12-132687315-T-C

Position:

chr12-132687315-T-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PS1_ModeratePP5

The NM_006231.4(POLE):c.1A>G(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 0.000056 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 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000062 ( 0 hom. )

Consequence

POLE
NM_006231.4 start_lost

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:7

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 11 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

PP5

Variant 12-132687315-T-C is Pathogenic according to our data. Variant chr12-132687315-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 405608.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=5, Pathogenic=1}.

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes

AF:

0.00000659

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000921

AC:

AN:

108632

Hom.:

AF XY:

0.00

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:

0.000114

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000616

AC:

AN:

1348212

Hom.:

Cov.:

AF XY:

0.0000661

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:

0.00

Gnomad4 FIN exome

AF:

0.000128

Gnomad4 NFE exome

AF:

0.0000691

Gnomad4 OTH exome

AF:

0.0000538

GnomAD4 genome

AF:

0.00000659

AC:

AN:

151754

Hom.:

Cov.:

AF XY:

0.0000135

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:2Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 18, 2023	This sequence change affects the initiator methionine of the POLE mRNA. The next in-frame methionine is located at codon 44. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 405608). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 06, 2023	Initiation codon variant in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -

Hereditary cancer-predisposing syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 25, 2019	The p.M1? variant (also known as c.1A>G), located in coding exon 1 of the POLE gene, results from an A to G substitution at nucleotide position 1. This alters the methionine at the translation initiation codon. 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, N-terminal truncation, or cause a shift in the mRNA reading frame; however there is an alternate in-frame methionine 43 amino acids from the initiation site and the significance of the N-terminus for this protein is not well established. Further, loss of function of POLE has not been clearly established as a mechanism of disease. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	May 11, 2021	- -

Colorectal cancer, susceptibility to, 12

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

Aug 30, 2017

- -

POLE-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 04, 2024

The POLE c.1A>G variant is predicted to disrupt the translation initiation site (Start Loss). This variant disrupts the initiating methionine of POLE. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.011% of alleles in individuals of European (Finnish) descent in gnomAD and has conflicting interpretations in ClinVar ranging from uncertain to pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/405608/). Of note, another variant disrupting the initiating methionine of POLE (c.1A>T) has been reported in the compound heterozygous state in patients with IMAGE-1 syndrome (Nakano et al. 2022. PubMed ID: 35534205). The next downstream methionine is found at amino acid 44. To date, there have been no functional studies to determine if p.Met44 is utilized as an alternative initiation site and how it would impact protein structure or function. Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Malignant tumor of breast

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The POLE p.Met1Val variant was not identified in the literature. The variant was identified in dbSNP (rs878854847) as â€šÃ„Ãºwith uncertain significance alleleâ€šÃ„Ã¹ and ClinVar (classified as uncertain significance by Invitae, GeneDx, Ambry Genetics and Counsyl). The variant was identified in control databases in 1 of 104,900 chromosomes at a frequency of 0.00001 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Finnish in 1 of 8614 chromosomes (freq: 0.0001), but was not observed in the African, Other, Latino, European, Ashkenazi Jewish, East Asian and South Asian populations. The c.1A>G variant occurs in the first base of the translation initiation site (the methionine amino acid start site), increasing the likelihood this variant may disrupt translation and lead to an abnormal protein product. The next in-frame methionine is located at codon 44, and it is not known whether the protein is translated from an alternate start site. 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. -

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

Jan 12, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Uncertain

0.084

BayesDel_noAF

Benign

-0.12

CADD

Benign

DANN

Benign

0.68

DEOGEN2

Benign

0.073

T;.

Eigen

Benign

-0.81

Eigen_PC

Benign

-0.86

FATHMM_MKL

Benign

0.025

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

-1.8

N;N

REVEL

Benign

0.23

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

0.0020

B;B

Vest4

0.70

MutPred

0.86

Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);

MVP

0.28

ClinPred

0.44

GERP RS

2.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.91

gMVP

0.64

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