12-132687300-C-G

Position:

chr12-132687300-C-G

Variant summary

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

The NM_006231.4(POLE):c.16G>C(p.Gly6Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00488 in 1,505,724 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G6S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0029 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0051 ( 27 hom. )

Consequence

POLE
NM_006231.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:21

Conservation

PhyloP100: -0.427

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0046218634).

BP6

Variant 12-132687300-C-G is Benign according to our data. Variant chr12-132687300-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 218680.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=10, Uncertain_significance=2, Benign=5}. Variant chr12-132687300-C-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00288 (438/152078) while in subpopulation NFE AF= 0.00499 (339/67942). AF 95% confidence interval is 0.00455. There are 0 homozygotes in gnomad4. There are 195 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 27 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLE	NM_006231.4 linkuse as main transcript	c.16G>C	p.Gly6Arg	missense_variant	1/49	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.16G>C	p.Gly6Arg	missense_variant	1/49	1	NM_006231.4	ENSP00000322570.5		Q07864

Frequencies

GnomAD3 genomes

AF:

0.00288

AC:

438

AN:

151968

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00106

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00131

Gnomad ASJ

AF:

0.00634

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.000474

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00499

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.00266

AC:

293

AN:

110214

Hom.:

AF XY:

0.00260

AC XY:

159

AN XY:

61082

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00241

Gnomad ASJ exome

AF:

0.00584

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000204

Gnomad FIN exome

AF:

0.000829

Gnomad NFE exome

AF:

0.00449

Gnomad OTH exome

AF:

0.00242

GnomAD4 exome

AF:

0.00510

AC:

6903

AN:

1353646

Hom.:

Cov.:

AF XY:

0.00505

AC XY:

3376

AN XY:

667944

show subpopulations

Gnomad4 AFR exome

AF:

0.000348

Gnomad4 AMR exome

AF:

0.00265

Gnomad4 ASJ exome

AF:

0.00453

Gnomad4 EAS exome

AF:

0.0000309

Gnomad4 SAS exome

AF:

0.000502

Gnomad4 FIN exome

AF:

0.000801

Gnomad4 NFE exome

AF:

0.00596

Gnomad4 OTH exome

AF:

0.00532

GnomAD4 genome

AF:

0.00288

AC:

438

AN:

152078

Hom.:

Cov.:

AF XY:

0.00262

AC XY:

195

AN XY:

74366

show subpopulations

Gnomad4 AFR

AF:

0.00106

Gnomad4 AMR

AF:

0.00131

Gnomad4 ASJ

AF:

0.00634

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000621

Gnomad4 FIN

AF:

0.000474

Gnomad4 NFE

AF:

0.00499

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.00266

Hom.:

Bravo

AF:

0.00316

ESP6500AA

AF:

0.000842

AC:

ESP6500EA

AF:

0.00197

AC:

ExAC

AF:

0.00138

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:21

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:8

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Nov 10, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 25, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	POLE: BS2 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
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 DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Feb 20, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

not specified

Benign:6

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 07, 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	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Apr 17, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Oct 15, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Jul 22, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 05, 2019	Variant summary: POLE c.16G>C (p.Gly6Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0027 in 110214 control chromosomes, predominantly at a frequency of 0.0045 within the Non-Finnish European subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 317 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 a benign polymorphism found primarily in populations of Non-Finnish European origin. c.16G>C has been reported in the literature in individuals affected with Colorectal Cancer (ex Kothari_2016). These report(s) do not provide unequivocal conclusions about association of the variant with Colorectal Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Nine of these ten have classified the variant as benign (n=3)/likely benign (n=6). Based on the evidence outlined above, the variant was re-evaluated as benign. -

Hereditary cancer-predisposing syndrome

Benign:3

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 06, 2019	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. -
Likely benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Dec 01, 2017	- -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Jul 31, 2020	- -

Colorectal cancer, susceptibility to, 12

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Dec 31, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Counsyl	Jul 06, 2016	- -

Carcinoma of colon

Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The POLE p.Gly6Arg variant was not identified in the literature nor was it identified in the MutDB database. The variant was identified in the following databases: dbSNP (ID: rs202220778) as â€šÃ„ÃºWith other alleleâ€šÃ„Ã¹, ClinVar and Clinvitae (9x as benign by Invitae and Ambry Genetics, as likely benign by Children's Hospital of Philadelphia, University of Washington Medical Center, Counsyl, GeneDx, Quest Diagnostics, Integrated Genetics, and as uncertain significance by Center for Pediatric Genomic Medicine). The variant was identified in control databases in 353 of 136976 chromosomes (2 homozygous) at a frequency of 0.0025 increasing the likelihood this could be a low frequency variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the African in 13 of 11652 chromosomes (freq: 0.0011), â€šÃ„ÃºOtherâ€šÃ„Ã¹ in 11 of 3924 chromosomes (freq: 0.003), Latino in 51 of 21270 chromosomes (freq: 0.002), European Non-Finnish in 220 of 52786 chromosomes (freq: 0.004), Ashkenazi Jewish in 44 of 7670 chromosomes (freq: 0.006), European Finnish in 10 of 11688 chromosomes (freq: 0.00085), and South Asian in 4 of 19714 chromosomes (freq: 0.000203). While the variant was not observed in the East Asian, populations. The p.Gly6Arg residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, 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 this variant meets our laboratory's criteria to be classified as benign. -

Colorectal cancer

Benign:1

Likely benign, criteria provided, single submitter

research

CSER _CC_NCGL, University of Washington

Nov 01, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.61

CADD

Benign

DANN

Benign

0.83

DEOGEN2

Benign

0.044

T;.

Eigen

Benign

-0.94

Eigen_PC

Benign

-0.95

FATHMM_MKL

Benign

0.0067

LIST_S2

Benign

0.68

T;T

M_CAP

Benign

0.074

MetaRNN

Benign

0.0046

T;T

MetaSVM

Benign

-0.91

MutationAssessor

Benign

0.55

N;.

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

-0.10

N;N

REVEL

Benign

0.032

Sift

Benign

0.22

T;T

Sift4G

Benign

0.76

T;T

Polyphen

0.0

B;B

Vest4

0.063

MVP

0.25

MPC

0.24

ClinPred

0.026

GERP RS

2.5

Varity_R

0.025

gMVP

0.28

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