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LYFE SCIENCES
Project: HERA
NM_000546.6:c.469G>T
p.Val157Phe  ·  TP53
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Classification rationale
1

The TP53 NM_000546.6:c.469G>T (p.Val157Phe, p.V157F) variant has been reported in ClinVar with Likely pathogenic and Pathogenic clinical submissions.

clinvar ↗
2

This variant is absent from gnomAD v2.1 and gnomAD v4.1, including 0 of 1,614,132 alleles in gnomAD v4.1, which supports PM2_Supporting under the TP53 VCEP threshold of less than 0.00003.

gnomad_v2 ↗ gnomad_v4 ↗ cspec ↗
3

In the TP53 VCEP functional framework, p.Val157Phe is assigned PS3 because Kato-based transactivation results are non-functional and the majority of other eligible assays show loss of function; additional published studies describe abnormal mutant behavior and structural destabilization consistent with impaired normal p53 activity.

PMID:16778209 ↗ PMID:21561095 ↗
4

SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, and although REVEL is 0.708 and BayesDel is 0.314073, the TP53 VCEP precomputed in silico table assigns c.469G>T as 'No evidence', so neither PP3 nor BP4 was applied.

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
gnomAD v2.1 evidence
v2.1
gnomAD v4.1 evidence
v4.1
01
Population
gnomAD v2.1Absent from gnomAD v2.1.
gnomAD v4.1This variant is present in gnomAD v4.1 (AF= 0; MAF= 0.00000%, 0/1614132 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/75036 alleles, homozygotes = 0).
gnomAD v2 ↗ gnomAD v4 ↗
ClinVar evidence
02
ClinVar
This variant has been reported in ClinVar as Likely pathogenic (4 clinical laboratories) and as Pathogenic (2 clinical laboratories). (ClinVarID = 12353)
ClinVar ↗
Functional evidence
03
Functional
OncoKB: Likely Oncogenic
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
OncoKB ↗
In silico evidence
04
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.708. BayesDel score = 0.314073.
SpliceAI ↗
COSMIC evidence
05
COSMIC
This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV52667015, n = 375 times).
COSMIC ↗
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant lies in a statistically significant hotspot.
ResidueV157
Hotspots ↗