rs143626223

Positions:

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The NM_006231.4(POLE):c.139C>T(p.Arg47Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00103 in 1,614,108 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00081 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0010 ( 0 hom. )

Consequence

POLE
NM_006231.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 3.51

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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.049753696).

BP6

Variant 12-132681203-G-A is Benign according to our data. Variant chr12-132681203-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 240391.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=6, Likely_benign=6, Benign=1}. Variant chr12-132681203-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000808 (123/152234) while in subpopulation NFE AF= 0.00129 (88/68020). AF 95% confidence interval is 0.00107. There are 0 homozygotes in gnomad4. There are 57 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLE	NM_006231.4 link	c.139C>T	p.Arg47Trp	missense_variant	2/49	ENST00000320574.10	NP_006222.2	Q07864

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLE	ENST00000320574.10 link	c.139C>T	p.Arg47Trp	missense_variant	2/49	1	NM_006231.4	ENSP00000322570.5		Q07864

Frequencies

GnomAD3 genomes

AF:

0.000802

AC:

122

AN:

152116

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00877

Gnomad AMR

AF:

0.000786

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.000661

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00129

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000787

AC:

198

AN:

251472

Hom.:

AF XY:

0.000868

AC XY:

118

AN XY:

135908

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000425

Gnomad FIN exome

AF:

0.00106

Gnomad NFE exome

AF:

0.00130

Gnomad OTH exome

AF:

0.00114

GnomAD4 exome

AF:

0.00105

AC:

1534

AN:

1461874

Hom.:

Cov.:

AF XY:

0.00102

AC XY:

742

AN XY:

727236

show subpopulations

Gnomad4 AFR exome

AF:

0.000269

Gnomad4 AMR exome

AF:

0.000134

Gnomad4 ASJ exome

AF:

0.0000765

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000568

Gnomad4 FIN exome

AF:

0.00116

Gnomad4 NFE exome

AF:

0.00122

Gnomad4 OTH exome

AF:

0.000778

GnomAD4 genome

AF:

0.000808

AC:

123

AN:

152234

Hom.:

Cov.:

AF XY:

0.000766

AC XY:

AN XY:

74436

show subpopulations

Gnomad4 AFR

AF:

0.000144

Gnomad4 AMR

AF:

0.000785

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.000661

Gnomad4 NFE

AF:

0.00129

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.00108

Hom.:

Bravo

AF:

0.000684

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.00208

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00116

AC:

ExAC

AF:

0.000865

AC:

105

EpiCase

AF:

0.00147

EpiControl

AF:

0.000830

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8Benign:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:3

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	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 04, 2022	The POLE c.139C>T; p.Arg47Trp variant (rs143626223) is reported in the literature in one individual with suspected Lynch syndrome, but without clear disease association (Kayser 2018). This variant is also reported in ClinVar (Variation ID: 240391) and is found in the general population with an overall allele frequency of 0.079% (223/282858 alleles) in the Genome Aggregation Database. The arginine at codon 47 is weakly conserved, and computational analyses predict that this variant is neutral (REVEL: 0.132). This variant is not located in the exonuclease domain (Palles 2013), and gene-disease association has not been established for variants outside of the exonuclease domain (Seifert 2019). However, given the lack of clinical and functional data, the significance of the p.Arg47Trp variant is uncertain at this time. References: Kayser et al. Copy number variation analysis and targeted NGS in 77 families with suspected Lynch syndrome reveals novel potential causative genes. Int J Cancer. 2018 Dec 1;143(11):2800-2813. PMID 29987844. Palles C et al. Germline mutations affecting the proofreading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas. Nat Genet. 2013 Feb;45(2):136-44. PMID: 23263490. Seifert BA et al. Determining the clinical validity of hereditary colorectal cancer and polyposis susceptibility genes using the Clinical Genome Resource Clinical Validity Framework. Genet Med. 2019 Jul;21(7):1507-1516. PMID: 30523343. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 19, 2021	This variant is associated with the following publications: (PMID: 29987844) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	POLE: BP4, BS1 -

not specified

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Jul 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 20, 2023	Variant summary: POLE c.139C>T (p.Arg47Trp) 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 0.00079 in 251472 control chromosomes (gnomAD), predominantly at a frequency of 0.0013 within the Non-Finnish European subpopulation in the gnomAD database. c.139C>T has been reported in the literature in individuals affected hereditary cancers (Kayser_2018, Mur_2020, Guindalini_2022) and inflammatory bowel disease (Biscaglia_2022). These reports do not provide unequivocal conclusions about association of the variant with Intrauterine Growth Retardation, Metaphyseal Dysplasia, Adrenal Hypoplasia Congenita, Genital Anomalies, And Immunodeficiency. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 34347074, 35264596, 29987844, 32792570). 13 submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments (VUS=8, likely benign=5). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Nov 26, 2016	- -

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:2

Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Jan 19, 2021	- -
Uncertain significance, no assertion criteria provided	clinical testing	True Health Diagnostics	Jul 13, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 22, 2024	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. -

Colorectal cancer, susceptibility to, 12

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Oct 19, 2024	The POLE c.139C>T (p.Arg47Trp) missense change has a maximum subpopulation frequency of 0.12% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). This variant is not located in the exonuclease domain. 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. This variant has been reported in individuals with colorectal cancer, inflammatory bowel disease, ovarian cancer, and non-cancer control individuals (PMID: 29641532, 29987844, 31240875, 32546565, 34347074). This variant was found to co-segregate in one family with glioblastoma and colorectal cancer (PMID: 37990341). 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. -
Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Sep 22, 2024	- -

Carcinoma of colon

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The POLE p.Arg47Trp variant was not identified in the literature nor was it identified in the MutDB, database. The variant was identified in dbSNP (ID: rs143626223) as "With other allele ", ClinVar (classified as likely benign by Invitae, GeneDx; as uncertain significance by Ambry Genetics and two clinical laboratories), and in Cosmic (1x in Genital tract) database. The variant was identified in control databases in 219 of 277204 chromosomes at a frequency of 0.0008 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 4 of 24032 chromosomes (freq: 0.0002), Other in 7 of 6464 chromosomes (freq: 0.001), Latino in 4 of 34420 chromosomes (freq: 0.0001), European in 161 of 126700 chromosomes (freq: 0.001), Finnish in 30 of 25784 chromosomes (freq: 0.001), and South Asian in 13 of 30782 chromosomes (freq: 0.0004), while the variant was not observed in the Ashkenazi Jewish, and East Asian, populations. The p.Arg47 residue is conserved in mammals but not in more distantly related organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume 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 the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Familial colorectal cancer

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Mendelics

Apr 09, 2024

- -

POLE-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 22, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.25

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.60

D;.

Eigen

Uncertain

0.47

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

0.98

D;D

M_CAP

Benign

0.027

MetaRNN

Benign

0.050

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.5

M;.

PrimateAI

Uncertain

0.56

PROVEAN

Pathogenic

-4.5

D;D

REVEL

Benign

0.13

Sift

Uncertain

0.0040

D;D

Sift4G

Uncertain

0.0040

D;D

Polyphen

0.99

D;D

Vest4

0.63

MVP

0.56

MPC

0.42

ClinPred

0.080

GERP RS

3.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.25

gMVP

0.61

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