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LYFE SCIENCES
Project: HERA
NM_000546.6:c.925C>T
p.Pro309Ser  ·  TP53
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Classification rationale
1

The TP53 c.925C>T (p.Pro309Ser; p.P309S) variant has been observed in somatic cancers in COSMIC (COSV52729434; n=5) and has been reported in ClinVar with predominantly uncertain significance submissions and one likely benign submission.

clinvar ↗ hotspots ↗
2

This variant is absent from gnomAD v2.1 and is present only once in gnomAD v4.1 (1/1614124 alleles; AF 6.19531e-07), which is below the TP53 VCEP PM2_Supporting threshold of 0.00003.

gnomad_v2 ↗ gnomad_v4 ↗ cspec ↗
3

In TP53 functional studies curated by the VCEP, Kato transactivation testing classified p.Pro309Ser as functional and Giacomelli data showed no loss of function, supporting BS3.

4

Computational evidence predicts no splice effect (SpliceAI max delta score 0.00), and the TP53 VCEP bioinformatic worksheet assigns BP4 for c.925C>T with BayesDel 0.138442; REVEL 0.607 was available but does not override the TP53-specific computational rule.

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= 6.19531e-07; MAF= 0.00006%, 1/1614124 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 1.59969e-05; MAF= 0.00160%, 1/62512 alleles, homozygotes = 0).
gnomAD v2 ↗ gnomAD v4 ↗
ClinVar evidence
02
ClinVar
This variant has been reported in ClinVar as Uncertain significance (4 clinical laboratories) and as Likely benign (1 clinical laboratory) and as Uncertain Significance (1 clinical laboratory). (ClinVarID = 458575)
ClinVar ↗
Functional evidence
03
Functional
OncoKB: Unknown Oncogenic Effect
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. TP53, a tumor suppressor in the DNA damage pathway, is the most frequently mutated gene in cancer.
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 has previously been reported in somatic cancers (COSMIC; COSV52729434, n = 5 times).
COSMIC ↗
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant does not lie in a statistically significant hotspot.
ResidueP309
Hotspots ↗