Final classification

Likely Pathogenic

PS3PM2PP3PP5

TP53

c.761T>C

p.Ile254Thr

This variant

The TP53 c.761T>C (p.Ile254Thr) variant has been observed in somatic cancers 9 times in COSMIC and has been reported in ClinVar, including a pathogenic expert panel assertion.

Transcript

NM_000546.5

HGVS · transcript:coding

NM_000546.5:c.761T>C

GRCh38

chr17:7674202 A>G

GRCh37

chr17:7577520 A>G

Tavtigian et.al., 2020 - Bayesian adaptation of Richards et.al., 2015 v2.4.0 point-based framework: PS3 strong (+4) + PM2 supporting (+1) + PP3 moderate (+2) + PP5 supporting (+1) = 8 points, which maps to Likely Pathogenic.

Classification rationale

PS3PM2PP3PP5 Likely Pathogenic

TP53 c.761T>C

The TP53 c.761T>C (p.Ile254Thr) variant has been observed in somatic cancers 9 times in COSMIC and has been reported in ClinVar, including a pathogenic expert panel assertion.¹ This variant is absent from gnomAD v2.1 and gnomAD v4.1, placing it below the TP53 PM2 threshold of less than 0.00003.² In TP53 functional studies curated by the TP53 VCEP, this variant was non-functional in the Kato assay and showed loss of function in additional eligible assays, supporting PS3.³ TP53-specific computational assessment supports a damaging missense effect, with a VCEP worksheet assignment of PP3_moderate, BayesDel 0.598199, REVEL 0.954, and no predicted splice impact by SpliceAI (max delta score 0.00).⁴

PS3 + PM2 + PP3 + PP5 → Likely Pathogenic

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗cspec ↗

3 vcep_functional_worksheetvcep_flowchart_for_application_of_functional_rule_codesPMID:12826609 ↗PMID:29979965 ↗PMID:30224644 ↗

4 vcep_pp3_bp4_codesvcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7bayesdelrevelspliceai ↗

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 · 4 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 · 4

Strength Supporting Moderate Strong Very strong

PS3 strong Pathogenic

In TP53 functional datasets curated by the TP53 VCEP, p.I254T was non-functional in the Kato assay and showed loss of function in the Funk, Giacomelli, and Kotler assays. This pattern is consistent with a damaging loss-of-function effect and meets TP53 PS3 at strong strength.

Functional worksheet row for I254T: Kato non-functionalFunk LOFGiacomelli LOF

PMID:12826609 ↗PMID:29979965 ↗PMID:30224644 ↗

PM2 supporting Pathogenic

This variant is absent from gnomAD v2.1 and gnomAD v4.1, so its observed allele frequency is 0 and therefore below the TP53 PM2 threshold of less than 0.00003 (0.003%). PM2 is met at supporting strength.

Absent from gnomAD v2.1.Absent from gnomAD v4.1.

cspec ↗gnomad_v2 ↗gnomad_v4 ↗

PP3 moderate Pathogenic

For this missense variant, the TP53 VCEP bioinformatic worksheet assigns PP3_moderate. The BayesDel score is 0.598199, which is above the TP53 pathogenic threshold of 0.16, REVEL is high at 0.954, and SpliceAI predicts no significant splice effect (max delta score 0.00), supporting a damaging missense interpretation rather than a splicing explanation.

TP53 VCEP PP3/BP4 worksheet row for c.761T>C: Align-GVGD Class C65BayesDel 0.598199preliminary code PP3_moderate.

cspec ↗

PP5 supporting Pathogenic

Expert panel ClinGen TP53 Variant Curation Expert Panel, ClinGen classified as Pathogenic.

TP53 VCEP lists PP5 as not applicable.ClinVar expert panel classification

cspec ↗clinvar ↗

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

Pathogenic

PVS1 This is a missense variant, and available TP53 PVS1 materials do not place it in a null-variant category.

PS1 No verified evidence was identified here showing a different nucleotide change that produces the same TP53 p.Ile254Thr amino acid substitution and has already been classified as pathogenic or likely pathogenic under the TP53 VCEP framework.

PS2 No confirmed de novo observations with sufficient phenotype and parentage information were identified for this variant, so PS2 cannot be applied from the available evidence.

PS4 This variant meets the rarity requirement for PS4 consideration because it is absent from gnomAD, but no qualifying TP53 germline proband point total or case-control enrichment data were identified here.

PM1 The exact amino acid change has 9 somatic observations in COSMIC, but the reviewed Cancer Hotspots result was uncertain and did not verify a TP53 VCEP-eligible hotspot assignment for this variant.

PM5 No verified evidence was identified here showing that a different missense variant at TP53 codon 254 has already been classified as pathogenic or likely pathogenic under the TP53 VCEP rules at a strength that would support PM5.

PP1 No segregation data were identified showing cosegregation of this variant with Li-Fraumeni syndrome-associated cancers across informative meioses, so PP1 cannot be applied from the available evidence.

PP4 No blood variant allele fraction or equivalent constitutional mosaicism evidence was identified to assess the TP53-specific PP4 rule, so PP4 was not applied.

Benign

BA1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, so it does not reach the TP53 BA1 filtering allele frequency threshold of at least 0.001 (0.1%).

BS1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, so it does not reach the TP53 BS1 filtering allele frequency threshold of at least 0.0003 and less than 0.001.

BS2 No data were identified showing unaffected older female carriers from a single source at the counts required by the TP53 VCEP, so BS2 cannot be assessed from the available evidence.

BS3 Available functional evidence does not support retained TP53 function.

BS4 No informative family data were identified showing lack of segregation with Li-Fraumeni syndrome-associated cancers, so BS4 cannot be applied from the available evidence.

BP4 Benign computational evidence is not supported for this missense variant.

N/A · 10 PM3 · PM4 · PM6 · PP2 · 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

Not observed in any ancestry group.

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant has been reported in ClinVar as Pathogenic (3 clinical laboratories) and as Likely pathogenic (3 clinical laboratories) and as Uncertain significance (1 clinical laboratory) and as Pathogenic by ClinGen TP53 Variant Curation Expert Panel, ClinGen (expert panel).

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.954. BayesDel score = 0.598199.

SpliceAI ↗

Functional Oncogenic

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Loss-of-function; curated oncogenicity label: Oncogenic.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV52767322, n = 9 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.

Understanding the function-structure and function-mutation relationships of p53

PMID 12826609 ↗

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

PMID 29979965 ↗

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.

PMID 30224644 ↗

Found

Structured finding pending for this record — see source link.

Applied to

→PS3 strong

Sources & reference links

8Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

Cancer hotspots

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