rs878854847

chr12-132687315-T-Achr12-132687315-T-Cchr12-132687315-T-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PS1_Moderate

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:8
• Conservation: PhyloP100: 1.68

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]

ACMG classification

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 [Conflicting_classifications_of_pathogenicity] in ClinVar as 540655

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POLE	NM_006231.4	c.1A>T	p.Met1?	start_lost	1/49	ENST00000320574.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLE	ENST00000320574.10	c.1A>T	p.Met1?	start_lost	1/49	1	NM_006231.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000791 AC: 12 AN: 151754 Hom.: 0 Cov.: 33

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: 6 AN: 108632 Hom.: 0 AF XY: 0.0000332 AC XY: 2 AN XY: 60230

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.: 0 Cov.: 32 AF XY: 0.000116 AC XY: 77 AN XY: 665276

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: 12 AN: 151754 Hom.: 0 Cov.: 33 AF XY: 0.0000540 AC XY: 4 AN XY: 74132

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.: 0

Bravo AF: 0.000106

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain: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	Mayo Clinic Laboratories, Mayo Clinic	Jun 24, 2022	PM2 -
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. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	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, criteria provided, single submitter

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	T
BayesDel_noAF	Uncertain	-0.060
Cadd	Benign	19
Dann	Benign	0.76
DEOGEN2	Benign	0.075	T;.
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.87
FATHMM_MKL	Benign	0.012	N
LIST_S2	Uncertain	0.90	D;D
M_CAP	Pathogenic	0.62	D
MetaRNN	Pathogenic	0.78	D;D
MetaSVM	Benign	-0.96	T
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	D
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

Other links and lift over

dbSNP: rs878854847; hg19: chr12-133263901; COSMIC: COSV57689061; COSMIC: COSV57689061;