rs5745068

Positions:

• chr12-132626154-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2165C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0057 (5 hom., cov: 33)
  • Exomes 𝑓: 0.0045 (34 hom.)
• Consequence: POLE NM_006231.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:18
• Conservation: PhyloP100: 5.92

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]

ACMG classification

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	UniProt
POLE	NM_006231.4	c.6494G>A	p.Arg2165His	missense_variant	46/49	ENST00000320574.10
POLE	XM_011534795.4	c.6494G>A	p.Arg2165His	missense_variant	46/48
POLE	XM_011534797.4	c.5573G>A	p.Arg1858His	missense_variant	38/40
POLE	XM_011534802.4	c.3482G>A	p.Arg1161His	missense_variant	22/24

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.00576 AC: 876 AN: 152190 Hom.: 5 Cov.: 33

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.: 7 AF XY: 0.00643 AC XY: 846 AN XY: 131578

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.: 34 Cov.: 32 AF XY: 0.00484 AC XY: 3505 AN XY: 724614

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.: 5 Cov.: 33 AF XY: 0.00603 AC XY: 449 AN XY: 74466

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.: 7

Bravo AF: 0.00637

TwinsUK AF: 0.00270 AC: 10

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.00772 AC: 34

ESP6500EA AF: 0.00628 AC: 54

ExAC AF: 0.00600 AC: 728

Asia WGS AF: 0.0120 AC: 41 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:18

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:10

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	Aug 14, 2017	- -
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, 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	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. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Jul 07, 2017	- -
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. -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 19, 2021	- -

not provided Benign:3

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	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	POLE: BS1, BS2 -

Hereditary cancer-predisposing syndrome Benign:3

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. -
Likely benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Sep 29, 2017	- -
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	T
BayesDel_noAF	Benign	-0.26
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.70	D;.
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.96	D;D
MetaRNN	Benign	0.012	T;T
MetaSVM	Benign	-0.84	T
MutationAssessor	Pathogenic	3.3	M;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.54	T
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	T
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

Other links and lift over

dbSNP: rs5745068; hg19: chr12-133202740; COSMIC: COSV105885285; COSMIC: COSV105885285;