Variant classification summary

NM_000546.6:c.599_600del

TP53 · NP_000537.3:p.(Asn200IlefsTer8) · NM_000546.6

GRCh37: chr17:7578248 AAT>A · GRCh38: chr17:7674930 AAT>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.(Asn200IlefsTer8)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

This two-base-pair deletion in TP53 exon 6 produces a frameshift (p.Asn200IlefsTer8) with a premature termination codon at approximately codon 207, upstream of p.Lys351 and predicted to undergo nonsense-mediated decay, satisfying PVS1 at very strong strength per the TP53 VCEP decision tree.

2

The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, meeting PM2_Supporting at an allele frequency below 0.003%.

3

Absence from population databases is consistent with a pathogenic role and does not satisfy any benign frequency criterion (BA1, BS1).

4

No variant-specific functional, segregation, de novo, or clinical observations were identified, and none of the reviewed publications mentions NM_000546.6:c.599_600del; therefore no additional pathogenic or benign criteria are met.

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 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 2-base-pair deletion in exon 6 produces a frameshift (p.Asn200IlefsTer8) with a premature termination codon at approximately codon 207, upstream of p.Lys351 and predicted to undergo nonsense-mediated decay, meeting PVS1 at very strong strength per the TP53 VCEP decision tree.	cspec vcep_pvs1_flowchart pvs1_variant_assessment pvs1_gene_context
PS1	N/A	PS1 (same amino acid change as a previously established pathogenic variant) applies to missense/substitution comparisons; this is a frameshift deletion with no same-change comparator, and the variant is absent from ClinVar.	cspec clinvar
PS2	Not met	No de novo observation of this variant was identified; no proband or confirmed parental testing data are available to tally de novo points.	cspec
PS3	Not met	No functional data exist for this frameshift variant. It is not present in the TP53 VCEP functional worksheet (which covers amino acid substitutions and single-amino-acid in-frame deletions), and none of the reviewed publications tested NM_000546.6:c.599_600del.	cspec vcep_functional_worksheet vcep_flowchart_for_application_of_functional_rule_codes oncokb
PS4	Not met	No affected-proband observations were identified; the variant is absent from ClinVar and COSMIC, and no case-control prevalence data are available to tally PS4 points.	clinvar cspec
PS5	N/A	PS5 is not a standard ACMG/AMP criterion and is not present in the TP53 VCEP framework.	cspec
PM1	Not met	This frameshift at codon 200 does not fall within a TP53 VCEP-defined hotspot codon (175, 245, 248, 249, 273, 282), which applies only to missense variants, and it is not a cancerhotspots.org missense change with qualifying somatic occurrences.	cspec
PM2	Met	The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, satisfying PM2_Supporting (allele frequency below 0.003%).	gnomad_v2 gnomad_v4 gnomad_canada cspec
PM3	N/A	TP53/Li-Fraumeni syndrome is autosomal dominant; PM3 (recessive trans observation) does not apply.	cspec
PM4	N/A	The TP53 VCEP marks PM4 as Not Applicable; in-frame length changes are addressed by the PVS1 flowchart and this variant is a frameshift already captured by PVS1.	cspec
PM5	N/A	PM5 applies to missense changes at a residue with an established pathogenic/likely pathogenic missense comparator; this is a frameshift, not a missense, and no comparator was identified.	cspec pm5_candidates clinvar
PM6	N/A	The TP53 VCEP uses points-based PS2 for de novo evidence and marks PM6 as Not Applicable.	cspec
PP1	Not met	No cosegregation data are available for this variant.	cspec
PP2	N/A	The TP53 VCEP marks PP2 as Not Applicable; additionally this is a frameshift, not a missense variant.	cspec
PP3	N/A	The TP53 VCEP PP3 in-silico rules apply only to missense variants, single-amino-acid in-frame deletions, and splice variants; this is a frameshift, and SpliceAI predicts no splice effect (max delta 0.048).	cspec spliceai vcep_pp3_bp4_codes vcep_tp53_single_amino_acid_deletions_bayesdel_scores_1
PP4	Not met	No proband phenotype or variant allele fraction (VAF) data are available to satisfy the TP53 VCEP PP4 rule, which requires somatic VAF observations (5-35%).	cspec
PP5	N/A	The TP53 VCEP marks PP5 as 'Not Applicable for this VCEP' (recommended not for use by the ClinGen SVI VCEP Review Committee).	cspec
BA1	Not met	The variant is absent from gnomAD and does not reach the stand-alone benign allele frequency threshold (>=0.1%).	gnomad_v2 gnomad_v4 gnomad_canada cspec
BS1	Not met	The variant is absent from gnomAD and does not meet the strong benign allele frequency threshold (>=0.0003).	gnomad_v2 gnomad_v4 gnomad_canada cspec
BS2	Not met	No unaffected adult (cancer-free female >=60 years) observations are available for this variant.	cspec
BS3	Not met	No functional data demonstrate a benign (normal function) effect for this frameshift variant; it is not present in the TP53 VCEP functional worksheet and no reviewed publication tested it.	cspec vcep_functional_worksheet
BS4	Not met	No segregation data are available to assess lack of segregation among affected family members.	cspec
BP1	N/A	The TP53 VCEP marks BP1 as Not Applicable (truncating variants account for only a portion of disease-causing TP53 variants).	cspec
BP2	N/A	The TP53 VCEP marks BP2 as Not Applicable.	cspec
BP3	N/A	The TP53 VCEP marks BP3 as Not Applicable (in-frame deletion/insertion in a repetitive region without known function); this is a frameshift.	cspec
BP4	N/A	The TP53 VCEP BP4 in-silico rules apply only to missense, single-amino-acid in-frame deletion, synonymous, and intronic variants; this is a frameshift, and SpliceAI predicts no splice impact (max delta 0.048).	cspec spliceai vcep_pp3_bp4_codes
BP5	N/A	The TP53 VCEP marks BP5 as Not Applicable.	cspec
BP6	N/A	The TP53 VCEP marks BP6 as 'Not Applicable for this VCEP' (recommended not for use by the ClinGen SVI VCEP Review Committee).	cspec
BP7	N/A	BP7 applies to synonymous or intronic variants without splicing impact; this is a frameshift deletion.	cspec spliceai

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