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<!DOCTYPE html>
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<title>POLE c.138del · p.Leu46Phefs*8 · Mutation Structural Analysis</title>
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<div class="sub">c.138del · <b style="color:var(--warn)">p.Leu46Phefs*8</b> · Germline Frameshift</div>
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<div class="pill"><b style="color:var(--warn)">TRUNCATING</b></div>
<div class="pill">Stop @ <b>pos 53</b></div>
<div class="pill"><b>52 aa</b> · 2.3% translated</div>
<div class="pill"><b style="color:#c0392b">PATHOGENIC</b></div>
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<b>Mechanistic anomaly under investigation:</b> c.138del carrier presents with PPAP phenotype and multiple cancers. First-order prediction (null/LOF) does not predict PPAP. See hypothesis panel below.
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<h3>Variant details</h3>
<div class="info-card">
<div class="k">HGVS coding</div>
<div class="v mono">c.138del</div>
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<div class="info-card">
<div class="k">HGVS protein</div>
<div class="v mono">p.Leu46Phefs*8</div>
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<div class="info-card">
<div class="k">Variant type</div>
<div class="v">Frameshift deletion (1 nt)</div>
</div>
<div class="info-card">
<div class="k">Consequence</div>
<div class="v">Premature termination codon at position 53 (52 aa translated)</div>
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<div class="k">Truncation</div>
<div class="v mono">52 / 2,286 residues (2.3%) · stop codon at position 53</div>
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<div class="k">Clinical classification</div>
<div class="v" style="color:#c0392b;font-weight:500">Pathogenic</div>
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<div class="k">Clinical phenotype</div>
<div class="v">PPAP / multiple primaries</div>
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<div class="info-card">
<div class="k">Predicted effect</div>
<div class="v">LOF (first-order) · NMD uncertain (PTC in exon 2)</div>
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<h3>Domain loss summary</h3>
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<h3 style="font-family:'JetBrains Mono',monospace;font-size:10px;text-transform:uppercase;letter-spacing:.22em;color:var(--ink-dim);margin-bottom:16px;font-weight:500">
Frameshift reading frame analysis · c.138del
</h3>
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<div style="font-size:9px;text-transform:uppercase;letter-spacing:.2em;color:var(--ink-faint);margin-bottom:8px">Mutant reading frame (c.138del)</div>
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<div style="font-size:9px;text-transform:uppercase;letter-spacing:.2em;color:var(--ink-faint);margin-bottom:8px">Interpretation</div>
<p style="font-family:'Fraunces',serif;font-size:12.5px;line-height:1.6;color:var(--ink);font-weight:300">
Deletion of a single nucleotide at c.138 (within codon 46, CTG→Leu) shifts the reading frame. The new frame encodes 7 aberrant amino acids (Phe-Gly-Val-Glu-Gly-Ser-Phe) before encountering a premature termination codon (TAG) at position 53. The translated peptide is 52 residues (the stop codon at position 53 is not translated).
</p>
<p style="font-family:'Fraunces',serif;font-size:12px;line-height:1.6;color:var(--ink-dim);margin-top:10px;font-weight:300">
The resulting 52-residue peptide (stop codon at position 53; 52 / 2,286 = 2.3% of the full-length protein) lacks all functional domains: no exonuclease activity, no polymerase activity, no C-terminal zinc-finger platform for holoenzyme assembly. The PTC is in <b>exon 2</b>; NMD prediction is uncertain. While the canonical EJC model predicts NMD, PTCs this close to the start codon may escape NMD via the AUG-proximity effect (Zhang & Maquat 1997), which is the basis of Hypothesis H1. Despite this first-order prediction, the carrier presents with a PPAP-consistent phenotype, creating an open mechanistic question.
</p>
<p style="font-family:'Fraunces',serif;font-size:12px;line-height:1.6;color:var(--ink-dim);margin-top:10px;font-weight:300">
In the heterozygous state, the remaining wild-type allele must support all leading-strand synthesis. Complete loss of both alleles would be lethal given Pol ε’s essential role in S-phase DNA replication.
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<div style="margin-top:5px;color:var(--ink-faint)">c.138del · p.Leu46Phefs*8</div>
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<span>~50 Å</span>
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<span>WT (ghost) vs mutant</span>
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<h3>Molecular consequence</h3>
<p style="font-family:'Fraunces',serif;font-size:12.5px;line-height:1.6;color:var(--ink);font-weight:300">
This <em style="color:var(--warn)">germline frameshift</em> truncates the POLE catalytic subunit after 52 residues (stop codon at position 53) of 2,286 — within the N-terminal domain, long before any catalytic residues are encoded.
