Variant classification summary

NM_000546.5:c.761T>C

TP53 · NP_000537.3:p.(Ile254Thr) · NM_000546.5

GRCh37: chr17:7577520 A>G · GRCh38: chr17:7674202 A>G

Gene: TP53 Transcript: NM_000546.5

Final call

Likely Pathogenic

PS3 strong PM2 supporting PP3 moderate PP5 supporting

Variant details

Gene

TP53

Transcript

NM_000546.5

Protein

NP_000537.3:p.(Ile254Thr)

gnomAD AF

ClinVar

OncoKB

Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

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.

2

This variant is absent from gnomAD v2.1 and gnomAD v4.1, placing it below the TP53 PM2 threshold of less than 0.00003.

3

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.

4

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).

Final determination: Tavtigian et.al., 2020 - Bayesian adaptation of Richards et.al., 2015 v2.4.0 point-based framework yields a total score of 8, 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	Not met	This is a missense variant, and available TP53 PVS1 materials do not place it in a null-variant category. SpliceAI predicts no splice effect (max delta score 0.00), so the TP53 PVS1 framework for truncating or splice-disrupting variants is not met.	cspec pvs1_gene_context pvs1_variant_assessment vcep_pvs1_flowchart spliceai
PS1	Not assessed	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.	cspec clinvar
PS2	Not assessed	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.	cspec vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
PS3	Met	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.	vcep_functional_worksheet vcep_flowchart_for_application_of_functional_rule_codes PMID:12826609 PMID:29979965 PMID:30224644
PS4	Not assessed	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. Therefore PS4 is not applied from the available evidence.	cspec vcep_ps4_points_table gnomad_v2 gnomad_v4 clinvar
PM1	Not assessed	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. Because TP53 PM1 depends on predefined hotspot codons or verified Cancer Hotspots counts, PM1 was not applied from the available evidence.	cspec hotspots
PM2	Met	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.	cspec gnomad_v2 gnomad_v4
PM3	N/A	PM3 is not used in the TP53 VCEP framework for this disorder context.	cspec
PM4	N/A	PM4 is not used in the TP53 VCEP framework for this disorder context.	cspec
PM5	Not assessed	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.	cspec clinvar
PM6	N/A	PM6 is not used in the TP53 VCEP framework for this disorder context.	cspec
PP1	Not assessed	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.	cspec vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
PP2	N/A	PP2 is not used in the TP53 VCEP framework for this disorder context.	cspec
PP3	Met	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.	cspec vcep_pp3_bp4_codes vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7 bayesdel revel spliceai
PP4	Not assessed	No blood variant allele fraction or equivalent constitutional mosaicism evidence was identified to assess the TP53-specific PP4 rule, so PP4 was not applied.	cspec
PP5	Met	Expert panel ClinGen TP53 Variant Curation Expert Panel, ClinGen classified as Pathogenic.	cspec clinvar
BA1	Not met	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%).	cspec gnomad_v2 gnomad_v4
BS1	Not met	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.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	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.	cspec
BS3	Not met	Available functional evidence does not support retained TP53 function. Instead, TP53 VCEP-curated assays show non-functional or loss-of-function results, so BS3 is not met.	vcep_functional_worksheet vcep_flowchart_for_application_of_functional_rule_codes PMID:12826609 PMID:29979965 PMID:30224644
BS4	Not assessed	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.	cspec vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
BP1	N/A	BP1 is not used in the TP53 VCEP framework.	cspec
BP2	N/A	BP2 is not used in the TP53 VCEP framework.	cspec
BP3	N/A	BP3 is not used in the TP53 VCEP framework.	cspec
BP4	Not met	Benign computational evidence is not supported for this missense variant. The BayesDel score is 0.598199, which is well above the TP53 benign thresholds, SpliceAI shows no splice effect (max delta score 0.00), and the TP53 VCEP bioinformatic worksheet assigns PP3_moderate rather than BP4.	cspec vcep_pp3_bp4_codes vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7 bayesdel spliceai revel
BP5	N/A	BP5 is not used in the TP53 VCEP framework.	cspec
BP6	N/A	BP6 is not used in the TP53 VCEP framework.	cspec
BP7	N/A	BP7 is a synonymous or eligible intronic variant rule and does not apply to this missense change.	cspec vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.