POLE c.138del · p.Leu46Phefs*8 · Mutation Structural Analysis

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POLE

c.138del · p.Leu46Phefs*8 · Germline Frameshift

TRUNCATING

Stop @ res 53

2.3% translated

PATHOGENIC

Mechanistic anomaly under investigation: c.138del carrier presents with PPAP phenotype and multiple cancers. First-order prediction (null/LOF) does not predict PPAP. See hypothesis panel below.

Variant details

HGVS coding

c.138del

HGVS protein

p.Leu46Phefs*8

Variant type

Frameshift deletion (1 nt)

Consequence

Premature termination codon at position 53

Truncation

53 / 2,286 residues (2.3%)

Clinical classification

Pathogenic

Clinical phenotype

PPAP / multiple primaries

Predicted effect

LOF (first-order) · NMD uncertain (PTC in exon 2)

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Procedural domain topology model

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PDB 9F6D · real atomic coordinates

AlphaFold Predicted Structure

Full-length 2,286 AA · pLDDT confidence

mutation · analysis

c.138del · p.Leu46Phefs*8

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~50 Å

WT (ghost) vs mutant

Molecular consequence

This germline frameshift truncates the POLE catalytic subunit at residue 53 of 2,286 — within the N-terminal domain, long before any catalytic residues are encoded.

The 3D comparison (left: ghost wild-type, right: translated fragment) illustrates the catastrophic structural loss. The small peptide retains none of the protein’s enzymatic or structural capabilities. Despite this first-order prediction, the carrier presents with a PPAP-consistent phenotype, creating an open mechanistic question.

Lost functional capacity

Polymerase activity

Completely absent

Exonuclease proofreading

Completely absent

DNA binding

Completely absent

Holoenzyme assembly (CTD)

Completely absent

NMD prediction

Uncertain (PTC in exon 2; AUG-proximity may allow escape)

NMD pathway

mRNA

c.138del transcript with PTC at codon 53 (exon 2)

↓

EJC

Exon junction complex >50 nt downstream of PTC

↓

UPF1

Pioneer round detects PTC-EJC configuration

↓

NMD?

Transcript may be degraded — or escape via AUG-proximity effect

Note: PTCs this close to the start codon may escape NMD via the AUG-proximity effect (Zhang & Maquat 1997). If translation re-initiates at a downstream AUG within the exonuclease domain, the resulting N-terminally truncated protein could lack proofreading but retain polymerase activity — the basis of Hypothesis H1.

Candidate mechanisms (H1–H5)

The carrier presents with a PPAP phenotype (polyposis, multiple primaries), but truncating POLE variants are not canonical PPAP drivers. Five hypotheses are under investigation:

          H1: NMD escape + downstream re-initiation
          low-moderate likelihood · very high impact
        

If the PTC escapes NMD via AUG-proximity and translation re-initiates at a downstream methionine within or beyond the exonuclease domain, the resulting protein could lack proofreading but retain polymerase activity — producing a PPAP-like ultra-mutator.
Decisive experiment: RT-PCR / ribosome profiling for re-initiation products; TMB + SBS10a/SBS10b signature in tumor tissue.

          H2: Second exonuclease-domain lesion is the real driver
          high likelihood · moderate impact
        

An undetected somatic or germline exonuclease-domain missense variant on the other allele may be the actual PPAP driver; c.138del is a bystander.
Decisive experiment: Deep sequencing of POLE exonuclease domain (both alleles); panel testing for POLD1/APC/MUTYH.

          H3: LOH unmasks second-hit EDM (c.138del as permissive modifier)
          moderate-high likelihood · high impact
        

LOH at 12q24.33 removes the functional allele; if a somatic EDM arises on the remaining allele, c.138del acts as a permissive modifier by eliminating the wild-type backup.
Decisive experiment: Tumor LOH analysis at the POLE locus; allele-specific sequencing.

          H4: Annotation/splicing artifact
          low-moderate likelihood · moderate impact
        

The molecular consequence may differ from in-silico prediction if the deletion affects a splice site or if an alternative transcript is used.
Decisive experiment: RNA-seq from patient tissue; verify transcript structure.

          H5: Phenocopy from another locus
          moderate likelihood · moderate impact
        

The PPAP phenotype may be caused by a variant in another gene (Lynch/MMR, POLD1, MUTYH, APC), and c.138del is incidental.
Decisive experiment: Comprehensive panel testing; MSI/MMR IHC; TMB signature analysis.

Cross-cutting discriminator

Tumor mutational burden (TMB) + SBS10a/SBS10b signature analysis would distinguish H1/H3 (POLE-driven, SBS10+) from H2/H5 (non-POLE-driven). Currently awaiting tumor tissue.

Clinical context

Unlike exonuclease-domain missense mutations (P286R, V411L) that produce a hypermutator phenotype through loss of proofreading with retained polymerase activity, this truncating variant is predicted to abolish the protein (first-order).

However, the carrier presents with a PPAP-consistent phenotype (polyposis, multiple primary cancers), creating a genotype-phenotype anomaly. The five candidate mechanisms (H1–H5) above are under investigation. The discriminating measurement is tumor mutational signature analysis (SBS10a/SBS10b), currently awaiting tissue.

Clinical interpretation

Clinical lab classification: Pathogenic. The carrier presents with a PPAP phenotype (polyposis, multiple primaries). The mechanistic basis is under investigation: a truncating POLE variant is not a canonical PPAP driver (which requires an active but proofreading-deficient polymerase), yet the clinical phenotype is observed. Five candidate mechanisms (H1–H5) are being evaluated. The discriminating measurement is tumor mutational signature analysis (SBS10a/SBS10b), currently awaiting tissue.

Classification per clinical lab report; framework: Mur et al., Genome Med 2023.

Comparison with known variants

c.138del

NTD · truncating

Frameshift → stop at res 53. Pathogenic. PPAP phenotype observed despite LOF prediction. Mechanism under investigation (H1–H5).

vs. characterized driver mutations ↓

P286R / V411L: Missense in EXO domain → gain of ultra-mutator phenotype (retained pol activity + lost proofreading)

c.138del: Truncating → loss of all activity (no protein produced due to NMD)

References

        Mur et al., Genome Med 15:85 (2023)

        Roske & Yeeles, NSMB 31:1921 (2024)

        Zhang & Maquat, EMBO J 16:826 (1997)

        Baranovskiy et al., Sci Rep 12:17436 (2022)

        Fischbach & Walsh (2024)

        Coorens et al., Nat Genet 53:1434 (2021)