Variant classification summary

NM_000546.6:c.700T>A

TP53 · NP_000537.3:p.(Tyr234Asn) · NM_000546.6

GRCh37: chr17:7577581 A>T · GRCh38: chr17:7674263 A>T

Gene: TP53 Transcript: NM_000546.6

Final call

Likely Pathogenic

PS3 strong PM2 supporting PP3 supporting

Variant details

Gene

TP53

Transcript

NM_000546.6

Protein

NP_000537.3:p.(Tyr234Asn)

gnomAD AF

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

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.

2

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%.

3

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.

4

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).

5

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).

Final determination: Tavtigian et.al., 2020 - Bayesian adaptation of Richards et.al., 2015 v2.4.0 point-based framework yields a total score of 6, which maps to Likely Pathogenic under the specified Tavtigian-style ranges.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	PVS1 is not applicable to missense variants. This variant (c.700T>A, p.Tyr234Asn) is a missense substitution, not a null variant (nonsense, frameshift, canonical splice site, initiation codon, or deletion). PVS1 variant assessment confirms variant class is not in any null-variant bucket.	pvs1_variant_assessment vcep_pvs1_flowchart
PS1	N/A	PS1 requires a different nucleotide change producing the same amino acid change (Tyr234Asn) that has been previously classified as pathogenic by the TP53 VCEP. Tyr234Asn can only be produced by c.700T>A (TAT→AAT); no alternative nucleotide substitution yields this amino acid change. No comparator exists.
PS2	Not met	No confirmed de novo occurrence identified for this variant. PS2 requires confirmed de novo origin (both maternity and paternity confirmed) in a proband with Li-Fraumeni syndrome-associated cancer. Neither ClinVar, IARC TP53, nor published literature contains a confirmed de novo report for c.700T>A (p.Tyr234Asn).	clinvar
PS3	Met	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
PS4	Not met	No case-control data or proband point tally meeting PS4 thresholds is available for this variant. PS4 requires proband counting with LFS-associated cancer points (Supporting ≥1, Moderate ≥2, Strong ≥4, Very Strong ≥8). Although this variant is recurrent in somatic cancers (COSMIC n=35), germline proband counts needed for PS4 scoring have not been compiled.	clinvar
PS5	N/A	PS5 is not a recognized ACMG/AMP criterion code. The standard ACMG/AMP 2015 framework does not include a PS5 criterion. No VCEP specification defines PS5 for TP53.
PM1	Not met	Codon 234 is not in the TP53 VCEP-defined major hotspot codon list (175, 245, 248, 249, 273, 282). The exact variant p.Tyr234Asn is not individually listed on cancerhotspots.org (exact_variant_listed='no'), precluding PM1_Supporting via the cancerhotspots pathway (which requires 2-9 somatic occurrences for the same amino acid change).	oncokb
PM2	Met	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.	gnomad_v2 gnomad_v4
PM5	Not met	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. While other missense variants at codon 234 (Y234C, Y234D, Y234H, Y234S) show functional PS3 evidence in the VCEP Functional-worksheet, no formal VCEP final classification (P/LP) for any codon 234 comparator variant was identified. PM5 cannot be applied without a formally classified comparator.	vcep_functional_worksheet
PM6	N/A	PM6 is designated 'Not Applicable' by the TP53 VCEP v2.4.0. The VCEP specifies that PM6 is not for use per ClinGen SVI VCEP Review Committee recommendation.	cspec
PP1	Not met	No cosegregation data available. PP1 requires cosegregation with LFS-associated cancers in multiple affected family members (Supporting: 3-4 meioses, Moderate: 5-6, Strong: ≥7 across >1 family). No published pedigree or family study with variant-specific cosegregation analysis was found.
PP2	N/A	PP2 is designated 'Not Applicable' by the TP53 VCEP v2.4.0. Missense variants are a common mechanism of disease in TP53; PP2 is not used per VCEP specification.	cspec
PP3	Met	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.	vcep_pp3_bp4_codes revel bayesdel spliceai
PP4	Not met	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. No VAF data or phenotype-specific information is available for this variant from the evidence reviewed.
PP5	N/A	PP5 is designated 'Not Applicable for this VCEP' by the TP53 VCEP v2.4.0. This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.	cspec
BA1	Not met	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. BA1 requires the variant to be common enough in population databases to be considered a benign polymorphism.	gnomad_v2 gnomad_v4
BS1	Not met	The variant is absent from gnomAD, below the TP53 VCEP BS1 threshold of FAF ≥0.0003 (0.03%) in any continental subpopulation. BS1 requires the variant to be more common than expected for a highly penetrant disorder like Li-Fraumeni syndrome.	gnomad_v2 gnomad_v4
BS2	Not met	No data on unrelated females ≥60 years of age without cancer carrying this variant. BS2 requires observation of the variant in healthy elderly females (≥8 for Strong, 4-7 for Moderate, 2-3 for Supporting) from a single source. No such observations have been reported.
BS3	Not met	BS3 is contradicted by existing functional evidence. The VCEP Functional-worksheet assigns PS3 to p.Tyr234Asn based on Non-functional status in Kato et al. data with loss of function across all other eligible assays (Giacomelli, Kotler, Funk). BS3 requires functional studies showing no damaging effect (Functional on Kato AND no LOF by majority of assays), which is the opposite of the observed evidence.	vcep_functional_worksheet
BS4	Not met	No evidence of lack of segregation in affected family members. BS4 requires observation that the variant does not segregate with LFS-associated cancers in family members. No family studies or segregation data are available for this variant.
BP1	N/A	BP1 is designated 'Not Applicable' by the TP53 VCEP v2.4.0. This rule code does not apply to TP53, as missense variants (not just truncating variants) are a well-established cause of Li-Fraumeni syndrome.	cspec
BP2	N/A	BP2 is designated 'Not Applicable' by the TP53 VCEP v2.4.0. The observation-in-trans criterion is not applicable per VCEP specification.	cspec
BP3	N/A	This is a single-nucleotide substitution (missense), not an in-frame deletion/insertion in a repetitive region. BP3 does not apply to substitution variants.
BP4	Not met	BP4 is contradicted by computational evidence. BayesDel score is 0.489361, far above the BP4_Supporting threshold (<0.16 and >−0.008) and BP4_Moderate threshold (≤−0.008). REVEL score is 0.941. The VCEP PP3-BP4-codes spreadsheet assigns PP3 (not BP4) to this variant. SpliceAI max delta is 0.00, confirming no confounding splice impact, but the in silico predictions uniformly support a deleterious effect.	vcep_pp3_bp4_codes revel bayesdel spliceai
BP5	N/A	BP5 is designated 'Not Applicable' by the TP53 VCEP v2.4.0. This criterion (variant found in a case with an alternate molecular basis for disease) is not for use per VCEP specification.	cspec
BP6	N/A	BP6 is designated 'Not Applicable for this VCEP' by the TP53 VCEP v2.4.0. This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.	cspec
BP7	N/A	BP7 applies to synonymous (silent) or intronic variants. This is a missense variant (c.700T>A, p.Tyr234Asn) resulting in an amino acid substitution, not a silent variant. BP7 is not applicable to missense changes.

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