Starting

Initialising…

POLE

Final classification

VUS

POLE c.4952+9A>G · p.?

POLE

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.

Gene

POLE

Transcript

NM_006231.4

HGVS · transcript:coding

NM_006231.4:c.4952+9A>G

Consequence

N/A

GRCh38

chr12:132642497 T>C

GRCh37

chr12:133219083 T>C

Basis León-Castillo et al. 2020 custom POLE framework using ACMG/AMP 2015 final category thresholds with POLE-specific criterion specifications ▾

León-Castillo et al. 2020 custom POLE framework using ACMG/AMP 2015 final category thresholds with POLE-specific criterion specifications

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 ↗

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

Benign evidence

—

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= 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