Variant classification summary

NM_000546.6:c.1001G>T

TP53 · NP_000537.3:p.(Gly334Val) · NM_000546.6

GRCh37: chr17:7574026 C>A · GRCh38: chr17:7670708 C>A

Gene: TP53 Transcript: NM_000546.6

Final call

VUS

PS3 moderate PM2 supporting

Variant details

Gene

TP53

Transcript

NM_000546.6

Protein

NP_000537.3:p.(Gly334Val)

gnomAD AF

ClinVar

Likely oncogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PS3 (Moderate): p.Gly334Val is partially functional in Kato transactivation but shows loss of function in two other assays (Giacomelli growth suppression, Kawaguchi oligomerization).

2

PM2 (Supporting): the variant is absent from gnomAD v4.1, gnomAD v2.1, and gnomAD-Canada.

3

VUS: the TP53 VCEP Tavtigian framework totals 3 points (PS3 +2, PM2 +1), within the Rule3 range of -1 to 5, so the variant is classified as a variant of uncertain significance.

Final determination: TP53 VCEP v2.4 point-based framework: score 3 falls in the -1 to 5 range (Rule3) mapping to Uncertain Significance.

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	Not applicable: this is a missense change (p.Gly334Val), not a null variant, so the protein-truncation criterion does not apply.	cspec
PS1	Not met	Not met: no other DNA change producing the same p.Gly334Val amino acid has been classified pathogenic or likely pathogenic.	cspec
PS2	Not assessed	Not assessed: no de novo observation or parental testing data was available for this variant.	cspec
PS3	Met	Met (Moderate): p.Gly334Val is partially functional in Kato transactivation but shows loss of function in two other assays (Giacomelli, Kawaguchi).	cspec vcep_functional_worksheet vcep_flowchart_for_application_of_functional_rule_codes PMID:12826609 PMID:30224644
PS4	Not assessed	Not assessed: no germline Li-Fraumeni cancer point totals from unrelated probands were available.	cspec clinvar
PM1	Not assessed	Not assessed: codon 334 is not on the TP53 VCEP PM1 codon list, and no verified hotspot occurrence count was available.	cspec PMID:12826609
PM2	Met	Met (Supporting): the variant is absent from gnomAD v4.1, gnomAD v2.1, and gnomAD-Canada population databases.	cspec gnomad_v4 gnomad_v2 gnomad_canada
PM3	N/A	Not applicable: TP53-related disease is autosomal dominant, so the recessive biallelic-evidence criterion PM3 does not apply.	cspec
PM4	N/A	Not applicable: this missense change does not alter protein length, the only situation PM4 covers.	cspec
PM5	Not met	Not met: no other substitution at codon 334 carries a formal pathogenic or likely pathogenic TP53 VCEP classification.	cspec vcep_functional_worksheet PMID:32675277 PMID:25584008 pm5_candidates
PM6	N/A	Not applicable: the TP53 VCEP removed PM6 and uses PS2 exclusively for de novo evidence.	cspec
PP1	Not assessed	Not assessed: no family segregation or meiosis count data was available.	cspec
PP2	N/A	Not applicable: the TP53 VCEP specification designates PP2 as not applicable for this gene.	cspec
PP3	Not met	Not met: Align-GVGD Class C15 falls below the C25-C65 range PP3 requires, despite BayesDel 0.56885.	vcep_pp3_bp4_codes bayesdel spliceai cspec
PP4	Not assessed	Not assessed: no variant allele fraction or independent observation count was available to assess clonal hematopoiesis.	cspec clinvar
PP5	N/A	Not applicable: the TP53 VCEP designates PP5 not applicable, and no expert-panel germline classification exists for this variant.	cspec clinvar
BA1	Not met	Not met: absent from gnomAD, so no allele frequency reaches the >=0.001 BA1 threshold.	cspec gnomad_v4 gnomad_v2 gnomad_canada
BS1	Not met	Not met: absent from gnomAD, so no allele frequency reaches the >=0.0003 BS1 threshold.	cspec gnomad_v4 gnomad_v2 gnomad_canada
BS2	Not assessed	Not assessed: no qualifying observations in unaffected women aged 60 or older, or in homozygotes, were available.	cspec
BS3	Not met	Not met: functional assays show loss of function, not the benign profile BS3 requires.	cspec vcep_functional_worksheet vcep_flowchart_for_application_of_functional_rule_codes
BS4	Not assessed	Not assessed: no family segregation data was available to test for non-segregation.	cspec
BP1	N/A	Not applicable: the TP53 VCEP specification designates BP1 as not applicable for this gene.	cspec
BP2	N/A	Not applicable: the TP53 VCEP specification designates BP2 as not applicable for this gene.	cspec
BP3	N/A	Not applicable: this is a missense change, not an in-frame indel, and the TP53 VCEP designates BP3 not applicable.	cspec
BP4	Not met	Not met: BayesDel 0.56885 is far above the <0.16 threshold BP4 requires.	vcep_pp3_bp4_codes bayesdel spliceai cspec
BP5	N/A	Not applicable: the TP53 VCEP designates BP5 as not applicable for this gene.	cspec
BP6	N/A	Not applicable: the TP53 VCEP designates BP6 not applicable, and no expert-panel benign classification exists for this variant.	cspec clinvar
BP7	N/A	Not applicable: BP7 applies only to synonymous or intronic variants, and this is a missense change.	cspec

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