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

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.

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

POLE NM_006231.4

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 18 assessed

MetEvidence satisfies this criterion.

Not metEvaluated against available evidence; threshold not reached.

Not assessedApplies in principle, but no evidence was found to evaluate it.

N/ADoesn't apply to this variant type.

Applied · 2

Strength Supporting Moderate Strong Very strong

PM2 supporting Pathogenic

This variant is rare in population databases. In gnomAD v2.1 the allele frequency is 0.00320% (9/281330), and in gnomAD v4.1 it is 0.00329% (53/1612366), both well below the project's non-VCEP PM2 threshold of 0.1%.

gnomAD v2.1 total AF 3.19909e-05.gnomAD v4.1 total AF 3.28709e-05.

gnomad_v2 ↗gnomad_v4 ↗

BP4 supporting review Benign

The local POLE BP4 rule cannot be used because p.Phe695Leu was not identified in the León-Castillo supplementary in silico tables. Under generic computational review, SpliceAI predicts no significant splice impact with a maximum delta score of 0.08, REVEL is 0.322, and BayesDel is -0.367686; taken together, the available computational evidence argues against a damaging effect.

Variant absent from local POLE supplementary computational tables.SpliceAI max delta score 0.08.REVEL score 0.322.

spliceai ↗

Assessed · not applied · 5 not met · 13 not assessed

Pathogenic

PS1 No evidence was identified showing a different nucleotide change that produces the same POLE p.Phe695Leu protein change and is already established as pathogenic or likely pathogenic.

PS2 No confirmed de novo occurrence with verified maternity and paternity was identified.

PS3 No variant-specific functional study demonstrating a damaging effect for p.Phe695Leu was identified in the reviewed evidence.

PS4 The local POLE framework applies PS4 only to exact variants that are recurrent in both COSMIC and TCGA endometrial carcinoma cohorts with a combined count of at least 10 and that belong to the established pathogenic hotspot set.

PM1 The local POLE framework does not award PM1 simply for being in POLE.

PM5 No evidence was identified that a different missense change at codon 695 is established as pathogenic or likely pathogenic for use as PM5.

PM6 No assumed de novo occurrence data were identified.

PP1 No segregation data were identified for this variant.

PP2 The reviewed evidence did not establish a gene-specific PP2 rule showing that POLE is a gene in which missense variation is a common mechanism with low background benign missense variation across the full protein.

PP3 The local POLE computational rule cannot be used because p.Phe695Leu was not identified in the León-Castillo supplementary in silico tables.

PP4 No phenotype information was provided that is sufficiently specific for a POLE-related hereditary syndrome to support PP4.

Benign

BA1 This variant does not meet the benign stand-alone frequency threshold.

BS1 This variant does not meet the strong benign frequency threshold.

BS2 The reviewed evidence did not establish a validated BS2 framework for this hereditary cancer context, and the absence of homozygotes alone is not sufficient to use BS2.

BS3 No variant-specific functional study showing normal or near-normal POLE function was identified.

BS4 No evidence showing lack of segregation with disease was identified.

BP2 No phase or co-occurrence data were identified to support or refute BP2.

BP5 No alternate molecular diagnosis or independent explanation for disease was provided for assessment under BP5.

N/A · 8 PVS1 · PM3 · PM4 · PP5 · BP1 · BP3 · BP6 · BP7

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

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