About TP53
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
TP53 c.833C>A, p.(Pro278His)
Classification
Likely pathogenic
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is likely pathogenic. Select a step to read what it means.
Likely pathogenic.A likely pathogenic classification under the recorded framework.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
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.
01The reasoning
How it was classified
The recorded framework is ClinGen TP53 VCEP v2.4.0. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 3
Benign evidence criteria: 0
Pathogenic criteria applied · 3
PS3Strong
PS3 · strong
The TP53 VCEP functional worksheet lists P278H with a final functional assignment of PS3.
PM2Supporting
PM2 · supporting
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.
PP3Moderate
PP3 · moderate
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.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Likely pathogenic
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.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
No screenshot for this evidence
Computational predictions
Not recorded
No SpliceAI or REVEL score is recorded in the fields used for this tile.
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB classifies this variant as Likely Oncogenic; biological effect: Likely Loss-of-function.
COSMIC
Cancer Hotspots
Somatic evidence
Not assessed
No COSMIC evidence statement is recorded in this case.
Context only
For specialists
Technical detail
ACMG/AMP criteria under ClinGen TP53 VCEP v2.4.0, with the data and sources behind each one.
28 criteria with recorded statuses: 3 met · 4 not met · 9 not assessed · 12 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
TP53 p.Pro278His has abnormal functional evidence, and the TP53 VCEP functional worksheet assigns PS3 for this amino acid substitution.
TP53 in silico assessment assigns c.833C>A as PP3_Moderate, with BayesDel 0.607821 and Class C65 supporting a deleterious missense effect.
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.
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.
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.
No criteria match.
Met · 3
PS3 StrongThe TP53 VCEP functional worksheet lists P278H with a final functional assignment of PS3. Details ▾Hide ▴
Rule
Use TP53 functional worksheet/flowchart for missense variants; worksheet pre-assignment for P278H is PS3.
Evidence considered
- Functional-worksheet row: P278H | NA | Non-functional | noLOF | LOF | LOF | NA | PS3
- TP53 functional flowchart and CSPEC designate PS3/BS3 assignment from eligible assays
Sources
vcep_f_u_n_c_t_i_o_n_a_l___w_o_r_k_s_h_e_e_tvcep_f_l_o_w_c_h_a_r_t___f_o_r___a_p_p_l_i_c_a_t_i_o_n___o_f___f_u_n_c_t_i_o_n_a_l___r_u_l_e___c_o_d_e_scspec ↗PMID:12826609 ↗PMID:29979965 ↗PMID:30224644 ↗
PM2 SupportingThe variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the TP53 PM2_Supporting threshold of less than 0.00003. Details ▾Hide ▴
Rule
TP53 PM2 is applied only at Supporting strength for allele frequency <0.00003 in gnomAD or another large population dataset.
Evidence considered
- gnomAD v2.1: absent
- gnomAD v4.1: absent
- TP53 PM2 threshold: allele frequency <0.00003; if multiple alleles in any ancestry group, frequency must be <0.00004
Sources
PP3 ModerateThe 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. Details ▾Hide ▴
Rule
For TP53 missense variants, use the pre-computed PP3/BP4 worksheet and in silico flowchart; c.833C>A is assigned PP3_moderate.
Evidence considered
- PP3-BP4-codes row: c.833C>A | p.Pro278His | Class C65 | 0.607821 | PP3_moderate
- SpliceAI max delta score = 0.00
- TP53 flowchart states no predicted splicing effect when SpliceAI <0.2
Sources
vcep_p_p_3___b_p_4___c_o_d_e_svcep_f_l_o_w_c_h_a_r_t___f_o_r___a_p_p_l_i_c_a_t_i_o_n___o_f___p_p_3___2_c___b_p_4___2_c___a_n_d___b_p_7spliceai ↗cspec ↗
Not met · 4 · evaluated, threshold not reached
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. Details ▾Hide ▴
Rule
TP53 BA1 requires FAF >=0.001 in a qualifying gnomAD continental subpopulation.
