Classification rationale

PS3PM2 BP4 VUS

TP53 c.520A>T

PS3 (strong) is met: R174W is non-functional in the Kato et al. assay and demonstrates loss of function across all eligible functional assays (Giacomelli, Kotler, Kawaguchi), per the TP53 VCEP Functional-worksheet pre-adjudicated assignment.¹ PM2_Supporting is met: the variant is absent from gnomAD v2.1 and v4.1, with an allele frequency below the VCEP threshold of 0.00003.² BP4_Supporting is met: the VCEP PP3-BP4-codes spreadsheet assigns BP4 to c.520A>T based on BayesDel score 0.149306 and SpliceAI max delta 0.0, indicating no predicted deleterious effect from in silico tools.³ PM1 is not met: codon 174 is not among the VCEP-defined hotspot codons (175, 245, 248, 249, 273, 282), and the variant is not listed in cancerhotspots.org. PS1 is not met: no alternate nucleotide change producing the same Arg174Trp amino acid substitution has been classified as Pathogenic or Likely Pathogenic by the TP53 VCEP. PS4, PS2, PP1, PP4, BS2, and BS4 remain not assessed due to absence of proband-level clinical, segregation, or population phenotype data. Applying the Tavtigian 2020 Bayesian point system: PS3 (+4) + PM2_Supporting (+1) + BP4_Supporting (-1) = 4 points. This falls within the VUS range (>= -1 and <= 5 points).⁴

PS3 + PM2 + BP4 → VUS

1 vcep_functional_worksheetPMID:12826609 ↗PMID:30224644 ↗PMID:29979965 ↗

2 gnomad_v2 ↗gnomad_v4 ↗

3 vcep_pp3_bp4_codesbayesdelspliceai ↗

4 final_classification_framework

Gene diagram · NM_000546.5 · variants mapped to exon structure

TP53 NM_000546.5

Fetching transcript structure from UCSC…

Applied criteria · 3 met · select any tile

Met

Not met

Not assessed

N/A

Strength very strong supporting

Pathogenic evidence

PVS

PS

PM

PP

Benign evidence

BA

BS

BP

—

Rationale

Select a criterion.

Sources

Evidence used

Gaps remaining

Rule

—

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

Absent from 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 Uncertain significance (1 clinical laboratory). (ClinVarID = 964680)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.634. BayesDel score = 0.149306.

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; COSV52961532, n = 28 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. 8 further PMIDs triaged but not cited — see Sources & References.

Altered-function p53 missense mutations identified in breast cancers can have subtle effects on transactivation.

PMID 20407015 ↗ · Jordan JJ et al. · 2010 May CLINVAR · functional

Searched

R174WArg174Trpc.520A>T

Found

R174W classified as FUNCTIONAL in yeast transactivation assay. Retained transactivation from p21-5' and GADD45 response elements indistinguishable from wild-type p53 at high expression levels. Categorized among 12/50 breast cancer-associated missense mutants that appeared similar to WT in transactivation capacity.

Variant

✓ Names this variant — characterised directly

Applied to

→PS3 supports · met

Why

Variant found to retain transcriptional function in yeast model. Noted but does not override the VCEP pre-adjudicated PS3 assignment based on Kato/Giacomelli/Kotler/Kawaguchi panel where R174W showed non-functional/LOF results.

R174W appeared similar to WT in their transactivation capacity

Location Table 1 (Functional Status column); Results, paragraph 7 ('R174W appeared similar to WT'); Figure 3 legend ('R174W and R267Q, do not affect the maximal level of transactivation'); Figure 4 legend ('A138V and R174W had similar transactivation potentials') · Context Isogenomic diploid yeast transactivation assay; GAL1-inducible p53 expression; ADE2 plate color assay and luciferase reporter; 11 human p53 target response elements assessed · full text

Sources & reference links

9Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 8 PMIDs not cited in assessment

11900253 ↗ Rescuing the function of mutant p53. ONCOKB

8023157 ↗ Crystal structure of a p53 tumor suppressor-DNA complex: understanding tumorigenic mutations. ONCOKB

12826609 ↗ Understanding the function-structure and function-mutation relationships of p53 tumor suppressor protein by high-resolution missense mutation analysis. CLINVAR

28826481 ↗ A comprehensive analysis of coregulator recruitment, androgen receptor function and gene expression in prostate cancer. CLINVAR

29979965 ↗ A Systematic p53 Mutation Library Links Differential Functional Impact to Cancer Mutation Pattern and Evolutionary Conservation. CLINVAR

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

17392385 ↗ American Cancer Society guidelines for breast screening with MRI as an adjunct to mammography. CLINVAR

28492532 ↗ Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. CLINVAR