Classification rationale

PM2 VUS

POLE c.2044G>A

The POLE c.2044G>A (p.Glu682Lys; p.E682K) variant has not been identified in the León-Castillo recurrent COSMIC/TCGA endometrial carcinoma POLE variant table and has been reported in ClinVar as a variant of uncertain significance.¹ This variant is present at very low frequency in gnomAD, with AF 4.16e-06 in v2.1 (1/240232 alleles) and AF 1.87e-06 in v4.1 (3/1600942 alleles), which is below the project's PM2 threshold of 0.1% and below benign frequency thresholds.² This missense change is not one of the exact POLE hotspot or recurrent exonuclease-domain substitutions specified by the León-Castillo framework for PM1 or PS4.³ Available computational evidence does not establish a POLE-specific deleterious or benign pattern for this exact variant because it was not identified in the León-Castillo supplementary computational tables, and SpliceAI predicts no significant splice impact (max delta score 0.04).⁴

PM2 → VUS

1 vcep_path_250_323_s002clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗

3 final_classification_frameworkvcep_path_250_323vcep_path_250_323_s002

4 vcep_path_250_323_s003vcep_path_250_323_s004spliceai ↗

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

POLE NM_006231.4

Fetching transcript structure from UCSC…

Applied criteria · 1 met · select any tile

Met

Not met

Not assessed

N/A

Strength very strong supporting

Pathogenic evidence

PVS

PS

PM

PP

Benign evidence

BA

BS

BP

—

Rationale

Select a criterion.

Sources

Evidence used

Gaps remaining

Rule

—

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 1.8739e-06; MAF= 0.00019%, 3/1600942 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 1.12233e-05; MAF= 0.00112%, 1/89100 alleles, homozygotes = 0); grpmax FAF= 2.8e-07.

v2.1

This variant is present in gnomAD v2.1 (AF= 4.16264e-06; MAF= 0.00042%, 1/240232 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 5.51876e-05; MAF= 0.00552%, 1/18120 alleles, homozygotes = 0).

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.00019% · 3 / 1,600,942
0 hom · FAF 2.8e-05%

South Asian 1 / 89,100	0.0011%
European (non-Finnish) 2 / 1,172,782	0.00017%

+ 8 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish, African/African American)

gnomAD v2.1

0.00042% · 1 / 240,232
0 hom

East Asian

1 / 18,120

0.0055%

+ 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, European (Finnish), European (non-Finnish), Remaining individuals, South Asian)

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant has been reported in ClinVar as Uncertain significance (2 clinical laboratories).

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04). REVEL score = 0.448. BayesDel score = 0.133134.

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB has not reviewed this specific variant; no variant-level oncogenicity or biological effect is available. Gene-level context: 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

7Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

Cancer hotspots