12-132632393-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_006231.4(POLE):c.6252A>G(p.Ser2084Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.608 in 1,613,180 control chromosomes in the GnomAD database, including 301,912 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S2084S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.66 ( 33668 hom., cov: 33)

Exomes 𝑓: 0.60 ( 268244 hom. )

Consequence

POLE
NM_006231.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: -4.33

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.91).

BP6

Variant 12-132632393-T-C is Benign according to our data. Variant chr12-132632393-T-C is described in ClinVar as Benign. ClinVar VariationId is 380217.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-4.33 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.783 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLE	NM_006231.4	MANE Select	c.6252A>G	p.Ser2084Ser	synonymous	Exon 45 of 49	NP_006222.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
POLE	ENST00000320574.10	TSL:1 MANE Select	c.6252A>G	p.Ser2084Ser	synonymous	Exon 45 of 49	ENSP00000322570.5
POLE	ENST00000535270.5	TSL:1	c.6171A>G	p.Ser2057Ser	synonymous	Exon 44 of 48	ENSP00000445753.1
POLE	ENST00000537064.5	TSL:1	n.*6003A>G		non_coding_transcript_exon	Exon 45 of 49	ENSP00000442578.1

Frequencies

GnomAD3 genomes

AF:

0.659

AC:

100172

AN:

151994

Hom.:

33636

Cov.:

show subpopulations

Gnomad AFR

AF:

0.767

Gnomad AMI

AF:

0.591

Gnomad AMR

AF:

0.736

Gnomad ASJ

AF:

0.526

Gnomad EAS

AF:

0.803

Gnomad SAS

AF:

0.626

Gnomad FIN

AF:

0.579

Gnomad MID

AF:

0.630

Gnomad NFE

AF:

0.588

Gnomad OTH

AF:

0.639

GnomAD2 exomes

AF:

0.644

AC:

161809

AN:

251400

AF XY:

0.632

show subpopulations

Gnomad AFR exome

AF:

0.767

Gnomad AMR exome

AF:

0.794

Gnomad ASJ exome

AF:

0.531

Gnomad EAS exome

AF:

0.813

Gnomad FIN exome

AF:

0.577

Gnomad NFE exome

AF:

0.585

Gnomad OTH exome

AF:

0.627

GnomAD4 exome

AF:

0.603

AC:

881194

AN:

1461068

Hom.:

268244

Cov.:

AF XY:

0.602

AC XY:

437719

AN XY:

726904

show subpopulations

African (AFR)

AF:

0.766

AC:

25640

AN:

33462

American (AMR)

AF:

0.784

AC:

35075

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.532

AC:

13914

AN:

26134

East Asian (EAS)

AF:

0.806

AC:

32002

AN:

39700

South Asian (SAS)

AF:

0.610

AC:

52580

AN:

86242

European-Finnish (FIN)

AF:

0.574

AC:

30680

AN:

53414

Middle Eastern (MID)

AF:

0.620

AC:

3573

AN:

5766

European-Non Finnish (NFE)

AF:

0.586

AC:

650802

AN:

1111260

Other (OTH)

AF:

0.612

AC:

36928

AN:

60366

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

18591

37181

55772

74362

92953

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

18026

36052

54078

72104

90130

<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:

0.659

AC:

100256

AN:

152112

Hom.:

33668

Cov.:

AF XY:

0.660

AC XY:

49103

AN XY:

74348

show subpopulations

African (AFR)

AF:

0.767

AC:

31821

AN:

41514

American (AMR)

AF:

0.737

AC:

11269

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.526

AC:

1824

AN:

3470

East Asian (EAS)

AF:

0.803

AC:

4149

AN:

5166

South Asian (SAS)

AF:

0.626

AC:

3013

AN:

4814

European-Finnish (FIN)

AF:

0.579

AC:

6121

AN:

10576

Middle Eastern (MID)

AF:

0.633

AC:

186

AN:

294

European-Non Finnish (NFE)

AF:

0.588

AC:

39979

AN:

67960

Other (OTH)

AF:

0.641

AC:

1356

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1718

3435

5153

6870

8588

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

798

1596

2394

3192

3990

<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:

0.614

Hom.:

73057

Bravo

AF:

0.675

Asia WGS

AF:

0.698

AC:

2425

AN:

3478

EpiCase

AF:

0.575

EpiControl

AF:

0.575

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (5)

not provided (4)

Colorectal cancer, susceptibility to, 12 (1)

Facial dysmorphism-immunodeficiency-livedo-short stature syndrome (1)

Hereditary cancer-predisposing syndrome (1)

Intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

0.41

(source)

DANN

Benign

0.41

PhyloP100

-4.3

Mutation Taster

=75/25

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over