rs771490182

Positions:

chr12-132626203-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_006231.4(POLE):c.6445C>T(p.Arg2149Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000657 in 1,613,790 control chromosomes in the GnomAD database, with no homozygous occurrence. 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).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000067 ( 0 hom. )

Consequence

POLE
NM_006231.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8B:1

Conservation

PhyloP100: 3.50

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 Likely_benign. Variant got -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.10631788).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
POLE	NM_006231.4 linkuse as main transcript	c.6445C>T	p.Arg2149Cys	missense_variant	46/49	ENST00000320574.10	NP_006222.2
POLE	XM_011534795.4 linkuse as main transcript	c.6445C>T	p.Arg2149Cys	missense_variant	46/48		XP_011533097.1
POLE	XM_011534797.4 linkuse as main transcript	c.5524C>T	p.Arg1842Cys	missense_variant	38/40		XP_011533099.1
POLE	XM_011534802.4 linkuse as main transcript	c.3433C>T	p.Arg1145Cys	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.6445C>T	p.Arg2149Cys	missense_variant	46/49	1	NM_006231.4	ENSP00000322570	P1

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000997

AC:

AN:

250724

Hom.:

AF XY:

0.000125

AC XY:

AN XY:

135650

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000869

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000588

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000353

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000671

AC:

AN:

1461464

Hom.:

Cov.:

AF XY:

0.0000770

AC XY:

AN XY:

727020

show subpopulations

Gnomad4 AFR exome

AF:

0.000209

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000441

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000414

Gnomad4 OTH exome

AF:

0.0000663

GnomAD4 genome

AF:

0.0000525

AC:

AN:

152326

Hom.:

Cov.:

AF XY:

0.0000671

AC XY:

AN XY:

74502

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.0000579

Hom.:

Bravo

AF:

0.0000491

ExAC

AF:

0.000107

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jan 26, 2021	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 28, 2024	- -

Colorectal cancer, susceptibility to, 12

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	A variant of uncertain significance was detected at POLE gene (c.6445C>T). This sequence change replaces arginine with cysteine at codon 2149 of the POLE protein (p.Arg2149Cys). The arginine residue is weakly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs771490182, ExAC 0.07%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with POLE-related disease. ClinVar contains an entry for this variant (Variation ID: 405704). In-silico predictions show benign computational verdict based on 8 benign predictions from BayesDel_addAF, DEOGEN2, EIGEN, M-CAP, MVP, MutationAssessor, PrimateAI and SIFT vs 4 pathogenic predictions from DANN, FATHMM-MKL, LIST-S2 and MutationTaster but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Oct 03, 2022	The POLE c.6445C>T (p.Arg2149Cys) missense change has a maximum subpopulation frequency of 0.059% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. To our knowledge, this variant has not been reported in the literature in individuals with POLE-related disease. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Jul 31, 2024

- -

Familial colorectal cancer

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mendelics

Jul 02, 2018

- -

Colorectal cancer, susceptibility to, 12;C3554576:Facial dysmorphism-immunodeficiency-livedo-short stature syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Polymerase proofreading-related adenomatous polyposis

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics

A heterozygous missense variation in exon 46 of the POLE gene that results in the amino acid substitution of Cystine for Arginine at codon 2149 was detected. The observed variant c.6445C>T (p.Arg2149Cys) not been reported in 1000 genomes and has MAF of 0.01% in gnomAD databases. The in silico prediction of the variant is disease causing by MutationTaster2 and CADD. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.42

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.10

T;.

Eigen

Benign

0.027

Eigen_PC

Benign

0.17

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.86

D;D

M_CAP

Benign

0.0053

MetaRNN

Benign

0.11

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.85

L;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Benign

0.23

PROVEAN

Benign

-1.3

N;N

REVEL

Benign

0.051

Sift

Benign

0.092

T;T

Sift4G

Uncertain

0.053

T;T

Polyphen

0.0010

B;.

Vest4

0.22

MutPred

0.47

Gain of catalytic residue at P2147 (P = 5e-04);.;

MVP

0.45

MPC

0.26

ClinPred

0.080

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.061

gMVP

0.35

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