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POLE
Final classification
Likely Pathogenic
PVS1PM2
POLE
c.941C>A
p.Ser314Ter
nonsense · exon 10
Gene context NCBI Gene ↗ OncoKB ↗

POLE encodes the catalytic subunit of DNA polymerase epsilon, the enzyme that replicates the leading strand of DNA during cell division and participates in DNA repair. It contains a proofreading domain that corrects replication errors, keeping the accumulation of mutations in check. Germline mutations in POLE cause polyposis and predispose to colorectal cancer, and are also linked to a rare syndrome of facial dysmorphism, immunodeficiency, livedo, and short stature. Somatic mutations, particularly in the proofreading domain, occur in colorectal and endometrial cancers, where they drive an ultra-mutated tumor phenotype and are associated with better responses to immune checkpoint inhibitors.

This variant

c.941C>A (p.Ser314Ter) destroys most of the proofreading domain of DNA polymerase epsilon, the enzyme that corrects replication errors during cell division, and is predicted to trigger nonsense-mediated decay. A Likely Pathogenic designation for this truncating variant aligns with POLE's established role in colorectal cancer predisposition and with the loss of proofreading capacity expected to compromise genomic stability.

Transcript
NM_006231.4
HGVS · transcript:coding
NM_006231.4:c.941C>A
GRCh38
chr12:132676173 G>T
GRCh37
chr12:133252759 G>T
Basis No ClinGen POLE CSPEC exists, so the local Leon-Castillo 2020 framework governs: PVS1 (Very Strong) plus PM2 (Moderate) combine to Likely Pathogenic. ▾
No ClinGen POLE CSPEC exists, so the local Leon-Castillo 2020 framework governs: PVS1 (Very Strong) plus PM2 (Moderate) combine to Likely Pathogenic.
Classification rationale
PVS1PM2 Likely Pathogenic
POLE c.941C>A nonsense · exon 10

PVS1 (Very Strong): nonsense variant p.(Ser314Ter) predicted to trigger nonsense-mediated decay, truncating >85% of the protein including the proofreading domain. PM2 (Moderate): variant absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0 population datasets. Combined, PVS1 (Very Strong) + PM2 (Moderate) yields Likely Pathogenic.

PVS1 + PM2 → Likely Pathogenic
Gene diagram · NM_006231.4 · variants mapped to exon structure
POLE NM_006231.4
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 17 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 2
Strength Supporting Moderate Strong Very strong
✓
PVS1 very strong review Pathogenic
Met (Very Strong): c.941C>A creates stop codon p.(Ser314Ter), predicted to trigger nonsense-mediated decay and remove >85% of POLE's 2286-aa protein. Flagged for human review: gene-disease mechanism and zygosity for this truncating allele are unconfirmed.
prefetch.json normalize step: NM_006231.4:c.941C>A predicted protein NP_006222.2:p.(Ser314Ter); position_first=313, position_last_predicted=314 confirms an early premature stop.variant_validator variant_exonic_positions places the variant in exon 10 (start_exon=end_exon='10') of the transcript.prefetch.json selector_short.exon.c lists 49 total coding exons for NM_006231.4, confirming the premature stop at codon 314 is 39 exons upstream of the terminal exon, well beyond the 50-bp NMD-escape boundary.
pvs1_generic_framework ↗
✓
PM2 moderate Pathogenic
Met (Moderate): absent from the gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0 population datasets.
gnomAD v2.1 reported GRCh37 12-133252759-G-T absent.gnomAD v4.1 reported GRCh38 chr12-132676173-G-T absent.gnomAD-Canada v1.0 reported GRCh38 12-132676173-G-T absent.
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
Assessed · not applied · 7 not met · 10 not assessed
Pathogenic
PS2 Not assessed: no proband phenotype, parental genotypes, or de novo testing results were available.
PS3 Not assessed: no functional assay data (e.g., proofreading activity or splicing assays) for this variant were available.
PM3 Not assessed: no proband with a pathogenic POLE variant in trans with this variant was reported.
PM6 Not assessed: no parental testing or reported de novo occurrence was available.
PP1 Not assessed: no family segregation data, such as relatives' genotypes or informative meioses, were reported.
PP3 Not met: SpliceAI max delta 0.132 falls in the gray zone (0.1-0.2), below the >0.2 PP3 threshold.
PP4 Not assessed: no proband phenotype specific to a POLE-associated condition was documented.
PP5 Not met: no ClinVar record for this exact variant exists, so no expert-panel pathogenic assertion supports PP5.
Benign
BA1 Not met: variant absent from the queried gnomAD datasets, so no allele frequency exists to meet a benign threshold.
BS1 Not met: variant absent from the queried gnomAD datasets, so no frequency exceeds that expected for POLE-associated disease.
BS2 Not met: no observation of this variant in well-phenotyped unaffected adults was provided.
BS3 Not assessed: no functional assay evidence showing a benign effect for this variant was available.
BS4 Not assessed: no affected relatives lacking this variant or other non-segregation observations were reported.
BP2 Not assessed: no co-occurrence data place this variant in cis or in trans with a pathogenic variant.
BP4 Not met: SpliceAI max delta 0.132 is above the <0.1 BP4 threshold.
BP5 Not assessed: no alternate molecular diagnosis fully explaining a documented phenotype was provided.
BP6 Not met: no ClinVar record for this exact variant exists, so no expert-panel benign assertion supports BP6.
N/A · 9 PS1 · PS4 · PM1 · PM4 · PM5 · PP2 · BP1 · BP3 · BP7
Research & evidence
Population frequency · supports pathogenic
gnomAD v4.1 screenshot
gnomAD v4.1
gnomAD v2.1 screenshot
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent · 0 / ?
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent · 0 / ?
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent · 0 / ?
0 hom
Not observed in any ancestry group.
gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗
ClinVar screenshot
ClinVar
This variant is absent from ClinVar.
ClinVar ↗
SpliceAI screenshot
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.13). BayesDel score = 0.655873.
SpliceAI ↗
Functional / OncoKB screenshot
Functional Unknown Oncogenic Effect
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. POLE, the catalytic subunit of DNA polymerase epsilon, is an enzyme involved in DNA replication and repair. Select POLE mutations lead to ultra-high m
OncoKB ↗
COSMIC screenshot
COSMIC
Cancer hotspots screenshot
Cancer hotspots
Somatic evidence Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
COSMIC ↗ Hotspots ↗
Sources & reference links
8Sources
ClinVar
gnomAD v2.1
gnomAD v4.1
gnomAD-Canada
SpliceAI
OncoKB
COSMIC
Cancer hotspots