LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-10-07
Case ID: NM_000546.6_c.997_1006del_20261007_135939
Framework: ACMG/AMP 2015
Variant classification summary

NM_000546.6:c.997_1006del

TP53  · NP_000537.3:p.(Arg333SerfsTer9)  · NM_000546.6
GRCh37: chr17:7574020 TCACGCCCACG>T  ·  GRCh38: chr17:7670702 TCACGCCCACG>T
Gene: TP53 Transcript: NM_000546.6
Final call
Likely Pathogenic
PVS1 very strong PM2 supporting
All criteria require review: For research and educational purposes only.
Variant details
Gene
TP53
Transcript
NM_000546.6
Protein
NP_000537.3:p.(Arg333SerfsTer9)
gnomAD AF
ClinVar
OncoKB
Likely Oncogenic
Classification rationale
Interpretation summary
Generated evidence synthesis
1
PVS1 very strong: the exon 10 frameshift creates a premature termination codon at p.341, upstream of p.Lys351 and outside the exon 10 NMD-escape region.
2
PM2 supporting: the variant is absent from gnomAD v4.1 and v2.1, with an observed allele frequency of 0.
Final determination: Under the ClinGen TP53 Expert Panel Version 2.4 Tavtigian-style point framework, PVS1 very strong contributes 8 points and PM2 supporting contributes 1 point; the total of 9 points maps to Likely Pathogenic.
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 Met, very strong: the exon 10 frameshift creates a PTC at p.341, upstream of p.Lys351 and outside the exon 10 NMD-escape region.
cspec vcep_pvs1_flowchart
PS1 N/A Not applicable: c.997_1006del produces p.(Arg333SerfsTer9), a frameshift rather than a same-amino-acid missense substitution.
cspec
PS2 Not assessed Not assessed: no proband cancer, parental testing, or confirmed parentage data are available to calculate the TP53 VCEP PS2 point total.
cspec vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
PS3 N/A Not applicable: the TP53 VCEP functional worksheet covers missense or in-frame deletions, whereas this variant is a frameshift producing p.Arg333SerfsTer9.
cspec vcep_flowchart_for_application_of_functional_rule_codes vcep_functional_worksheet PMID:16007150
PS4 Not assessed Not assessed: no proband phenotype or PS4 point total is available to compare with the VCEP thresholds of 1-1.5, 2-3.5, 4-7.5, or >=8 points.
cspec vcep_ps4_points_table
PM1 N/A Not applicable: the TP53 PM1 rule covers missense hotspots, whereas c.997_1006del is a p.Arg333SerfsTer9 frameshift.
cspec vcep_hotspots_vision_instruction
PM2 Met Met at supporting strength: the variant is absent from gnomAD v4.1 and v2.1, with observed frequency 0, below the TP53 PM2 threshold of <0.00003.
cspec gnomad_v4 gnomad_v2
PM3 N/A Not applicable: TP53 VCEP version 2.4 explicitly designates PM3 as not applicable for this autosomal dominant disorder.
cspec
PM4 N/A Not applicable: PM4 is explicitly unavailable in the TP53 VCEP specification, and this variant is a frameshift rather than an in-frame change.
cspec
PM5 N/A Not applicable: PM5 requires a missense variant, but c.997_1006del causes the frameshift p.(Arg333SerfsTer9).
cspec PMID:16007150
PM6 N/A Not applicable: the TP53 VCEP explicitly replaces PM6 with PS2 for all de novo evidence.
cspec
PP1 Not assessed Not assessed: no affected variant-positive relatives, obligate carriers, family structure, or documented meioses are available for PP1 assignment.
cspec vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
PP2 N/A Not applicable: the TP53 VCEP excludes PP2, and c.997_1006del is a frameshift rather than a missense variant.
cspec
PP3 N/A Not applicable: this variant is a frameshift, outside TP53 VCEP PP3 scope for missense, splice-region/intronic, and single-amino-acid in-frame deletion variants.
cspec vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7 vcep_pp3_bp4_codes vcep_tp53_single_amino_acid_deletions_bayesdel_scores_1
PP4 Not assessed Not assessed: VAF and multigene-panel context are unavailable for comparison with the VCEP PP4 ranges of 5-25% or 5-35%.
cspec
PP5 N/A Not applicable: the TP53 VCEP prohibits PP5, and ClinVar has no exact-variant expert-panel classification for this deletion.
cspec clinvar
BA1 Not met Not met: the variant is absent from gnomAD v4.1 and v2.1, rather than reaching the TP53 BA1 threshold of FAF >=0.001.
cspec gnomad_v4 gnomad_v2
BS1 Not met Not met: the variant is absent from gnomAD v4.1 and v2.1, rather than having TP53 BS1 FAF >=0.0003 and <0.001.
cspec gnomad_v4 gnomad_v2
BS2 Not assessed Not assessed: no qualifying healthy female carrier count, age, cancer status, single-source provenance, or VAF data is available for the TP53 BS2 thresholds.
cspec
BS3 N/A Not applicable: no BS3 assignment exists for this frameshift, and the governing worksheet's R333 results are missense substitutions rather than p.Arg333SerfsTer9.
cspec vcep_flowchart_for_application_of_functional_rule_codes vcep_functional_worksheet PMID:16007150
BS4 Not assessed Not assessed: no affected relatives with relevant LFS-associated cancers and documented absence of the variant are available to establish non-segregation.
cspec vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
BP1 N/A Not applicable: the TP53 VCEP excludes BP1, and c.997_1006del is a truncating frameshift.
cspec
BP2 N/A Not applicable: TP53 VCEP version 2.4 explicitly designates BP2 as not applicable for this disorder.
cspec
BP3 N/A Not applicable: BP3 is restricted to in-frame changes in repetitive regions, whereas this variant is a TP53 protein-truncating frameshift.
cspec
BP4 N/A Not applicable: this variant is a frameshift, outside TP53 VCEP BP4 scope for missense, splice-region/intronic, and single-amino-acid in-frame deletion variants.
cspec vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7 vcep_pp3_bp4_codes vcep_tp53_single_amino_acid_deletions_bayesdel_scores_1
BP5 N/A Not applicable: the TP53 VCEP explicitly designates BP5 as not applicable and provides no governing BP5 rule.
cspec
BP6 N/A Not applicable: the TP53 VCEP prohibits BP6, and ClinVar has no exact-variant expert-panel benign classification for this deletion.
cspec clinvar
BP7 N/A Not applicable: this variant is a frameshift, whereas TP53 VCEP BP7 applies only to synonymous or intronic variants.
cspec vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7
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