Variant rs878854847 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1

The NM_006231.4(POLE):c.1A>T(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000116 in 1,499,966 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

POLE
NM_006231.4 start_lost

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:8

Conservation

PhyloP100: 1.68

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_pathogenic. Variant got 8 ACMG points.

PVS1

Start lost variant, no new inframe start found.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLE	NM_006231.4 linkuse as main transcript	c.1A>T	p.Met1?	start_lost	1/49	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.1A>T	p.Met1?	start_lost	1/49	1	NM_006231.4	ENSP00000322570	P1

Frequencies

GnomAD3 genomes

AF:

0.0000791

AC:

AN:

151754

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000162

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000552

AC:

AN:

108632

Hom.:

AF XY:

0.0000332

AC XY:

AN XY:

60230

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000128

Gnomad OTH exome

AF:

0.000310

GnomAD4 exome

AF:

0.000120

AC:

162

AN:

1348212

Hom.:

Cov.:

AF XY:

0.000116

AC XY:

AN XY:

665276

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000415

Gnomad4 EAS exome

AF:

0.0000313

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000149

Gnomad4 OTH exome

AF:

0.0000538

GnomAD4 genome

AF:

0.0000791

AC:

AN:

151754

Hom.:

Cov.:

AF XY:

0.0000540

AC XY:

AN XY:

74132

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000162

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000232

Hom.:

Bravo

AF:

0.000106

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Nov 01, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 12, 2018	The c.1A>T variant in the POLE gene alters the initiator Methionine codon, and the resultant protein would be described as ?p.Met1?? to signify that it is not known if the loss of Met1 prevents all protein translation or if an abnormal protein is produced using an alternate Methionine codon. This variant has not, to our knowledge, been published in the literature as a germline pathogenic or benign variant. POLE c.1A>T was observed at an allele frequency of 0.01% (4/37,104) in individuals of European ancestry in large population cohorts (Lek 2016). While some missense variants have been recognized as an underlying cause of Polymerase Proofreading-Associated Polyposis (PPAP), there are no data at this time to support that loss-of-function variants confer the same cancer risks. We therefore consider POLE c.1A>T to be a variant of unknown significance with respect to cancer. To date, the majority of publications regarding POLE and colorectal cancer risk are confined to missense variants within the exonuclease domain (Palles 2013, Spier 2015). However, a splice variant and a frameshift variant have been reported. Pachlopnik Schmid et al. (2012) observed a splice variant at the +3 position in intron 34, in the homozygous state, in 11 family members with facial dysmorphism, immunodeficiency, livedo, and short stature (FILS) from a large consanguineous family; however, they noted that all heterozygous carriers were asymptomatic and did not have a history of cancer. While Smith et al. (2013) identified a POLE frameshift variant in a 26 year old with a history of colorectal cancer, no family history was provided and segregation analysis was not completed. As described above, facial dysmorphism, immunodeficiency, livedo, and short stature (FILS) appears to be a rare autosomal recessive condition associated with two loss-of-function variants in POLE (Pachlopnik Schmid 2012). For individuals and family members of reproductive age, assessment of the reproductive risk associated with being a carrier of a potential loss of function POLE variant may be considered. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 24, 2022	PM2 -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 21, 2024	This sequence change affects the initiator methionine of the POLE mRNA. The next in-frame methionine is located at codon 44. This variant is present in population databases (no rsID available, gnomAD 0.01%). Disruption of the initiator codon has been observed in individual(s) with clinical features of autosomal recessive FILS syndrome (PMID: 30503519). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 240415). For these reasons, this variant has been classified as Pathogenic. -

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 15, 2016	The p.Met1? variant in POLE has not been previously reported in individuals with colorectal cancer (CRC). Data from large population studies is insufficient to assess its frequency (due to a lack of coverage). This variant disrupts the tran slation initiation start codon (ATG). Although this expected to severely impact the protein the precise effect is unclear. In addition, the POLE gene has not ye t been widely studied and to date, virtually all variants reported in patients w ith CRC represent missense changes. In summary, the clinical significance of the p.Met1? variant is uncertain. -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Feb 06, 2024	- -

Intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 26, 2019

- -

Colorectal cancer, susceptibility to, 12

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

Sep 26, 2016

- -

POLE-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 10, 2024

The POLE c.1A>T variant is predicted to disrupt the translation initiation site (Start Loss). This variant has been reported with a second putative loss-of-function variant, in three individuals from two families with IMAGe syndrome (Logan et al. 2018. PubMed ID: 30503519). This variant is reported in 0.013% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/12-133263901-T-A). To date, null variants have not been conclusively shown to cause autosomal dominant colorectal cancer susceptibility. In ClinVar, this variant has conflicting classifications including uncertain significance and pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/240415/). Five additional start-loss changes in POLE are documented in gnomAD, and interpreted as variants of uncertain significance in ClinVar, and to our knowledge, none of these have been reported in the literature as causative for disease. Although we suspect this variant may be pathogenic for autosomal recessive IMAGe syndrome, 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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 21, 2019

The p.M1L variant (also known as c.1A>T), located in coding exon 1 of the POLE gene, results from an A to T substitution at nucleotide position 1. This alters the methionine residue at the initiation codon. Sequence variations that modify the initiation codon are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame. However, loss of function of POLE has not been clearly established as a mechanism of disease for colorectal cancer (CRC)/polyposis risk. This alteration has been reported in the compound heterozygous state with a pathogenic POLE mutation in individuals with intrauterine growth restriction, metaphyseal dysplasia, adrenal hypoplasia congenita, and genital anomalies (IMAGe) syndrome (Logan CV et al. Am J Hum Genet, 2018 12;103:1038-1044). However, there is an in-frame methionine 43 amino acids downstream from the initiation site, which may result in N-terminal truncation of unknown functional significance. Based on the supporting evidence, the clinical significance of this alteration for CRC/polyposis risk and IMAGe syndrome is unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.027

BayesDel_noAF

Uncertain

-0.060

CADD

Benign

DANN

Benign

0.76

DEOGEN2

Benign

0.075

T;.

Eigen

Benign

-0.81

Eigen_PC

Benign

-0.87

FATHMM_MKL

Benign

0.012

LIST_S2

Uncertain

0.90

D;D

M_CAP

Pathogenic

0.62

MetaRNN

Pathogenic

0.78

D;D

MetaSVM

Benign

-0.96

MutationTaster

Benign

1.0

D;D;N

PROVEAN

Benign

-1.5

N;N

REVEL

Benign

0.26

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

0.0

B;B

Vest4

0.76

MutPred

0.87

Loss of methylation at R4 (P = 0.1269);Loss of methylation at R4 (P = 0.1269);

MVP

0.31

ClinPred

0.81

GERP RS

2.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.94

gMVP

0.53

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