12-132635996-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_006231.4(POLE):c.5707C>T(p.Leu1903Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.154 in 1,613,292 control chromosomes in the GnomAD database, including 19,799 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L1903L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.15 ( 1904 hom., cov: 33)

Exomes 𝑓: 0.15 ( 17895 hom. )

Consequence

POLE
NM_006231.4 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.271

Publications

28 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.73).

BP6

Variant 12-132635996-G-A is Benign according to our data. Variant chr12-132635996-G-A is described in CliVar as Benign. Clinvar id is 380216.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-132635996-G-A is described in CliVar as Benign. Clinvar id is 380216.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-132635996-G-A is described in CliVar as Benign. Clinvar id is 380216.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-132635996-G-A is described in CliVar as Benign. Clinvar id is 380216.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.271 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.189 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLE	NM_006231.4 link	c.5707C>T	p.Leu1903Leu	synonymous_variant	Exon 42 of 49	ENST00000320574.10	NP_006222.2	Q07864
POLE	XM_011534795.4 link	c.5707C>T	p.Leu1903Leu	synonymous_variant	Exon 42 of 48		XP_011533097.1
POLE	XM_011534797.4 link	c.4786C>T	p.Leu1596Leu	synonymous_variant	Exon 34 of 40		XP_011533099.1
POLE	XM_011534802.4 link	c.2695C>T	p.Leu899Leu	synonymous_variant	Exon 18 of 24		XP_011533104.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLE	ENST00000320574.10 link	c.5707C>T	p.Leu1903Leu	synonymous_variant	Exon 42 of 49	1	NM_006231.4	ENSP00000322570.5		Q07864

Frequencies

GnomAD3 genomes

AF:

0.153

AC:

23269

AN:

152128

Hom.:

1895

Cov.:

show subpopulations

Gnomad AFR

AF:

0.141

Gnomad AMI

AF:

0.270

Gnomad AMR

AF:

0.195

Gnomad ASJ

AF:

0.152

Gnomad EAS

AF:

0.105

Gnomad SAS

AF:

0.104

Gnomad FIN

AF:

0.146

Gnomad MID

AF:

0.158

Gnomad NFE

AF:

0.158

Gnomad OTH

AF:

0.135

GnomAD2 exomes

AF:

0.155

AC:

38817

AN:

250976

AF XY:

0.151

show subpopulations

Gnomad AFR exome

AF:

0.143

Gnomad AMR exome

AF:

0.223

Gnomad ASJ exome

AF:

0.153

Gnomad EAS exome

AF:

0.111

Gnomad FIN exome

AF:

0.147

Gnomad NFE exome

AF:

0.157

Gnomad OTH exome

AF:

0.164

GnomAD4 exome

AF:

0.154

AC:

225645

AN:

1461046

Hom.:

17895

Cov.:

AF XY:

0.152

AC XY:

110677

AN XY:

726824

show subpopulations

African (AFR)

AF:

0.143

AC:

4786

AN:

33462

American (AMR)

AF:

0.219

AC:

9796

AN:

44638

Ashkenazi Jewish (ASJ)

AF:

0.152

AC:

3975

AN:

26118

East Asian (EAS)

AF:

0.102

AC:

4057

AN:

39682

South Asian (SAS)

AF:

0.102

AC:

8815

AN:

86172

European-Finnish (FIN)

AF:

0.147

AC:

7862

AN:

53366

Middle Eastern (MID)

AF:

0.147

AC:

847

AN:

5768

European-Non Finnish (NFE)

AF:

0.159

AC:

176183

AN:

1111480

Other (OTH)

AF:

0.154

AC:

9324

AN:

60360

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

8937

17875

26812

35750

44687

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6258

12516

18774

25032

31290

<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:

0.153

AC:

23296

AN:

152246

Hom.:

1904

Cov.:

AF XY:

0.153

AC XY:

11415

AN XY:

74438

show subpopulations

African (AFR)

AF:

0.141

AC:

5850

AN:

41546

American (AMR)

AF:

0.195

AC:

2985

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.152

AC:

527

AN:

3472

East Asian (EAS)

AF:

0.105

AC:

544

AN:

5186

South Asian (SAS)

AF:

0.104

AC:

503

AN:

4826

European-Finnish (FIN)

AF:

0.146

AC:

1551

AN:

10608

Middle Eastern (MID)

AF:

0.160

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.158

AC:

10758

AN:

67994

Other (OTH)

AF:

0.135

AC:

285

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1027

2054

3082

4109

5136

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

260

520

780

1040

1300

<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:

0.155

Hom.:

3654

Bravo

AF:

0.156

Asia WGS

AF:

0.135

AC:

471

AN:

3478

EpiCase

AF:

0.148

EpiControl

AF:

0.150

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Oct 03, 2016

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

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

- -

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Clinical Genetics, Academic Medical Center

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

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 19, 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.5707C>T (p.Leu1903Leu) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a polymorphism outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may affect ESE sites. However, these predictions have yet to be confirmed by functional studies. This variant was found in 18491/120772 control chromosomes (1507 homozygotes) at a frequency of 0.1531067, which is approximately 10779 times the estimated maximal expected allele frequency of a pathogenic POLE variant (0.0000142), suggesting this variant is likely a benign polymorphism. Taken together, this variant is classified as benign. -

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

- -

Hereditary cancer-predisposing syndrome

Benign:1

May 20, 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. -

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 16, 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

BayesDel_noAF

Benign

-0.73

CADD

Benign

0.29

(source)

DANN

Benign

0.46

PhyloP100

-0.27

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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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