Evidence considered
- gnomAD v4.1: absent
- TP53 BA1 threshold: FAF >=0.001 in a qualifying continental subpopulation
Sources
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. Details ▾Hide ▴
Rule
TP53 BS1 requires FAF >=0.0003 and <0.001 in a qualifying gnomAD continental subpopulation.
Evidence considered
- gnomAD v4.1: absent
- TP53 BS1 threshold: FAF >=0.0003 and <0.001 in a qualifying continental subpopulation
Sources
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. Details ▾Hide ▴
Rule
TP53 BS3 applies only when eligible functional evidence supports no loss of function or only partial loss within rule-defined bounds.
Evidence considered
- Functional worksheet assignment for P278H is PS3
- BS3 requires functional evidence consistent with retained or only partial function
Sources
BP4 BP4 is not met because the TP53 VCEP in silico worksheet assigns PP3_moderate, not BP4, for c.833C>A. Details ▾Hide ▴
Rule
TP53 missense BP4 is applied only for variants meeting benign BayesDel and splicing thresholds; c.833C>A is pre-assigned PP3_moderate instead.
Evidence considered
- PP3-BP4-codes row for c.833C>A assigns PP3_moderate
Sources
vcep_p_p_3___b_p_4___c_o_d_e_scspec ↗
Not assessed · 9 · no assessment recorded
PS1 PS1 was not assessed because no TP53 VCEP-classified pathogenic or likely pathogenic variant producing the same amino acid change was explicitly retrieved. Details ▾Hide ▴
Rule
PS1 Strong for same amino acid change previously asserted Pathogenic by TP53 VCEP; PS1 Moderate for same amino acid change previously asserted Likely Pathogenic by TP53 VCEP.
Evidence considered
- TP53 PS1 requires a variant already asserted as Pathogenic or Likely Pathogenic under TP53 VCEP specifications
Still missing
- Need an explicitly retrieved TP53 VCEP-classified variant with the same amino acid substitution.
Sources
PS2 PS2 was not assessed because no de novo data, parental testing, or proband point tally was provided. Details ▾Hide ▴
Rule
PS2 uses TP53 point thresholds: Supporting 1 point, Moderate 2-3 points, Strong 4-7 points, Very Strong >=8 points.
Evidence considered
- TP53 PS2 is points-based
- No de novo case data retrieved in the workspace
Still missing
- Need confirmed or assumed de novo data and LFS cancer point scoring information.
Sources
cspec ↗vcep_t_a_b_l_e___o_f___l_f_s___c_a_n_c_e_r_s___a_n_d___p_o_i_n_t_s___f_o_r___p_s_2___a_n_d___p_p_1___c_o_d_e___a_p_p_l_i_c_a_t_i_o_n
PS4 PS4 was not assessed because no germline proband-based Li-Fraumeni syndrome point data were retrieved. Details ▾Hide ▴
Rule
PS4 thresholds: Supporting 1-1.5 points, Moderate 2-3.5 points, Strong 4-7.5 points, Very Strong >=8 points.
Evidence considered
- TP53 PS4 requires points-based case evidence
- No proband point data retrieved
Still missing
- Need proband-level LFS-associated cancer observations and point tally.
Sources
cspec ↗vcep_p_s_4___p_o_i_n_t_s___t_a_b_l_e
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. Details ▾Hide ▴
Rule
PM1 Moderate for codons 175/245/248/249/273/282 or same amino acid change with >=10 cancerhotspots.org somatic occurrences; PM1 Supporting for 2-9 occurrences.
Evidence considered
- TP53 PM1 automatic codons are 175, 245, 248, 249, 273, 282
- OncoKB: Likely Oncogenic; Likely Loss-of-function
- Hotspot evidence sentence states statistically significant hotspot but no exact same-AA count
Still missing
- Need exact cancerhotspots.org same-amino-acid occurrence count for p.Pro278His.
