Classification rationale

PM2 BP4 VUS

POLE c.2083T>C

The POLE c.2083T>C (p.Phe695Leu; p.F695L) variant has not been identified as a recurrent POLE hotspot in the León-Castillo endometrial carcinoma datasets or Cancer Hotspots and has been reported in ClinVar mainly as uncertain significance, with some likely benign submissions.¹ This variant is rare in population databases, with an allele frequency of 0.00320% in gnomAD v2.1 and 0.00329% in gnomAD v4.1, both below the project's 0.1% PM2 threshold.² Computational evidence does not support a damaging effect: SpliceAI predicts no significant splice impact (maximum delta score 0.08), REVEL is 0.322, and BayesDel is -0.367686.³

PM2 + BP4 → VUS

1 vcep_path_250_323_s002hotspots ↗clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗

3 spliceai ↗revelbayesdel

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

POLE NM_006231.4

Fetching transcript structure from UCSC…

Applied criteria · 2 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= 3.28709e-05; MAF= 0.00329%, 53/1612366 alleles, homozygotes = 0) and has highest observed frequency in the Middle Eastern population (AF= 0.000164636; MAF= 0.01646%, 1/6074 alleles, homozygotes = 0); grpmax FAF= 9.22e-05.

v2.1

This variant is present in gnomAD v2.1 (AF= 3.19909e-05; MAF= 0.00320%, 9/281330 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000139626; MAF= 0.01396%, 1/7162 alleles, homozygotes = 0); grpmax FAF= 1.091e-05.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.0033% · 53 / 1,612,366
0 hom · FAF 0.0092%

Middle Eastern 1 / 6,074	0.016%
African/African American 12 / 74,864	0.016%
East Asian 4 / 44,814	0.0089%
South Asian 4 / 90,848	0.0044%
Admixed American 2 / 59,774	0.0033%
European (non-Finnish) 29 / 1,179,132	0.0025%
Remaining individuals 1 / 62,424	0.0016%

+ 3 not observed (European (Finnish), Amish, Ashkenazi Jewish)

gnomAD v2.1

0.0032% · 9 / 281,330
0 hom · FAF 0.0011%

Remaining individuals 1 / 7,162	0.014%
African/African American 2 / 24,936	0.008%
South Asian 2 / 30,356	0.0066%
East Asian 1 / 19,874	0.005%
European (non-Finnish) 3 / 128,562	0.0023%

+ 3 not observed (Admixed American, Ashkenazi Jewish, European (Finnish))

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant has been reported in ClinVar as Uncertain significance (5 clinical laboratories) and as Likely benign (2 clinical laboratories).

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.08). REVEL score = 0.322. BayesDel score = -0.367686.

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

7Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

Cancer hotspots