</p>
<p style="font-family:'Fraunces',serif;font-size:12px;line-height:1.6;color:var(--ink-dim);margin-top:10px;font-weight:300">
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.
</p>
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<div class="panel">
<h3>Lost functional capacity</h3>
<div class="info-card">
<div class="k">Polymerase activity</div>
<div class="v" style="color:var(--warn)">Completely absent</div>
</div>
<div class="info-card">
<div class="k">Exonuclease proofreading</div>
<div class="v" style="color:var(--warn)">Completely absent</div>
</div>
<div class="info-card">
<div class="k">DNA binding</div>
<div class="v" style="color:var(--warn)">Completely absent</div>
</div>
<div class="info-card">
<div class="k">Holoenzyme assembly (CTD)</div>
<div class="v" style="color:var(--warn)">Completely absent</div>
</div>
<div class="info-card">
<div class="k">NMD prediction</div>
<div class="v" style="color:var(--ink)">Uncertain (PTC in exon 2; AUG-proximity may allow escape)</div>
</div>
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<h3>NMD pathway</h3>
<div class="nmd-diagram">
<div class="nmd-step">
<div class="nmd-icon">mRNA</div>
<div class="nmd-desc">c.138del transcript with PTC at codon 53 (exon 2)</div>
</div>
<div class="nmd-arrow">↓</div>
<div class="nmd-step">
<div class="nmd-icon">EJC</div>
<div class="nmd-desc">Exon junction complex >50 nt downstream of PTC</div>
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<div class="nmd-arrow">↓</div>
<div class="nmd-step">
<div class="nmd-icon">UPF1</div>
<div class="nmd-desc">Pioneer round detects PTC-EJC configuration</div>
</div>
<div class="nmd-arrow">↓</div>
<div class="nmd-step nmd-degraded">
<div class="nmd-icon">NMD?</div>
<div class="nmd-desc">Transcript may be degraded — or escape via AUG-proximity effect</div>
</div>
</div>
<p style="font-family:'Fraunces',serif;font-size:11px;line-height:1.5;color:var(--ink-faint);margin-top:8px;font-weight:300">
<b>Note:</b> 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.
</p>
</div>
<div class="panel" style="background:rgba(90,184,216,0.06);border:1px solid rgba(90,184,216,0.2)">
<h3 style="color:#5ab8d8">Candidate mechanisms (H1–H5)</h3>
<p style="font-family:'Fraunces',serif;font-size:11px;line-height:1.5;color:var(--ink-dim);margin-bottom:12px;font-weight:300">
The carrier presents with a PPAP phenotype (polyposis, multiple primaries), but truncating POLE variants are not canonical PPAP drivers. Five hypotheses are under investigation:
</p>
<details style="margin-bottom:8px;border-left:2px solid #e67e22;padding-left:10px">
<summary style="font-family:'JetBrains Mono',monospace;font-size:10.5px;font-weight:500;color:var(--ink);cursor:pointer">
H1: NMD escape + downstream re-initiation
<span style="font-size:9px;color:#e67e22;margin-left:6px">low-moderate likelihood · very high impact</span>
</summary>
<p style="font-family:'Fraunces',serif;font-size:11px;line-height:1.5;color:var(--ink-dim);margin-top:6px;font-weight:300">
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.
<br><b>Decisive experiment:</b> RT-PCR / ribosome profiling for re-initiation products; TMB + SBS10a/SBS10b signature in tumor tissue.
</p>
</details>
<details style="margin-bottom:8px;border-left:2px solid #3498db;padding-left:10px">
<summary style="font-family:'JetBrains Mono',monospace;font-size:10.5px;font-weight:500;color:var(--ink);cursor:pointer">
H2: Second exonuclease-domain lesion is the real driver
<span style="font-size:9px;color:#3498db;margin-left:6px">high likelihood · moderate impact</span>
</summary>
<p style="font-family:'Fraunces',serif;font-size:11px;line-height:1.5;color:var(--ink-dim);margin-top:6px;font-weight:300">
An undetected somatic or germline exonuclease-domain missense variant on the other allele may be the actual PPAP driver; c.138del is a bystander.
<br><b>Decisive experiment:</b> Deep sequencing of POLE exonuclease domain (both alleles); panel testing for POLD1/APC/MUTYH.
