# NM_006231.4(POLE):c.800del (p.Pro267fs)

https://sugi.bio/variant/pole-p-pro267fs

## Summary

**POLE p.Pro267fs (c.800del)** is classified **Conflicting classifications of pathogenicity** in POLE (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-12-13). Associated with hereditary neoplastic syndrome.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · 2 submitters · 1 linked condition

## For patients & families {#patients}

This is a change in the POLE gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 2 submitters, and is linked to hereditary neoplastic syndrome.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Clinical trials | 31 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0019921/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [POLE](https://sugi.bio/atlas/gene/POLE/) |
| Protein change (HGVS p.) | p.Pro267fs |
| Coding change (HGVS c.) | c.800del |
| MANE Select transcript | [NM_006231](https://www.ncbi.nlm.nih.gov/nuccore/NM_006231) |
| Variant type | Deletion |
| Location | chr12:132677364-132677364 (GRCh38) |
| ClinVar | [VCV3666385](https://www.ncbi.nlm.nih.gov/clinvar/variation/3666385/) |

**All HGVS expressions:** `LRG_789:g.15161del`, `LRG_789t1:c.799del`, `NC_000012.11:g.133253951del`, `NC_000012.12:g.132677365del`, `NG_033840.1:g.15161del`, `NM_006231.2:c.800delC`, `NM_006231.4:c.800del`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP -4.136, GERP -3.07 — fast-evolving / accelerated position
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.75, pLI 2.7396e-38. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 8 of 49**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**POLE** population constraint: LOEUF 0.75, pLI 2.7396e-38, missense-Z 2.6706; ClinGen dosage — haploinsufficiency 1/3, triplosensitivity 0/3. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **POLE-related polyposis and colorectal cancer syndrome** — Definitive (AD)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 80.32, 31% of residues very-high.

**18 experimental structure(s)** (PDB): [5VBN](https://www.rcsb.org/structure/5VBN), [7PFO](https://www.rcsb.org/structure/7PFO), [7PLO](https://www.rcsb.org/structure/7PLO), [9B8S](https://www.rcsb.org/structure/9B8S), [9B8T](https://www.rcsb.org/structure/9B8T), [9F6D](https://www.rcsb.org/structure/9F6D).

## What this gene does {#gene-function}

*Describes the biological roles of POLE (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** POLE's established molecular role includes DNA binding.


### Pathways affected {#pathways}

POLE participates in **10 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Activation of the pre-replicative complex](https://reactome.org/content/detail/R-HSA-68962) | curated |
| [DNA replication initiation](https://reactome.org/content/detail/R-HSA-68952) | curated |
| [Dual Incision in GG-NER](https://reactome.org/content/detail/R-HSA-5696400) | curated |
| [Dual incision in TC-NER](https://reactome.org/content/detail/R-HSA-6782135) | curated |
| [Gap-filling DNA repair synthesis and ligation in GG-NER](https://reactome.org/content/detail/R-HSA-5696397) | curated |
| [Gap-filling DNA repair synthesis and ligation in TC-NER](https://reactome.org/content/detail/R-HSA-6782210) | curated |
| [HDR through Homologous Recombination (HRR)](https://reactome.org/content/detail/R-HSA-5685942) | curated |
| [PCNA-Dependent Long Patch Base Excision Repair](https://reactome.org/content/detail/R-HSA-5651801) | curated |
| [Recognition of DNA damage by PCNA-containing replication complex](https://reactome.org/content/detail/R-HSA-110314) | curated |
| [Termination of translesion DNA synthesis](https://reactome.org/content/detail/R-HSA-5656169) | curated |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** DNA binding, chromatin binding, DNA-directed DNA polymerase activity.

**Biological process:** G1/S transition of mitotic cell cycle, DNA synthesis involved in DNA repair, DNA replication, DNA-templated DNA replication, base-excision repair, gap-filling, nucleotide-excision repair, DNA gap filling.

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2024-12-13.

**Submitter consensus:** conflicting (1 Uncertain significance, 1 Pathogenic).

**Submission history:** 2 submissions (2024); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-12-13 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2024-09-08 |

## Associated conditions {#conditions}

[hereditary neoplastic syndrome](https://sugi.bio/atlas/disease/hereditary-neoplastic-syndrome/).

**Reported phenotype names (ClinVar):** Hereditary cancer-predisposing syndrome, not provided, none provided, Hereditary Cancer Syndrome, Hereditary neoplastic syndrome, Neoplastic Syndromes, Hereditary, Tumor predisposition.

## Similar variants {#similar}

Related POLE variant pages (same residue, condition, or type): [POLE p.Pro267Ala](/variant/pole-p-pro267ala), [POLE p.Pro267Leu](/variant/pole-p-pro267leu), [POLE c.1359+4_1359+74del](/variant/pole-c-1359-plus-4-1359-plus-74del), [POLE c.206_211delCCGAGA](/variant/pole-c-206-211delccgaga), [POLE c.3459+4del](/variant/pole-c-3459-plus-4del), [POLE p.Ala1288_Leu1295del](/variant/pole-p-ala1288-leu1295del), [POLE p.Gln1950_Glu1956del](/variant/pole-p-gln1950-glu1956del), [POLE p.Glu1965_Glu1969del](/variant/pole-p-glu1965-glu1969del).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 3666385). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*