12-132687314-A-G

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PVS1PP5

The NM_006231.4(POLE):c.2T>C(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000107 in 1,501,040 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

POLE
NM_006231.4 start_lost

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:3

Conservation

PhyloP100: 2.26

Publications

3 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: Likely_pathogenic. The variant received 9 ACMG points.

PVS1

Start lost variant, next in-frame start position is after 20 pathogenic variants. Next in-frame start position is after 44 codons. Genomic position: 132681212. Lost 0.019 part of the original CDS.

PP5

Variant 12-132687314-A-G is Pathogenic according to our data. Variant chr12-132687314-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 246154.

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.2T>C	p.Met1?	start_lost	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.2T>C	p.Met1?	start_lost	Exon 1 of 49	ENSP00000322570.5	Q07864
POLE	ENST00000535270.5	TSL:1	c.2T>C	p.Met1?	start_lost	Exon 1 of 48	ENSP00000445753.1	F5H1D6
POLE	ENST00000537064.5	TSL:1	n.2T>C		non_coding_transcript_exon	Exon 1 of 49	ENSP00000442578.1	F5H7E4

Frequencies

GnomAD3 genomes

AF:

0.00000659

AC:

AN:

151838

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000276

AC:

AN:

108772

AF XY:

0.0000166

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000144

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000111

AC:

AN:

1349202

Hom.:

Cov.:

AF XY:

0.00000751

AC XY:

AN XY:

665772

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

28570

American (AMR)

AF:

0.000123

AC:

AN:

32572

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24144

East Asian (EAS)

AF:

0.0000312

AC:

AN:

32010

South Asian (SAS)

AF:

0.00

AC:

AN:

75456

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39046

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4948

European-Non Finnish (NFE)

AF:

0.00000946

AC:

AN:

1056670

Other (OTH)

AF:

0.00

AC:

AN:

55786

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000000396128), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.388

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.00000659

AC:

AN:

151838

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74160

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41408

American (AMR)

AF:

0.0000655

AC:

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5150

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10496

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67906

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000227

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

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 (1)

Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.076

BayesDel_noAF

Benign

-0.14

CADD

Benign

(source)

DANN

Benign

0.78

DEOGEN2

Benign

0.068

Eigen

Benign

-0.62

Eigen_PC

Benign

-0.66

FATHMM_MKL

Benign

0.021

LIST_S2

Uncertain

0.90

M_CAP

Pathogenic

0.70

MetaRNN

Pathogenic

0.98

MetaSVM

Benign

-0.98

PhyloP100

2.3

PROVEAN

Benign

-1.9

REVEL

Benign

0.20

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

0.067

Vest4

0.71

MutPred

0.93

Gain of catalytic residue at M1 (P = 0.0112)

MVP

0.29

ClinPred

0.39

GERP RS

3.7

PromoterAI

-0.041

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.91

gMVP

0.69

Mutation Taster

=19/181

disease causing

(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

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over