</p>
</details>
<details style="margin-bottom:8px;border-left:2px solid #9b59b6;padding-left:10px">
<summary style="font-family:'JetBrains Mono',monospace;font-size:10.5px;font-weight:500;color:var(--ink);cursor:pointer">
H3: LOH unmasks second-hit EDM (c.138del as permissive modifier)
<span style="font-size:9px;color:#9b59b6;margin-left:6px">moderate-high likelihood · high impact</span>
</summary>
<p style="font-family:'Fraunces',serif;font-size:11px;line-height:1.5;color:var(--ink-dim);margin-top:6px;font-weight:300">
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.
<br><b>Decisive experiment:</b> Tumor LOH analysis at the POLE locus; allele-specific sequencing.
</p>
</details>
<details style="margin-bottom:8px;border-left:2px solid var(--ink-faint);padding-left:10px">
<summary style="font-family:'JetBrains Mono',monospace;font-size:10.5px;font-weight:500;color:var(--ink);cursor:pointer">
H4: Annotation/splicing artifact
<span style="font-size:9px;color:var(--ink-faint);margin-left:6px">low-moderate likelihood · moderate impact</span>
</summary>
<p style="font-family:'Fraunces',serif;font-size:11px;line-height:1.5;color:var(--ink-dim);margin-top:6px;font-weight:300">
The molecular consequence may differ from in-silico prediction if the deletion affects a splice site or if an alternative transcript is used.
<br><b>Decisive experiment:</b> RNA-seq from patient tissue; verify transcript structure.
</p>
</details>
<details style="margin-bottom:8px;border-left:2px solid #2ecc71;padding-left:10px">
<summary style="font-family:'JetBrains Mono',monospace;font-size:10.5px;font-weight:500;color:var(--ink);cursor:pointer">
H5: Phenocopy from another locus
<span style="font-size:9px;color:#2ecc71;margin-left:6px">moderate likelihood · moderate impact</span>
</summary>
<p style="font-family:'Fraunces',serif;font-size:11px;line-height:1.5;color:var(--ink-dim);margin-top:6px;font-weight:300">
The PPAP phenotype may be caused by a variant in another gene (Lynch/MMR, POLD1, MUTYH, APC), and c.138del is incidental.
<br><b>Decisive experiment:</b> Comprehensive panel testing; MSI/MMR IHC; TMB signature analysis.
</p>
</details>
<div style="background:rgba(230,126,34,0.06);border:1px solid rgba(230,126,34,0.2);border-radius:2px;padding:10px 12px;margin-top:12px;margin-bottom:12px">
<p style="font-family:'JetBrains Mono',monospace;font-size:9.5px;line-height:1.5;color:#e67e22;font-weight:500;margin-bottom:6px">Recessive POLE phenotypes (LOF consequences)</p>
<p style="font-family:'Fraunces',serif;font-size:11px;line-height:1.5;color:var(--ink-dim);font-weight:300;margin-bottom:6px">
Biallelic loss-of-function or hypomorphic POLE variants cause recessive syndromes distinct from PPAP. These are the established consequences of POLE LOF and belong on the differential for any truncating variant:
</p>
<ul style="font-family:'Fraunces',serif;font-size:11px;line-height:1.6;color:var(--ink-dim);font-weight:300;margin:0;padding-left:18px">
<li><b style="color:var(--ink)">FILS syndrome</b> (MIM 615139) — facial dysmorphism, immunodeficiency, livedo, short stature. Biallelic, from variants outside the exonuclease domain and/or protein-disrupting alleles.</li>
<li><b style="color:var(--ink)">IMAGe-I syndrome</b> (MIM 618336) — IUGR, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, immunodeficiency, DLBCL (Logan et al., <em>AJHG</em> 2018). Biallelic POLE deficiency.</li>
</ul>
<p style="font-family:'Fraunces',serif;font-size:11px;line-height:1.5;color:var(--ink-faint);margin-top:6px;font-weight:300">
Notably, no reported patient with either syndrome shows complete absence of POLE expression — consistent with POLE being essential for S-phase DNA replication, and directly relevant to evaluating what a 52-residue product could mean.
</p>
</div>
<div style="background:rgba(90,184,216,0.08);border:1px solid rgba(90,184,216,0.15);border-radius:2px;padding:8px 10px;margin-top:10px">
<p style="font-family:'JetBrains Mono',monospace;font-size:9.5px;line-height:1.5;color:#5ab8d8;font-weight:500;margin-bottom:4px">Cross-cutting discriminator</p>
<p style="font-family:'Fraunces',serif;font-size:11px;line-height:1.5;color:var(--ink-dim);font-weight:300">
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.
