NM_000546.5:c.580delC

TP53 · NP_000537.3:p.(Ile195SerfsTer52) · NM_000546.5

GRCh37: chr17:7578268 AG>A · GRCh38: chr17:7674950 AG>A

Gene: TP53 Transcript: NM_000546.5

Final call

Likely Pathogenic

PVS1 very strong PM2 supporting

Variant details

Gene

TP53

Transcript

NM_000546.5

Protein

NP_000537.3:p.(Ile195SerfsTer52)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_000546.5:c.580delC (p.Ile195SerfsTer52) is a frameshift deletion in exon 6 of TP53, producing a premature termination codon at position 246, upstream of p.Lys351, and is predicted to undergo nonsense-mediated decay. Under the TP53 VCEP PVS1 decision tree (v2.4.0), PVS1 is applied at very strong weight (8 points).

This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0. Under the TP53 VCEP PM2 specifications, variants with an allele frequency below 0.00003 qualify for PM2 at supporting level (1 point).

The variant is absent from ClinVar and has not been reported in COSMIC. No variant-specific functional data are available from the TP53 VCEP functional worksheet (which covers missense and in-frame deletions only). No proband phenotype, de novo, segregation, or VAF data are available in the case materials to assess PS2, PS4, PP1, PP4, BS2, or BS4.

Total weighted points: PVS1 (8) + PM2_Supporting (1) = 9 points. Per the TP53 VCEP Tavtigian Bayesian point-based classification framework (v2.4.0), 6-9 points corresponds to Likely Pathogenic.

