rs73155056

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_StrongBS1BS2

The NM_006231.4(POLE):c.6763A>T(p.Ile2255Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00424 in 1,612,582 control chromosomes in the GnomAD database, including 40 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict 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. I2255M) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0048 ( 6 hom., cov: 33)

Exomes 𝑓: 0.0042 ( 34 hom. )

Consequence

POLE
NM_006231.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.266

Publications

5 publications found

Variant links:

COSMIC-nc: COSV104629482

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=0.002878487).

BP6

Variant 12-132624795-T-A is Benign according to our data. Variant chr12-132624795-T-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 221175.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 = 0.00485 (738/152290) while in subpopulation NFE AF = 0.00538 (366/68020). AF 95% confidence interval is 0.00493. There are 6 homozygotes in GnomAd4. There are 441 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 6 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
POLE	NM_006231.4 link	c.6763A>T	p.Ile2255Phe	missense_variant	Exon 49 of 49	ENST00000320574.10	NP_006222.2
POLE	XM_011534795.4 link	c.*385A>T		downstream_gene_variant			XP_011533097.1
POLE	XM_011534797.4 link	c.*385A>T		downstream_gene_variant			XP_011533099.1
POLE	XM_011534802.4 link	c.*385A>T		downstream_gene_variant			XP_011533104.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLE	ENST00000320574.10 link	c.6763A>T	p.Ile2255Phe	missense_variant	Exon 49 of 49	1	NM_006231.4	ENSP00000322570.5

Frequencies

GnomAD3 genomes

AF:

0.00485

AC:

738

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000603

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00314

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.0265

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00538

Gnomad OTH

AF:

0.00527

GnomAD2 exomes

AF:

0.00469

AC:

1175

AN:

250552

AF XY:

0.00451

show subpopulations

Gnomad AFR exome

AF:

0.000862

Gnomad AMR exome

AF:

0.00162

Gnomad ASJ exome

AF:

0.00228

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0261

Gnomad NFE exome

AF:

0.00421

Gnomad OTH exome

AF:

0.00391

GnomAD4 exome

AF:

0.00418

AC:

6100

AN:

1460292

Hom.:

Cov.:

AF XY:

0.00407

AC XY:

2955

AN XY:

726564

show subpopulations

African (AFR)

AF:

0.000449

AC:

AN:

33438

American (AMR)

AF:

0.00148

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00272

AC:

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.000510

AC:

AN:

86226

European-Finnish (FIN)

AF:

0.0249

AC:

1331

AN:

53408

Middle Eastern (MID)

AF:

0.000867

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00393

AC:

4363

AN:

1110564

Other (OTH)

AF:

0.00340

AC:

205

AN:

60346

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

334

668

1001

1335

1669

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

148

296

444

592

740

<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:

0.00485

AC:

738

AN:

152290

Hom.:

Cov.:

AF XY:

0.00592

AC XY:

441

AN XY:

74474

show subpopulations

African (AFR)

AF:

0.000602

AC:

AN:

41548

American (AMR)

AF:

0.00314

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00173

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.000207

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0265

AC:

281

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00538

AC:

366

AN:

68020

Other (OTH)

AF:

0.00521

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

109

146

182

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00418

Hom.:

Bravo

AF:

0.00249

TwinsUK

AF:

0.00458

AC:

ALSPAC

AF:

0.00415

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00500

AC:

ExAC

AF:

0.00432

AC:

525

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.00354

EpiControl

AF:

0.00314

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:20

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:8

Aug 31, 2017

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 14, 2018

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 25, 2017

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. -

Dec 01, 2016

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 12, 2022

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

The POLE p.Ile2255Phe variant was not identified in the literature nor was it identified in the Cosmic or MutDB databases. The variant was identified in dbSNP (ID: rs73155056) â€šÃ„ÃºWith Uncertain significance, other alleleâ€šÃ„Ã¹ and ClinVar (classified benign by Invitae and Ambry Genetics; and as likely benign by Counsyl, GeneDx, and Quest Diagnostics Nichols Insitute San Juan Capistrano). The variant was identified in control databases in 1455 (13 homozygous) of 276312 chromosomes at a frequency of 0.005, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was identified in the following populations: Finnish in 687 (12 homozygous) of 25786 chromosomes (freq: 0.03), African in 21 of 24016 chromosomes (freq: 0.0009), Other in 40 of 6460 chromosomes (freq: 0.006), Latino in 56 (1 homozygous) of 34420 chromosomes (freq: 0.002), European Non-Finnish in 612 of 125828 chromosomes (freq: 0.005), Ashkenazi Jewish in 22 of 10152 chromosomes (freq: 0.002), and South Asian in 17 of 30782 chromosomes (freq: 0.0006); it was not observed in the East Asian population. The p.Ile2255 residue is conserved in mammals but not in more distantly related organisms. However, four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood the variant Phe impacts the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign. -

not provided

Benign:7

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

POLE: BP4, BS2 -

Clinical Genetics, Academic Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Colorectal cancer, susceptibility to, 12

Benign:2

Jun 07, 2016

Counsyl

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

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:2

Nov 10, 2017

True Health Diagnostics

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jun 05, 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

Aug 20, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.43

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.23

T;.

Eigen

Benign

-0.45

Eigen_PC

Benign

-0.36

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.90

D;D

MetaRNN

Benign

0.0029

T;T

MetaSVM

Benign

-0.87

MutationAssessor

Benign

1.7

L;.

PhyloP100

0.27

PrimateAI

Benign

0.35

PROVEAN

Benign

-2.0

N;N

REVEL

Benign

0.12

Sift

Benign

0.062

T;T

Sift4G

Benign

0.071

T;T

Polyphen

0.022

B;.

Vest4

0.44

MVP

0.24

MPC

0.32

ClinPred

0.010

GERP RS

2.5

Varity_R

0.28

gMVP

0.70

Mutation Taster

=61/39

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over