LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-05-26
Case ID: NM_000546.6_c.832_839dup_20260526_193213
Framework: ACMG/AMP 2015
Variant classification summary

NM_000546.6:c.832_839dup

TP53  · NP_000537.3:p.(Arg280SerfsTer68)  · NM_000546.6
GRCh37: chr17:7577098 T>TCTCCCAGG  ·  GRCh38: chr17:7673780 T>TCTCCCAGG
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.(Arg280SerfsTer68)
gnomAD AF
ClinVar
OncoKB
Likely Oncogenic
Classification rationale
Interpretation summary
Generated evidence synthesis
1
The TP53 c.832_839dup (p.Arg280SerfsTer68) variant has not been observed in COSMIC and has not been reported in ClinVar.
2
This variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, supporting rarity below the TP53 VCEP PM2 threshold.
3
The duplication causes a frameshift predicted to truncate TP53 at p.Arg280SerfsTer68, and because the premature stop is upstream of p.Lys351, the TP53 VCEP PVS1 flowchart supports PVS1.
4
SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 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 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 variant is a frameshift duplication in TP53 predicted to produce p.(Arg280SerfsTer68). Under the TP53 VCEP PVS1 flowchart, frameshift variants with a premature termination codon upstream of p.Lys351 are expected to undergo nonsense-mediated decay and meet PVS1.
cspec vcep_pvs1_flowchart pvs1_gene_context pvs1_variant_assessment
PM2 Met This variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, which is below the TP53 VCEP PM2 threshold of less than 0.00003 overall and below 0.00004 within any non-founder ancestry group.
cspec gnomad_v2 gnomad_v4 gnomad_canada
BA1 Not met This variant is absent from population databases and does not reach the TP53 VCEP BA1 stand-alone benign threshold of at least 0.001.
cspec gnomad_v2 gnomad_v4 gnomad_canada
BS1 Not met This variant is absent from population databases and does not reach the TP53 VCEP BS1 benign threshold of at least 0.0003 in a qualifying ancestry group.
cspec gnomad_v2 gnomad_v4 gnomad_canada
PP3 N/A The TP53 VCEP PP3 framework is defined for missense variants, single amino acid in-frame deletions, and non-canonical splice-relevant exonic or intronic variants. This variant is a frameshift duplication, so PP3 is not applied. SpliceAI predicts no significant splice impact with a maximum delta score of 0.00.
cspec vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7 spliceai
BP4 N/A The TP53 VCEP BP4 framework is defined for missense variants, single amino acid in-frame deletions, and selected silent or intronic variants. This variant is a frameshift duplication, so BP4 is not applied, although SpliceAI predicts no significant splice impact with a maximum delta score of 0.00.
cspec vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7 spliceai
PS3 N/A The TP53 VCEP PS3 framework applies to missense variants and small in-frame deletions using eligible functional assays. This frameshift duplication is outside that assay-based framework, and no variant-specific TP53 VCEP functional worksheet entry was identified for this variant.
cspec vcep_flowchart_for_application_of_functional_rule_codes vcep_functional_worksheet
BS3 N/A The TP53 VCEP BS3 framework applies to missense variants and small in-frame deletions using eligible functional assays. This frameshift duplication is outside that framework, and no evidence was identified showing retained TP53 function for this variant.
cspec vcep_flowchart_for_application_of_functional_rule_codes vcep_functional_worksheet
PS4 Not assessed No proband-based Li-Fraumeni syndrome point data were identified to determine whether the TP53 VCEP PS4 thresholds are met. Population rarity supports eligibility to consider PS4, but case-level observations were not available.
cspec vcep_ps4_points_table gnomad_v2 gnomad_v4
PS2 Not assessed No confirmed de novo observations or point-based PS2 evidence were identified for this variant.
cspec vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
PP1 Not assessed No segregation data were identified to assess cosegregation with Li-Fraumeni syndrome-associated cancers.
cspec vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
PP4 Not assessed No phenotype-specific TP53 VCEP PP4 evidence was identified, including no low-variant-allele-fraction observation data needed for this rule.
cspec
BS2 Not assessed No data were identified showing this variant in unrelated females aged at least 60 years without cancer from a single source, so BS2 cannot be assessed.
cspec
BS4 Not assessed No family data were identified showing lack of segregation with Li-Fraumeni syndrome-associated cancers, so BS4 cannot be assessed.
cspec
PS1 N/A PS1 is a same-amino-acid-change rule for variants that create an established pathogenic or likely pathogenic protein substitution. This variant is a frameshift duplication, so PS1 does not apply.
cspec
PM1 N/A The TP53 VCEP PM1 rule is defined for missense hotspot variants. This variant is a frameshift duplication, so PM1 does not apply.
cspec hotspots
PM5 N/A The TP53 VCEP PM5 rule uses classic same-residue missense logic. This variant is not missense-like, and the PM5 candidate review marked the rule as not applicable.
cspec pm5_candidates
BP7 N/A BP7 is defined for synonymous and selected intronic variants. This variant is a frameshift duplication, so BP7 does not apply.
cspec vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7
PM4 N/A PM4 is not used in the TP53 VCEP framework.
cspec
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
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
PP2 N/A PP2 is not used in the TP53 VCEP framework.
cspec
PP5 N/A PP5 is not used in the TP53 VCEP framework.
cspec
PM3 N/A PM3 is not used in the TP53 VCEP framework.
cspec
PM6 N/A PM6 is not used in the TP53 VCEP framework.
cspec
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