Classification rationale

PM2 VUS

POLE c.2137G>A

The POLE c.2137G>A (p.Glu713Lys; p.E713K) variant has not been identified as a recurrent somatic POLE hotspot in the endometrial carcinoma datasets summarized by León-Castillo et al. and has been reported in ClinVar as a variant of uncertain significance.¹ This variant is rare in population databases, with an allele frequency of 0.00081% (2/247784) in gnomAD v2.1 and 0.00031% (5/1608750) in gnomAD v4.1, and it is absent from gnomAD-Canada.² Computational evidence does not support a splice-disrupting effect, with a SpliceAI maximum delta score of 0.01, and the missense predictor scores are not strongly damaging (REVEL 0.246; BayesDel -0.033673).³

PM2 → VUS

1 vcep_path_250_323_s002clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

3 spliceai ↗revelbayesdel

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= 3.108e-06; MAF= 0.00031%, 5/1608750 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 4.24737e-06; MAF= 0.00042%, 5/1177198 alleles, homozygotes = 0); grpmax FAF= 1.24e-06.

v2.1

This variant is present in gnomAD v2.1 (AF= 8.07155e-06; MAF= 0.00081%, 2/247784 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.78209e-05; MAF= 0.00178%, 2/112228 alleles, homozygotes = 0); grpmax FAF= 2.96e-06.

🇨🇦 CA

Absent from gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.00031% · 5 / 1,608,750
0 hom · FAF 0.00012%

European (non-Finnish)

5 / 1,177,198

0.00042%

+ 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)

gnomAD v2.1

0.00081% · 2 / 247,784
0 hom · FAF 0.0003%

European (non-Finnish)

2 / 112,228

0.0018%

+ 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (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 has been reported in ClinVar as Uncertain significance (2 clinical laboratories). (ClinVarID = 473514)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.246. BayesDel score = -0.033673.

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 previously been reported in somatic cancers (COSMIC; COSV106057460, n = 1 times).

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

Triaged references · 2 PMIDs not cited in assessment

25394175 ↗ A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment. CLINVAR

28492532 ↗ Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. CLINVAR