130

AC XY:

942

AN XY:

727194

show subpopulations

Gnomad4 AFR exome

AF:

0.000269

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.0000749

Gnomad4 NFE exome

AF:

0.00174

Gnomad4 OTH exome

AF:

0.000795

GnomAD4 genome

AF:

0.00116

AC:

176

AN:

152294

Hom.:

Cov.:

AF XY:

0.00114

AC XY:

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.000289

Gnomad4 AMR

AF:

0.000916

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00215

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.00177

Hom.:

Bravo

AF:

0.00111

TwinsUK

AF:

0.00458

AC:

ALSPAC

AF:

0.00182

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00128

AC:

ExAC

AF:

0.000865

AC:

105

EpiCase

AF:

0.00147

EpiControl

AF:

0.00130

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8Benign:10Other:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:4Other:1

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 21, 2020	This variant is associated with the following publications: (PMID: 26648449, 30374176, 30680046, 30971823, 30414346, 29454559, 29120461, 29185122, 28873162, 27720647, 27153395, 25224212, 26251183) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	POLE: BS1 -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jan 31, 2023	- -

Colorectal cancer, susceptibility to, 12

Uncertain:3Benign:1Other:1

Likely benign, criteria provided, single submitter	research	University of Washington Department of Laboratory Medicine, University of Washington	Mar 28, 2018	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Jul 05, 2016	- -
not provided, no classification provided	phenotyping only	GenomeConnect - Invitae Patient Insights Network	-	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. -
Uncertain significance, no assertion criteria provided	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Aug 13, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Apr 19, 2023	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. -

not specified

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 20, 2020	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Jul 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 04, 2018	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. -

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 26, 2019	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. -
Uncertain significance, no assertion criteria provided	clinical testing	True Health Diagnostics	Feb 01, 2018	- -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Feb 04, 2021	- -

Colorectal cancer

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

CSER _CC_NCGL, University of Washington

Oct 01, 2016

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. -

POLE-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 02, 2024

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). -

Hereditary cancer

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Mendelics

Jan 23, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.71

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Uncertain

0.010

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.37

T;.

Eigen

Uncertain

0.19

Eigen_PC

Benign

0.13

FATHMM_MKL

Uncertain

0.93

LIST_S2

Pathogenic

0.98

D;D

M_CAP

Benign

0.045

MetaRNN

Benign

0.044

T;T

MetaSVM

Benign

-0.68

MutationAssessor

Pathogenic

2.9

M;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Pathogenic

0.81

PROVEAN

Uncertain

-3.4

D;D

REVEL

Benign

0.29

Sift

Uncertain

0.0020

D;D

Sift4G

Uncertain

0.0040

D;D

Polyphen

1.0

D;D

Vest4

0.65

MutPred

0.37

Gain of catalytic residue at Q292 (P = 0);.;

MVP

0.37

MPC

0.75

ClinPred

0.11

GERP RS

1.9

Varity_R

0.53

gMVP

0.62

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over