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.1 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 0.00003.2 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.3 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).4
TP53
Final classification
Likely Pathogenic
TP53 c.469G>T · p.Val157Phe
TP53
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.
TP53 VCEP v2.4.0 CSPEC point-based final-classification framework (Tavtigian et al., 2020 Bayesian adaptation): PS3_Strong (4) + PM1_Moderate (2) + PM2_Supporting (1) = 7 points, which falls in the 6-9 point range for Likely Pathogenic.
Classification rationale
PS3PM1PM2
Likely Pathogenic
TP53 c.469G>T
PS3 + PM1 + PM2
→
Likely Pathogenic
1
COSMICClinVar
2
gnomAD v2.1gnomAD v4.1TP53 VCEP
3
Functional-worksheet.xlsx
4
Cancer HotspotsPP3-BP4-codes.xlsxSpliceAI
Gene diagram
· NM_000546.5 · variants mapped to exon structure
TP53
NM_000546.5
Fetching transcript structure from UCSC…
Applied criteria · 3 met · select any tile
Met
Not met
Not assessed
N/A
Strength
very strong
supporting
Pathogenic evidence
PVS
PS
PM
PP
Benign evidence
BA
BS
BP
—
—
—
Rationale
Select a criterion.
Sources
Evidence used
Gaps remaining
Rule
—
Research & evidence
Population frequency · supports pathogenic
gnomAD v4.1
gnomAD v2.1
v4.1
This 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).
v2.1
Absent from gnomAD v2.1.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / 1,614,132
0 hom
0 hom
Not observed in any ancestry group.
+ 10 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American, European (non-Finnish))
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
Functional
Likely Oncogenic
OncoKB classifies this variant as Likely Oncogenic; biological effect: Likely Loss-of-function.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV52667015, n = 366 times).
Hotspots
This variant lies in a statistically significant hotspot.
Literature · how each cited paper was used
3papers cited
Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why.
PMID PMID:15037740
Found
Structured finding pending for this record — see source link.
Applied to
→PS3 supports · met
PMID PMID:16778209
Found
Structured finding pending for this record — see source link.
Applied to
→PS3 supports · met
PMID PMID:21561095
Found
Structured finding pending for this record — see source link.
Applied to
→PS3 supports · met
Sources & reference links