Variant classification summary

NM_000546.6:c.395A>T

TP53 · NP_000537.3:p.(Lys132Met) · NM_000546.6

GRCh37: chr17:7578535 T>A · GRCh38: chr17:7675217 T>A

Gene: TP53 Transcript: NM_000546.6

Final call

Likely Pathogenic

PS3 strong PM2 supporting PP3 moderate

Variant details

Gene

TP53

Transcript

NM_000546.6

Protein

NP_000537.3:p.(Lys132Met)

gnomAD AF

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PS3 (strong): p.Lys132Met is non-functional in the Kato et al. yeast transactivation assay and shows loss of function by the majority of other eligible functional assays (Giacomelli, Kotler, Kawaguchi), meeting the TP53 VCEP PS3 criteria at strong strength.

2

PM2_Supporting: The variant is absent from all gnomAD population databases (v2.1, v4.1, Canada), with an allele frequency of 0, satisfying the VCEP PM2_Supporting threshold of <0.00003.

3

PP3_Moderate: Per the VCEP PP3-BP4-codes spreadsheet, c.395A>T is pre-assigned PP3_moderate. The variant has aGVGD Class C65, BayesDel score 0.18419 (≥0.16), REVEL 0.924, and SpliceAI max delta 0.00.

4

Tavtigian point sum: PS3 (+4) + PM2_Supporting (+1) + PP3_Moderate (+2) = 7 points. Per TP53 VCEP v2.4 point-based rules, 6-9 points = Likely Pathogenic.

