12-132687315-T-G

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1

The NM_006231.4(POLE):c.1A>C(p.Met1?) variant causes a initiator codon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000107 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 0.000046 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000067 ( 0 hom. )

Consequence

POLE
NM_006231.4 initiator_codon

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:5

Conservation

PhyloP100: 1.68

Publications

5 publications found

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 Gene-Disease associations (from GenCC):

POLE-related polyposis and colorectal cancer syndrome
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
colorectal cancer, susceptibility to, 12
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
facial dysmorphism-immunodeficiency-livedo-short stature syndrome
Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency
Inheritance: AR Classification: STRONG Submitted by: G2P
IMAGe syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Polymerase proofreading-related adenomatous polyposis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

POLE links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

PVS1

Start lost variant, next in-frame start position is after 20 pathogenic variants. Next in-frame start position is after 44 codons. Genomic position: 132681212. Lost 0.019 part of the original CDS.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLE	NM_006231.4 link	c.1A>C	p.Met1?	initiator_codon_variant	Exon 1 of 49	ENST00000320574.10	NP_006222.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLE	ENST00000320574.10 link	c.1A>C	p.Met1?	initiator_codon_variant	Exon 1 of 49	1	NM_006231.4	ENSP00000322570.5

Frequencies

GnomAD3 genomes

AF:

0.0000461

AC:

AN:

151754

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:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000184

AC:

AN:

108632

AF XY:

0.0000166

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000256

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000668

AC:

AN:

1348212

Hom.:

Cov.:

AF XY:

0.00000601

AC XY:

AN XY:

665276

show subpopulations

African (AFR)

AF:

0.0000351

AC:

AN:

28522

American (AMR)

AF:

0.00

AC:

AN:

32526

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24112

East Asian (EAS)

AF:

0.00

AC:

AN:

31934

South Asian (SAS)

AF:

0.0000265

AC:

AN:

75392

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38934

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4934

European-Non Finnish (NFE)

AF:

0.00000568

AC:

AN:

1056122

Other (OTH)

AF:

0.00

AC:

AN:

55736

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

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:

0.0000461

AC:

AN:

151754

Hom.:

Cov.:

AF XY:

0.0000270

AC XY:

AN XY:

74132

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41358

American (AMR)

AF:

0.00

AC:

AN:

15252

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5146

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10490

Middle Eastern (MID)

AF:

0.00

AC:

AN:

312

European-Non Finnish (NFE)

AF:

0.000103

AC:

AN:

67904

Other (OTH)

AF:

0.00

AC:

AN:

2084

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.561

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

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:

0.000116

Hom.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Uncertain:2

May 04, 2017

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant alters the initiator Methionine codon, and the resultant protein would be described asâ€œp.Met1?â€ to signify that it is not known if the loss of Met1 prevents all protein translation or if an abnormal protein isproduced using an alternate Methionine codon. POLE c.1A>C has not been previously published as a pathogenicvariant, nor has it been reported as a benign polymorphism to our knowledge. Based on currently available evidence,we consider it to be a variant of uncertain significance.

Dec 26, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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: 405585). For these reasons, this variant has been classified as Pathogenic.

Sep 08, 2017

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Colorectal cancer, susceptibility to, 12

Uncertain:1

Dec 20, 2021

MGZ Medical Genetics Center

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Hereditary cancer-predisposing syndrome

Uncertain:1

Dec 24, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.M1? variant (also known as c.1A>C), located in coding exon 1 of the POLE gene, results from an A to C substitution at nucleotide position 1. This alters the methionine residue at the initiation codon (ATG). Another variant at this codon (c.1A>T) has been identified in conjunction with a second POLE variant (c.1686+32C>G) in individuals with features consistent with POLE deficiency; in at least one instance, the variants were identified in trans (Logan CV et al. Am J Hum Genet, 2018 Dec;103:1038-1044). This amino acid position is well conserved in available vertebrate species. In addition to the clinical data presented in the literature, 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. Based on the supporting evidence, this alteration is pathogenic for POLE deficiency; however, the association of this alteration with POLE-related polymerase proofreading-associated polyposis (PPAP) and POLE-related CMMRD-like syndrome is unknown.

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:1

Aug 25, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.098

BayesDel_noAF

Uncertain

-0.060

CADD

Benign

(source)

DANN

Benign

0.64

DEOGEN2

Benign

0.075

T;.

Eigen

Benign

-0.81

Eigen_PC

Benign

-0.87

FATHMM_MKL

Benign

0.013

LIST_S2

Uncertain

0.90

D;D

M_CAP

Pathogenic

0.62

MetaRNN

Pathogenic

0.98

D;D

MetaSVM

Benign

-0.96

MutationAssessor

Benign

0.0

.;.

PhyloP100

1.7

PROVEAN

Benign

-1.5

N;N

REVEL

Benign

0.26

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Vest4

0.76

ClinPred

0.50

GERP RS

2.5

PromoterAI

-0.081

Neutral

(source)

Varity_R

0.94

gMVP

0.53

Mutation Taster

=20/180

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over