POLE

Final classification

VUS

POLE c.3799G>A · p.Glu1267Lys

POLE

PM2_Supporting is met: NM_006231.3:c.3799G>A (p.Glu1267Lys) is absent from gnomAD v2.1 (0/244,852 alleles), v4.1, and gnomAD-Canada v1.0, meeting the PM2 threshold of allele frequency <0.1%.

Gene

POLE

Transcript

NM_006231.3

HGVS · transcript:coding

NM_006231.3:c.3799G>A

Consequence

N/A

GRCh38

chr12:132649512 C>T

GRCh37

chr12:133226098 C>T

Basis Only one pathogenic supporting criterion (PM2_Supporting: absent from gnomAD) and one benign supporting criterion (BP4_Supporting: benign in silico predictions) are met. No very strong, strong, or moderate criteria are met. Under the León-Castillo et al. 2020 custom POLE framework (which retains standard ACMG/AMP 2015 final combination thresholds), a single supporting criterion is insufficient to reach Pathogenic, Likely Pathogenic, Likely Benign, or Benign. The presence of conflicting PM2_Supporting (pathogenic direction) and BP4_Supporting (benign direction) evidence results in VUS. ▾

Only one pathogenic supporting criterion (PM2_Supporting: absent from gnomAD) and one benign supporting criterion (BP4_Supporting: benign in silico predictions) are met. No very strong, strong, or moderate criteria are met. Under the León-Castillo et al. 2020 custom POLE framework (which retains standard ACMG/AMP 2015 final combination thresholds), a single supporting criterion is insufficient to reach Pathogenic, Likely Pathogenic, Likely Benign, or Benign. The presence of conflicting PM2_Supporting (pathogenic direction) and BP4_Supporting (benign direction) evidence results in VUS.

Classification rationale

PM2 BP4 VUS

POLE c.3799G>A

PM2_Supporting is met: NM_006231.3:c.3799G>A (p.Glu1267Lys) is absent from gnomAD v2.1 (0/244,852 alleles), v4.1, and gnomAD-Canada v1.0, meeting the PM2 threshold of allele frequency <0.1%.¹ BP4_Supporting is met: multiple in silico tools predict a benign effect — REVEL score 0.262, BayesDel score 0.061, and SpliceAI max delta 0.07 (no splice impact).² PVS1 is not applicable: this is a missense variant outside the scope of the ClinGen SVI PVS1 null-variant framework (PMC6185798).³ The variant is absent from ClinVar, COSMIC, and cancerhotspots.org. No variant-specific functional data or literature reports were identified.⁴ The León-Castillo et al. 2020 custom POLE framework criteria (PM1, PS4, PP3, BP4) were assessed: the variant is not in the exonuclease domain, not recurrent in EC cohorts, and absent from Supplementary Tables S1-S3.⁵ Overall, with only PM2_Supporting and BP4_Supporting met, and all other criteria not met or not applicable, this variant is classified as a Variant of Uncertain Significance (VUS).⁶

PM2 + BP4 → VUS

1 gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

2 revelbayesdelspliceai ↗

3 pvs1_generic_framework ↗pvs1_variant_assessment

4 clinvar ↗oncokb ↗

5 vcep_path_250_323vcep_path_250_323_s002vcep_path_250_323_s003vcep_path_250_323_s004

6 final_classification_framework

Gene diagram · NM_006231.3 · variants mapped to exon structure

POLE NM_006231.3

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 21 assessed

Applied · 2

Strength Supporting Moderate Strong Very strong

✓

PM2 supporting Pathogenic

This variant is absent from gnomAD v2.1 (0/244,852 alleles, AF = 0.000%), absent from gnomAD v4.1, and absent from gnomAD-Canada v1.0, meeting the PM2 threshold for absence from population databases (AF < 0.1%).

gnomAD v2.1: 0/244852 allelesAF = 0.000%

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

✓

BP4 supporting Benign

The León-Castillo custom POLE framework BP4 rule requires the variant to be in Supplementary Table S2/S3 with REVEL class 'Likely benign' and ≥4 benign in silico results; the variant is absent from the tables, falling back to generic assessment. Multiple lines of computational evidence suggest a benign impact: REVEL score 0.262 (benign-leaning), BayesDel score 0.061 (strongly benign-leaning), and SpliceAI max delta 0.07 (no predicted splice impact). Multiple in silico tools concordantly predict no damaging effect.

REVEL score: 0.262 (benign-leaning)BayesDel score: 0.061 (benign-leaning)SpliceAI max delta: 0.07 (no splice impact)

spliceai ↗

Assessed · not applied

Pathogenic

PS1 No alternative nucleotide change at c.3799 has been reported as pathogenic.

PS2 No de novo observation has been reported for this variant.

PS3 No variant-specific or range-based functional data exists for p.Glu1267Lys.

PS4 The León-Castillo custom POLE framework requires the exact variant to be recurrent in both COSMIC and TCGA endometrial carcinoma cohorts with a combined count ≥10.

PM1 The León-Castillo custom POLE framework restricts PM1 to exonuclease-domain missense variants (residues ~1-471).

PM5 No pathogenic missense variant at the same codon (1267) was identified.

PM6 No de novo observation has been reported for this variant.

PP1 No co-segregation data are available.

PP2 PP2 requires a gene with a low rate of benign missense variation where missense variants are a common disease mechanism.

PP3 The León-Castillo custom POLE framework PP3 rule requires the variant to be listed in Supplementary Table S2 or S3 with REVEL class 'likely disease causing' and ≤1 benign in silico result; E1267K is absent from both tables.

PP4 No proband phenotype or clinical data have been provided.

PP5 This variant is absent from ClinVar.

Benign

BA1 The variant is absent from gnomAD v2.1 (0/244,852 alleles, AF = 0.000%), absent from gnomAD v4.1, and absent from gnomAD-Canada v1.0.

BS1 The variant is absent from all gnomAD populations.

BS2 No homozygous observations exist in gnomAD (0 homozygotes across all populations).

BS3 No well-established in vitro or in vivo functional studies exist showing that p.Glu1267Lys has no damaging effect on protein function or splicing.

BS4 No family segregation data are available.

BP1 BP1 applies when a missense variant occurs in a gene where primarily truncating variants cause disease.

BP2 No observation of this variant in trans with a pathogenic POLE variant has been reported.

BP5 No alternate molecular basis for disease has been identified in this case.

BP6 This variant is absent from ClinVar.

N/A · 2 PVS1 · BP7

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

Absent from gnomAD v4.1.

v2.1

This variant is present in gnomAD v2.1 (AF= 0; MAF= 0.00000%, 0/244852 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/15080 alleles, homozygotes = 0).

🇨🇦 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 / 244,852
0 hom

Not observed in any ancestry group.

+ 8 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Remaining individuals, South Asian)

gnomAD Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant is absent from ClinVar.

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.07). REVEL score = 0.262. BayesDel score = 0.0614221.

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 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