</p>
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<h3>Clinical context</h3>
<p style="font-family:'Fraunces',serif;font-size:12px;line-height:1.6;color:var(--ink-dim);font-weight:300">
Unlike exonuclease-domain missense mutations (P286R, V411L) that produce a <em>hypermutator phenotype</em> through loss of proofreading with retained polymerase activity, this truncating variant is predicted to abolish the protein (first-order).
</p>
<p style="font-family:'Fraunces',serif;font-size:12px;line-height:1.6;color:var(--ink-dim);margin-top:10px;font-weight:300">
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.
</p>
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<h3 style="color:#c0392b">Clinical interpretation</h3>
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<p style="font-family:'Fraunces',serif;font-size:12px;line-height:1.6;color:var(--ink);font-weight:300">
Clinical lab classification: <b style="color:#c0392b;font-weight:500">Pathogenic</b>. 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.
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<p style="font-family:'JetBrains Mono',monospace;font-size:9.5px;line-height:1.5;color:var(--ink-faint);margin-top:10px;letter-spacing:0.02em">
Classification per clinical lab report.
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<p style="font-family:'JetBrains Mono',monospace;font-size:9.5px;line-height:1.5;color:#e67e22;margin-top:8px;letter-spacing:0.02em">
<b>Framework scope note:</b> The Mur et al. 2023 gene-specific ACMG/AMP framework covers <em>germline variants in the exonuclease domain</em> of POLE/POLD1. c.138del is both (a) a loss-of-function variant and (b) located outside the exonuclease domain (codon 46, NTD). It falls outside the Mur framework by both criteria. In particular, PVS1 (null variant ⇒ pathogenic) is explicitly excluded from the framework because LOF is not the PPAP mechanism. No ClinGen VCEP for POLE/POLD1 exists as of this review; the Mur framework is the appropriate gene-specific standard but is not an FDA-recognised 3-star specification.
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<h3>Comparison with known variants</h3>
<div class="mutation" style="cursor:default">
<div class="head">
<div class="name">c.138del</div>
<div class="loc">NTD · truncating</div>
</div>
<div class="text">Frameshift → 52 aa translated (stop at pos 53). <b style="color:#c0392b">Pathogenic</b>. PPAP phenotype observed despite LOF prediction. Mechanism under investigation (H1–H5).</div>
</div>
<div style="font-size:10px;color:var(--ink-faint);padding:6px 0;border-bottom:1px dashed var(--line);margin-bottom:6px">vs. characterized driver mutations ↓</div>
<div style="font-size:10.5px;color:var(--ink-dim);line-height:1.5;padding:4px 0">
<b style="color:var(--ink)">P286R / V411L:</b> Missense in EXO domain → <em>gain</em> of ultra-mutator phenotype (retained pol activity + lost proofreading)<br><br>
<b style="color:var(--ink)">c.138del:</b> Truncating → <em>loss</em> of all activity (no protein produced due to NMD)
</div>
</div>
<div class="panel" style="border-top:1px solid var(--line)">
<h3 style="font-size:10px;color:var(--ink-faint);letter-spacing:0.08em">References</h3>
<div style="font-family:'JetBrains Mono',monospace;font-size:9px;line-height:1.65;color:var(--ink-faint)">
Mur et al., <em>Genome Med</em> 15:85 (2023)<br>
Roske & Yeeles, <em>NSMB</em> 31:1921–1931 (2024)<br>
Zhang & Maquat, <em>EMBO J</em> 16:826 (1997)<br>
Logan et al., <em>AJHG</em> 103:1038 (2018) [IMAGe-I]<br>
FILS syndrome (MIM 615139)<br>
Baranovskiy et al., <em>Sci Rep</em> 12:17436 (2022)<br>
Fischbach & Walsh (2024)<br>
Coorens et al., <em>Nat Genet</em> 53:1434 (2021)
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<span class="ax">variant · <b>c.138del (p.Leu46Phefs*8)</b></span>
<span class="ax">class · <b>pathogenic (germline frameshift)</b></span>
<span class="ax">status · <b>mechanism under investigation</b></span>
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<small style="display:block;margin-top:4px;opacity:0.5;font-size:0.55rem">Research and educational use only. Not for clinical decision-making. Variant classifications shown reflect cited sources and may differ from current clinical laboratory assessments.</small>
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