León-Castillo et al. 2020 custom POLE framework · vleon-castillo-2020-custom-framework-v1
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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's established pathogenic mechanism centers on missense mutations in its proofreading exonuclease domain, where the five recurrent hotspots reside. p.Arg1111Gln maps to exon 27, outside that domain, and is vanishingly rare in population databases. The VUS classification reflects a variant too rare to be dismissed as common but with no evidence tying it to a known POLE disease mechanism.
Transcript
NM_006231.4
HGVS · transcript:coding
NM_006231.4:c.3332G>A
GRCh38
chr12:132657914 C>T
GRCh37
chr12:133234500 C>T
Only PM2 is met (Supporting; highest population AF 0.0109% vs the 0.1% threshold), reaching no Pathogenic or Benign combination, so the variant is classified Uncertain Significance.
Classification rationale
PM2VUS
POLE c.3332G>A
PM2 (Supporting): extremely low population frequency — gnomAD total AFs 0.0024-0.0035%, highest subpopulation 0.0109%, zero homozygotes, all below the 0.1% threshold. Overall: Uncertain Significance — a single Supporting criterion (PM2) satisfies no Pathogenic, Likely Pathogenic, or Benign combination.
PM2→VUS
LYFE Sciences is an AI system, and it can make mistakes. Criteria
may be applied incorrectly, sources may be misread, and a confident-looking
classification can still be wrong. Double-check every criterion and
its underlying evidence before relying on any call.
Gene diagram
· NM_006231.4 · variants mapped to exon structure
POLENM_006231.4
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in POLE—click a row to locate it on the plot · use the link column to open its page
Protein
Location
Classification
Link
Applied criteria · 1 applied · 24 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 · 1
Strength Supporting Moderate Strong Very strong
✓
PM2supportingPathogenic
Met (Supporting): all population frequencies are far below the 0.1% threshold (highest subpopulation 0.0109%), with zero homozygotes.
gnomAD v2.1 (exome): 6/251,478 alleles, AF 2.39e-05 (0.0024%), 0 homozygotes, grpmax FAF 7.01e-06 (source_registry key gnomad_v2)gnomAD v4.1 (joint): 57/1,614,138 alleles, AF 3.53e-05 (0.0035%), 0 homozygotes, joint grpmax FAF 3.15e-05; highest subpopulation Finnish AF 1.09e-04 (0.0109%) (source_registry key gnomad_v4)PM2 criterion definition from Richards et al. 2015 ACMG/AMP (PMID 25741868), applied via generic_acmg_combination_rules; project non-VCEP gnomAD PM2 threshold AF <0.1% (max observed 0.0109%, met)
Assessed · not applied
· 13 not met · 11 not assessed
Pathogenic
PS1Not met: no source establishes p.Arg1111Gln as pathogenic — ClinVar classifies this exact variant as uncertain significance across three laboratories.
PS2Not assessed: no de novo occurrence or parental-testing data was available for this variant.
PS3Not assessed: insufficient functional-study evidence was available to evaluate this variant.
PS4Not met: the variant's somatic recurrence (n=4) falls below the required >=10 in both COSMIC and TCGA endometrial cohorts.
PM1Not met: residue 1111 lies outside the exonuclease-domain hotspot region occupied by the framework's established pathogenic substitutions.
PM3Not assessed: no biallelic or trans-phase observation with a pathogenic variant was available.
PM4Not met: the substitution causes no protein length change (no in-frame indel or stop-loss).
PM5Not met: no pathogenic missense at residue 1111 with a different amino-acid change has been reported.
PM6Not assessed: no de novo occurrence (assumed or confirmed) has been reported for this variant.
PP1Not assessed: no family segregation data was available for this variant.
PP2Not assessed: no gene-level missense-constraint metric (e.g., gnomAD Z-score) was available to evaluate this gene.
PP3Not met: REVEL score 0.36 is below the >=0.932 supporting threshold.
PP4Not assessed: no proband phenotype or family-history data was available.
PP5Not met: no expert-panel ClinVar classification exists; all three submissions are single-submitter laboratories reporting uncertain significance.
Benign
BA1Not met: highest allele frequency (0.0109%) is roughly two orders of magnitude below the >1% BA1 threshold.
BS1Not met: highest allele frequency (0.0109%) is about 30-fold below the >0.3% BS1 threshold.
BS2Not met: POLE cancer predisposition is adult-onset and incompletely penetrant, so the full-penetrance-at-early-age precondition is unmet.
BS3Not assessed: insufficient functional-study evidence was available.
BS4Not assessed: no family non-segregation data was available for this variant.
BP1Not met: missense is an established POLE disease mechanism (five recurrent exonuclease-domain hotspots), so BP1 cannot apply.
BP2Not assessed: no cis/trans phase data relative to a pathogenic variant was available.
BP4Not met: REVEL score 0.36 is above the <=0.016 benign supporting threshold.
BP5Not assessed: no data on an alternate molecular basis of disease was available.
BP6Not met: no expert-panel ClinVar classification exists; all three submissions are single-submitter laboratories reporting uncertain significance.
N/A · 3PVS1 · BP3 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 3.5313e-05; MAF= 0.00353%, 57/1614138 alleles, homozygotes = 0) and has highest observed frequency in the European (Finnish) population (AF= 0.000109317; MAF= 0.01093%, 7/64034 alleles, homozygotes = 0); grpmax FAF= 3.15e-05.
v2.1
This variant is present in gnomAD v2.1 (AF= 2.38589e-05; MAF= 0.00239%, 6/251478 alleles, homozygotes = 0) and has highest observed frequency in the European (Finnish) population (AF= 9.23873e-05; MAF= 0.00924%, 2/21648 alleles, homozygotes = 0); grpmax FAF= 7.01e-06.
🇨🇦 CA
Not available in gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.0035%
· 57 / 1,614,138
0 hom · FAF 0.0032%
European (Finnish)
7 / 64,034
0.011%
European (non-Finnish)
48 / 1,179,978
0.0041%
African/African American
1 / 75,050
0.0013%
South Asian
1 / 91,082
0.0011%
+ 6 not observed (Remaining individuals, Admixed American, Amish, East Asian, Middle Eastern, Ashkenazi Jewish)
gnomAD v2.1
0.0024%
· 6 / 251,478
0 hom · FAF 0.0007%
European (Finnish)
2 / 21,648
0.0092%
African/African American
1 / 16,256
0.0062%
European (non-Finnish)
3 / 113,760
0.0026%
+ 5 not observed (Admixed American, Ashkenazi Jewish, East Asian, Remaining individuals, South Asian)
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
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV57681369, n = 4 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Triaged references · 1 PMID not cited in assessment
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
