NM_006231.4:c.6494G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_006231.4(POLE):c.6494G>A(p.Arg2165His) variant causes a missense change. The variant allele was found at a frequency of 0.00458 in 1,609,618 control chromosomes in the GnomAD database, including 39 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2165C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0057 ( 5 hom., cov: 33)

Exomes 𝑓: 0.0045 ( 34 hom. )

Consequence

POLE
NM_006231.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:19

Conservation

PhyloP100: 5.92

Publications

16 publications found

Variant links:

COSMIC-nc: COSV105885285

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: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, 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=0.011993051).

BP6

Variant 12-132626154-C-T is Benign according to our data. Variant chr12-132626154-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 220837.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00574 (875/152308) while in subpopulation EAS AF = 0.0108 (56/5184). AF 95% confidence interval is 0.00854. There are 5 homozygotes in GnomAd4. There are 449 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 5 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006231.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLE	NM_006231.4	MANE Select	c.6494G>A	p.Arg2165His	missense	Exon 46 of 49	NP_006222.2	Q07864

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
POLE	ENST00000320574.10	TSL:1 MANE Select	c.6494G>A	p.Arg2165His	missense	Exon 46 of 49	ENSP00000322570.5	Q07864
POLE	ENST00000535270.5	TSL:1	c.6413G>A	p.Arg2138His	missense	Exon 45 of 48	ENSP00000445753.1	F5H1D6
POLE	ENST00000537064.5	TSL:1	n.*6245G>A		non_coding_transcript_exon	Exon 46 of 49	ENSP00000442578.1	F5H7E4

Frequencies

GnomAD3 genomes

AF:

0.00576

AC:

876

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00823

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00524

Gnomad ASJ

AF:

0.00836

Gnomad EAS

AF:

0.0108

Gnomad SAS

AF:

0.0104

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.00431

Gnomad OTH

AF:

0.00861

GnomAD2 exomes

AF:

0.00589

AC:

1432

AN:

243000

AF XY:

0.00643

show subpopulations

Gnomad AFR exome

AF:

0.00887

Gnomad AMR exome

AF:

0.00273

Gnomad ASJ exome

AF:

0.0118

Gnomad EAS exome

AF:

0.00999

Gnomad FIN exome

AF:

0.000426

Gnomad NFE exome

AF:

0.00387

Gnomad OTH exome

AF:

0.00938

GnomAD4 exome

AF:

0.00446

AC:

6493

AN:

1457310

Hom.:

Cov.:

AF XY:

0.00484

AC XY:

3505

AN XY:

724614

show subpopulations

African (AFR)

AF:

0.00876

AC:

292

AN:

33352

American (AMR)

AF:

0.00293

AC:

129

AN:

44034

Ashkenazi Jewish (ASJ)

AF:

0.00925

AC:

241

AN:

26046

East Asian (EAS)

AF:

0.00574

AC:

227

AN:

39532

South Asian (SAS)

AF:

0.0144

AC:

1230

AN:

85614

European-Finnish (FIN)

AF:

0.000359

AC:

AN:

52956

Middle Eastern (MID)

AF:

0.0309

AC:

172

AN:

5574

European-Non Finnish (NFE)

AF:

0.00339

AC:

3758

AN:

1110004

Other (OTH)

AF:

0.00706

AC:

425

AN:

60198

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

399

797

1196

1594

1993

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

156

312

468

624

780

<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:

0.00574

AC:

875

AN:

152308

Hom.:

Cov.:

AF XY:

0.00603

AC XY:

449

AN XY:

74466

show subpopulations

African (AFR)

AF:

0.00820

AC:

341

AN:

41574

American (AMR)

AF:

0.00523

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00836

AC:

AN:

3470

East Asian (EAS)

AF:

0.0108

AC:

AN:

5184

South Asian (SAS)

AF:

0.0104

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.000188

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00431

AC:

293

AN:

68030

Other (OTH)

AF:

0.00852

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

122

162

203

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00504

Hom.:

Bravo

AF:

0.00637

TwinsUK

AF:

0.00270

AC:

ALSPAC

AF:

0.00234

AC:

ESP6500AA

AF:

0.00772

AC:

ESP6500EA

AF:

0.00628

AC:

ExAC

AF:

0.00600

AC:

728

Asia WGS

AF:

0.0120

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (10)

not provided (4)

Hereditary cancer-predisposing syndrome (3)

Colorectal cancer, susceptibility to, 12 (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.26

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.70

Eigen

Uncertain

0.56

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.96

MetaRNN

Benign

0.012

MetaSVM

Benign

-0.84

MutationAssessor

Pathogenic

3.3

PhyloP100

5.9

PrimateAI

Uncertain

0.54

PROVEAN

Uncertain

-3.7

REVEL

Benign

0.26

Sift

Benign

0.035

Sift4G

Uncertain

0.050

Polyphen

0.99

Vest4

0.63

MVP

0.52

MPC

0.58

ClinPred

0.042

GERP RS

3.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.37

gMVP

0.58

Mutation Taster

=89/11

polymorphism

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over