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POLE
Final classification
VUS
PM2PP3
POLE
c.2706+5G>A
p.?
unknown · exon 23i
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

POLE germline alterations predispose to polyposis and colorectal cancer, largely through loss of proofreading fidelity. This intronic splice-region variant is classified as a VUS: it is extremely rare in the population and predicted to alter splicing, but without RNA or functional evidence its impact on POLE proofreading and cancer risk remains unconfirmed.

Transcript
NM_006231.4
HGVS · transcript:coding
NM_006231.4:c.2706+5G>A
GRCh38
chr12:132663999 C>T
GRCh37
chr12:133240585 C>T
Basis Under the custom POLE framework (León-Castillo et al. 2020), the variant meets only PM2 and PP3 at Supporting strength, below the threshold for any Pathogenic, Likely Pathogenic, Benign, or Likely Benign classification. ▾
Under the custom POLE framework (León-Castillo et al. 2020), the variant meets only PM2 and PP3 at Supporting strength, below the threshold for any Pathogenic, Likely Pathogenic, Benign, or Likely Benign classification.
Classification rationale
PM2PP3 VUS
POLE c.2706+5G>A unknown · exon 23i

PM2 (Supporting): gnomAD v4.1 total allele frequency 1.74e-05, below the 0.1% rarity threshold, with no homozygotes. PP3 (Supporting): SpliceAI maximum delta 0.381 (donor gain) exceeds the 0.2 threshold, predicting a splice impact. Overall classification VUS: two Supporting criteria (PM2, PP3) do not meet any Pathogenic, Likely Pathogenic, Benign, or Likely Benign combination rule.

PM2 + PP3 → VUS
Gene diagram · NM_006231.4 · variants mapped to exon structure
POLE NM_006231.4
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 19 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
✓
PM2 supporting Pathogenic
Met (Supporting): gnomAD v4.1 total allele frequency 1.74e-05, far below the 0.1% rarity threshold, with no homozygotes.
gnomAD v4.1 contains 28 alternate alleles among 1,613,748 alleles (AF 1.73509e-05), group maximum FAF 1.454e-05, and zero homozygotes; the highest listed population AF is 3.33267e-05 in Admixed American individuals.gnomAD v2.1 contains 2 alternate alleles among 251,362 alleles (AF 7.95665e-06), zero homozygotes, and highest listed population AF 2.89218e-05 in Admixed American individuals.The variant is below the 0.1% PM2 rarity threshold used for this review.
gnomad_v4 ↗gnomad_v2 ↗
✓
PP3 supporting Pathogenic
Met (Supporting): SpliceAI maximum delta 0.381 (donor gain) exceeds the 0.2 splice-impact threshold.
SpliceAI Lookup for NM_006231.4:c.2706+5G>A reports DS_DG 0.381 and maximum delta 0.381.The generic non-missense workflow applies PP3_Supporting when SpliceAI maximum delta is >0.2. This threshold is attributed to Walker et al. 2023 (PMID:36413997), which provides the published calibration basis named for this threshold.
spliceai ↗
Assessed · not applied · 7 not met · 12 not assessed
Pathogenic
PVS1 Not assessed: this intronic splice-region variant has no RNA evidence establishing a null protein consequence (p.?).
PS2 Not assessed: no parental testing documents the variant as de novo in the proband.
PS3 Not assessed: no validated functional assay data were available; SpliceAI prediction is not a functional assay.
PS4 Not met: the POLE rule requires an exact recurrent missense hotspot, but this intronic variant is absent from COSMIC.
PM3 Not assessed: no observations establish the variant in trans with a pathogenic variant in an affected individual.
PM4 Not assessed: with no established protein consequence (p.?) there is no in-frame length change to evaluate.
PM6 Not assessed: no case record describes the variant as de novo without parental testing.
PP1 Not assessed: no affected relatives or informative meioses were available to evaluate cosegregation.
PP4 Not assessed: no patient phenotype data establish a presentation highly specific for a POLE-associated disorder.
PP5 Not met: no ClinVar expert-panel pathogenic assertion exists for this exact variant; only single-submitter Likely benign and VUS.
Benign
BA1 Not met: highest gnomAD v4.1 allele frequency 3.33e-05 is far below the 1% BA1 threshold.
BS1 Not met: highest observed allele frequency 3.33e-05 is below the 0.3% BS1 threshold.
BS2 Not met: zero homozygotes observed among 1,613,748 gnomAD v4.1 alleles.
BS3 Not assessed: no validated functional assay demonstrates a benign effect of this variant.
BS4 Not assessed: no unaffected relatives with confirmed absence of the variant were documented.
BP2 Not assessed: no phase-resolved observation places the variant in trans or in cis with a pathogenic variant.
BP4 Not met: SpliceAI maximum delta 0.381 exceeds the 0.1 BP4 threshold, so no benign splice prediction.
BP5 Not assessed: no alternate molecular diagnosis fully explaining the phenotype was identified.
BP6 Not met: no ClinVar expert-panel benign assertion exists; a single-submitter Likely benign call is ineligible.
N/A · 7 PS1 · PM1 · PM5 · PP2 · BP1 · BP3 · BP7
Research & evidence
Population frequency
gnomAD v4.1 screenshot
gnomAD v4.1
gnomAD v2.1 screenshot
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 1.73509e-05; MAF= 0.00174%, 28/1613748 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 3.33267e-05; MAF= 0.00333%, 2/60012 alleles, homozygotes = 0); grpmax FAF= 1.454e-05.
v2.1
This variant is present in gnomAD v2.1 (AF= 7.95665e-06; MAF= 0.00080%, 2/251362 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 2.89218e-05; MAF= 0.00289%, 1/34576 alleles, homozygotes = 0).
🇨🇦 CA
Not available in gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.0017% · 28 / 1,613,748
0 hom · FAF 0.0015%
Admixed American
2 / 60,012
0.0033%
European (non-Finnish)
25 / 1,180,038
0.0021%
South Asian
1 / 91,064
0.0011%
+ 7 not observed (Remaining individuals, European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish, African/African American)
gnomAD v2.1
0.0008% · 2 / 251,362
0 hom
Admixed American
1 / 34,576
0.0029%
European (non-Finnish)
1 / 113,678
0.00088%
+ 6 not observed (African/African American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian)
gnomAD Canada 🇨🇦
Absent · 0 / ?
0 hom
Not observed in any ancestry group.
gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗
ClinVar screenshot
ClinVar
This variant has been reported in ClinVar as Uncertain significance (4 clinical laboratories) and as Likely benign (1 clinical laboratory). (ClinVarID = 221094)
ClinVar ↗
SpliceAI screenshot
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 0.38).
SpliceAI ↗
Functional No data
No calibrated functional assay or RNA evidence was identified for this variant.
OncoKB ↗
COSMIC screenshot
COSMIC
Somatic evidence
COSMIC
This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant cancer hotspot.
COSMIC ↗
Sources & reference links
7Sources
ClinVar
gnomAD v2.1
gnomAD v4.1
gnomAD-Canada
SpliceAI
OncoKB
COSMIC
Triaged references · 3 PMIDs not cited in assessment
25741868 ↗ Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. CLINVAR
25394175 ↗ A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment. CLINVAR
28492532 ↗ Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. CLINVAR