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	Frameshift deletion c.580del produces a premature termination codon at p.Ile195SerfsTer52 (PTC at codon 246), upstream of p.Lys351. The PTC is located in exon 6, not in exon 11 or the 3'-most 50 nucleotides of exon 10, and is therefore predicted to undergo nonsense-mediated decay. Per the TP53 VCEP PVS1 flowchart (v2.4.0), PVS1 at very strong weight is applied to frameshift-induced PTCs upstream of p.Lys351 that are predicted to undergo NMD.	cspec pvs1_gene_context pvs1_variant_assessment vcep_pvs1_flowchart
PS1	N/A	PS1 applies to a different nucleotide change producing the same amino acid change as a previously established pathogenic variant. This variant is a frameshift deletion, not an amino acid substitution, and PS1 is not applicable to this variant class under the TP53 VCEP specifications.	cspec
PS2	Not assessed	No de novo proband data or LFS cancer type scoring information available in the case materials. PS2 requires proband cancer data scored per the Table of LFS Cancers and Points for PS2 and PP1 Code Application.
PS3	N/A	The TP53 VCEP PS3/BS3 functional assay pathway applies to missense variants and small in-frame deletions, assessed via the Functional-worksheet.xlsx (Kato, Funk, Giacomelli, Kotler, Kawaguchi assays). This variant is a frameshift deletion producing a truncated protein, not a missense or in-frame deletion. The VCEP functional rules do not cover frameshift truncations for PS3/BS3 assessment. The Functional-worksheet.xlsx contains entries for amino acid substitutions at position 195 but no entry for the frameshift p.Ile195SerfsTer52.	cspec vcep_functional_worksheet vcep_flowchart_for_application_of_functional_rule_codes
PS4	Not assessed	No proband data with Li-Fraumeni syndrome cancer type scoring available. PS4 requires tallying proband points per the VCEP PS4 Points Table (strongly associated cancers: 4 points; moderately associated: 2 points) and Chompret criteria assessment.
PS5	N/A	PS5 is not included in the TP53 VCEP ACMG/AMP Specifications v2.4.0 criteria set. Not applicable under the governing VCEP framework.	cspec
PM1	N/A	VCEP PM1 applies exclusively to missense variants at codons 175, 245, 248, 249, 273, 282 or germline missense variants in cancerhotspots.org with somatic occurrence thresholds. This variant is a frameshift deletion, not a missense variant, and PM1 is not applicable to this variant class under the TP53 VCEP specifications.	cspec
PM2	Met	This variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0. Under the TP53 VCEP PM2 specifications, variants with an allele frequency below 0.00003 (0.003%) qualify for PM2 at supporting level. Complete absence from population databases satisfies this threshold.	gnomad_v2 gnomad_v4 gnomad_canada
PM4	N/A	PM4 is explicitly marked as not applicable in the TP53 VCEP ACMG/AMP Specifications v2.4.0.	cspec
PM5	N/A	VCEP PM5 applies exclusively to missense variants at an amino acid residue where a different pathogenic or likely pathogenic missense variant has been previously identified. This variant is a frameshift deletion, not a missense substitution, and PM5 is not applicable to this variant class.	cspec pm5_candidates
PM6	N/A	PM6 is explicitly marked as not applicable in the TP53 VCEP ACMG/AMP Specifications v2.4.0. The VCEP uses a combined PS2/PM6 rule under the PS2 criterion.	cspec
PP1	Not assessed	No cosegregation data available. VCEP PP1 requires observation of cosegregation in 3-4 meioses (supporting), 5-6 meioses (moderate), or ≥7 meioses across >1 family (strong), with affected individuals having LFS-associated cancers.
PP2	N/A	PP2 is explicitly marked as not applicable in the TP53 VCEP ACMG/AMP Specifications v2.4.0.	cspec
PP3	N/A	VCEP PP3 applies to missense, synonymous, intronic, and single amino acid in-frame deletion variants using aGVGD/BayesDel scores and SpliceAI predictions. This variant is a frameshift deletion, which is not covered by the VCEP PP3/BP4 flowchart or the PP3-BP4-codes.xlsx or the TP53 single amino acid deletion BayesDel spreadsheet. The variant is not listed in any VCEP in silico code assignment resource.	cspec vcep_pp3_bp4_codes vcep_tp53_single_amino_acid_deletions_bayesdel_scores_1 spliceai
PP4	Not assessed	No variant allele fraction (VAF) data available. VCEP PP4 requires observation of the variant with VAF 5-35% (supporting) or at least 2 independent observations with VAF 5-25% (moderate) to support constitutional mosaicism or low-level somatic findings.
PP5	N/A	PP5 is explicitly marked as not applicable for this VCEP in the TP53 VCEP ACMG/AMP Specifications v2.4.0, per ClinGen Sequence Variant Interpretation VCEP Review Committee recommendation.	cspec
BA1	Not met	The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. VCEP BA1 requires a filtering allele frequency ≥0.001 (0.1%) in a continental subpopulation with ≥2,000 alleles tested and ≥2 alleles present. Absence from population databases does not meet the BA1 threshold.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. VCEP BS1 requires a filtering allele frequency ≥0.0003 (0.03%) in a continental subpopulation with ≥2,000 alleles tested and ≥2 alleles present. Absence from population databases does not meet the BS1 threshold.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not assessed	No data on cancer-free females ≥60 years of age available. VCEP BS2 requires 2-3 (supporting), 4-7 (moderate), or ≥8 (strong) unrelated females who have reached at least 60 years without cancer, all from a single source.
BS3	N/A	The TP53 VCEP BS3/PS3 functional assay pathway applies to missense variants and small in-frame deletions, assessed via the Functional-worksheet.xlsx. This variant is a frameshift deletion producing a truncated protein, not a missense or in-frame deletion, and is not covered by the VCEP functional rules.	cspec vcep_functional_worksheet vcep_flowchart_for_application_of_functional_rule_codes
BS4	Not assessed	No segregation data available. VCEP BS4 requires lack of segregation in affected family members diagnosed with LFS-associated cancers.
BP1	N/A	BP1 is explicitly marked as not applicable in the TP53 VCEP ACMG/AMP Specifications v2.4.0. Truncating variants account for a significant portion of disease-causing variants in TP53.	cspec
BP2	N/A	BP2 is explicitly marked as not applicable in the TP53 VCEP ACMG/AMP Specifications v2.4.0.	cspec
BP3	N/A	BP3 is explicitly marked as not applicable in the TP53 VCEP ACMG/AMP Specifications v2.4.0.	cspec
BP4	N/A	VCEP BP4 applies to missense, synonymous, intronic, and single amino acid in-frame deletion variants using BayesDel scores and SpliceAI predictions. This variant is a frameshift deletion, which is not covered by the VCEP PP3/BP4 flowchart or associated spreadsheets.	cspec vcep_pp3_bp4_codes vcep_tp53_single_amino_acid_deletions_bayesdel_scores_1
BP5	N/A	BP5 is explicitly marked as not applicable in the TP53 VCEP ACMG/AMP Specifications v2.4.0.	cspec
BP6	N/A	BP6 is explicitly marked as not applicable for this VCEP in the TP53 VCEP ACMG/AMP Specifications v2.4.0, per ClinGen Sequence Variant Interpretation VCEP Review Committee recommendation.	cspec
BP7	N/A	VCEP BP7 applies to synonymous (silent) or intronic variants. This variant is a frameshift deletion, not a synonymous or intronic variant, and BP7 is not applicable.	cspec

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