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LYFE SCIENCES
Project: HERA
NM_000546.5:c.469G>T
p.Val157Phe  ·  TP53
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Classification rationale
1

The TP53 c.469G>T (p.Val157Phe) variant has been observed in somatic cancers in COSMIC (COSV52667015; n=366) and has not been reported in ClinVar.

2

This variant is absent from gnomAD v2.1 and absent from gnomAD v4.1 (0/1614132 alleles; AF 0.00000%), which is below the TP53 PM2_Supporting threshold of less than 0.00003.

3

TP53 expert panel functional data classify p.Val157Phe as PS3 because the variant is non-functional in Kato, shows loss of function in Funk and Kotler, and is loss-of-function by the majority of eligible assays.

4

Cancer Hotspots shows p.Val157Phe in 67 tumors at the significant TP53 V157 hotspot residue (77 tumors at the residue overall), supporting PM1, while the TP53 bioinformatic worksheet assigns no PP3/BP4 evidence and SpliceAI predicts no splice impact (max delta score 0.00).

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 is absent from ClinVar.
ClinVar ↗
Functional evidence
03
Functional
OncoKB: Likely Oncogenic
OncoKB classifies this variant as Likely Oncogenic; biological effect: Likely Loss-of-function.
OncoKB ↗
In silico evidence
04
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
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 = 366 times).
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant lies in a statistically significant hotspot.
ResidueV157
Hotspots ↗