POLE

Final classification

VUS

POLE c.4189C>A · p.Leu1397Ile

POLE

NM_006231.3:c.4189C>A (p.Leu1397Ile) is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, meeting PM2 at Supporting strength.

Gene

POLE

Transcript

NM_006231.3

HGVS · transcript:coding

NM_006231.3:c.4189C>A

Consequence

N/A

GRCh38

chr12:132643938 G>T

GRCh37

chr12:133220524 G>T

Basis Only one criterion is met: PM2 at Supporting strength (absent from gnomAD v2.1, v4.1, and gnomAD-Canada). No pathogenic, likely pathogenic, benign, or likely benign combination threshold is satisfied under ACMG/AMP 2015 rules. Per the León-Castillo et al. 2020 custom POLE framework, criterion triggering and strength are customized (PM1, PS4, PP3, BP4), but final classification combination follows standard ACMG/AMP 2015 thresholds, which explicitly state that all other combinations default to VUS. ▾

Only one criterion is met: PM2 at Supporting strength (absent from gnomAD v2.1, v4.1, and gnomAD-Canada). No pathogenic, likely pathogenic, benign, or likely benign combination threshold is satisfied under ACMG/AMP 2015 rules. Per the León-Castillo et al. 2020 custom POLE framework, criterion triggering and strength are customized (PM1, PS4, PP3, BP4), but final classification combination follows standard ACMG/AMP 2015 thresholds, which explicitly state that all other combinations default to VUS.

Classification rationale

PM2 VUS

POLE c.4189C>A

NM_006231.3:c.4189C>A (p.Leu1397Ile) is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, meeting PM2 at Supporting strength.¹ No other pathogenic or benign criteria are met. The variant is a C-terminal missense change outside the exonuclease domain, with no functional data, no clinical observations, no segregation data, and indeterminate computational predictions (REVEL 0.329, BayesDel -0.262).² With only PM2_Supporting met, the evidence is insufficient to classify this variant as pathogenic or likely pathogenic, and insufficient to classify as benign or likely benign. This variant is classified as a Variant of Uncertain Significance (VUS) per ACMG/AMP 2015 guidelines.³

PM2 → VUS

1 gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

2 revelbayesdelspliceai ↗clinvar ↗oncokb ↗

3 generic_acmg_combination_rules

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

POLE NM_006231.3

Fetching transcript structure from UCSC…

Applied criteria · 1 applied · 21 assessed

Applied · 1

Strength Supporting Moderate Strong Very strong

✓

PM2 supporting Pathogenic

NM_006231.3:c.4189C>A (p.Leu1397Ile) is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, indicating it is not observed in large population cohorts.

Absent from gnomAD v2.1 (0 alleles)gnomAD v4.1 (0 alleles)and gnomAD-Canada v1.0 (0 alleles).

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

Assessed · not applied

Pathogenic

PS1 No pathogenic missense variant has been identified at codon 1397.

PS2 No de novo observations have been reported for NM_006231.3:c.4189C>A.

PS3 No functional studies have been performed on p.Leu1397Ile or a systematically characterized range that includes residue 1397.

PS4 The variant is absent from the León-Castillo Supplementary Table S1 and is not recurrent in COSMIC or TCGA endometrial carcinoma cohorts.

PM1 Residue 1397 is in the C-terminal region of POLE, well outside the exonuclease domain (residues ~268–471).

PM6 No de novo observations of NM_006231.3:c.4189C>A have been reported.

PP1 No segregation data are available for NM_006231.3:c.4189C>A.

PP2 No HCI prior score is available for this variant.

PP3 The variant is absent from León-Castillo Supplementary Tables S2 and S3, so the custom PP3_Supporting rule does not apply.

PP4 No clinical phenotype data are available for NM_006231.3:c.4189C>A.

PP5 No reputable source has classified NM_006231.3:c.4189C>A as pathogenic.

Benign

BA1 The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada.

BS1 The variant is absent from all population databases.

BS2 No homozygous or compound heterozygous observations of NM_006231.3:c.4189C>A have been reported.

BS3 No functional studies have been performed demonstrating a benign effect for p.Leu1397Ile.

BS4 No segregation or family data are available for NM_006231.3:c.4189C>A.

BP1 Although this is a missense variant, POLE disease mechanism is not restricted to loss-of-function/truncating variants.

BP2 No co-occurrence data are available.

BP4 The variant is absent from León-Castillo Supplementary Tables S2 and S3, so the custom BP4_Supporting rule does not apply.

BP5 No reputable source has classified NM_006231.3:c.4189C>A as benign.

BP6 No reputable source has classified NM_006231.3:c.4189C>A as benign.

N/A · 3 PVS1 · PM5 · BP7

Research & evidence

Population frequency

gnomAD v4.1

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

This variant is absent from ClinVar.

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.329. BayesDel score = -0.262205.

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