rs5745068

Positions:

chr12-132626154-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_006231.4(POLE):c.6494G>A(p.Arg2165His) variant causes a missense change. The variant allele was found at a frequency of 0.00458 in 1,609,618 control chromosomes in the GnomAD database, including 39 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. R2165R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0057 ( 5 hom., cov: 33)

Exomes 𝑓: 0.0045 ( 34 hom. )

Consequence

POLE
NM_006231.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:19

Conservation

PhyloP100: 5.92

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.011993051).

BP6

Variant 12-132626154-C-T is Benign according to our data. Variant chr12-132626154-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 220837.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-132626154-C-T is described in Lovd as [Benign]. Variant chr12-132626154-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00574 (875/152308) while in subpopulation EAS AF= 0.0108 (56/5184). AF 95% confidence interval is 0.00854. There are 5 homozygotes in gnomad4. There are 449 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 5 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
POLE	NM_006231.4 linkuse as main transcript	c.6494G>A	p.Arg2165His	missense_variant	46/49	ENST00000320574.10	NP_006222.2
POLE	XM_011534795.4 linkuse as main transcript	c.6494G>A	p.Arg2165His	missense_variant	46/48		XP_011533097.1
POLE	XM_011534797.4 linkuse as main transcript	c.5573G>A	p.Arg1858His	missense_variant	38/40		XP_011533099.1
POLE	XM_011534802.4 linkuse as main transcript	c.3482G>A	p.Arg1161His	missense_variant	22/24		XP_011533104.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLE	ENST00000320574.10 linkuse as main transcript	c.6494G>A	p.Arg2165His	missense_variant	46/49	1	NM_006231.4	ENSP00000322570	P1

Frequencies

GnomAD3 genomes

AF:

0.00576

AC:

876

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00823

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00524

Gnomad ASJ

AF:

0.00836

Gnomad EAS

AF:

0.0108

Gnomad SAS

AF:

0.0104

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.00431

Gnomad OTH

AF:

0.00861

GnomAD3 exomes

AF:

0.00589

AC:

1432

AN:

243000

Hom.:

AF XY:

0.00643

AC XY:

846

AN XY:

131578

show subpopulations

Gnomad AFR exome

AF:

0.00887

Gnomad AMR exome

AF:

0.00273

Gnomad ASJ exome

AF:

0.0118

Gnomad EAS exome

AF:

0.00999

Gnomad SAS exome

AF:

0.0141

Gnomad FIN exome

AF:

0.000426

Gnomad NFE exome

AF:

0.00387

Gnomad OTH exome

AF:

0.00938

GnomAD4 exome

AF:

0.00446

AC:

6493

AN:

1457310

Hom.:

Cov.:

AF XY:

0.00484

AC XY:

3505

AN XY:

724614

show subpopulations

Gnomad4 AFR exome

AF:

0.00876

Gnomad4 AMR exome

AF:

0.00293

Gnomad4 ASJ exome

AF:

0.00925

Gnomad4 EAS exome

AF:

0.00574

Gnomad4 SAS exome

AF:

0.0144

Gnomad4 FIN exome

AF:

0.000359

Gnomad4 NFE exome

AF:

0.00339

Gnomad4 OTH exome

AF:

0.00706

GnomAD4 genome

AF:

0.00574

AC:

875

AN:

152308

Hom.:

Cov.:

AF XY:

0.00603

AC XY:

449

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.00820

Gnomad4 AMR

AF:

0.00523

Gnomad4 ASJ

AF:

0.00836

Gnomad4 EAS

AF:

0.0108

Gnomad4 SAS

AF:

0.0104

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.00431

Gnomad4 OTH

AF:

0.00852

Alfa

AF:

0.00504

Hom.:

Bravo

AF:

0.00637

TwinsUK

AF:

0.00270

AC:

ALSPAC

AF:

0.00234

AC:

ESP6500AA

AF:

0.00772

AC:

ESP6500EA

AF:

0.00628

AC:

ExAC

AF:

0.00600

AC:

728

Asia WGS

AF:

0.0120

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:19

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:10

Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 14, 2017	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Jul 07, 2017	- -
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	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 29, 2018	Variant summary: POLE c.6494G>A (p.Arg2165His) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0057 in 269142 control chromosomes in the gnomAD database, including 10 homozygotes. The observed variant frequency is approximately 402 fold above the estimated maximal expected allele frequency for a pathogenic variant in POLE causing Colorectal Cancer phenotype (1.4e-05), strongly suggesting that the variant is benign. The variant c.6494G>A has been reported in the literature in individuals affected with Colorectal Cancer. These report(s) do not provide unequivocal conclusions about the association of the variant with Colorectal Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, with all laboratories classifying the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 17, 2017	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. -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 19, 2021	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The POLE p.Arg2165His variant was identified in 6 of 600 proband chromosomes (frequency: 0.01) from individuals or families with endometrial carcinoma and breast cancer (Wong 2016, Maxwell 2016). The variant was also identified in the following databases: dbSNP (ID: rs5745068) as "With other allele", ClinVar (4x likely benign, 1x benign), and Clinvitae. The variant was not identified in Cosmic or the MutDB database. The variant was identified in control databases in 1538 of 269142 chromosomes (10 homozygous) at a frequency of 0.006 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 191 of 23136 chromosomes (freq: 0.008), Other in 48 of 6318 chromosomes (freq: 0.008), Latino in 93 of 33642 chromosomes (freq: 0.003), European in 474 of 122460 chromosomes (freq: 0.004), Ashkenazi Jewish in 117 of 9978 chromosomes (freq: 0.01), East Asian in 180 of 18418 chromosomes (freq: 0.01), Finnish in 8 of 25212 chromosomes (freq: 0.0003), and South Asian in 427 of 29978 chromosomes (freq: 0.01). The p.Arg2165 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of 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 this variant meets our laboratory's criteria to be classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	POLE: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 05, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Hereditary cancer-predisposing syndrome

Benign:3

Likely benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Sep 29, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	May 26, 2015	This alteration is classified as likely 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. -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	May 11, 2021	- -

Colorectal cancer, susceptibility to, 12

Benign:2

Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Counsyl	Jun 08, 2016	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.26

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.70

D;.

Eigen

Uncertain

0.56

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.96

D;D

MetaRNN

Benign

0.012

T;T

MetaSVM

Benign

-0.84

MutationAssessor

Pathogenic

3.3

M;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.54

PROVEAN

Uncertain

-3.7

D;D

REVEL

Benign

0.26

Sift

Benign

0.035

D;D

Sift4G

Uncertain

0.050

T;T

Polyphen

0.99

D;.

Vest4

0.63

MVP

0.52

MPC

0.58

ClinPred

0.042

GERP RS

3.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.37

gMVP

0.58

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