rs5744751

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_006231.4(POLE):c.755C>T(p.Ala252Val) variant causes a missense change. The variant allele was found at a frequency of 0.0991 in 1,613,392 control chromosomes in the GnomAD database, including 8,666 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.077 ( 602 hom., cov: 32)

Exomes 𝑓: 0.10 ( 8064 hom. )

Consequence

POLE
NM_006231.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 5.64

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:

POLE (HGNC:):

POLE links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0018293858).

BP6

Variant 12-132677409-G-A is Benign according to our data. Variant chr12-132677409-G-A is described in ClinVar as [Benign]. Clinvar id is 380210.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-132677409-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.108 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLE	NM_006231.4 linkuse as main transcript	c.755C>T	p.Ala252Val	missense_variant	8/49	ENST00000320574.10	NP_006222.2	Q07864

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLE	ENST00000320574.10 linkuse as main transcript	c.755C>T	p.Ala252Val	missense_variant	8/49	1	NM_006231.4	ENSP00000322570.5		Q07864

Frequencies

GnomAD3 genomes

AF:

0.0770

AC:

11705

AN:

152046

Hom.:

602

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0178

Gnomad AMI

AF:

0.206

Gnomad AMR

AF:

0.0543

Gnomad ASJ

AF:

0.111

Gnomad EAS

AF:

0.102

Gnomad SAS

AF:

0.0576

Gnomad FIN

AF:

0.107

Gnomad MID

AF:

0.0728

Gnomad NFE

AF:

0.110

Gnomad OTH

AF:

0.0684

GnomAD3 exomes

AF:

0.0860

AC:

21621

AN:

251472

Hom.:

1088

AF XY:

0.0872

AC XY:

11852

AN XY:

135912

show subpopulations

Gnomad AFR exome

AF:

0.0155

Gnomad AMR exome

AF:

0.0423

Gnomad ASJ exome

AF:

0.113

Gnomad EAS exome

AF:

0.109

Gnomad SAS exome

AF:

0.0551

Gnomad FIN exome

AF:

0.109

Gnomad NFE exome

AF:

0.106

Gnomad OTH exome

AF:

0.101

GnomAD4 exome

AF:

0.101

AC:

148220

AN:

1461228

Hom.:

8064

Cov.:

AF XY:

0.100

AC XY:

72931

AN XY:

726958

show subpopulations

Gnomad4 AFR exome

AF:

0.0153

Gnomad4 AMR exome

AF:

0.0432

Gnomad4 ASJ exome

AF:

0.112

Gnomad4 EAS exome

AF:

0.109

Gnomad4 SAS exome

AF:

0.0530

Gnomad4 FIN exome

AF:

0.108

Gnomad4 NFE exome

AF:

0.110

Gnomad4 OTH exome

AF:

0.0990

GnomAD4 genome

AF:

0.0769

AC:

11700

AN:

152164

Hom.:

602

Cov.:

AF XY:

0.0760

AC XY:

5650

AN XY:

74380

show subpopulations

Gnomad4 AFR

AF:

0.0177

Gnomad4 AMR

AF:

0.0542

Gnomad4 ASJ

AF:

0.111

Gnomad4 EAS

AF:

0.102

Gnomad4 SAS

AF:

0.0572

Gnomad4 FIN

AF:

0.107

Gnomad4 NFE

AF:

0.110

Gnomad4 OTH

AF:

0.0691

Alfa

AF:

0.101

Hom.:

1974

Bravo

AF:

0.0713

TwinsUK

AF:

0.110

AC:

407

ALSPAC

AF:

0.115

AC:

442

ESP6500AA

AF:

0.0159

AC:

ESP6500EA

AF:

0.107

AC:

923

ExAC

AF:

0.0857

AC:

10401

Asia WGS

AF:

0.100

AC:

346

AN:

3478

EpiCase

AF:

0.101

EpiControl

AF:

0.102

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 06, 2015	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. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Oct 03, 2016	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 24, 2016	Variant summary: The POLE c.755C>T (p.Ala252Val) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a benign outcome (Mutation Taster not captured due to low p-value). This variant was found in 10401/121392 control chromosomes (545 homozygotes) at a frequency of 0.0856811, which is 6032 times the estimated maximal expected allele frequency of a pathogenic POLE variant (0.0000142), highly suggesting this variant is a benign polymorphism. The variant has been identified in patients, but not at a significantly higher frequency than in healthy controls (Kane_Cancer Res_2014). Taken together, this variant is classified as benign. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Colorectal cancer, susceptibility to, 12

Benign:1

Benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

Hereditary cancer-predisposing syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 21, 2015

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.53

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Benign

0.029

T;.

Eigen

Benign

-0.21

Eigen_PC

Benign

-0.024

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.87

D;D

MetaRNN

Benign

0.0018

T;T

MetaSVM

Benign

-0.91

MutationAssessor

Benign

0.17

N;.

PrimateAI

Benign

0.40

PROVEAN

Benign

-0.36

N;N

REVEL

Benign

0.081

Sift

Benign

0.35

T;T

Sift4G

Benign

0.56

T;T

Polyphen

0.0070

B;B

Vest4

0.26

MPC

0.21

ClinPred

0.013

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.062

gMVP

0.35

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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