rs5744990

Positions:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_006231.4(POLE):c.5707C>T(p.Leu1903Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.154 in 1,613,292 control chromosomes in the GnomAD database, including 19,799 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.15 ( 1904 hom., cov: 33)

Exomes 𝑓: 0.15 ( 17895 hom. )

Consequence

POLE
NM_006231.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -0.271

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.73).

BP6

Variant 12-132635996-G-A is Benign according to our data. Variant chr12-132635996-G-A is described in ClinVar as [Benign]. Clinvar id is 380216.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-132635996-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-0.271 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.189 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.5707C>T	p.Leu1903Leu	synonymous_variant	42/49	ENST00000320574.10	NP_006222.2	Q07864
POLE	XM_011534795.4 linkuse as main transcript	c.5707C>T	p.Leu1903Leu	synonymous_variant	42/48		XP_011533097.1
POLE	XM_011534797.4 linkuse as main transcript	c.4786C>T	p.Leu1596Leu	synonymous_variant	34/40		XP_011533099.1
POLE	XM_011534802.4 linkuse as main transcript	c.2695C>T	p.Leu899Leu	synonymous_variant	18/24		XP_011533104.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLE	ENST00000320574.10 linkuse as main transcript	c.5707C>T	p.Leu1903Leu	synonymous_variant	42/49	1	NM_006231.4	ENSP00000322570.5		Q07864

Frequencies

GnomAD3 genomes

AF:

0.153

AC:

23269

AN:

152128

Hom.:

1895

Cov.:

show subpopulations

Gnomad AFR

AF:

0.141

Gnomad AMI

AF:

0.270

Gnomad AMR

AF:

0.195

Gnomad ASJ

AF:

0.152

Gnomad EAS

AF:

0.105

Gnomad SAS

AF:

0.104

Gnomad FIN

AF:

0.146

Gnomad MID

AF:

0.158

Gnomad NFE

AF:

0.158

Gnomad OTH

AF:

0.135

GnomAD3 exomes

AF:

0.155

AC:

38817

AN:

250976

Hom.:

3199

AF XY:

0.151

AC XY:

20461

AN XY:

135658

show subpopulations

Gnomad AFR exome

AF:

0.143

Gnomad AMR exome

AF:

0.223

Gnomad ASJ exome

AF:

0.153

Gnomad EAS exome

AF:

0.111

Gnomad SAS exome

AF:

0.106

Gnomad FIN exome

AF:

0.147

Gnomad NFE exome

AF:

0.157

Gnomad OTH exome

AF:

0.164

GnomAD4 exome

AF:

0.154

AC:

225645

AN:

1461046

Hom.:

17895

Cov.:

AF XY:

0.152

AC XY:

110677

AN XY:

726824

show subpopulations

Gnomad4 AFR exome

AF:

0.143

Gnomad4 AMR exome

AF:

0.219

Gnomad4 ASJ exome

AF:

0.152

Gnomad4 EAS exome

AF:

0.102

Gnomad4 SAS exome

AF:

0.102

Gnomad4 FIN exome

AF:

0.147

Gnomad4 NFE exome

AF:

0.159

Gnomad4 OTH exome

AF:

0.154

GnomAD4 genome

AF:

0.153

AC:

23296

AN:

152246

Hom.:

1904

Cov.:

AF XY:

0.153

AC XY:

11415

AN XY:

74438

show subpopulations

Gnomad4 AFR

AF:

0.141

Gnomad4 AMR

AF:

0.195

Gnomad4 ASJ

AF:

0.152

Gnomad4 EAS

AF:

0.105

Gnomad4 SAS

AF:

0.104

Gnomad4 FIN

AF:

0.146

Gnomad4 NFE

AF:

0.158

Gnomad4 OTH

AF:

0.135

Alfa

AF:

0.155

Hom.:

3043

Bravo

AF:

0.156

Asia WGS

AF:

0.135

AC:

471

AN:

3478

EpiCase

AF:

0.148

EpiControl

AF:

0.150

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	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 -
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, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Oct 03, 2016	- -

not provided

Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 19, 2016	Variant summary: The POLE c.5707C>T (p.Leu1903Leu) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a polymorphism outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may affect ESE sites. However, these predictions have yet to be confirmed by functional studies. This variant was found in 18491/120772 control chromosomes (1507 homozygotes) at a frequency of 0.1531067, which is approximately 10779 times the estimated maximal expected allele frequency of a pathogenic POLE variant (0.0000142), suggesting this variant is likely a benign polymorphism. Taken together, this variant is classified as benign. -
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 20, 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

BayesDel_noAF

Benign

-0.73

CADD

Benign

0.29

DANN

Benign

0.46

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