Final classification

VUS

PS3PM2

TP53

c.476C>T

p.Ala159Val

missense · exon 5

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

NM_000546.5:c.476C>T (p.Ala159Val) affects TP53, whose p53 tumor-suppressor function protects cells from DNA damage and whose inherited disruption causes Li-Fraumeni syndrome.

Transcript

NM_000546.5

HGVS · transcript:coding

NM_000546.5:c.476C>T

GRCh38

chr17:7675136 G>A

GRCh37

chr17:7578454 G>A

VUS: PS3 strong (+4) plus PM2 supporting (+1) totals 5 points under the TP53 VCEP point-based framework.

Classification rationale

PS3PM2 VUS

TP53 c.476C>T missense · exon 5

PS3 strong: A159V is non-functional in Kato data and loss of function in most additional eligible assays. PM2 supporting: c.476C>T is absent from gnomAD v2.1 and v4.1.

PS3 + PM2 → VUS

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_000546.5 · variants mapped to exon structure

TP53 NM_000546.5

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 14 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 · 2

Strength Supporting Moderate Strong Very strong

PS3 strong Pathogenic

Met, strong: the VCEP worksheet assigns PS3 because A159V is non-functional by Kato and LOF in three additional eligible assays.

Functional-worksheet.xlsx, Supplementary Table S3, row A159V: Kato = Non-functional; Funk = LOF; Giacomelli = LOF; Kotler = LOF; Kawaguchi = NA; preliminary functional code = PS3.ClinGen TP53 VCEP PS3 strong rule: non-functional on Kato et al. data AND loss of function (LOF) by the majority of other eligible assays.Flowchart-for-application-of-functional-rule-codes.pdf: eligible functional studies include Kato, Funk, Giacomelli, Kotler, and Kawaguchi.

cspec ↗vcep_flowchart_for_application_of_functional_rule_codes ↗vcep_functional_worksheet ↗PMID:12826609 ↗PMID:29979965 ↗

PM2 supporting Pathogenic

Met at supporting strength: the variant is absent from gnomAD v2.1 and v4.1, consistent with allele frequency 0 below the VCEP's 0.00003 threshold.

TP53 VCEP PM2 rule: apply at supporting level when allele frequency is <0.00003 (0.003%) in gnomAD or another large sequenced population.gnomAD v2.1 all-comers result for NC_000017.10:g.7578454G>A / NM_000546.5:c.476C>T: absent, observed allele frequency 0.gnomAD v4.1 all-comers result for NC_000017.11:g.7675136G>A / NM_000546.5:c.476C>T: absent, observed allele frequency 0.

cspec ↗gnomad_v2 ↗gnomad_v4 ↗

Assessed · not applied · 5 not met · 9 not assessed

Pathogenic

PS1 Not assessed: no qualifying alternate-nucleotide variant producing the same p.Ala159Val change was identified for comparison under the VCEP rule.

PS2 Not assessed: no variant-specific de novo observation, parental confirmation, or proband cancer-point tally is available to reach the VCEP's 1-point PS2 threshold.

PS4 Not assessed: no proband phenotype or case-control enrichment is available to assign the VCEP's PS4 point thresholds of 1-1.5, 2-3.5, 4-7.5, or ≥8.

PM1 Not assessed: A159 is a reported hotspot, but the required cancerhotspots same-amino-acid count of at least 10 is unavailable.

PM5 Not assessed: zero same-residue comparator variants were available for TP53 residue 159 under the VCEP PM5 requirements.

PP1 Not assessed: no variant-positive relatives with LFS-associated cancer or countable meioses are documented against the VCEP's minimum 3-meiosis supporting threshold.

PP3 Not met: TP53 Supplementary Table S2 pre-assigns c.476C>T (BayesDel 0.272813, Class C0) as ‘No evidence’ for PP3.

PP4 Not assessed: no qualifying multigene-panel VAF observation is available for the VCEP PP4 thresholds of 5-35% or at least two observations at 5-25%.

Benign

BA1 Not met: the variant is absent from gnomAD v2.1 and v4.1, rather than reaching the VCEP's FAF threshold of at least 0.001.

BS1 Not met: the variant is absent from gnomAD v2.1 and v4.1, rather than reaching the VCEP's FAF interval of at least 0.0003 but below 0.001.

BS2 Not assessed: no qualifying count of unrelated female carriers aged at least 60 years without cancer is available from a single source.

BS3 Not met: the VCEP worksheet assigns PS3, with Kato non-functional and LOF classifications in three additional eligible assays, not benign functional evidence.

BS4 Not assessed: no affected family members with variant-negative testing are documented to demonstrate the VCEP's required lack of segregation.

BP4 Not met: BayesDel 0.272813 exceeds the TP53 BP4 Supporting cutoff of <0.16, despite SpliceAI max delta 0.003 being below 0.2.

N/A · 12 PVS1 · PM3 · PM4 · PM6 · PP2 · PP5 · BP1 · BP2 · BP3 · BP5 · BP6 · BP7

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

Absent from gnomAD v4.1.

v2.1

Absent from gnomAD v2.1.

🇨🇦 CA

Not available in gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

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

This variant has been reported in ClinVar as Likely pathogenic (3 clinical laboratories) and as Pathogenic (2 clinical laboratories) and as Likely Pathogenic (1 clinical laboratory). (ClinVarID = 458545)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.774. BayesDel score = 0.272813.

SpliceAI ↗

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

Cancer hotspots

Somatic evidence Hotspot

COSMIC

This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV52674926, n = 106 times).

Hotspots

This variant lies in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

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. 2 further PMIDs triaged but not cited — see Sources & references.

A Systematic p53 Mutation Library Links Differential Functional Impact to Cancer Mutation Pattern and Evolutionary Conservation.

PMID 29979965 ↗ · Kotler E et al. · 2018 Jul 5 ONCOKB · functional

Searched

c.476C>Tp.Ala159Valp.A159V

Found

The supplied paper extraction is not available for this PMID in paper_extracts.json; the VCEP Functional-worksheet.xlsx row for A159V nevertheless records the Kotler assay class as LOF. The Kotler result is cited as a pre-assigned VCEP worksheet value, not independently inferred from unextracted paper text.

Variant

✓ Names this variant

Applied to

→PS3 strong

The VCEP worksheet records A159V as LOF in the Kotler assay, contributing to the majority-eligible-assay PS3 assignment.

Location Functional-worksheet.xlsx, Supplementary Table S3, row A159V · Context VCEP supplementary functional-assay worksheet value for the Kotler in vitro growth assay in H1299 human cells.

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.

30224644 ↗ Mutational processes shape the landscape of TP53 mutations in human cancer.

Sources & reference links

9Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 2 PMIDs not cited in assessment

27328919 ↗ TP53 Variations in Human Cancers: New Lessons from the IARC TP53 Database and Ge ONCOKB

8285583 ↗ Absence of hereditary mutations in exons 5 through 9 of the p53 gene and exon 24 ONCOKB

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