Starting

Initialising…

POLE

Final classification

VUS

POLE c.1367C>T · p.Ala456Val

POLE

The POLE c.1367C>T (p.Ala456Val) variant has been observed in somatic cancers in COSMIC (COSV57673561, n=2) and has not been reported in ClinVar.

Gene

POLE

Transcript

NM_006231.4

HGVS · transcript:coding

NM_006231.4:c.1367C>T

Consequence

N/A

GRCh38

chr12:132673270 G>A

GRCh37

chr12:133249856 G>A

Basis León-Castillo et al. 2020 custom POLE framework for criterion specification, using ACMG/AMP 2015 final classification combination thresholds as defined in the explicit final-classification framework. ▾

León-Castillo et al. 2020 custom POLE framework for criterion specification, using ACMG/AMP 2015 final classification combination thresholds as defined in the explicit final-classification framework.

Classification rationale

PM2PP3 VUS

POLE c.1367C>T

The POLE c.1367C>T (p.Ala456Val) variant has been observed in somatic cancers in COSMIC (COSV57673561, n=2) and has not been reported in ClinVar.¹ The variant is absent from gnomAD v2.1 and gnomAD v4.1, with an observed population frequency of 0 that is below the project's PM2 threshold of 0.1%.² In León-Castillo Supplementary Table S3, p.Ala456Val is listed as likely disease causing with 0 benign in silico results, meeting the local POLE PP3 rule; SpliceAI predicts no significant splice impact with a maximum delta score of 0.10.³

PM2 + PP3 → VUS

1 cosmic ↗clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗

3 vcep_p_a_t_h___2_5_0___3_2_3___s_0_0_4spliceai ↗

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 is absent from ClinVar.

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.10).

SpliceAI ↗

Functional Likely Oncogenic

OncoKB has not reviewed this specific variant; no variant-level oncogenicity or biological effect is available. Gene-level context: 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; COSV57673561, n = 2 times).

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