NM_000546.6:c.267del

TP53 · NP_000537.3:p.(Ser90ProfsTer33) · NM_000546.6

GRCh37: chr17:7579419 AG>A · GRCh38: chr17:7676101 AG>A

Gene: TP53 Transcript: NM_000546.6

Final call

Likely Pathogenic

PVS1 very strong PM2 supporting

Variant details

Gene

TP53

Transcript

NM_000546.6

Protein

NP_000537.3:p.(Ser90ProfsTer33)

gnomAD AF

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

The TP53 c.267del (p.Ser90ProfsTer33) variant has been observed in somatic cancers in COSMIC (30 occurrences) and has been reported in ClinVar with Pathogenic and Likely pathogenic germline submissions.

This variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, placing its allele frequency below the TP53 PM2 threshold of less than 0.00003.

This early frameshift creates a premature stop at codon 122, which is well upstream of the TP53 VCEP p.Lys351 cutoff for predicted nonsense-mediated decay and supports PVS1 at very strong strength.

SpliceAI predicts no significant splice impact for this variant (max delta score 0.07), and this does not weaken the TP53 null-variant interpretation.

Final determination: Tavtigian et.al., 2020 - Bayesian adaptation of Richards et.al., 2015 v2.4.0 point-based framework yields a total score of 9, 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	Met	This frameshift variant, NM_000546.6:c.267del (p.Ser90ProfsTer33), introduces a premature termination codon at codon 122, well upstream of the TP53 VCEP p.Lys351 cutoff for nonsense-mediated decay; under the TP53 PVS1 flowchart, a frameshift-induced premature stop predicted to undergo nonsense-mediated decay supports PVS1 at very strong strength.	cspec pvs1_gene_context pvs1_variant_assessment vcep_pvs1_flowchart
PS4	Not assessed	This variant has been reported in somatic cancers and in ClinVar, but no variant-specific TP53 proband data with Li-Fraumeni syndrome point totals were identified to show that the PS4 threshold was met.	clinvar cspec vcep_ps4_points_table
PP4	Not assessed	No blood variant allele fraction data or constitutional mosaicism evidence was identified, so the TP53-specific PP4 criteria based on low-level variant observations cannot be assessed.	cspec
PS2	Not assessed	No de novo occurrence with confirmed maternity and paternity was identified, so PS2 cannot be applied.	cspec vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
PP1	Not assessed	No segregation data were identified for this variant, so PP1 cannot be applied.	cspec vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
BS4	Not assessed	No informative lack-of-segregation data were identified in affected family members, so BS4 cannot be applied.	cspec
PM2	Met	This variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0; an observed allele frequency of 0 is below the TP53 VCEP PM2 threshold of less than 0.00003.	gnomad_v2 gnomad_v4 gnomad_canada cspec
BA1	Not met	This variant is absent from population databases, so its allele frequency is below the TP53 BA1 threshold of 0.001 and BA1 is not met.	gnomad_v2 gnomad_v4 gnomad_canada cspec
BS1	Not met	This variant is absent from population databases, so its allele frequency is below the TP53 BS1 threshold of 0.0003 and BS1 is not met.	gnomad_v2 gnomad_v4 gnomad_canada cspec
BS2	Not assessed	No evidence was identified showing this variant in unrelated females aged 60 years or older without cancer from a single source, so BS2 cannot be applied.	cspec
PS1	N/A	PS1 applies to a different nucleotide change that results in the same amino acid substitution as an established TP53 pathogenic or likely pathogenic variant. This variant is a frameshift and does not meet that rule structure.	cspec
PM1	N/A	PM1 in the TP53 framework applies to missense variants at specified hotspot codons or recurrent somatic missense substitutions. This variant is a frameshift, and no hotspot-based missense rule applies.	cspec hotspots
PM5	N/A	PM5 in the TP53 framework is classic same-residue missense logic. This variant is a frameshift and is not eligible for PM5.	cspec pm5_candidates
PP3	N/A	SpliceAI predicts no significant splice impact for this variant (max delta score 0.07, below the TP53 splice-evidence threshold of 0.2), and the TP53 PP3 framework is not designed to add separate computational evidence for this early frameshift in this context.	spliceai cspec vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7
BP4	N/A	SpliceAI predicts no significant splice impact for this variant (max delta score 0.07), but the TP53 BP4 framework does not provide a benign computational code for this frameshift context.	spliceai cspec vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7
BP7	N/A	BP7 applies to synonymous or qualifying intronic variants without predicted splice impact. This variant is a frameshift and BP7 does not apply.	cspec vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7
PS3	N/A	The TP53 VCEP PS3 framework and supporting functional worksheet are designed for missense variants and small in-frame deletions. This variant is a frameshift, so PS3 is not applied from those resources.	cspec vcep_flowchart_for_application_of_functional_rule_codes vcep_functional_worksheet
BS3	N/A	The TP53 VCEP BS3 framework and supporting functional worksheet are designed for missense variants and small in-frame deletions. This variant is a frameshift, so BS3 is not applied from those resources.	cspec vcep_flowchart_for_application_of_functional_rule_codes vcep_functional_worksheet
PM4	N/A	PM4 is designated not applicable in the TP53 VCEP framework.	cspec
BP3	N/A	BP3 is designated not applicable in the TP53 VCEP framework.	cspec
BP1	N/A	BP1 is designated not applicable in the TP53 VCEP framework.	cspec
PP2	N/A	PP2 is designated not applicable in the TP53 VCEP framework.	cspec
BP2	N/A	BP2 is designated not applicable in the TP53 VCEP framework.	cspec
PM3	N/A	PM3 is designated not applicable in the TP53 VCEP framework.	cspec
PM6	N/A	PM6 is designated not applicable in the TP53 VCEP framework; de novo evidence is handled through PS2.	cspec
BP5	N/A	BP5 is designated not applicable in the TP53 VCEP framework.	cspec
PP5	N/A	PP5 is not for use in the TP53 VCEP framework.	cspec
BP6	N/A	BP6 is not for use in the TP53 VCEP framework.	cspec

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.