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LYFE SCIENCES
Project: HERA
NM_000546.6:c.587G>T
p.Arg196Leu  ·  TP53
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Classification rationale
1

The TP53 c.587G>T (p.Arg196Leu; p.R196L) variant has been observed in somatic cancers in COSMIC (COSV52667931, n=3) and has been reported in ClinVar as a variant of uncertain significance.

clinvar ↗
2

This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the TP53 VCEP PM2_Supporting population threshold of 0.00003.

gnomad_v2 ↗ gnomad_v4 ↗ cspec ↗
3

In TP53 VCEP-curated functional datasets, Kato transactivation data were partially functional and other eligible assays showed no loss of function, supporting BS3_Supporting rather than PS3.

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

TP53 VCEP in silico criteria assign PP3_Moderate for c.587G>T based on aGVGD Class C65 with BayesDel 0.583489; SpliceAI shows no significant splice effect (max delta 0.14), and REVEL is high at 0.933.

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 Uncertain significance (5 clinical laboratories). (ClinVarID = 100814)
ClinVar ↗
Functional evidence
03
Functional
OncoKB: Inconclusive
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Inconclusive; curated oncogenicity label: Inconclusive.
OncoKB ↗
In silico evidence
04
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.14). REVEL score = 0.933. BayesDel score = 0.583489.
SpliceAI ↗
COSMIC evidence
05
COSMIC
This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV52667931, n = 3 times).
COSMIC ↗
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant lies in a statistically significant hotspot.
ResidueR196
Hotspots ↗