12-132687300-C-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_006231.4(POLE):c.16G>C(p.Gly6Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00488 in 1,505,724 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G6S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0029 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0051 ( 27 hom. )

Consequence

POLE
NM_006231.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:23

Conservation

PhyloP100: -0.427

Publications

7 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: 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0046218634).

BP6

Variant 12-132687300-C-G is Benign according to our data. Variant chr12-132687300-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 218680.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00288 (438/152078) while in subpopulation NFE AF = 0.00499 (339/67942). AF 95% confidence interval is 0.00455. There are 0 homozygotes in GnomAd4. There are 195 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 27 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.16G>C	p.Gly6Arg	missense	Exon 1 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.16G>C	p.Gly6Arg	missense	Exon 1 of 49	ENSP00000322570.5	Q07864
POLE	ENST00000535270.5	TSL:1	c.16G>C	p.Gly6Arg	missense	Exon 1 of 48	ENSP00000445753.1	F5H1D6
POLE	ENST00000537064.5	TSL:1	n.16G>C		non_coding_transcript_exon	Exon 1 of 49	ENSP00000442578.1	F5H7E4

Frequencies

GnomAD3 genomes

AF:

0.00288

AC:

438

AN:

151968

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00106

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00131

Gnomad ASJ

AF:

0.00634

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.000474

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00499

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00266

AC:

293

AN:

110214

AF XY:

0.00260

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00241

Gnomad ASJ exome

AF:

0.00584

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000829

Gnomad NFE exome

AF:

0.00449

Gnomad OTH exome

AF:

0.00242

GnomAD4 exome

AF:

0.00510

AC:

6903

AN:

1353646

Hom.:

Cov.:

AF XY:

0.00505

AC XY:

3376

AN XY:

667944

show subpopulations

African (AFR)

AF:

0.000348

AC:

AN:

28764

American (AMR)

AF:

0.00265

AC:

AN:

32890

Ashkenazi Jewish (ASJ)

AF:

0.00453

AC:

110

AN:

24304

East Asian (EAS)

AF:

0.0000309

AC:

AN:

32414

South Asian (SAS)

AF:

0.000502

AC:

AN:

75762

European-Finnish (FIN)

AF:

0.000801

AC:

AN:

38696

Middle Eastern (MID)

AF:

0.00189

AC:

AN:

4762

European-Non Finnish (NFE)

AF:

0.00596

AC:

6319

AN:

1060006

Other (OTH)

AF:

0.00532

AC:

298

AN:

56048

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.442

Heterozygous variant carriers

351

703

1054

1406

1757

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

246

492

738

984

1230

<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:

0.00288

AC:

438

AN:

152078

Hom.:

Cov.:

AF XY:

0.00262

AC XY:

195

AN XY:

74366

show subpopulations

African (AFR)

AF:

0.00106

AC:

AN:

41538

American (AMR)

AF:

0.00131

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00634

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5152

South Asian (SAS)

AF:

0.000621

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.000474

AC:

AN:

10546

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00499

AC:

339

AN:

67942

Other (OTH)

AF:

0.00237

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

124

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.00266

Hom.:

Bravo

AF:

0.00316

ESP6500AA

AF:

0.000842

AC:

ESP6500EA

AF:

0.00197

AC:

ExAC

AF:

0.00138

AC:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (10)

not specified (6)

Hereditary cancer-predisposing syndrome (5)

Colorectal cancer, susceptibility to, 12 (2)

Carcinoma of colon (1)

Colorectal cancer (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.61

CADD

Benign

(source)

DANN

Benign

0.83

DEOGEN2

Benign

0.044

Eigen

Benign

-0.94

Eigen_PC

Benign

-0.95

FATHMM_MKL

Benign

0.0067

LIST_S2

Benign

0.68

M_CAP

Benign

0.074

MetaRNN

Benign

0.0046

MetaSVM

Benign

-0.91

MutationAssessor

Benign

0.55

PhyloP100

-0.43

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

-0.10

REVEL

Benign

0.032

Sift

Benign

0.22

Sift4G

Benign

0.76

Polyphen

0.0

Vest4

0.063

MVP

0.25

MPC

0.24

ClinPred

0.026

GERP RS

2.5

PromoterAI

-0.012

Neutral

(source)

Varity_R

0.025

gMVP

0.28

Mutation Taster

=100/0

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