NM_000546.6(TP53):c.266_267del

TP53 · NP_000537.3:p.(Pro89LeufsTer59) · NM_000546.6

GRCh37: chr17:7579419 AGG>A · GRCh38: chr17:7676101 AGG>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.(Pro89LeufsTer59)

gnomAD AF

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

PVS1 (Very Strong): frameshift creates a premature stop at residue ~147, upstream of p.Lys351, predicted to trigger nonsense-mediated decay.

PM2 (Supporting): variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, consistent with an allele frequency below the 0.00003 threshold.

Synthesis: 9 points under the TP53 VCEP v2.4 point framework (PVS1 +8, PM2 +1) fall in the 6-9 range, giving Likely Pathogenic (Rule 2).

Final determination: TP53 VCEP v2.4 Tavtigian point-based rules: total point value of 9 (PVS1 very strong = 8 points + PM2 supporting = 1 point) falls within the Rule2 range (>=6 and <=9), yielding 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): 2-bp frameshift deletion creates a premature stop at residue ~147, upstream of p.Lys351, predicted to trigger nonsense-mediated decay.	cspec vcep_pvs1_flowchart pvs1_gene_context pvs1_variant_assessment
PS1	N/A	Not applicable: PS1 compares missense substitutions with the same amino acid change; this variant is a frameshift deletion, not a missense.	cspec
PS2	Not assessed	Not assessed: no proband phenotype or parental-testing data was available to establish a confirmed de novo occurrence.	cspec
PS3	N/A	Not applicable: eligible functional assays cover only missense and in-frame deletions, and no assay data exists for this frameshift.	cspec vcep_flowchart_for_application_of_functional_rule_codes vcep_functional_worksheet
PS4	Not assessed	Not assessed: no variant-specific germline proband phenotypes were available to assign Li-Fraumeni syndrome cancer points.	cspec vcep_ps4_points_table
PM1	N/A	Not applicable: PM1 covers missense variants at six designated hotspot codons; this frameshift at codon 89 is neither missense nor a hotspot codon.	cspec
PM2	Met	Met (Supporting): variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, consistent with an allele frequency below the 0.00003 threshold.	cspec gnomad_v2 gnomad_v4 gnomad_canada
PM3	N/A	Not applicable: the TP53 VCEP specification explicitly states PM3 does not apply to TP53/Li-Fraumeni syndrome.	cspec
PM4	N/A	Not applicable: the TP53 framework excludes PM4, and this out-of-frame deletion is adjudicated entirely by the PVS1 pathway.	cspec
PM5	N/A	Not applicable: PM5 compares missense changes at the same residue by Grantham distance; a frameshift has no single amino acid to compare.	cspec pm5_candidates
PM6	N/A	Not applicable: the TP53 VCEP discontinued PM6 and uses PS2 exclusively for de novo evidence.	cspec
PP1	Not assessed	Not assessed: no affected relatives, variant-positive family members, or meiosis counts were available for cosegregation analysis.	cspec vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
PP2	N/A	Not applicable: the TP53 VCEP v2.4 specification marks PP2 as not applicable at all strength levels.	cspec
PP3	N/A	Not applicable: PP3 in silico tools apply only to missense, synonymous, and in-frame deletion variants; this frameshift falls outside that scope.	cspec vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7 spliceai
PP4	Not assessed	Not assessed: no qualifying variant allele fraction observation was provided for this variant.	cspec
PP5	N/A	Not applicable: PP5 is excluded by the TP53 VCEP, and the ClinVar record has no expert-panel submission.	cspec clinvar
BA1	Not met	Not met: BA1 requires a gnomAD allele frequency of at least 0.001; the variant is absent from all queried gnomAD datasets.	cspec gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	Not met: BS1 requires a gnomAD allele frequency between 0.0003 and 0.001; the variant is absent from all queried gnomAD datasets.	cspec gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not assessed	Not assessed: no documented cancer-free TP53 carriers meeting the VCEP age thresholds were available.	cspec
BS3	N/A	Not applicable: BS3 functional assays apply only to missense and in-frame deletions, and no functional data exists for this frameshift.	cspec vcep_flowchart_for_application_of_functional_rule_codes vcep_functional_worksheet
BS4	Not assessed	Not assessed: no affected-family-member genotypes or documented non-segregation were available.	cspec vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
BP1	N/A	Not applicable: the TP53 VCEP v2.4 specification marks BP1 as not applicable for this gene.	cspec
BP2	N/A	Not applicable: the TP53 VCEP v2.4 specification explicitly lists BP2 as not applicable for TP53.	cspec
BP3	N/A	Not applicable: the TP53 VCEP excludes BP3, and this variant is an out-of-frame deletion, not an in-frame indel.	cspec
BP4	N/A	Not applicable: BP4 applies only to missense, synonymous, and intronic variants, not to frameshift deletions.	cspec vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7 spliceai
BP5	N/A	Not applicable: BP5 is excluded by the TP53 VCEP specification.	cspec
BP6	N/A	Not applicable: BP6 is excluded by the TP53 VCEP, and the ClinVar record has no Benign/Likely benign assertion.	cspec clinvar
BP7	N/A	Not applicable: BP7 applies only to synonymous or intronic variants; this is a coding frameshift deletion.	cspec

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