Sources
PM5 PM5 was not assessed because no explicitly retrieved TP53 VCEP-classified pathogenic or likely pathogenic alternate missense variant at codon 278 was available. Details ▾Hide ▴
Rule
PM5 Strong for >=2 different TP53 VCEP pathogenic missense variants at the residue; Moderate for 1 pathogenic; Supporting for 1 likely pathogenic with clinical data supporting pathogenicity.
Evidence considered
- TP53 PM5 requires previously classified TP53 VCEP missense variant(s) at the same residue
Still missing
- Need TP53 VCEP-classified alternate missense variant(s) at residue 278.
Sources
PP1 PP1 was not assessed because no segregation data or meiosis count was provided. Details ▾Hide ▴
Rule
PP1 Supporting for 3-4 meioses, Moderate for 5-6, Strong for >=7 across >1 family.
Evidence considered
- TP53 PP1 is meiosis-based
- No segregation evidence retrieved
Still missing
- Need cosegregation data and count of informative meioses.
Sources
cspec ↗vcep_t_a_b_l_e___o_f___l_f_s___c_a_n_c_e_r_s___a_n_d___p_o_i_n_t_s___f_o_r___p_s_2___a_n_d___p_p_1___c_o_d_e___a_p_p_l_i_c_a_t_i_o_n
PP4 PP4 was not assessed because no low-VAF constitutional mosaicism observations were provided. Details ▾Hide ▴
Rule
PP4 Moderate for at least 2 independent observations with VAF 5-25%; Supporting for observation with VAF 5-35%.
Evidence considered
- TP53 PP4 depends on observed variant allele fraction in qualifying cases
- No VAF-based observations retrieved
Still missing
- Need one or more independent observations with qualifying TP53 blood VAF values.
Sources
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. Details ▾Hide ▴
Rule
BS2 Supporting for 2-3 unrelated females >=60 years without cancer, Moderate for 4-7, Strong for >=8 from a single source.
Evidence considered
- TP53 BS2 is based on unaffected older female carriers from a single source
- No qualifying unaffected carrier data retrieved
Still missing
- Need qualifying unaffected carrier counts from a single source.
Sources
BS4 BS4 was not assessed because no nonsegregation data in affected relatives with Li-Fraumeni syndrome-associated cancers were provided. Details ▾Hide ▴
Rule
TP53 BS4 applies to lack of segregation in affected family members with LFS-associated cancers.
Evidence considered
- No family nonsegregation evidence retrieved
Still missing
- Need family-based nonsegregation data in affected relatives.
Sources
Not applicable · 12· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/APVS1 is not applicable because NM_000546.6:c.833C>A is a missense variant, not a null or canonical splice variant addressed by the TP53 PVS1 framework. Details ▾Hide ▴
Rule
TP53 PVS1 framework is for null/splice/frameshift/nonsense/CNV variants.
Evidence considered
- p.(Pro278His) missense consequence
- TP53 PVS1 flowchart applies to null, splice, frameshift, nonsense, and CNV variants
Sources
cspec ↗vcep_p_v_s_1___f_l_o_w_c_h_a_r_t
PM3 N/APM3 is not applicable under the TP53 specifications. Details ▾Hide ▴
PM4 N/APM4 is not applicable because this is a missense substitution rather than a protein length-changing in-frame indel or stop-loss variant. Details ▾Hide ▴
Evidence considered
- p.(Pro278His) missense consequence
- TP53 CSPEC marks PM4 as not applicable
Sources
PM6 N/APM6 is not applicable under the TP53 specifications. Details ▾Hide ▴
PP2 N/APP2 is not applicable under the TP53 specifications. Details ▾Hide ▴
PP5 N/APP5 is not applicable under the TP53 specifications. Details ▾Hide ▴
BP1 N/ABP1 is not applicable under the TP53 specifications. Details ▾Hide ▴
BP2 N/ABP2 is not applicable under the TP53 specifications for this review. Details ▾Hide ▴
BP3 N/ABP3 is not applicable under the TP53 specifications. Details ▾Hide ▴
BP5 N/ABP5 is not applicable under the TP53 specifications. Details ▾Hide ▴
BP6 N/ABP6 is not applicable under the TP53 specifications. Details ▾Hide ▴
BP7 N/ABP7 is not applicable because this is a missense variant rather than a synonymous or qualifying intronic variant. Details ▾Hide ▴
Rule
TP53 BP7 is for synonymous or qualifying intronic variants with no splice impact.
