rs5744800

Positions:

Variant summary

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

The NM_006231.4(POLE):c.2089C>T(p.Pro697Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000843 in 1,612,760 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict 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. P697R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0043 ( 4 hom., cov: 32)

Exomes 𝑓: 0.00048 ( 7 hom. )

Consequence

POLE
NM_006231.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 0.588

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=0.0044955015).

BP6

Variant 12-132668440-G-A is Benign according to our data. Variant chr12-132668440-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 240422.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-132668440-G-A is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00431 (656/152312) while in subpopulation AFR AF= 0.0151 (626/41570). AF 95% confidence interval is 0.0141. There are 4 homozygotes in gnomad4. There are 318 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 4 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLE	NM_006231.4 linkuse as main transcript	c.2089C>T	p.Pro697Ser	missense_variant	19/49	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.2089C>T	p.Pro697Ser	missense_variant	19/49	1	NM_006231.4	ENSP00000322570	P1

Frequencies

GnomAD3 genomes

AF:

0.00428

AC:

651

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0150

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000917

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.00100

AC:

251

AN:

250172

Hom.:

AF XY:

0.000769

AC XY:

104

AN XY:

135184

show subpopulations

Gnomad AFR exome

AF:

0.0124

Gnomad AMR exome

AF:

0.00102

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000545

Gnomad SAS exome

AF:

0.000197

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000530

Gnomad OTH exome

AF:

0.000329

GnomAD4 exome

AF:

0.000481

AC:

703

AN:

1460448

Hom.:

Cov.:

AF XY:

0.000441

AC XY:

320

AN XY:

726394

show subpopulations

Gnomad4 AFR exome

AF:

0.0142

Gnomad4 AMR exome

AF:

0.00126

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000675

Gnomad4 OTH exome

AF:

0.00116

GnomAD4 genome

AF:

0.00431

AC:

656

AN:

152312

Hom.:

Cov.:

AF XY:

0.00427

AC XY:

318

AN XY:

74470

show subpopulations

Gnomad4 AFR

AF:

0.0151

Gnomad4 AMR

AF:

0.000916

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.000396

Hom.:

Bravo

AF:

0.00496

ESP6500AA

AF:

0.0109

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00116

AC:

141

EpiCase

AF:

0.00

EpiControl

AF:

0.000178

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Dec 08, 2017	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Sep 29, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 26, 2019	Variant summary: POLE c.2089C>T (p.Pro697Ser) results in a non-conservative amino acid change located in the DNA-directed DNA polymerase, family B, multifunctional domain of 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 0.001 in 250172 control chromosomes, predominantly at a frequency of 0.012 within the African or African-American subpopulation in the gnomAD database, including 3 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 845 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 African or African-American origin. To our knowledge, no occurrence of c.2089C>T in individuals affected with Colorectal Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Six 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. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 09, 2018	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, 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	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 11, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jul 12, 2017	- -
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:2

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 17, 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	Apr 17, 2020	- -

Colorectal cancer, susceptibility to, 12

Benign:1

Benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

Malignant tumor of breast

Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The POLE p.Pro697Ser variant was identified in 1 of 2080 proband chromosomes (frequency: 0.0005) from individuals with advanced cancer (Mandelker 2017). The variant was identified in dbSNP (rs5744800) as â€šÃ„Ãºwith uncertain significance, other alleleâ€šÃ„Ã¹ and ClinVar (classified as benign by Invitae, GeneDx, PreventionGenetics and Quest Diagnostics; and as likely benign by Ambry Genetics, Children's Mercy Hospital and 1 other submitter). The variant was identified in control databases in 384 of 281,564 chromosomes (4 homozygous) at a frequency of 0.001 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 331 of 24,940 chromosomes (freq: 0.01, increasing the likelihood this could be a low frequency benign variant), Latino in 36 of 35,200 chromosomes (freq: 0.001), Other in 3 of 7170 chromosomes (freq: 0.004), South Asian in 6 of 30,394 chromosomes (freq: 0.0002), European in 7 of 128,630 chromosomes (freq: 0.00005), and East Asian in 1 of 19,892 chromosomes (freq: 0.00005); it was not observed in the Ashkenazi Jewish or Finnish populations. The p.Pro697 residue is conserved in in mammals but not in more distantly related organisms however 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) 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.063

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.64

CADD

Benign

0.11

DANN

Benign

0.70

DEOGEN2

Benign

0.24

T;.

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.35

LIST_S2

Benign

0.81

T;T

MetaRNN

Benign

0.0045

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

L;.

MutationTaster

Benign

0.99

N;N;N

PrimateAI

Benign

0.31

PROVEAN

Uncertain

-3.2

D;D

REVEL

Benign

0.13

Sift

Benign

0.24

T;T

Sift4G

Benign

0.56

T;T

Polyphen

0.0010

B;B

Vest4

0.074

MVP

0.11

MPC

0.21

ClinPred

0.014

GERP RS

-0.54

RBP_binding_hub_radar

1.1

RBP_regulation_power_radar

2.2

Varity_R

0.062

gMVP

0.44

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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