Starting

Initialising…

POLE

Final classification

VUS

POLE c.745C>A · p.Arg249=

POLE

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.

Gene

POLE

Transcript

NM_006231.4

HGVS · transcript:coding

NM_006231.4:c.745C>A

Consequence

N/A

GRCh38

chr12:132677419 G>T

GRCh37

chr12:133254005 G>T

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

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

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

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

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