Evidence considered
- p.(Pro278His) missense consequence
- TP53 BP7 framework applies to synonymous/intronic variants
Sources
cspec ↗vcep_f_l_o_w_c_h_a_r_t___f_o_r___a_p_p_l_i_c_a_t_i_o_n___o_f___p_p_3___2_c___b_p_4___2_c___a_n_d___b_p_7
Identifiers
- Gene
- TP53
- Transcript
- NM_000546.6
- Coding (HGVS c.)
- NM_000546.6:c.833C>A
- Protein (HGVS p.)
- NP_000537.3:p.(Pro278His)
- GRCh38
- chr17:7673787 G>T
- GRCh37
- chr17:7577105 G>T
Gene diagram
Every interpreted variant in TP53, mapped onto the exon structure of NM_000546.6. Select a row to find it on the plot.
TP53NM_000546.6
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in TP53
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
Allele count data not recorded
gnomAD v2.1
Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 ModerateThe 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. Details ▾Hide ▴
Rule
For TP53 missense variants, use the pre-computed PP3/BP4 worksheet and in silico flowchart; c.833C>A is assigned PP3_moderate.
Evidence considered
- PP3-BP4-codes row: c.833C>A | p.Pro278His | Class C65 | 0.607821 | PP3_moderate
- SpliceAI max delta score = 0.00
- TP53 flowchart states no predicted splicing effect when SpliceAI <0.2
Sources
vcep_p_p_3___b_p_4___c_o_d_e_svcep_f_l_o_w_c_h_a_r_t___f_o_r___a_p_p_l_i_c_a_t_i_o_n___o_f___p_p_3___2_c___b_p_4___2_c___a_n_d___b_p_7spliceai ↗cspec ↗
BP4 BP4 is not met because the TP53 VCEP in silico worksheet assigns PP3_moderate, not BP4, for c.833C>A. Details ▾Hide ▴
Rule
TP53 missense BP4 is applied only for variants meeting benign BayesDel and splicing thresholds; c.833C>A is pre-assigned PP3_moderate instead.
Evidence considered
- PP3-BP4-codes row for c.833C>A assigns PP3_moderate
Sources
vcep_p_p_3___b_p_4___c_o_d_e_scspec ↗
BP7 N/ABP7 is not applicable because this is a missense variant rather than a synonymous or qualifying intronic variant. Details ▾Hide ▴
Rule
TP53 BP7 is for synonymous or qualifying intronic variants with no splice impact.
Evidence considered
- p.(Pro278His) missense consequence
- TP53 BP7 framework applies to synonymous/intronic variants
Sources
cspec ↗vcep_f_l_o_w_c_h_a_r_t___f_o_r___a_p_p_l_i_c_a_t_i_o_n___o_f___p_p_3___2_c___b_p_4___2_c___a_n_d___b_p_7
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
Captured gnomAD v4.1 source record
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Captured SpliceAI source record
Open source ↗
ClinVar
Captured ClinVar source record
Open source ↗
COSMIC
Captured COSMIC source record
Cancer hotspots
Captured Cancer Hotspots source record
OncoKB
Captured OncoKB source record
Open source ↗
ClinGen CSpec
Captured ClinGen CSpec source record
Open source ↗
All source links
- ClinGen CSpec ↗cspec.genome.network/cspec/ui/svi/doc/135637581
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/376646/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/17-7577105-G-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr17-7673787-G-T?dataset=gnomad_r4
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000546.6%3Ac.833C…
- OncoKB ↗www.oncokb.org/gene/TP53/P278H
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
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.
Somatic
This variant has previously been reported in somatic cancers (COSMIC; COSV52665769, n = 29 times).