Variant 12-132687315-T-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PS1_Moderate

The NM_006231.4(POLE):c.1A>C(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 0.0000107 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 start_lost

Scores

Clinical Significance

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

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 Pathogenic. Variant got 10 ACMG points.

PVS1

Start lost variant, no new inframe start found.

PS1

Another start lost variant in NM_006231.4 (POLE) was described as [Pathogenic] in Lovd

Transcripts

RefSeq

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

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

GnomAD3 exomes

AF:

0.0000184

AC:

AN:

108632

Hom.:

AF XY:

0.0000166

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:

0.0000512

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

Gnomad4 AFR exome

AF:

0.0000351

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000265

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000568

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000461

AC:

AN:

151754

Hom.:

Cov.:

AF XY:

0.0000270

AC XY:

AN XY:

74132

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:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.00

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

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 08, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 22, 2023	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2017	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. -

Colorectal cancer, susceptibility to, 12

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

MGZ Medical Genetics Center

Dec 20, 2021

- -

Hereditary cancer-predisposing syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 03, 2018

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. However, there exists a possible alternate initiation site just 43 residues downstream. This amino acid position is well conserved on limited sequence alignment. Variations that modify the initiation codon (ATG) are expected to result in either loss of translation initiation or N-terminal truncation. However, as neither this specific alteration nor loss-of-function as a mechanism of pathogenicity have been well-described in the POLE gene, the clinical significance of this variant remains 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

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 25, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.098

BayesDel_noAF

Uncertain

-0.060

CADD

Benign

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

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

0.50

GERP RS

2.5

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