Classification rationale

PM2 BP4 VUS

POLE c.4952+9A>G

The POLE c.4952+9A>G (p.?) variant has not been identified in the León-Castillo endometrial carcinoma recurrence table and has been reported in ClinVar as Likely benign by one clinical laboratory.¹ This variant is absent from gnomAD v2.1 and present once in gnomAD v4.1 (1/1613298 alleles; AF 6.20e-07), which supports rarity but does not establish pathogenic enrichment.² SpliceAI predicts low splice impact for NM_006231.4 with a maximum delta score of 0.07, arguing against a clinically meaningful splicing effect.³

PM2 + BP4 → VUS

1 vcep_path_250_323_s002clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗

3 spliceai ↗

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 · 20 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 absent from gnomAD v2.1 and present once in gnomAD v4.1 (1/1613298 alleles; AF 6.20e-07; highest population AF 1.10e-05 in South Asian individuals), which is below the project's PM2 threshold of 0.1% and supports rarity in the general population.

gnomAD v2.1 absentgnomAD v4.1 total AF 6.19848e-07South Asian AF 1.09813e-05

gnomad_v2 ↗gnomad_v4 ↗

BP4 supporting Benign

Computational splicing prediction supports no meaningful splice effect. SpliceAI for NM_006231.4 shows DS_AG 0.00, DS_AL 0.01, DS_DG 0.07, and DS_DL 0.00, with a maximum delta score of 0.07, which is below commonly used concern thresholds for splice disruption.

SpliceAI max delta score 0.07

spliceai ↗

Assessed · not applied · 4 not met · 16 not assessed

Pathogenic

PS2 No confirmed de novo data with verified maternity and paternity were identified for this variant.

PS3 No published functional assay demonstrating an abnormal effect of this specific intronic variant was identified.

PS4 The local POLE framework limits PS4 to exact recurrent exonuclease-domain missense variants in the established pathogenic set with combined COSMIC and TCGA endometrial carcinoma counts of at least 10.

PM3 No phase data or recessive case evidence relevant to PM3 were identified.

PM4 This variant is intronic and does not directly demonstrate a protein length change.

PM6 No assumed de novo evidence without full parental confirmation was identified.

PP1 No segregation data were identified for this variant.

PP3 Available computational evidence does not support a damaging splicing effect.

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

PP5 No reputable-source pathogenic classification was used as stand-alone evidence for this variant.

Benign

BA1 This variant does not meet the BA1 population threshold.

BS1 This variant does not meet the BS1 population threshold.

BS2 No evidence was identified showing this variant in healthy adult individuals at a level sufficient for BS2.

BS3 No published functional study demonstrating a normal effect of this specific variant was identified.

BS4 No segregation data were identified showing lack of segregation with disease.

BP2 No phase information was identified to assess BP2.

BP3 This criterion was not assessed because the variant is not an in-frame deletion or insertion in a repetitive region.

BP5 No alternate molecular explanation sufficient to account for the phenotype independently of this variant was identified.

BP6 Although ClinVar contains a Likely benign submission for this variant, a reputable-source benign assertion was not used as stand-alone evidence.

BP7 This intronic +9 variant has low predicted splice impact by SpliceAI, but no additional conservation-based or framework-specific BP7 assessment was available to support formal application of BP7.

N/A · 6 PVS1 · PS1 · PM1 · PM5 · PP2 · BP1

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 6.19848e-07; MAF= 0.00006%, 1/1613298 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 1.09813e-05; MAF= 0.00110%, 1/91064 alleles, homozygotes = 0).

v2.1

Absent from gnomAD v2.1.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

6.2e-05% · 1 / 1,613,298
0 hom

South Asian

1 / 91,064

0.0011%

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

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 (1 clinical laboratory).

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.07).

SpliceAI ↗

Functional No data

No calibrated functional assay or RNA evidence was identified for this variant.

OncoKB ↗

COSMIC

Somatic evidence

COSMIC

This variant has not previously been reported in somatic cancers (COSMIC).

Hotspots

This variant does not lie in a statistically significant cancer hotspot.

COSMIC ↗

Sources & reference links

6Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

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