12-132626230-C-T

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.6418G>A(p.Glu2140Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0187 in 1,613,774 control chromosomes in the GnomAD database, including 387 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. E2140Q) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.014 ( 25 hom., cov: 33)

Exomes 𝑓: 0.019 ( 362 hom. )

Consequence

POLE
NM_006231.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:20

Conservation

PhyloP100: 4.03

Publications

17 publications found

Variant links:

COSMIC-nc: COSV57676946

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=0.0039714277).

BP6

Variant 12-132626230-C-T is Benign according to our data. Variant chr12-132626230-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 220866.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0136 (2069/152264) while in subpopulation NFE AF = 0.0214 (1456/68012). AF 95% confidence interval is 0.0205. There are 25 homozygotes in GnomAd4. There are 955 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 25 AD,AR 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.6418G>A	p.Glu2140Lys	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.6418G>A	p.Glu2140Lys	missense	Exon 46 of 49	ENSP00000322570.5	Q07864
POLE	ENST00000535270.5	TSL:1	c.6337G>A	p.Glu2113Lys	missense	Exon 45 of 48	ENSP00000445753.1	F5H1D6
POLE	ENST00000537064.5	TSL:1	n.*6169G>A		non_coding_transcript_exon	Exon 46 of 49	ENSP00000442578.1	F5H7E4

Frequencies

GnomAD3 genomes

AF:

0.0136

AC:

2070

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00393

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.00589

Gnomad ASJ

AF:

0.00606

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00228

Gnomad FIN

AF:

0.0292

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0214

Gnomad OTH

AF:

0.00815

GnomAD2 exomes

AF:

0.0147

AC:

3687

AN:

251010

AF XY:

0.0144

show subpopulations

Gnomad AFR exome

AF:

0.00271

Gnomad AMR exome

AF:

0.00356

Gnomad ASJ exome

AF:

0.00576

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.0287

Gnomad NFE exome

AF:

0.0237

Gnomad OTH exome

AF:

0.0132

GnomAD4 exome

AF:

0.0192

AC:

28112

AN:

1461510

Hom.:

362

Cov.:

AF XY:

0.0188

AC XY:

13694

AN XY:

727064

show subpopulations

African (AFR)

AF:

0.00338

AC:

113

AN:

33478

American (AMR)

AF:

0.00449

AC:

201

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00586

AC:

153

AN:

26126

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39700

South Asian (SAS)

AF:

0.00191

AC:

165

AN:

86250

European-Finnish (FIN)

AF:

0.0286

AC:

1519

AN:

53108

Middle Eastern (MID)

AF:

0.00156

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.0225

AC:

24979

AN:

1111982

Other (OTH)

AF:

0.0161

AC:

971

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

1671

3342

5014

6685

8356

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

868

1736

2604

3472

4340

<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:

0.0136

AC:

2069

AN:

152264

Hom.:

Cov.:

AF XY:

0.0128

AC XY:

955

AN XY:

74450

show subpopulations

African (AFR)

AF:

0.00392

AC:

163

AN:

41568

American (AMR)

AF:

0.00588

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00606

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5166

South Asian (SAS)

AF:

0.00228

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.0292

AC:

310

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0214

AC:

1456

AN:

68012

Other (OTH)

AF:

0.00759

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

106

212

318

424

530

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

130

<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:

0.0194

Hom.:

128

Bravo

AF:

0.0121

TwinsUK

AF:

0.0240

AC:

ALSPAC

AF:

0.0272

AC:

105

ESP6500AA

AF:

0.00386

AC:

ESP6500EA

AF:

0.0210

AC:

181

ExAC

AF:

0.0157

AC:

1906

Asia WGS

AF:

0.00202

AC:

AN:

3478

EpiCase

AF:

0.0195

EpiControl

AF:

0.0199

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (9)

not provided (6)

Hereditary cancer-predisposing syndrome (3)

Colorectal cancer, susceptibility to, 12 (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.48

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.23

Eigen

Benign

-0.14

Eigen_PC

Benign

-0.012

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.96

MetaRNN

Benign

0.0040

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.60

PhyloP100

4.0

PrimateAI

Uncertain

0.51

PROVEAN

Uncertain

-2.5

REVEL

Benign

0.027

Sift

Benign

0.087

Sift4G

Benign

0.39

Polyphen

0.29

Vest4

0.33

MPC

0.25

ClinPred

0.016

GERP RS

3.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Varity_R

0.15

gMVP

0.34

Mutation Taster

=99/1

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over