Variant classification summary

NM_000546.6:c.469G>T

TP53 · NP_000537.3:p.(Val157Phe) · NM_000546.6

GRCh37: chr17:7578461 C>A · GRCh38: chr17:7675143 C>A

Gene: TP53 Transcript: NM_000546.6

Final call

VUS

PS3 strong PM2 supporting

Variant details

Gene

TP53

Transcript

NM_000546.6

Protein

NP_000537.3:p.(Val157Phe)

gnomAD AF

0.0 (v4.1)

ClinVar

Likely pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The TP53 NM_000546.6:c.469G>T (p.Val157Phe, p.V157F) variant has been reported in ClinVar with Likely pathogenic and Pathogenic clinical submissions.

2

This variant is absent from gnomAD v2.1 and gnomAD v4.1, including 0 of 1,614,132 alleles in gnomAD v4.1, which supports PM2_Supporting under the TP53 VCEP threshold of less than 0.00003.

3

In the TP53 VCEP functional framework, p.Val157Phe is assigned PS3 because Kato-based transactivation results are non-functional and the majority of other eligible assays show loss of function; additional published studies describe abnormal mutant behavior and structural destabilization consistent with impaired normal p53 activity.

4

SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, and although REVEL is 0.708 and BayesDel is 0.314073, the TP53 VCEP precomputed in silico table assigns c.469G>T as 'No evidence', so neither PP3 nor BP4 was applied.

Final determination: Tavtigian et.al., 2020 - Bayesian adaptation of Richards et.al., 2015 v2.4.0 point-based framework yields a total score of 5, which maps to VUS 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	This variant is a missense substitution, p.(Val157Phe), and does not fall into the TP53 null-variant or canonical splice categories used for PVS1. SpliceAI predicts no meaningful splice effect (max delta score 0.00), so available evidence does not support applying PVS1.	cspec pvs1_gene_context pvs1_variant_assessment spliceai vcep_pvs1_flowchart
PS1	Not assessed	No previously classified TP53 variant producing the same amino acid change through a different nucleotide substitution was confirmed, so PS1 was not applied.	cspec clinvar
PS2	Not assessed	No confirmed de novo occurrence of this exact variant with interpretable TP53 VCEP point scoring was identified, so PS2 was not applied.	cspec clinvar PMID:27993330
PS3	Met	In the TP53 VCEP functional worksheet, p.(Val157Phe) is assigned PS3. The worksheet records non-functional Kato transactivation results and loss-of-function findings across the majority of other eligible assays, which supports a damaging effect on normal p53 function.	cspec vcep_flowchart_for_application_of_functional_rule_codes vcep_functional_worksheet PMID:16778209 PMID:21561095
PS4	Not assessed	This variant has been reported in ClinVar, but no proband-level Li-Fraumeni syndrome point total meeting TP53 VCEP PS4 thresholds was established from the available evidence. PS4 was therefore not applied.	cspec clinvar vcep_ps4_points_table
PM1	Not assessed	Codon 157 is not one of the TP53 codons that automatically qualify for PM1, and the available Cancer Hotspots review did not verify an exact hotspot count for this amino acid change. PM1 was not applied from the current evidence.	cspec hotspots
PM2	Met	This variant is absent from gnomAD v2.1 and gnomAD v4.1, with 0/1,614,132 alleles observed in gnomAD v4.1 (AF 0.0). This is below the TP53 VCEP PM2 threshold of less than 0.00003, so PM2_Supporting is met.	cspec gnomad_v2 gnomad_v4
PM3	N/A	PM3 is not applicable in the TP53 VCEP framework.	cspec
PM4	N/A	PM4 is not applicable in the TP53 VCEP framework.	cspec
PM5	Not assessed	No validated same-residue TP53 comparator variant meeting the TP53 VCEP PM5 requirements was confirmed, so PM5 was not applied.	cspec pm5_candidates clinvar
PM6	N/A	PM6 is not applicable in the TP53 VCEP framework.	cspec
PP1	Not assessed	No segregation data with enough informative meioses to meet TP53 VCEP thresholds were identified, so PP1 was not applied.	cspec clinvar vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
PP2	N/A	PP2 is not applicable in the TP53 VCEP framework.	cspec
PP3	Not met	Computational results show REVEL 0.708, BayesDel 0.314073, and no predicted splice effect by SpliceAI (max delta score 0.00). However, the TP53 VCEP precomputed PP3/BP4 table lists NM_000546.6:c.469G>T as 'No evidence', so PP3 was not applied.	cspec revel bayesdel spliceai vcep_pp3_bp4_codes vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7
PP4	Not assessed	No low-variant-allele-fraction constitutional mosaic observation meeting the TP53 VCEP PP4 requirements was identified, so PP4 was not applied.	cspec
PP5	N/A	PP5 is not applicable in the TP53 VCEP framework.	cspec
BA1	Not met	This variant is absent from gnomAD v4.1 (0/1,614,132 alleles; AF 0.0), which is below the TP53 VCEP BA1 threshold of at least 0.001. BA1 is not met.	cspec gnomad_v4
BS1	Not met	This variant is absent from gnomAD v4.1 (0/1,614,132 alleles; AF 0.0), which is below the TP53 VCEP BS1 threshold of at least 0.0003. BS1 is not met.	cspec gnomad_v4
BS2	Not assessed	No source documenting unaffected older female carriers in numbers sufficient for TP53 VCEP BS2 was identified, so BS2 was not applied.	cspec
BS3	Not met	Available functional evidence does not show retained or near-normal p53 activity. Instead, the TP53 VCEP functional worksheet assigns p.(Val157Phe) to PS3, so BS3 is not met.	cspec vcep_flowchart_for_application_of_functional_rule_codes vcep_functional_worksheet PMID:16778209 PMID:21561095
BS4	Not assessed	No family data showing lack of segregation with Li-Fraumeni syndrome-associated cancers were identified, so BS4 was not applied.	cspec vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
BP1	N/A	BP1 is not applicable in the TP53 VCEP framework.	cspec
BP2	N/A	BP2 is not applicable in the TP53 VCEP framework.	cspec
BP3	N/A	BP3 is not applicable in the TP53 VCEP framework.	cspec
BP4	Not met	SpliceAI predicts no splice effect (max delta score 0.00), but BayesDel is 0.314073 rather than below the benign thresholds, and the TP53 VCEP precomputed PP3/BP4 table assigns NM_000546.6:c.469G>T as 'No evidence'. BP4 is not met.	cspec bayesdel spliceai vcep_pp3_bp4_codes vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7
BP5	N/A	BP5 is not applicable in the TP53 VCEP framework.	cspec
BP6	N/A	BP6 is not applicable in the TP53 VCEP framework.	cspec
BP7	N/A	BP7 applies to synonymous or certain intronic variants without predicted splice impact. This variant is missense, so BP7 is not applicable.	cspec vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7

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