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LYFE SCIENCES
Project: HERA
NM_006231.4:c.1367C>T
p.Ala456Val  ·  POLE
León-Castillo et al. 2020 custom POLE framework · vleon-castillo-2020-custom-framework-v1
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Classification rationale
1

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.

cosmic ↗ clinvar ↗
2

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%.

gnomad_v2 ↗ gnomad_v4 ↗
3

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.

spliceai ↗
Applied criteria
Met
Not met
Not assessed
N/A
Very strong
Strong
Moderate
Supporting
Pathogenic evidence
PVS
PVS1
PS
PS1
PS2
PS3
PS4
PM
PM1
PM2
PM3
PM4
PM5
PM6
PP
PP1
PP2
PP3
PP4
PP5
Benign evidence
BA
BA1
BS
BS1
BS2
BS3
BS4
BP
BP1
BP2
BP3
BP4
BP5
BP6
BP7
PVS1
—
—
Rationale
Select a criterion to inspect its explanation.
Evidence used
  • —
Gaps remaining
  • —
Rule
—
Publications
—
Research and evidence
ClinVar evidence
02
ClinVar
This variant is absent from ClinVar.
ClinVar ↗
Functional evidence
03
Functional
OncoKB: 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 ↗
In silico evidence
04
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.10).
SpliceAI ↗
COSMIC evidence
05
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).
COSMIC ↗
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant does not lie in a statistically significant hotspot.
ResidueA456
Hotspots ↗