rs5744751

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_006231.4(POLE):c.755C>T(p.Ala252Val) variant causes a missense change. The variant allele was found at a frequency of 0.0991 in 1,613,392 control chromosomes in the GnomAD database, including 8,666 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A252P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.077 ( 602 hom., cov: 32)

Exomes 𝑓: 0.10 ( 8064 hom. )

Consequence

POLE
NM_006231.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 5.64

Publications

48 publications found

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 Gene-Disease associations (from GenCC):

POLE-related polyposis and colorectal cancer syndrome
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
colorectal cancer, susceptibility to, 12
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
facial dysmorphism-immunodeficiency-livedo-short stature syndrome
Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency
Inheritance: AR Classification: STRONG Submitted by: G2P
IMAGe syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Polymerase proofreading-related adenomatous polyposis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

POLE links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0018293858).

BP6

Variant 12-132677409-G-A is Benign according to our data. Variant chr12-132677409-G-A is described in ClinVar as Benign. ClinVar VariationId is 380210.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.108 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLE	NM_006231.4 link	c.755C>T	p.Ala252Val	missense_variant	Exon 8 of 49	ENST00000320574.10	NP_006222.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLE	ENST00000320574.10 link	c.755C>T	p.Ala252Val	missense_variant	Exon 8 of 49	1	NM_006231.4	ENSP00000322570.5

Frequencies

GnomAD3 genomes

AF:

0.0770

AC:

11705

AN:

152046

Hom.:

602

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0178

Gnomad AMI

AF:

0.206

Gnomad AMR

AF:

0.0543

Gnomad ASJ

AF:

0.111

Gnomad EAS

AF:

0.102

Gnomad SAS

AF:

0.0576

Gnomad FIN

AF:

0.107

Gnomad MID

AF:

0.0728

Gnomad NFE

AF:

0.110

Gnomad OTH

AF:

0.0684

GnomAD2 exomes

AF:

0.0860

AC:

21621

AN:

251472

AF XY:

0.0872

show subpopulations

Gnomad AFR exome

AF:

0.0155

Gnomad AMR exome

AF:

0.0423

Gnomad ASJ exome

AF:

0.113

Gnomad EAS exome

AF:

0.109

Gnomad FIN exome

AF:

0.109

Gnomad NFE exome

AF:

0.106

Gnomad OTH exome

AF:

0.101

GnomAD4 exome

AF:

0.101

AC:

148220

AN:

1461228

Hom.:

8064

Cov.:

AF XY:

0.100

AC XY:

72931

AN XY:

726958

show subpopulations

African (AFR)

AF:

0.0153

AC:

511

AN:

33480

American (AMR)

AF:

0.0432

AC:

1931

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.112

AC:

2927

AN:

26126

East Asian (EAS)

AF:

0.109

AC:

4315

AN:

39694

South Asian (SAS)

AF:

0.0530

AC:

4570

AN:

86250

European-Finnish (FIN)

AF:

0.108

AC:

5788

AN:

53400

Middle Eastern (MID)

AF:

0.0673

AC:

388

AN:

5766

European-Non Finnish (NFE)

AF:

0.110

AC:

121816

AN:

1111422

Other (OTH)

AF:

0.0990

AC:

5974

AN:

60368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

6288

12576

18864

25152

31440

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4332

8664

12996

17328

21660

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0769

AC:

11700

AN:

152164

Hom.:

602

Cov.:

AF XY:

0.0760

AC XY:

5650

AN XY:

74380

show subpopulations

African (AFR)

AF:

0.0177

AC:

736

AN:

41522

American (AMR)

AF:

0.0542

AC:

828

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.111

AC:

385

AN:

3468

East Asian (EAS)

AF:

0.102

AC:

526

AN:

5174

South Asian (SAS)

AF:

0.0572

AC:

276

AN:

4822

European-Finnish (FIN)

AF:

0.107

AC:

1136

AN:

10594

Middle Eastern (MID)

AF:

0.0748

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.110

AC:

7457

AN:

67990

Other (OTH)

AF:

0.0691

AC:

146

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

542

1084

1627

2169

2711

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

142

284

426

568

710

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0967

Hom.:

2597

Bravo

AF:

0.0713

TwinsUK

AF:

0.110

AC:

407

ALSPAC

AF:

0.115

AC:

442

ESP6500AA

AF:

0.0159

AC:

ESP6500EA

AF:

0.107

AC:

923

ExAC

AF:

0.0857

AC:

10401

Asia WGS

AF:

0.100

AC:

346

AN:

3478

EpiCase

AF:

0.101

EpiControl

AF:

0.102

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Oct 03, 2016

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Nov 06, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

May 24, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: The POLE c.755C>T (p.Ala252Val) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a benign outcome (Mutation Taster not captured due to low p-value). This variant was found in 10401/121392 control chromosomes (545 homozygotes) at a frequency of 0.0856811, which is 6032 times the estimated maximal expected allele frequency of a pathogenic POLE variant (0.0000142), highly suggesting this variant is a benign polymorphism. The variant has been identified in patients, but not at a significantly higher frequency than in healthy controls (Kane_Cancer Res_2014). Taken together, this variant is classified as benign.

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Hereditary cancer-predisposing syndrome

Benign:2

May 21, 2015

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as 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.

Jul 10, 2025

GeneKor MSA

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Colorectal cancer, susceptibility to, 12

Benign:1

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Colorectal cancer, susceptibility to, 12;C3554576:Facial dysmorphism-immunodeficiency-livedo-short stature syndrome;C5193036:Intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency

Benign:1

Jul 13, 2020

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.53

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.029

T;.

Eigen

Benign

-0.21

Eigen_PC

Benign

-0.024

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.87

D;D

MetaRNN

Benign

0.0018

T;T

MetaSVM

Benign

-0.91

MutationAssessor

Benign

0.17

N;.

PhyloP100

5.6

PrimateAI

Benign

0.40

PROVEAN

Benign

-0.36

N;N

REVEL

Benign

0.081

Sift

Benign

0.35

T;T

Sift4G

Benign

0.56

T;T

Vest4

0.26

ClinPred

0.013

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.062

gMVP

0.35

Mutation Taster

=87/13

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over