Classification rationale

PM2 VUS

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

Gene diagram · NM_006231.4 · variants mapped to exon structure

POLE NM_006231.4

Fetching transcript structure from UCSC…

Applied criteria · 1 applied · 24 assessed

Applied · 1

Strength Supporting Moderate Strong Very strong

✓

PM2 supporting Pathogenic

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)

gnomad_v2 ↗gnomad_v4 ↗

Assessed · not applied

Pathogenic

PS1 Not met: no source establishes p.Arg1111Gln as pathogenic — ClinVar classifies this exact variant as uncertain significance across three laboratories.

PS2 Not assessed: no de novo occurrence or parental-testing data was available for this variant.

PS3 Not assessed: insufficient functional-study evidence was available to evaluate this variant.

PS4 Not met: the variant's somatic recurrence (n=4) falls below the required >=10 in both COSMIC and TCGA endometrial cohorts.

PM1 Not met: residue 1111 lies outside the exonuclease-domain hotspot region occupied by the framework's established pathogenic substitutions.

PM3 Not assessed: no biallelic or trans-phase observation with a pathogenic variant was available.

PM4 Not met: the substitution causes no protein length change (no in-frame indel or stop-loss).

PM5 Not met: no pathogenic missense at residue 1111 with a different amino-acid change has been reported.

PM6 Not assessed: no de novo occurrence (assumed or confirmed) has been reported for this variant.

PP1 Not assessed: no family segregation data was available for this variant.

PP2 Not assessed: no gene-level missense-constraint metric (e.g., gnomAD Z-score) was available to evaluate this gene.

PP3 Not met: REVEL score 0.36 is below the >=0.932 supporting threshold.

PP4 Not assessed: no proband phenotype or family-history data was available.

PP5 Not met: no expert-panel ClinVar classification exists; all three submissions are single-submitter laboratories reporting uncertain significance.

Benign

BA1 Not met: highest allele frequency (0.0109%) is roughly two orders of magnitude below the >1% BA1 threshold.

BS1 Not met: highest allele frequency (0.0109%) is about 30-fold below the >0.3% BS1 threshold.

BS2 Not met: POLE cancer predisposition is adult-onset and incompletely penetrant, so the full-penetrance-at-early-age precondition is unmet.

BS3 Not assessed: insufficient functional-study evidence was available.

BS4 Not assessed: no family non-segregation data was available for this variant.

BP1 Not met: missense is an established POLE disease mechanism (five recurrent exonuclease-domain hotspots), so BP1 cannot apply.

BP2 Not assessed: no cis/trans phase data relative to a pathogenic variant was available.

BP4 Not met: REVEL score 0.36 is above the <=0.016 benign supporting threshold.

BP5 Not assessed: no data on an alternate molecular basis of disease was available.

BP6 Not met: no expert-panel ClinVar classification exists; all three submissions are single-submitter laboratories reporting uncertain significance.

N/A · 3 PVS1 · 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)

gnomAD Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar as Uncertain significance (3 clinical laboratories). (ClinVarID = 405761)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.36. BayesDel score = -0.0290682.

SpliceAI ↗

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

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

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.

COSMIC ↗ Hotspots ↗

Sources & reference links

8Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

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