12-132632300-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_006231.4(POLE):c.6330+15G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.456 in 1,601,652 control chromosomes in the GnomAD database, including 170,711 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.50 ( 19553 hom., cov: 32)

Exomes 𝑓: 0.45 ( 151158 hom. )

Consequence

POLE
NM_006231.4 intron

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.184

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 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 (BayesDel_noAF=-0.94).

BP6

Variant 12-132632300-C-T is Benign according to our data. Variant chr12-132632300-C-T is described in ClinVar as [Benign]. Clinvar id is 380218.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-132632300-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.682 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
POLE	NM_006231.4 link	c.6330+15G>A	intron_variant	Intron 45 of 48	ENST00000320574.10	NP_006222.2	Q07864
POLE	XM_011534795.4 link	c.6330+15G>A	intron_variant	Intron 45 of 47		XP_011533097.1
POLE	XM_011534797.4 link	c.5409+15G>A	intron_variant	Intron 37 of 39		XP_011533099.1
POLE	XM_011534802.4 link	c.3318+15G>A	intron_variant	Intron 21 of 23		XP_011533104.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLE	ENST00000320574.10 link	c.6330+15G>A		intron_variant	Intron 45 of 48	1	NM_006231.4	ENSP00000322570.5		Q07864

Frequencies

GnomAD3 genomes

AF:

0.500

AC:

75845

AN:

151806

Hom.:

19538

Cov.:

show subpopulations

Gnomad AFR

AF:

0.591

Gnomad AMI

AF:

0.324

Gnomad AMR

AF:

0.543

Gnomad ASJ

AF:

0.381

Gnomad EAS

AF:

0.701

Gnomad SAS

AF:

0.559

Gnomad FIN

AF:

0.433

Gnomad MID

AF:

0.497

Gnomad NFE

AF:

0.434

Gnomad OTH

AF:

0.500

GnomAD2 exomes

AF:

0.494

AC:

122871

AN:

248930

AF XY:

0.489

show subpopulations

Gnomad AFR exome

AF:

0.584

Gnomad AMR exome

AF:

0.571

Gnomad ASJ exome

AF:

0.388

Gnomad EAS exome

AF:

0.704

Gnomad FIN exome

AF:

0.430

Gnomad NFE exome

AF:

0.430

Gnomad OTH exome

AF:

0.472

GnomAD4 exome

AF:

0.452

AC:

654914

AN:

1449730

Hom.:

151158

Cov.:

AF XY:

0.454

AC XY:

327967

AN XY:

721740

show subpopulations

Gnomad4 AFR exome

AF:

0.582

AC:

19356

AN:

33246

Gnomad4 AMR exome

AF:

0.565

AC:

25183

AN:

44566

Gnomad4 ASJ exome

AF:

0.388

AC:

10098

AN:

26042

Gnomad4 EAS exome

AF:

0.697

AC:

27627

AN:

39634

Gnomad4 SAS exome

AF:

0.546

AC:

46916

AN:

85990

Gnomad4 FIN exome

AF:

0.427

AC:

22785

AN:

53368

Gnomad4 NFE exome

AF:

0.429

AC:

472550

AN:

1101332

Gnomad4 Remaining exome

AF:

0.460

AC:

27572

AN:

59904

Heterozygous variant carriers

16094

32189

48283

64378

80472

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Exome Hom

Variant carriers

14556

29112

43668

58224

72780

<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:

0.500

AC:

75892

AN:

151922

Hom.:

19553

Cov.:

AF XY:

0.502

AC XY:

37291

AN XY:

74268

show subpopulations

Gnomad4 AFR

AF:

0.590

AC:

0.590369

AN:

0.590369

Gnomad4 AMR

AF:

0.543

AC:

0.543009

AN:

0.543009

Gnomad4 ASJ

AF:

0.381

AC:

0.381488

AN:

0.381488

Gnomad4 EAS

AF:

0.701

AC:

0.700931

AN:

0.700931

Gnomad4 SAS

AF:

0.558

AC:

0.557956

AN:

0.557956

Gnomad4 FIN

AF:

0.433

AC:

0.433384

AN:

0.433384

Gnomad4 NFE

AF:

0.434

AC:

0.433591

AN:

0.433591

Gnomad4 OTH

AF:

0.502

AC:

0.502379

AN:

0.502379

Heterozygous variant carriers

1928

3857

5785

7714

9642

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Genome Hom

Variant carriers

676

1352

2028

2704

3380

<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:

0.456

Hom.:

3077

Bravo

AF:

0.510

Asia WGS

AF:

0.578

AC:

2008

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Oct 30, 2015

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. -

Oct 03, 2016

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

not provided

Benign:4

Nov 20, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 19, 2016

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: c.6330+15G>A in POLE gene is an intronic change that involves a non-conserved nucleotide. 5/5 programs in Alamut predict that this variant does not affect normal splicing, however no functional studies supporting this notion were published at the time of evaluation. The variant is present in the control population dataset of ExAC at frequency of 49% (58808/119032 chrs tested), including numerous homozygous occurrences. The observed frequency greatly exceeds the maximum expected allele frequency for a pathogenic variant of 0.0014%, suggesting that it is a benign polymorphism. The variant of interest has not, to our knowledge, been reported in affected individuals or cited by reputable databases/clinical laboratories. Taking together, based on the prevalence of this variant in general population the variant was classified as Benign. -

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:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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

Benign:1

Oct 25, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Colorectal cancer, susceptibility to, 12

Benign:1

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

POLE-related polyposis and colorectal cancer syndrome

Benign:1

Jul 13, 2020

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Facial dysmorphism-immunodeficiency-livedo-short stature syndrome

Benign:1

Oct 25, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.94

CADD

Benign

0.59

DANN

Benign

0.47

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism (auto)

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over