12-132677388-C-T

Position:

chr12-132677388-C-T

Variant summary

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

The ENST00000320574.10(POLE):c.776G>A(p.Arg259His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0094 in 1,613,816 control chromosomes in the GnomAD database, including 97 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R259C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0059 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0098 ( 96 hom. )

Consequence

POLE
ENST00000320574.10 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:23

Conservation

PhyloP100: 7.87

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=0.005420238).

BP6

Variant 12-132677388-C-T is Benign according to our data. Variant chr12-132677388-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 221085.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-132677388-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00588 (895/152208) while in subpopulation NFE AF= 0.0102 (696/68010). AF 95% confidence interval is 0.0096. There are 1 homozygotes in gnomad4. There are 414 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 96 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLE	NM_006231.4 linkuse as main transcript	c.776G>A	p.Arg259His	missense_variant	8/49	ENST00000320574.10	NP_006222.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLE	ENST00000320574.10 linkuse as main transcript	c.776G>A	p.Arg259His	missense_variant	8/49	1	NM_006231.4	ENSP00000322570	P1

Frequencies

GnomAD3 genomes

AF:

0.00588

AC:

895

AN:

152090

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00227

Gnomad AMI

AF:

0.00877

Gnomad AMR

AF:

0.00347

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000576

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00273

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0102

Gnomad OTH

AF:

0.00527

GnomAD3 exomes

AF:

0.00522

AC:

1312

AN:

251450

Hom.:

AF XY:

0.00514

AC XY:

698

AN XY:

135900

show subpopulations

Gnomad AFR exome

AF:

0.00209

Gnomad AMR exome

AF:

0.00237

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000435

Gnomad SAS exome

AF:

0.000523

Gnomad FIN exome

AF:

0.00319

Gnomad NFE exome

AF:

0.00943

Gnomad OTH exome

AF:

0.00489

GnomAD4 exome

AF:

0.00977

AC:

14276

AN:

1461608

Hom.:

Cov.:

AF XY:

0.00940

AC XY:

6834

AN XY:

727124

show subpopulations

Gnomad4 AFR exome

AF:

0.00203

Gnomad4 AMR exome

AF:

0.00284

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.000202

Gnomad4 SAS exome

AF:

0.000417

Gnomad4 FIN exome

AF:

0.00300

Gnomad4 NFE exome

AF:

0.0120

Gnomad4 OTH exome

AF:

0.00836

GnomAD4 genome

AF:

0.00588

AC:

895

AN:

152208

Hom.:

Cov.:

AF XY:

0.00556

AC XY:

414

AN XY:

74404

show subpopulations

Gnomad4 AFR

AF:

0.00227

Gnomad4 AMR

AF:

0.00347

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000578

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00273

Gnomad4 NFE

AF:

0.0102

Gnomad4 OTH

AF:

0.00522

Alfa

AF:

0.00815

Hom.:

Bravo

AF:

0.00574

TwinsUK

AF:

0.0146

AC:

ALSPAC

AF:

0.0132

AC:

ESP6500AA

AF:

0.00204

AC:

ESP6500EA

AF:

0.0101

AC:

ExAC

AF:

0.00529

AC:

642

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.0104

EpiControl

AF:

0.00954

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:23

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:11

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	POLE: PM5, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 06, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 30, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 2021	This variant is associated with the following publications: (PMID: 24525744, 22573403, 24480973, 29458332) -
Likely benign, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	May 27, 2022	- -

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 20, 2019	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Jan 30, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 30, 2021	Variant summary: POLE c.776G>A (p.Arg259His) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0052 in 251450 control chromosomes in the gnomAD database, including 8 homozygotes. The observed variant frequency is approximately 367 fold of 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. To our knowledge, no occurrence of c.776G>A in individuals affected with POLE associated Colorectal Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Twelve clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 31, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -

Colorectal cancer, susceptibility to, 12

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Counsyl	Aug 23, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Nov 14, 2019	- -

Hereditary cancer-predisposing syndrome

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 19, 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. -
Likely benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Nov 17, 2017	- -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Mar 18, 2021	- -

Carcinoma of colon

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The POLE p.Arg259His variant was identified in 1 of 104 proband chromosomes (frequency: 0.01) from individuals or families with colon cancer (Kane 2014). The variant was identified in dbSNP (ID: rs61732929) as With other allele, ClinVar (1x as benign by Invitae; 5x as likely benign by Counsyl, GeneDx, Ambry Genetics, Childrenâ€šÃ„Ã´s Mercy Hospital, and Quest Diagnostics Nichols Institute San Juan Capistrano; and 1x as uncertain significance by University of Chicago), Cosmic, and MutDB. The variant was identified in control databases in 1459 of 277200 chromosomes (8 homozygous) at a frequency of 0.005, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was seen in the following populations: African in 55 of 24024 chromosomes (freq: 0.002), Other in 24 of 6466 chromosomes (freq: 0.004), Latino in 81 of 34418 chromosomes (freq: 0.002), European Non-Finnish in 1184 of 126702 chromosomes (freq: 0.01), East Asian in 10 of 18868 chromosomes (freq: 0.0005), Finnish in 89 of 25790 chromosomes (freq: 0.003), and South Asian in 16 of 30780 chromosomes (freq: 0.0005), while the variant was not observed in the Ashkenazi Jewish population. The p.Arg259 residue is conserved in mammals but not in more distantly related organisms; however, 4 of 5 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.18

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.14

T;.

Eigen

Uncertain

0.24

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

D;D

MetaRNN

Benign

0.0054

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.5

L;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-1.6

N;N

REVEL

Benign

0.14

Sift

Benign

0.20

T;T

Sift4G

Benign

0.23

T;T

Polyphen

0.13

B;B

Vest4

0.59

MVP

0.33

MPC

0.27

ClinPred

0.020

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.14

gMVP

0.51

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