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NM_000546.6:c.833C>T
p.Pro278Leu · TP53
ClinGen TP53 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for TP53 Version 2.4 · v2.4
0%
complete
Final classification
Likely Pathogenic
PS3PM2PP3
TP53
c.833C>T
p.Pro278Leu
missense · exon 8
Gene context NCBI Gene ↗ OncoKB ↗

TP53 encodes the p53 tumor suppressor protein, a transcription factor that responds to cellular stress such as DNA damage by switching on genes that trigger cell cycle arrest, DNA repair, senescence, or programmed cell death. In healthy cells, p53 is kept at low levels by constant degradation, but stress signals stabilize and activate it to protect against damaged cells surviving and dividing. Inherited mutations in TP53 cause Li-Fraumeni syndrome, a condition marked by a high risk of developing multiple cancers at a young age. TP53 is the most commonly mutated gene across human cancers, and loss of its normal function promotes tumor growth, spread, drug resistance, and genomic instability.

This variant

TP53 encodes a stress-responsive tumor suppressor, and inherited loss-of-function TP53 variants cause Li-Fraumeni syndrome with a high risk of multiple early-onset cancers.

Transcript
NM_000546.6
HGVS · transcript:coding
NM_000546.6:c.833C>T
GRCh38
chr17:7673787 G>A
GRCh37
chr17:7577105 G>A
Likely Pathogenic: PS3 strong, PM2 supporting, and PP3 moderate total 7 points under the TP53 VCEP Version 2.4 point-based framework.
Classification rationale
PS3PM2PP3 Likely Pathogenic
TP53 c.833C>T missense · exon 8

PS3 strong: P278L is non-functional in Kato data and loss of function in the majority of additional eligible assays. PM2 supporting: gnomAD v4.1 allele frequency is 6.1957e-07, below the TP53 VCEP threshold. PP3 moderate: the TP53 VCEP assigns PP3_moderate for BayesDel class C65 score 0.583698.

