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LYFE SCIENCES
Project: HERA
NM_000546.5:c.761T>C
p.Ile254Thr  ·  TP53
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Classification rationale
1

The TP53 c.761T>C (p.Ile254Thr) variant has been observed in somatic cancers 9 times in COSMIC and has been reported in ClinVar, including a pathogenic expert panel assertion.

clinvar ↗
2

This variant is absent from gnomAD v2.1 and gnomAD v4.1, placing it below the TP53 PM2 threshold of less than 0.00003.

gnomad_v2 ↗ gnomad_v4 ↗ cspec ↗
3

In TP53 functional studies curated by the TP53 VCEP, this variant was non-functional in the Kato assay and showed loss of function in additional eligible assays, supporting PS3.

PMID:12826609 ↗ PMID:29979965 ↗ PMID:30224644 ↗
4

TP53-specific computational assessment supports a damaging missense effect, with a VCEP worksheet assignment of PP3_moderate, BayesDel 0.598199, REVEL 0.954, and no predicted splice impact by SpliceAI (max delta score 0.00).

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
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Rationale
Select a criterion to inspect its explanation.
Evidence used
  • —
Gaps remaining
  • —
Rule
—
Publications
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Research and evidence
ClinVar evidence
02
ClinVar
This variant has been reported in ClinVar as Pathogenic (3 clinical laboratories) and as Likely pathogenic (3 clinical laboratories) and as Uncertain significance (1 clinical laboratory) and as Pathogenic by ClinGen TP53 Variant Curation Expert Panel, ClinGen (expert panel).
ClinVar ↗
Functional evidence
03
Functional
OncoKB: Oncogenic
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Loss-of-function; curated oncogenicity label: Oncogenic.
OncoKB ↗
In silico evidence
04
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.954. BayesDel score = 0.598199.
SpliceAI ↗
COSMIC evidence
05
COSMIC
This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV52767322, n = 9 times).
COSMIC ↗
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant lies in a statistically significant hotspot.
ResidueI254
Hotspots ↗