chr12-132643252-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_006231.4(POLE):c.4523G>A(p.Arg1508His) variant causes a missense change. The variant allele was found at a frequency of 0.00178 in 1,613,782 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0016 ( 0 hom., cov: 34)

Exomes 𝑓: 0.0018 ( 3 hom. )

Consequence

POLE
NM_006231.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:17

Conservation

PhyloP100: 6.09

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 made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.011168927).

BP6

Variant 12-132643252-C-T is Benign according to our data. Variant chr12-132643252-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 240525.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=6, Benign=4, Uncertain_significance=5}. Variant chr12-132643252-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00156 (237/152342) while in subpopulation AFR AF= 0.00214 (89/41578). AF 95% confidence interval is 0.00178. There are 0 homozygotes in gnomad4. There are 102 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLE	NM_006231.4 link	c.4523G>A	p.Arg1508His	missense_variant	Exon 35 of 49	ENST00000320574.10	NP_006222.2	Q07864

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLE	ENST00000320574.10 link	c.4523G>A	p.Arg1508His	missense_variant	Exon 35 of 49	1	NM_006231.4	ENSP00000322570.5		Q07864

Frequencies

GnomAD3 genomes

AF:

0.00156

AC:

237

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00215

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000589

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00193

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.00110

AC:

272

AN:

247234

Hom.:

AF XY:

0.00110

AC XY:

147

AN XY:

133854

show subpopulations

Gnomad AFR exome

AF:

0.00250

Gnomad AMR exome

AF:

0.00107

Gnomad ASJ exome

AF:

0.000604

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.00160

Gnomad OTH exome

AF:

0.00149

GnomAD4 exome

AF:

0.00180

AC:

2637

AN:

1461440

Hom.:

Cov.:

AF XY:

0.00177

AC XY:

1290

AN XY:

726980

show subpopulations

Gnomad4 AFR exome

AF:

0.00203

Gnomad4 AMR exome

AF:

0.00114

Gnomad4 ASJ exome

AF:

0.000765

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.000207

Gnomad4 NFE exome

AF:

0.00217

Gnomad4 OTH exome

AF:

0.00124

GnomAD4 genome

AF:

0.00156

AC:

237

AN:

152342

Hom.:

Cov.:

AF XY:

0.00137

AC XY:

102

AN XY:

74504

show subpopulations

Gnomad4 AFR

AF:

0.00214

Gnomad4 AMR

AF:

0.000588

Gnomad4 ASJ

AF:

0.000865

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.00193

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00164

Hom.:

Bravo

AF:

0.00162

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.00182

AC:

ESP6500AA

AF:

0.00250

AC:

ESP6500EA

AF:

0.00140

AC:

ExAC

AF:

0.00107

AC:

130

EpiCase

AF:

0.000981

EpiControl

AF:

0.00113

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6Benign:17

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:10

Jan 09, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

POLE: BP4, BS2 -

Jun 23, 2017

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The POLE c.4523G>A (p.Arg1508His) variant involves the alteration of a conserved nucleotide. 2/4 in silico tools predict a benign outcome for this variant. This variant was found in 128/120124 control chromosomes at a frequency of 0.0010656, which is approximately 75 times the estimated maximal expected allele frequency of a pathogenic POLE variant (0.0000142), suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely benign. An internal LCA sample reports the variant to co-occur with two pathogenic MUTYH variants, c.1187G>A and c.536A>G. Taken together, this variant is classified as benign. -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 16, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BS1 -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 09, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 25801821, 29458332, 30171174, 29320758) -

Clinical Genetics, Academic Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified

Uncertain:2Benign:2

Mar 25, 2017

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 31, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely 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: This variant is not present in HGMD and has not been reported in affected individuals. It is classified in ClinVar with 1 star as Likely Benign by Invitae and VUS by GeneDx. It is present in ExAC with a frequency of 0.27% (high frequency for disease incidence and gene contribution). 2 mammals have a Histidine at this position. -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 21, 2021

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:2

Nov 17, 2020

Sema4, Sema4

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Feb 28, 2024

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Mar 15, 2018

True Health Diagnostics

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Facial dysmorphism-immunodeficiency-livedo-short stature syndrome

Uncertain:1

Apr 29, 2021

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Carcinoma of colon

Benign:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The POLE p.Arg1508His variant was not identified in the literature. The variant was identified in dbSNP (ID: rs142508245) as "With other allele ", ClinVar (classified as benign by Integrated Genetics/Laboratory Corporation of America; as likely benign by Invitae, Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine; as uncertain significance by GeneDx, Ambry Genetics and Quest Diagnostics Nichols Institute San Juan Capistrano), Clinvitae, Cosmic (1x stomach), MutDB, or LOVD 3.0 (3x likely benign). The variant was identified in control databases in 309 of 272998 chromosomes at a frequency of 0.001 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 54 of 23804 chromosomes (freq: 0.002), Other in 9 of 6386 chromosomes (freq: 0.001), Latino in 34 of 34334 chromosomes (freq: 0.001), European in 200 of 123186 chromosomes (freq: 0.002), Ashkenazi Jewish in 6 of 10012 chromosomes (freq: 0.001), Finnish in 5 of 25736 chromosomes (freq: 0.0002), and South Asian in 1 of 30718 chromosomes (freq: 0.00003); it was not observed in the East Asian population. The p.Arg1508 residue is conserved in mammals but not in more distantly related organisms however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

Colorectal cancer, susceptibility to, 12

Benign:1

Aug 22, 2023

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

POLE-related disorder

Benign:1

Mar 17, 2022

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.41

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Uncertain

0.43

T;.

Eigen

Benign

-0.26

Eigen_PC

Benign

-0.11

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.85

D;T

M_CAP

Benign

0.0093

MetaRNN

Benign

0.011

T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

1.2

L;.

PrimateAI

Benign

0.44

PROVEAN

Uncertain

-2.6

D;D

REVEL

Benign

0.28

Sift

Benign

0.085

T;T

Sift4G

Benign

0.11

T;T

Polyphen

0.0020

B;B

Vest4

0.34

MVP

0.35

MPC

0.24

ClinPred

0.049

GERP RS

5.1

Varity_R

0.14

gMVP

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