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 7, 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	N/A	PVS1 applies only to null variants (nonsense, frameshift, canonical ±1,2 splice sites, initiation codons, CNVs) per the TP53 VCEP PVS1 flowchart. This variant is a missense substitution (p.Lys132Met) and does not qualify for PVS1.	vcep_pvs1_flowchart pvs1_variant_assessment
PS1	N/A	PS1 requires a different nucleotide change producing the same amino acid substitution (Lys132Met). K132M can only arise from c.395A>T in an AAG codon; no alternate single-nucleotide substitution produces the same K132M protein change.
PS2	Not met	No de novo observation data are available for this variant in the case materials. Per TP53 VCEP PS2 rules, de novo points require confirmed parentage and proband cancer type scoring; no such data were present.
PS3	Met	Per the TP53 VCEP Functional Worksheet (Supplementary Table S3), p.Lys132Met (K132M) is non-functional in the Kato et al. yeast-based transactivation assay and demonstrates loss of function (LOF) by the majority of other eligible functional assays (Giacomelli LOF, Kotler LOF, Kawaguchi LOF). This satisfies the VCEP PS3 rule: non-functional on Kato et al. data AND LOF by the majority of other eligible assays → PS3 at strong strength.	vcep_functional_worksheet PMID:12826609 PMID:30224644 PMID:29979965
PS4	Not met	No proband-level phenotype data with Li-Fraumeni syndrome cancer point scoring are available. Per TP53 VCEP PS4 rules, point scoring requires probands meeting Chompret criteria with LFS-associated cancers; no such data were present in the case materials.
PS5	N/A	PS5 is not a criterion in the TP53 VCEP v2.4 framework. Under the VCEP, same-residue missense comparator evidence is assessed via PM5. Since the TP53 VCEP framework takes precedence, PS5 is not applied.
PM1	Not met	Codon 132 is not among the VCEP-specified hotspot codons (175, 245, 248, 249, 273, 282). Although the codon lies in a statistically significant hotspot per cancerhotspots.org, the exact amino acid change K132M is not listed on cancerhotspots.org and the residue does not meet the VCEP PM1 moderate threshold of ≥10 somatic occurrences for the same amino acid change.
PM2	Met	The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada (allele frequency = 0). This satisfies the TP53 VCEP PM2_Supporting requirement: allele frequency <0.00003 (0.003%).	gnomad_v2 gnomad_v4 gnomad_canada
PM5	Not met	Multiple missense variants at codon 132 are recorded in the VCEP Functional Worksheet (K132E, K132N, K132Q, K132R, K132T all assigned PS3), but none have a confirmed VCEP-classified pathogenic or likely pathogenic determination. The TP53 VCEP PM5 rule requires comparator variants to be classified as P/LP per VCEP specifications; without confirmed VCEP-classified comparators at codon 132, PM5 cannot be applied.	vcep_functional_worksheet pm5_candidates
PM6	N/A	The TP53 VCEP explicitly marks PM6 as not applicable; de novo evidence is assessed under PS2 in this framework.
PP1	Not met	No cosegregation data are available for this variant. Per TP53 VCEP PP1 rules, meioses must be counted in individuals carrying the variant who also have LFS-associated cancers; no such segregation data were present.
PP2	N/A	The TP53 VCEP marks PP2 as not applicable for TP53; the gene has a high rate of pathogenic missense variation and this criterion is not used.
PP3	Met	Per the TP53 VCEP PP3-BP4-codes spreadsheet (Supplementary Table S2), c.395A>T (p.Lys132Met) is pre-assigned PP3_moderate. The variant meets VCEP PP3 moderate criteria: aGVGD Class C65 and BayesDel score 0.18419 ≥0.16, with SpliceAI max delta 0.00 (no predicted splicing impact). REVEL score 0.924 further supports a deleterious computational prediction.	vcep_pp3_bp4_codes bayesdel revel spliceai
PP4	Not met	No variant allele fraction (VAF) data from patient samples are available. Per TP53 VCEP PP4 rules, the criterion requires observation of the variant with VAF 5-35% to assess somatic mosaicism; no such clinical VAF data were present.
PP5	N/A	The TP53 VCEP explicitly marks PP5 as 'Not Applicable for this VCEP' per ClinGen Sequence Variant Interpretation VCEP Review Committee recommendations.
BA1	Not met	The variant is absent from gnomAD v2.1 and v4.1. BA1 requires a filtering allele frequency ≥0.001 (0.1%) in a continental subpopulation; the variant's AF of 0 does not meet this threshold.	gnomad_v2 gnomad_v4
BS1	Not met	The variant is absent from gnomAD v2.1 and v4.1. BS1 requires a filtering allele frequency ≥0.0003 in a continental subpopulation; the variant's AF of 0 does not meet this threshold.	gnomad_v2 gnomad_v4
BS2	Not met	No data are available on cancer-free females aged ≥60 carrying this variant. Per TP53 VCEP BS2 rules, at least 2 unrelated cancer-free females ≥60 years from a single source are needed for supporting strength; no such individuals have been reported.
BS3	Not met	K132M is non-functional on Kato et al. data and shows LOF across all eligible assays per the VCEP Functional Worksheet. BS3 requires functional evidence of no damaging effect (functional or partially functional on Kato AND no LOF). The variant's consistent LOF profile contradicts BS3.	vcep_functional_worksheet
BS4	Not met	No segregation data are available showing lack of segregation in affected family members with LFS-associated cancers. Per TP53 VCEP BS4 rules, lack of segregation must be demonstrated in family members diagnosed with LFS cancers.
BP1	N/A	The TP53 VCEP marks BP1 as not applicable for TP53; truncating variants account for only a portion of disease-causing variants in this gene.
BP2	N/A	The TP53 VCEP marks BP2 as not applicable for TP53/Li-Fraumeni syndrome.
BP3	N/A	In-frame deletion/insertion criterion; this variant is a missense substitution.
BP4	Not met	The variant is classified as aGVGD Class C65 (pathogenic) with BayesDel score 0.18419. Per TP53 VCEP BP4 rules: BP4_Moderate requires BayesDel ≤-0.008 (not met, and additionally excluded for Class C65); BP4_Supporting requires BayesDel <0.16 and >-0.008 (not met, as 0.18419 >0.16, and excluded for Class C65). No BP4 strength applies.	vcep_pp3_bp4_codes bayesdel spliceai
BP5	N/A	The TP53 VCEP marks BP5 as not applicable; alternative molecular basis evidence is not evaluated under this code.
BP6	N/A	The TP53 VCEP explicitly marks BP6 as 'Not Applicable for this VCEP' per ClinGen Sequence Variant Interpretation VCEP Review Committee recommendations. ClinVar classification alone cannot be used to apply BP6 under this framework.
BP7	N/A	BP7 applies to synonymous (silent) or intronic variants. This variant is a missense substitution (c.395A>T, p.Lys132Met) and does not qualify.

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