rs755709875

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_006231.4(POLE):c.431A>G(p.His144Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000615 in 1,609,384 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H144N) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000059 ( 0 hom. )

Consequence

POLE
NM_006231.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:13

Conservation

PhyloP100: 7.94

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 was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.889

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLE	NM_006231.4 link	c.431A>G	p.His144Arg	missense_variant	Exon 6 of 49	ENST00000320574.10	NP_006222.2	Q07864

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLE	ENST00000320574.10 link	c.431A>G	p.His144Arg	missense_variant	Exon 6 of 49	1	NM_006231.4	ENSP00000322570.5		Q07864

Frequencies

GnomAD3 genomes

AF:

0.0000854

AC:

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000598

AC:

AN:

251020

AF XY:

0.0000737

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000794

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.0000590

AC:

AN:

1457198

Hom.:

Cov.:

AF XY:

0.0000622

AC XY:

AN XY:

723750

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

AC:

AN:

33396

Gnomad4 AMR exome

AF:

0.00

AC:

AN:

44628

Gnomad4 ASJ exome

AF:

0.00

AC:

AN:

26100

Gnomad4 EAS exome

AF:

0.00

AC:

AN:

39554

Gnomad4 SAS exome

AF:

0.0000580

AC:

AN:

86172

Gnomad4 FIN exome

AF:

0.00

AC:

AN:

53396

Gnomad4 NFE exome

AF:

0.0000650

AC:

AN:

1108002

Gnomad4 Remaining exome

AF:

0.0000997

AC:

AN:

60190

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000854

AC:

AN:

152186

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74340

show subpopulations

Gnomad4 AFR

AF:

0.0000483

AC:

0.0000482602

AN:

0.0000482602

Gnomad4 AMR

AF:

0.0000654

AC:

0.000065445

AN:

0.000065445

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.00

AC:

AN:

Gnomad4 FIN

AF:

0.00

AC:

AN:

Gnomad4 NFE

AF:

0.000147

AC:

0.000146981

AN:

0.000146981

Gnomad4 OTH

AF:

0.00

AC:

AN:

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000266

Hom.:

Bravo

AF:

0.0000642

ExAC

AF:

0.0000659

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:6

Jun 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 22, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 144 of the POLE protein (p.His144Arg). This variant is present in population databases (rs755709875, gnomAD 0.01%). This missense change has been observed in individual(s) with colorectal cancer (PMID: 29212164). ClinVar contains an entry for this variant (Variation ID: 405687). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt POLE protein function with a positive predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Mar 16, 2020

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 07, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Observed in individuals with a personal or family history of breast/ovarian cancer, colorectal cancer and/or polyps cancer (PMID: 29212164, 32522261, 35980532); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32522261, 29212164, 35980532) -

Apr 02, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Uncertain:2

Aug 14, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.His144Arg variant in POLE has not been previously reported in individuals with colorectal cancer but has been reported by other clinical laboratories in C linVar (Variation ID: 405687). It has also been identified in 3/30758 South Asia n chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadins titute.org; dbSNP rs755709875). Computational prediction tools and conservation analysis suggest that the p.His144Arg variant may impact the protein, though thi s information is not predictive enough to determine pathogenicity. In summary, t he clinical significance of the p.His144Arg variant is uncertain. ACMG/AMP Crite ria applied: PP3, PM2. -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Colorectal cancer, susceptibility to, 12;C3554576:Facial dysmorphism-immunodeficiency-livedo-short stature syndrome;C5193036:Intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency

Uncertain:2

Dec 27, 2023

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 08, 2025

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Colorectal cancer, susceptibility to, 12

Uncertain:1

Aug 14, 2021

MGZ Medical Genetics Center

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

POLE-related disorder

Uncertain:1

Dec 11, 2023

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The POLE c.431A>G variant is predicted to result in the amino acid substitution p.His144Arg. This variant was identified in an individual affected with colorectal cancer whose tumor was microsatellite stable, but the variant was classified as uncertain (Table S3, Raskin et al. 2017. PubMed ID: 29212164). This variant was also described in an individual who underwent hereditary cancer testing; however, other variants of uncertain significance in other genes were also present (Velaquez et al. 2020. PubMed ID: 32522261, Table S1). This variant is reported in 0.0098% of alleles in individuals of South Asian descent in gnomAD and is classified in ClinVar as a variant of uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/405687/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Hereditary cancer-predisposing syndrome

Uncertain:1

Dec 18, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.H144R variant (also known as c.431A>G), located in coding exon 6 of the POLE gene, results from an A to G substitution at nucleotide position 431. The histidine at codon 144 is replaced by arginine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Pathogenic

0.16

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.60

D;.

Eigen

Pathogenic

0.90

Eigen_PC

Pathogenic

0.83

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

1.0

D;D

M_CAP

Benign

0.065

MetaRNN

Pathogenic

0.89

D;D

MetaSVM

Benign

-1.1

MutationAssessor

Pathogenic

3.3

M;.

PrimateAI

Pathogenic

0.85

PROVEAN

Pathogenic

-7.2

D;D

REVEL

Uncertain

0.63

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.96

MutPred

0.72

Gain of catalytic residue at L139 (P = 0.0098);.;

MVP

0.58

MPC

0.86

ClinPred

0.80

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.93

gMVP

0.82

Mutation Taster

=5/95

disease causing

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