Classification rationale

PM2 BP7 VUS

POLE c.745C>A

The POLE c.745C>A (p.Arg249=) variant has not been observed in COSMIC and has been reported in ClinVar as likely benign by two clinical laboratory submissions.¹ This variant is absent from gnomAD v2.1 and gnomAD v4.1.² This variant is not listed among the recurrent or hotspot POLE exonuclease-domain substitutions in the León-Castillo POLE review materials.³ This is a synonymous change outside the canonical splice dinucleotides, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.03.⁴

PM2 + BP7 → VUS

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗

3 vcep_path_250_323vcep_path_250_323_s002

4 spliceai ↗pvs1_variant_assessment

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 · 17 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 moderate review Pathogenic

This variant is absent from gnomAD v2.1 and gnomAD v4.1. The observed allele frequency is 0 in both datasets, which is below the 0.1% PM2 threshold.

Absent from gnomAD v2.1.Absent from gnomAD v4.1.

gnomad_v2 ↗gnomad_v4 ↗

BP7 supporting Benign

This is a synonymous variant outside the canonical splice dinucleotides, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.03. Available evidence does not support an effect on RNA splicing.

Protein consequence is p.(Arg249=)/p.(R249=).Canonical splice consensus flag is false.SpliceAI max delta score 0.03.

spliceai ↗

Assessed · not applied · 4 not met · 13 not assessed

Pathogenic

PS2 No confirmed de novo occurrence data were identified for this variant.

PS3 No published functional study was identified that directly tested this exact synonymous variant.

PS4 This variant has not been reported in COSMIC and is not listed among the recurrent POLE endometrial carcinoma variants in Supplementary Table S1.

PM1 This synonymous variant is not one of the exact POLE exonuclease-domain hotspot or recurrent missense substitutions specified in the local POLE PM1 framework, and no statistically significant hotspot evidence was identified at Arg249.

PM3 No trans configuration data or recessive-case evidence were identified for this variant.

PM6 No assumed de novo occurrence data were identified for this variant.

PP1 No segregation data were identified for this variant.

PP4 No phenotype-specific evidence was identified to show that the observed clinical presentation is highly specific for a POLE-related disorder caused by this variant.

PP5 No independent use of external pathogenic assertions was made for this variant.

Benign

BA1 This variant is absent from gnomAD v2.1 and gnomAD v4.1.

BS1 This variant is absent from gnomAD v2.1 and gnomAD v4.1.

BS2 No dataset was identified showing this variant in well-phenotyped unaffected individuals at a frequency sufficient for BS2.

BS3 No well-established functional study was identified showing a benign effect for this exact variant.

BS4 No evidence was identified that this variant fails to segregate with disease in a family.

BP2 No phase data were identified to show this variant in trans with a pathogenic variant for a dominant disorder or in cis with a pathogenic variant.

BP5 No alternate molecular explanation or case-level context was identified that would support BP5 for this variant.

BP6 No independent use of external benign assertions was made for this criterion.

N/A · 9 PVS1 · PS1 · PM4 · PM5 · PP2 · PP3 · BP1 · BP3 · BP4

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

Absent from gnomAD v4.1.

v2.1

Absent from gnomAD v2.1.

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 v4 ↗ gnomAD v2 ↗

ClinVar

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

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03).

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.

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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