12-132643940-T-C

Variant names:

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.4187A>G(p.Asn1396Ser) variant causes a missense change. The variant allele was found at a frequency of 0.129 in 1,613,604 control chromosomes in the GnomAD database, including 14,816 homozygotes. In-silico tool predicts 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. N1396D) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.13 ( 1426 hom., cov: 33)

Exomes 𝑓: 0.13 ( 13390 hom. )

Consequence

POLE
NM_006231.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: 4.75

Publications

32 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=0.0022000074).

BP6

Variant 12-132643940-T-C is Benign according to our data. Variant chr12-132643940-T-C is described in ClinVar as Benign. ClinVar VariationId is 380215.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.175 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLE	NM_006231.4 link	c.4187A>G	p.Asn1396Ser	missense_variant	Exon 33 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.4187A>G	p.Asn1396Ser	missense_variant	Exon 33 of 49	1	NM_006231.4	ENSP00000322570.5

Frequencies

GnomAD3 genomes

AF:

0.128

AC:

19529

AN:

152024

Hom.:

1425

Cov.:

show subpopulations

Gnomad AFR

AF:

0.151

Gnomad AMI

AF:

0.0912

Gnomad AMR

AF:

0.122

Gnomad ASJ

AF:

0.160

Gnomad EAS

AF:

0.00809

Gnomad SAS

AF:

0.186

Gnomad FIN

AF:

0.0338

Gnomad MID

AF:

0.155

Gnomad NFE

AF:

0.134

Gnomad OTH

AF:

0.136

GnomAD2 exomes

AF:

0.115

AC:

28939

AN:

251316

AF XY:

0.120

show subpopulations

Gnomad AFR exome

AF:

0.146

Gnomad AMR exome

AF:

0.0784

Gnomad ASJ exome

AF:

0.156

Gnomad EAS exome

AF:

0.00832

Gnomad FIN exome

AF:

0.0373

Gnomad NFE exome

AF:

0.132

Gnomad OTH exome

AF:

0.136

GnomAD4 exome

AF:

0.130

AC:

189344

AN:

1461462

Hom.:

13390

Cov.:

AF XY:

0.131

AC XY:

95450

AN XY:

727028

show subpopulations

African (AFR)

AF:

0.149

AC:

4998

AN:

33478

American (AMR)

AF:

0.0849

AC:

3796

AN:

44700

Ashkenazi Jewish (ASJ)

AF:

0.159

AC:

4163

AN:

26128

East Asian (EAS)

AF:

0.00413

AC:

164

AN:

39698

South Asian (SAS)

AF:

0.175

AC:

15082

AN:

86238

European-Finnish (FIN)

AF:

0.0415

AC:

2219

AN:

53414

Middle Eastern (MID)

AF:

0.156

AC:

901

AN:

5768

European-Non Finnish (NFE)

AF:

0.135

AC:

149771

AN:

1111660

Other (OTH)

AF:

0.137

AC:

8250

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

8115

16231

24346

32462

40577

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5356

10712

16068

21424

26780

<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:

0.128

AC:

19541

AN:

152142

Hom.:

1426

Cov.:

AF XY:

0.124

AC XY:

9216

AN XY:

74396

show subpopulations

African (AFR)

AF:

0.151

AC:

6274

AN:

41482

American (AMR)

AF:

0.122

AC:

1868

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.160

AC:

555

AN:

3472

East Asian (EAS)

AF:

0.00830

AC:

AN:

5180

South Asian (SAS)

AF:

0.185

AC:

893

AN:

4818

European-Finnish (FIN)

AF:

0.0338

AC:

359

AN:

10608

Middle Eastern (MID)

AF:

0.153

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.134

AC:

9132

AN:

67982

Other (OTH)

AF:

0.137

AC:

289

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

882

1764

2647

3529

4411

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

222

444

666

888

1110

<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:

0.131

Hom.:

5354

Bravo

AF:

0.134

TwinsUK

AF:

0.133

AC:

492

ALSPAC

AF:

0.127

AC:

490

ESP6500AA

AF:

0.136

AC:

601

ESP6500EA

AF:

0.135

AC:

1164

ExAC

AF:

0.118

AC:

14342

Asia WGS

AF:

0.107

AC:

372

AN:

3478

EpiCase

AF:

0.147

EpiControl

AF:

0.142

ClinVar

Significance: Benign

Submissions summary: Benign:14

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

- -

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 -

Nov 02, 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. -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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:4

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.4187A>G (p.Asn1396Ser) variant involves the alteration of a conserved nucleotide with 2/3 in silico tools (SNPs&GO and MutationTaster not captured due to low reliability index and p-value) predict a benign outcome, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 14342/121366 control chromosomes (1035 homozygotes, 1/8, freq.: 0.1181715), which significantly exceeds the estimated maximal expected allele frequency for a pathogenic POLE variant of 1/70422 (0.0000142), suggesting this variant is likely a benign polymorphism. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories. Therefore, taking all available lines of evidence into consideration, the variant of interest is classified as Benign. -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Nov 21, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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 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. -

Dec 23, 2024

Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The missense variant NM_006231.4(POLE):c.4187A>G (p.Asn1396Ser) has been reported to ClinVar as Benign with a status of (2 stars) criteria provided, multiple submitters, no conflicts (Variation ID 380215 as of 2024-12-05). The p.Asn1396Ser variant is predicted to introduce a novel acceptor splice site at this position by 3 of 4 splice site algorithms, but it's impact on the gene product is unknown. The p.Asn1396Ser missense variant is predicted to be damaging by both SIFT and PolyPhen2. The nucleotide c.4187 in POLE is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Benign -

Intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency

Benign:1

Oct 25, 2021

Genome-Nilou Lab

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

- -

Facial dysmorphism-immunodeficiency-livedo-short stature syndrome

Benign:1

Oct 25, 2021

Genome-Nilou Lab

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

0.088

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.49

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.55

D;.

Eigen

Benign

0.16

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.96

D;D

MetaRNN

Benign

0.0022

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.4

M;.

PhyloP100

4.7

PrimateAI

Benign

0.42

PROVEAN

Uncertain

-3.3

D;D

REVEL

Benign

0.067

Sift

Uncertain

0.023

D;D

Sift4G

Benign

0.064

T;T

Polyphen

0.068

B;B

Vest4

0.53

MPC

0.24

ClinPred

0.028

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.17

gMVP

0.43

Mutation Taster

=95/5

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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