Variant classification summary

NM_000546.6:c.1154del

TP53 · NP_000537.3:p.(Phe385SerfsTer37) · NM_000546.6

GRCh37: chr17:7572954 GA>G · GRCh38: chr17:7669636 GA>G

Gene: TP53 Transcript: NM_000546.6

Final call

VUS

PVS1 moderate PM2 supporting

Variant details

Gene

TP53

Transcript

NM_000546.6

Protein

NP_000537.3:p.(Phe385SerfsTer37)

gnomAD AF

6.195303216725336e-07 (v4.1)

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PVS1_Moderate applied: frameshift variant c.1154del (p.Phe385SerfsTer37) produces a premature termination codon downstream of the natural stop codon, qualifying for PVS1 at moderate strength per the TP53 VCEP PVS1 flowchart.

2

PM2_Supporting applied: variant is extremely rare in population databases (gnomAD v4.1 AF 6.2e-07, 1/1,614,126 alleles), well below the VCEP PM2_Supporting threshold of 0.003%.

3

Total pathogenic points: 3 (PVS1_Moderate = 2, PM2_Supporting = 1). Per Tavtigian point-based system adopted by TP53 VCEP v2.4, a score of 3 falls in the range -1 to 5, consistent with Uncertain Significance.

4

Functional evidence could not be applied: the TP53 VCEP functional worksheet covers missense variants and small in-frame deletions only; frameshift variants are not represented.

5

This variant has been observed in somatic cancers (COSMIC, n=2) and is absent from ClinVar. OncoKB classifies it as Likely Oncogenic with a Likely Loss-of-function biological effect.

Final determination: ClinGen TP53 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for TP53 Version 2.4 v2.4 point-based framework yields a total score of 3, 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	Met	Frameshift variant NM_000546.6:c.1154del (p.Phe385SerfsTer37) produces a premature termination codon at position 421, downstream of the natural stop codon at p.Asp393. Per the TP53 VCEP PVS1 flowchart, frameshift-induced PTC downstream of the natural stop codon is assigned PVS1_Moderate.	vcep_pvs1_flowchart cspec
PS1	Not met	No same-position nucleotide variant has been classified as pathogenic or likely pathogenic under the TP53 VCEP specifications. PS1 requires a different nucleotide change at the same position with a previously established VCEP P/LP classification, which is not available for c.1154del.	cspec pm5_candidates
PS2	Not met	No de novo observation data are available for this variant. No trio or parentage-confirmed studies have been reported.
PS3	Not met	The TP53 VCEP functional assay worksheet (Supplementary Table S3) covers missense variants and small in-frame deletions only; frameshift variants including c.1154del are not represented. No variant-specific functional data from the literature was identified for NM_000546.6:c.1154del. The five OncoKB-associated publications discuss TP53 at the gene level but none mention this specific variant.	vcep_functional_worksheet oncokb
PS4	Not met	No case-control data or proband counts with Li-Fraumeni syndrome-associated cancers are available. Proband point tally cannot be performed without clinical phenotype data.
PS5	N/A	Not in the assessment list for this adjudication.
PM1	Not met	The TP53 VCEP restricts PM1 to missense variants at codons 175, 245, 248, 249, 273, 282 (moderate), or cancerhotspots.org with sufficient somatic occurrences. This is a frameshift deletion at codon 385, not a missense variant in a VCEP-defined hotspot codon.	cspec
PM2	Met	This variant is extremely rare in population databases. gnomAD v4.1 total allele frequency is 6.2e-07 (1/1,614,126 alleles; 0.000062%), well below the TP53 VCEP PM2_Supporting threshold of 0.003%. The highest subpopulation frequency is South Asian at 0.0011% (1/91,080), below the 0.004% threshold for multiple alleles within a genetic ancestry group. Absent from gnomAD v2.1 and gnomAD-Canada.	gnomad_v4 gnomad_v2 cspec
PM4	N/A	PM4 is explicitly marked as Not Applicable by the TP53 VCEP.
PM5	N/A	PM5 under TP53 VCEP applies only to missense variants at an amino acid residue where a different missense P/LP variant has been identified. This is a frameshift deletion, not a missense variant.	cspec pm5_candidates
PM6	N/A	PM6 is explicitly marked as Not Applicable by the TP53 VCEP (combined with PS2).
PP1	Not met	No cosegregation data are available. No family studies with meioses counts have been reported for this variant.
PP2	N/A	PP2 is explicitly marked as Not Applicable by the TP53 VCEP.
PP3	N/A	TP53 VCEP PP3 rules cover missense variants (BayesDel), single amino acid in-frame deletions (BayesDel), and splice variants (SpliceAI). This is a frameshift deletion, not covered by VCEP in silico codes. SpliceAI predicts no splicing impact (max delta 0.00).	vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7 spliceai
PP4	Not met	No patient phenotype data or variant allele fraction (VAF) information is available. VCEP PP4 requires observation of the variant with VAF 5-35% in patients with Li-Fraumeni syndrome phenotype.
PP5	N/A	PP5 is explicitly marked as Not Applicable by the TP53 VCEP.
BA1	Not met	The highest subpopulation allele frequency is South Asian at 0.0011% (AF 1.1e-05), well below the VCEP BA1 threshold of 0.1% (FAF ≥0.001). Only 1 allele observed; BA1 requires ≥2 alleles in a continental subpopulation with ≥2,000 alleles tested.	gnomad_v4 cspec
BS1	Not met	The highest subpopulation allele frequency is South Asian at 0.0011% (AF 1.1e-05), below the VCEP BS1 threshold of 0.03% (FAF ≥0.0003). Only 1 allele observed; BS1 requires ≥2 alleles in a continental subpopulation.	gnomad_v4 cspec
BS2	Not met	No data on unrelated females who have reached at least 60 years of age without cancer. VCEP BS2 requires ≥2 such individuals from a single source.
BS3	Not met	The TP53 VCEP functional assay worksheet covers missense variants and small in-frame deletions only. This frameshift variant is not represented. No variant-specific benign functional data identified in the literature.	vcep_functional_worksheet
BS4	Not met	No segregation data available. VCEP BS4 requires lack of segregation in affected family members with LFS-associated cancers.
BP1	N/A	BP1 is explicitly marked as Not Applicable by the TP53 VCEP.
BP2	N/A	BP2 is explicitly marked as Not Applicable by the TP53 VCEP.
BP3	N/A	BP3 is explicitly marked as Not Applicable by the TP53 VCEP.
BP4	N/A	TP53 VCEP BP4 rules cover missense variants (BayesDel), single amino acid in-frame deletions (BayesDel), and splice variants (SpliceAI). This is a frameshift deletion, not covered by VCEP in silico codes.	vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7
BP5	N/A	BP5 is explicitly marked as Not Applicable by the TP53 VCEP.
BP6	N/A	BP6 is explicitly marked as Not Applicable by the TP53 VCEP.
BP7	N/A	BP7 under TP53 VCEP applies to synonymous (silent) and intronic variants only. This is a frameshift deletion.

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.