PS3 + PM2 + PP3 → Likely Pathogenic
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
Met, strong: the VCEP row for P278L pre-assigns PS3 after Kato shows non-functional activity and three additional eligible assays show loss of function.
Functional-worksheet.xlsx, Supplementary Table S3, row P278L: Kato class = Non-functional; Funk class = LOF; Giacomelli class = LOF; Kotler class = LOF; Kawaguchi class = NA; preliminary functional code = PS3.Flowchart-for-application-of-functional-rule-codes.pdf, page 1: eligible functional studies include Kato (PMID: 12826609), Funk (PMID 39774325), Giacomelli (PMID: 30224644), Kotler (PMID: 29979965), and Kawaguchi (PMID: 16007150).The exact nucleotide and three-letter protein notations were not present in the functional worksheet text, but the exact one-letter protein change P278L was present and matches the case normalization p.(Pro278Leu)/p.(P278L).
cspec ↗vcep_flowchart_for_application_of_functional_rule_codes ↗vcep_functional_worksheet ↗PMID:12826609 ↗
PM2 supporting Pathogenic
Met at supporting: gnomAD v4.1 total AF is 6.1957e-07, below the VCEP PM2 threshold of 0.00003, with zero homozygotes.
ClinGen TP53 VCEP v2.4 PM2 rule: apply at supporting level when AF is <0.00003; if multiple alleles occur within an ancestry group, that group's AF must be <0.00004; founder-effect groups including Remaining are ignored.gnomAD v4.1 all-comers total: 1/1,614,026 alleles, AF 6.195687058324959e-07, homozygotes 0.gnomAD v4.1 highest reported subpopulation: Remaining individuals, 1/62,508 alleles, AF 1.599795226211045e-05, homozygotes 0; Remaining is ignored under the VCEP rule and the frequency is nevertheless below 0.00004.
cspec ↗gnomad_v4 ↗
PP3 moderate Pathogenic
Met at moderate strength: the VCEP table assigns PP3_moderate for BayesDel C65 score 0.583698 for c.833C>T/p.Pro278Leu.
PP3-BP4-codes.xlsx, Supplementary Table S2 row: c.833C>T | p.Pro278Leu | Class C65 | BayesDel 0.583698 | PP3_moderate | 0.01.The VCEP flowchart states that PP3/BP4/BP7 application uses no predicted splicing difference with SpliceAI < 0.2; the case SpliceAI maximum delta score is 0.006.The exact variant notations c.833C>T, p.Pro278Leu, and p.P278L were searched in all three on-record TP53 files named for this group; the exact lookup row was found in PP3-BP4-codes.xlsx only.
cspec ↗vcep_pp3_bp4_codes ↗spliceai ↗
Assessed · not applied · 4 not met · 9 not assessed
Pathogenic
PS1 Not assessed: SpliceAI is 0.006, but no differently encoded p.Pro278Leu variant with a VCEP-qualified pathogenic assertion is documented.
PS2 Not assessed: the report calls p.Pro278Leu non-confirmed de novo, with the mother untested and insufficient proband cancer details to assign the VCEP PS2 points.
PS4 Not assessed: p.Pro278Leu is reported with multiple cancers, but missing proband ages and LFS-criteria details prevent assigning the required PS4 point total.
PM1 Not assessed: p.Pro278Leu is not in the six listed codons, and the cancerhotspots.org same-change count required for the alternative PM1 path is unavailable.
PM5 Not assessed: p.Pro278Ser and p.Pro278Thr are reported at residue 278, but neither has a VCEP-qualified pathogenicity assertion required for PM5.
PP1 Not assessed: the family history lists two sons with multiple tumours but provides no tested-relative variant status or countable cosegregating meioses for PP1.
PP4 Not assessed: no qualifying multigene-panel VAF observations are available for p.Pro278Leu under the VCEP's 5-25% or 5-35% PP4 rules.
Benign
BA1 Not met: the highest observed frequency is 1.5998e-05 in the VCEP-excluded Remaining group, below the 0.001 BA1 threshold.
BS1 Not met: no eligible ancestry group reaches the 0.0003 BS1 threshold with at least two observed alleles.
BS2 Not assessed: gnomAD reports zero homozygotes but lacks the VCEP-required counts of unrelated cancer-free females aged at least 60 years.
BS3 Not met: P278L is non-functional in Kato and shows loss of function in three additional eligible assay columns, contradicting both BS3 rule paths.
BS4 Not assessed: affected relatives are reported, but their p.Pro278Leu testing results are unavailable, so lack of segregation cannot be established.
BP4 Not met: BP4 is excluded for VCEP BayesDel class C65 missense variants despite SpliceAI maximum delta 0.006 below 0.2.
N/A · 12 PVS1 · PM3 · PM4 · PM6 · PP2 · PP5 · BP1 · BP2 · BP3 · BP5 · BP6 · BP7
Research & evidence
Population frequency · supports pathogenic
gnomAD v4.1 screenshot
gnomAD v4.1
gnomAD v2.1 screenshot
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 6.19569e-07; MAF= 0.00006%, 1/1614026 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 1.5998e-05; MAF= 0.00160%, 1/62508 alleles, homozygotes = 0).
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
6.2e-05% · 1 / 1,614,026
0 hom
Remaining individuals
1 / 62,508
0.0016%
+ 9 not observed (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
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent · 0 / ?
0 hom
Not observed in any ancestry group.
gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗
ClinVar screenshot
ClinVar
This variant has been reported in ClinVar as Pathogenic (3 clinical laboratories). (ClinVarID = 232497)
ClinVar ↗
SpliceAI screenshot
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.94. BayesDel score = 0.583698.
SpliceAI ↗
Functional / OncoKB screenshot
Functional Likely Oncogenic
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
OncoKB ↗
COSMIC screenshot
COSMIC
Cancer hotspots screenshot
Cancer hotspots
Somatic evidence Hotspot
COSMIC
This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV52678063, n = 155 times).
Hotspots
This variant lies in a statistically significant hotspot.
COSMIC ↗ Hotspots ↗
Literature · how each cited paper was used
1papers cited
Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why. 6 further PMIDs triaged but not cited — see Sources & references.
Rule & framework references · cited for criterion definitions, not variant evidence
12826609 ↗ Understanding the function-structure and function-mutation relationships of p53 tumor suppressor protein by high-resolution missense mutation analysis.
Sources & reference links
9Sources
CSpec VCEP
ClinVar
gnomAD v2.1
gnomAD v4.1
gnomAD-Canada
SpliceAI
OncoKB
COSMIC
Cancer hotspots
Triaged references · 6 PMIDs not cited in assessment
16861262 ↗ Inactive full-length p53 mutants lacking dominant wild-type p53 inhibition highlight loss of heterozygosity as an important aspect of p53 status in human cancers. ONCOKB
11370630 ↗ Detection of 11 germline inactivating TP53 mutations and absence of TP63 and HCHK2 mutations in 17 French families with Li-Fraumeni or Li-Fraumeni-like syndrome. CLINVAR
15993273 ↗ Hereditary breast cancer syndromes in a Turkish population. Results of molecular germline analysis. CLINVAR
17392385 ↗ American Cancer Society guidelines for breast screening with MRI as an adjunct t CLINVAR
18978813 ↗ Crystal structure of a p53 core tetramer bound to DNA. CLINVAR
19556618 ↗ High frequency of de novo mutations in Li-Fraumeni syndrome. CLINVAR