chr12-132675796-CAAACCACCTTTGGATCAGATGAGCCTGAACCCAAGTCACAGCAGTCAGAG-GGTGTAGAAC

Position:

• chr12-132675796-CAAACCACCTTTGGATCAGATGAGCCTGAACCCAAGTCACAGCAGTCAGAG-GGTGTAGAAC

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_006231.4(POLE):​c.1021-26_1045delinsGTTCTACACC variant causes a splice acceptor, coding sequence, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: POLE NM_006231.4 splice_acceptor, coding_sequence, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2
• Conservation: PhyloP100: 9.05

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 11 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-132675796-CAAACCACCTTTGGATCAGATGAGCCTGAACCCAAGTCACAGCAGTCAGAG-GGTGTAGAAC is Pathogenic according to our data. Variant chr12-132675796-CAAACCACCTTTGGATCAGATGAGCCTGAACCCAAGTCACAGCAGTCAGAG-GGTGTAGAAC is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 420813.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLE	NM_006231.4	c.1021-26_1045delinsGTTCTACACC		splice_acceptor_variant, coding_sequence_variant, intron_variant	11/49	ENST00000320574.10	NP_006222.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLE	ENST00000320574.10	c.1021-26_1045delinsGTTCTACACC		splice_acceptor_variant, coding_sequence_variant, intron_variant	11/49	1	NM_006231.4	ENSP00000322570	P1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 26, 2023	This variant results in the deletion of part of exon 11 (c.1021-26_1045delinsGTTCTACACC) of the POLE gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in POLE are known to be pathogenic (PMID: 23230001, 25948378, 30503519). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with POLE-related conditions. ClinVar contains an entry for this variant (Variation ID: 420813). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Feb 12, 2018	This combined deletion and insertion is denoted POLE c.1021-26_1045del51ins10 and consists of a deletion of 51 nucleotides and the addition of 10 nucleotides at the intron/exon boundary of exon 11. The normal sequence, with the bases that are deleted and duplicated in brackets, is agac[del51][insgttctacacc]AACA where the capital letters are exonic and the lower case are intronic. This variant has not, to our knowledge, been published in the literature. This variant removes the canonical splice acceptor site as well as the first 25 nucleotides of exon 11 and is predicted to cause abnormal gene splicing, leading to either an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. However, while missense variants located within the exonuclease domain of the POLE gene have been recognized as an underlying cause of Polymerase Proofreading-Associated Polyposis (PPAP), an autosomal dominant condition associated with polyposis and an increased risk for colon cancer (Palles 2013, Spier 2015), there are no data to support that loss-of-function variants, such as this one, confer the same cancer risks. Smith et al. (2013) identified a POLE frameshift variant in a 26 year old with a history of colorectal cancer, but no information about family history was provided. Based on current evidence, we consider this variant to be of uncertain significance with respect to cancer. A recessive disease associated with POLE has been reported in the literature. In one large consanguineous family, 14 affected relatives with a syndrome called FILS (facial dysmorphism, immunodeficiency, livedo, and short stature) were all found to be homozygous for POLE c.4444+3A>G, a splice variant which results in a small proportion (~10%) of normal POLE transcript (Pachlopnik Schmid 2012). In addition, an unrelated individual with a suspected chromosome instability syndrome was also found to be homozygous for POLE c.4444+3A>G (Thiffault 2015). We cannot assess whether the variant identified in the current patient would cause the same recessive disease. Individuals and family members of reproductive age may choose to consider assessment of potential reproductive risks. -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 29, 2022

The c.1021-26_1045del51insGTTCTACACC variant spans the canonical acceptor site of coding exon 11 in the POLE gene. This variant results from a deletion of 51 nucleotides and insertion of GTTCTACACC nucleotides at positions c.1021-26 to c.1045. The canonical acceptor site is highly conserved in available vertebrate species. Using the BDGP splice site prediction tool, the native acceptor site could not be reliably predicted. However, the ESEfinder splice site prediction tool predicts the creation of a new alternate splice acceptor site that would result in an in-frame transcript; however, direct evidence is unavailable. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. However, 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. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1555229232; hg19: chr12-133252382;