Functional studies demonstrate that p.Tyr234Asn is non-functional in the Kato et al. transactivation assay with loss of function across all other eligible assays (Giacomelli, Kotler, Funk), meeting PS3 at strong strength per the TP53 VCEP v2.4.0 Functional-worksheet.1 This variant is absent from gnomAD v2.1 and v4.1 population databases (allele count = 0), meeting PM2_Supporting per the TP53 VCEP threshold of allele frequency <0.003%.2 Computational evidence supports a deleterious effect: aGVGD Class C35, BayesDel score 0.489, REVEL score 0.941, with no predicted splicing impact (SpliceAI max delta 0.00). The TP53 VCEP PP3-BP4-codes spreadsheet assigns PP3 at supporting level.3 This variant has been reported in ClinVar as Pathogenic by two clinical laboratories and Likely pathogenic by one laboratory (ClinVar Variation ID 376692), and has been observed in somatic cancers (COSMIC, n=35).4 Applying the TP53 VCEP v2.4.0 Tavtigian point system: PS3_Strong (+5) + PM2_Supporting (+1) + PP3_Supporting (+0.5) = 6.5 total points, which falls within the Likely Pathogenic range (6-9 points).5
TP53
Final classification
Likely Pathogenic
TP53 c.700T>A · p.Tyr234Asn
TP53
Functional studies demonstrate that p.Tyr234Asn is non-functional in the Kato et al. transactivation assay with loss of function across all other eligible assays (Giacomelli, Kotler, Funk), meeting PS3 at strong strength per the TP53 VCEP v2.4.0 Functional-worksheet.
Tavtigian et.al., 2020 - Bayesian adaptation of Richards et.al., 2015 v2.4.0 point-based framework: PS3 strong (+4) + PM2 supporting (+1) + PP3 supporting (+1) = 6 points, which maps to Likely Pathogenic.
Classification rationale
PS3PM2PP3
Likely Pathogenic
TP53 c.700T>A
PS3 + PM2 + PP3
→
Likely Pathogenic
Gene diagram
· NM_000546.6 · variants mapped to exon structure
TP53
NM_000546.6
Fetching transcript structure from UCSC…
Applied criteria · 3 applied · 12 assessed
Applied · 3
Strength
Supporting
Moderate
Strong
Very strong
✓
PS3
strong
Pathogenic
The TP53 VCEP Functional-worksheet (Supplementary Table S3) assigns PS3 at strong strength to p.Tyr234Asn. Kato et al. functional data classifies this variant as Non-functional, and the majority of other eligible assays (Giacomelli, Kotler, Funk) all demonstrate loss of function (LOF). This satisfies the VCEP PS3 rule: 'Non-functional on Kato et al. data AND loss of function (LOF) by the majority of other eligible assays.'
VCEP Functional-worksheet.xlsx: Y234N → Kato: Non-functionalGiacomelli: LOFKotler: LOF
✓
PM2
supporting
Pathogenic
This variant is absent from gnomAD v2.1 and v4.1, meeting the TP53 VCEP PM2_Supporting threshold of allele frequency <0.00003 (0.003%). The variant has zero alleles across all population databases examined, well below the PM2_Supporting cutoff.
Absent from gnomAD v2.1 (exomes)absent from gnomAD v4.1 (exomes + genomes)absent from gnomAD-Canada v1.0.
✓
PP3
supporting
Pathogenic
The TP53 VCEP PP3-BP4-codes spreadsheet (Supplementary Table S2) directly assigns PP3 to c.700T>A (p.Tyr234Asn). This variant falls in aGVGD Class C35 (C25-C55 range) with BayesDel score 0.489361 (≥0.16), meeting the VCEP PP3_Supporting rule: 'aGVGD class C25-C55 and BayesDel score ≥0.16.' SpliceAI max delta score is 0.00, confirming no confounding splice effect. REVEL score of 0.941 provides additional corroboration of deleterious prediction.
PP3-BP4-codes.xlsx: c.700T>A → Class C35BayesDel 0.489361 → PP3REVEL 0.941
Assessed · not applied
Pathogenic
PS2
No confirmed de novo occurrence identified for this variant.
PS4
No case-control data or proband point tally meeting PS4 thresholds is available for this variant.
PM1
Codon 234 is not in the TP53 VCEP-defined major hotspot codon list (175, 245, 248, 249, 273, 282).
PM5
PM5 requires a missense variant at the same amino acid residue (Y234) where a different missense change has been previously classified as pathogenic or likely pathogenic according to the TP53 VCEP specifications.
PP1
No cosegregation data available.
PP4
PP4 for TP53 VCEP requires observation of the variant at low variant allele fraction (VAF 5-35%) suggesting constitutional mosaicism or clonal hematopoiesis, with specific phenotype context.
Benign
BA1
The variant is absent from gnomAD v2.1 and v4.1, far below the TP53 VCEP BA1 threshold of filtering allele frequency (FAF) ≥0.001 (0.1%) in any continental subpopulation.
BS1
The variant is absent from gnomAD, below the TP53 VCEP BS1 threshold of FAF ≥0.0003 (0.03%) in any continental subpopulation.
BS2
No data on unrelated females ≥60 years of age without cancer carrying this variant.
BS3
BS3 is contradicted by existing functional evidence.
BS4
No evidence of lack of segregation in affected family members.
BP4
BP4 is contradicted by computational evidence.
N/A · 11
PVS1 · PS1 · PM6 · PP2 · PP5 · 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.
🇨🇦 CA
This variant is absent from gnomAD-Canada.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Pathogenic (2 clinical laboratories) and as Likely pathogenic (1 clinical laboratory). (ClinVarID = 376692)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.941. BayesDel score = 0.489361.
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.
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; COSV52730114, n = 35 times).
Hotspots
This variant lies in a statistically significant hotspot.
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. 3 further PMIDs triaged but not cited — see Sources & References.
Understanding the function-structure and function-mutation relationships of p53 tumor suppressor protein by high-resolution missense mutation analysis.
Found
Structured finding pending for this record — see source link.
Applied to
→PS3 supports · met
A Systematic p53 Mutation Library Links Differential Functional Impact to Cancer Mutation Pattern and Evolutionary Conservation.
Found
Structured finding pending for this record — see source link.
Applied to
→PS3 supports · met
Mutational processes shape the landscape of TP53 mutations in human cancer.
Found
Structured finding pending for this record — see source link.
Applied to
→PS3 supports · met
Sources & reference links
Triaged references · 3 PMIDs not cited in assessment
27328919 ↗
TP53 Variations in Human Cancers: New Lessons from the IARC TP53 Database and Genomics Data.
ONCOKB
28492532 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
CLINVAR