TP53 p.Pro278His has abnormal functional evidence, and the TP53 VCEP functional worksheet assigns PS3 for this amino acid substitution.1 TP53 in silico assessment assigns c.833C>A as PP3_Moderate, with BayesDel 0.607821 and Class C65 supporting a deleterious missense effect.2 SpliceAI predicts a max delta score of 0.00, which is below the TP53 splice-impact threshold of 0.2 and does not indicate a predicted splice effect.3 The variant is absent from gnomAD v4.1, and absence from population databases is consistent with the TP53 PM2_Supporting threshold of less than 0.00003.4 Using the generic ACMG/AMP combination rules as a fallback because explicit TP53 VCEP final Tavtigian score thresholds were not explicitly retrieved, PS3 with PP3_Moderate and PM2_Supporting supports a Likely Pathogenic classification.5
Final classification
Likely pathogenic
PS3PM2PP3
TP53
c.833C>A
p.Pro278His
This variant
TP53 p.Pro278His has abnormal functional evidence, and the TP53 VCEP functional worksheet assigns PS3 for this amino acid substitution.
Fallback generic ACMG/AMP combination rules were used because the workspace explicitly retrieved TP53 VCEP criterion specifications and noted a Tavtigian points-based system, but did not explicitly retrieve the TP53 VCEP final point-to-classification thresholds. Under the generic ACMG/AMP fallback, PS3 + PP3_Moderate + PM2_Supporting supports Likely Pathogenic.
Classification rationale
PS3PM2PP3
Likely pathogenic
TP53 c.833C>A
PS3 + PM2 + PP3
→
Likely pathogenic
1
vcep_f_u_n_c_t_i_o_n_a_l___w_o_r_k_s_h_e_e_t
2
vcep_p_p_3___b_p_4___c_o_d_e_s
5
generic_acmg_combination_rules
LYFE Sciences is an AI system, and it can make mistakes. Criteria
may be applied incorrectly, sources may be misread, and a confident-looking
classification can still be wrong. Double-check every criterion and
its underlying evidence before relying on any call.
Gene diagram
· NM_000546.6 · variants mapped to exon structure
TP53
NM_000546.6
Fetching transcript structure from UCSC…
Applied criteria · 3 applied · 13 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 3
Strength
Supporting
Moderate
Strong
Very strong
PS3
Strong
Pathogenic
The TP53 VCEP functional worksheet lists P278H with a final functional assignment of PS3.
Functional-worksheet row: P278H | NA | Non-functional | noLOF | LOF | LOF | NA | PS3TP53 functional flowchart and CSPEC designate PS3/BS3 assignment from eligible assays
PM2
Supporting
Pathogenic
The variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the TP53 PM2_Supporting threshold of less than 0.00003.
gnomAD v2.1: absentgnomAD v4.1: absentTP53 PM2 threshold: allele frequency <0.00003; if multiple alleles in any ancestry group, frequency must be <0.00004
PP3
Moderate
Pathogenic
The TP53 VCEP PP3/BP4 worksheet assigns c.833C>A (p.Pro278His) as PP3_moderate with BayesDel score 0.607821 and Class C65; SpliceAI max delta score is 0.00, which is below the 0.2 splice-impact threshold used in the TP53 in silico flowchart.
PP3-BP4-codes row: c.833C>A | p.Pro278His | Class C65 | 0.607821 | PP3_moderateSpliceAI max delta score = 0.00TP53 flowchart states no predicted splicing effect when SpliceAI <0.2
Assessed · not applied
· 4 not met · 9 not assessed
Pathogenic
PS1
PS1 was not assessed because no TP53 VCEP-classified pathogenic or likely pathogenic variant producing the same amino acid change was explicitly retrieved.
PS2
PS2 was not assessed because no de novo data, parental testing, or proband point tally was provided.
PS4
PS4 was not assessed because no germline proband-based Li-Fraumeni syndrome point data were retrieved.
PM1
PM1 was not applied because codon 278 is not one of the TP53 codons with automatic PM1 at moderate strength, and the available hotspot evidence did not explicitly provide a cancerhotspots.org same-amino-acid count meeting the TP53 PM1 threshold.
PM5
PM5 was not assessed because no explicitly retrieved TP53 VCEP-classified pathogenic or likely pathogenic alternate missense variant at codon 278 was available.
PP1
PP1 was not assessed because no segregation data or meiosis count was provided.
PP4
PP4 was not assessed because no low-VAF constitutional mosaicism observations were provided.
Benign
BA1
BA1 is not met because the variant is absent from gnomAD and therefore does not reach the TP53 BA1 filtering allele frequency threshold of at least 0.001.
BS1
BS1 is not met because the variant is absent from gnomAD and therefore does not reach the TP53 BS1 threshold of filtering allele frequency at least 0.0003.
BS2
BS2 was not assessed because no single-source dataset of unrelated cancer-free females aged at least 60 years carrying this variant was provided.
BS3
BS3 is not met because the TP53 VCEP functional worksheet assigns PS3 rather than BS3 for P278H, consistent with abnormal functional evidence rather than retained function.
BS4
BS4 was not assessed because no nonsegregation data in affected relatives with Li-Fraumeni syndrome-associated cancers were provided.
BP4
BP4 is not met because the TP53 VCEP in silico worksheet assigns PP3_moderate, not BP4, for c.833C>A.
N/A · 12
PVS1 · PM3 · PM4 · PM6 · PP2 · PP5 · BP1 · BP2 · BP3 · BP5 · BP6 · BP7
Research & evidence
Population frequency · supports pathogenic
gnomAD v4.1
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (4 clinical laboratories) and as Likely pathogenic (1 clinical laboratory) and as Pathogenic (1 clinical laboratory).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
Functional
OncoKB classifies this variant as Likely Oncogenic; biological effect: Likely Loss-of-function.
COSMIC
Cancer hotspots
Somatic evidence
COSMIC
This variant has previously been reported in somatic cancers (COSMIC; COSV52665769, n = 29 times).
Hotspots
This variant does not lie in a statistically significant cancer 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.
Understanding the function-structure and function-mutation relationships of p53
Found
Structured finding pending for this record — see source link.
Applied to
→PS3
Strong
A Systematic p53 Mutation Library Links Differential Functional Impact to Cancer
Found
Structured finding pending for this record — see source link.
Applied to
→PS3
Strong
Mutational processes shape the landscape of TP53 mutations in human cancer.
Found
Structured finding pending for this record — see source link.
Applied to
→PS3
Strong
Sources & reference links