NM_000546.6: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): 2-bp frameshift deletion introducing a premature stop codon upstream of p.Lys351, predicted to trigger nonsense-mediated decay.

PM2 (Supporting): variant is absent from gnomAD v4.1, v2.1, and gnomAD-Canada v1.0 (allele frequency below 0.00003).

Together these score 9 points under ClinGen TP53 VCEP Rule 2 (6-9 points), giving a final classification of Likely Pathogenic.

Final determination: TP53 VCEP v2.4 point-based rule: total score of 9 satisfies Rule2 (score 6-9) = 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 codon upstream of p.Lys351, predicting nonsense-mediated decay.	vcep_pvs1_flowchart cspec
PS1	N/A	Not applicable: PS1 compares same-amino-acid missense changes, but this is a frameshift, not a missense substitution.	cspec
PS2	Not assessed	Not assessed: no proband phenotype, parental testing, or family-history information was available to evaluate de novo occurrence.	cspec
PS3	N/A	Not applicable: functional assay evidence covers only missense and in-frame variants; this frameshift is outside that framework.	vcep_flowchart_for_application_of_functional_rule_codes vcep_functional_worksheet pvs1_variant_assessment
PS4	Not assessed	Not assessed: no phenotype, cancer-type, case-count, or control data was available to score population enrichment.	cspec
PM1	N/A	Not applicable: PM1 covers missense variants in hotspot codons; this is a frameshift at codon 89, outside both.	cspec
PM2	Met	Met (Supporting): variant is absent from gnomAD v4.1, v2.1, and gnomAD-Canada v1.0, consistent with an allele frequency below 0.00003.	cspec gnomad_v4 gnomad_v2 gnomad_canada
PM3	N/A	Not applicable: the ClinGen TP53 Expert Panel specifications designate PM3 as not applicable for TP53.	cspec
PM4	N/A	Not applicable: PM4 targets in-frame length changes, and the TP53 VCEP marks it not applicable for this gene.	cspec
PM5	N/A	Not applicable: PM5 requires a pathogenic missense at the same residue; this is a frameshift, so no comparator exists.	cspec
PM6	N/A	Not applicable: the TP53 VCEP dropped PM6 in favor of PS2 for de novo evidence.	cspec
PP1	Not assessed	Not assessed: no relatives, carrier status, phase, or meiosis information was available to evaluate cosegregation.	cspec
PP2	N/A	Not applicable: the TP53 VCEP designates PP2 as not applicable for TP53.	cspec
PP3	N/A	Not applicable: in silico predictors are scoped to missense, synonymous, and intronic variants; this frameshift is outside all of them.	cspec
PP4	Not assessed	Not assessed: no variant allele fraction (VAF 5-35%) or tumor observations were available for this variant.	cspec
PP5	N/A	Not applicable: PP5 requires an expert-panel assertion; the ClinVar record has only a single-submitter Pathogenic assertion.	cspec clinvar
BA1	Not met	Not met: variant is absent from population databases, so no allele frequency reaches the >=0.001 benign threshold.	cspec gnomad_v4 gnomad_v2 gnomad_canada
BS1	Not met	Not met: variant is absent from population databases, so no allele frequency falls in the 0.0003-0.001 BS1 range.	cspec gnomad_v4 gnomad_v2 gnomad_canada
BS2	Not assessed	Not assessed: no healthy-adult carrier or homozygote observations were available for this variant.	cspec
BS3	N/A	Not applicable: BS3 functional assays cover only missense and in-frame deletions; this frameshift is outside that scope.	vcep_flowchart_for_application_of_functional_rule_codes vcep_functional_worksheet pvs1_variant_assessment
BS4	Not assessed	Not assessed: no family segregation data was available; absence of data is not evidence against segregation.	cspec
BP1	N/A	Not applicable: BP1 targets missense variants, and the TP53 VCEP marks it not applicable for TP53.	cspec
BP2	N/A	Not applicable: the ClinGen TP53 Expert Panel designates BP2 as not applicable for TP53.	cspec
BP3	N/A	Not applicable: BP3 covers in-frame indels in nonfunctional repeats; this frameshift lies in coding exon 4.	cspec
BP4	N/A	Not applicable: BP4 in silico evidence is scoped to missense, synonymous, and intronic variants; this frameshift is outside that scope.	cspec
BP5	N/A	Not applicable: the TP53 VCEP marks BP5 as not applicable for TP53.	cspec
BP6	N/A	Not applicable: BP6 requires an expert-panel benign assertion; none exists for this variant.	cspec clinvar
BP7	N/A	Not applicable: BP7 applies only to synonymous or intronic variants; this is a coding frameshift deletion.	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.