Variant classification summary

NM_000546.5:c.202G>T

TP53 · NP_000537.3:p.(Glu68Ter) · NM_000546.5

GRCh37: chr17:7579485 C>A · GRCh38: chr17:7676167 C>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.(Glu68Ter)

gnomAD AF

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PVS1 very strong: the exon 4 p.Glu68Ter premature stop is upstream of p.Lys351 and outside TP53's exon 10/11 NMD escape regions.

2

PM2 supporting: the variant is absent from gnomAD v4.1, with an observed allele frequency of 0 below the TP53 VCEP threshold.

Final determination: Under the TP53 VCEP Version 2.4 Tavtigian-style point framework, PVS1 very strong contributes 8 points and PM2 supporting contributes 1 point; the total of 9 points maps to 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: the exon 4 p.Glu68Ter stop is upstream of p.Lys351 and outside TP53's exon 10/11 NMD escape regions.	cspec vcep_pvs1_flowchart
PS1	N/A	Not applicable: the variant is nonsense, p.Glu68Ter, and no alternate nucleotide change producing the same amino-acid consequence is documented.	cspec
PS2	Not assessed	Not assessed: no documented de novo proband, parental testing, or maternity/paternity confirmation is available to assign PS2 points under the VCEP thresholds.	cspec vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
PS3	N/A	Not applicable: TP53 VCEP PS3 covers missense or small in-frame deletions, whereas c.202G>T is a nonsense p.(Glu68Ter) variant with no exact worksheet entry.	cspec vcep_flowchart_for_application_of_functional_rule_codes vcep_functional_worksheet PMID:30224644
PS4	Not assessed	Not assessed: ClinVar records bilateral breast cancer, but age, HER2 status, LFS criteria, and qualifying case-control enrichment needed for TP53 PS4 are unavailable.	cspec vcep_ps4_points_table clinvar
PM1	N/A	Not applicable: p.Glu68Ter is a nonsense variant at codon 68, outside the TP53 VCEP’s specified missense codons 175, 245, 248, 249, 273, and 282.	cspec vcep_hotspots_vision_instruction
PM2	Met	Met at supporting: gnomAD v4.1 observed allele frequency is 0, below the TP53 VCEP PM2 threshold of <0.00003.	cspec gnomad_v4 gnomad_v2
PM3	N/A	Not applicable: the TP53 VCEP Version 2.4 explicitly excludes PM3 because Li-Fraumeni syndrome is autosomal dominant.	cspec
PM4	N/A	Not applicable: TP53 VCEP Version 2.4 explicitly excludes PM4, and this variant is a nonsense loss-of-function allele.	cspec
PM5	N/A	Not applicable: PM5 requires a missense variant, whereas this case variant is the nonsense consequence p.Glu68Ter.	cspec pm5_candidates
PM6	N/A	Not applicable: the TP53 VCEP dropped PM6 and requires all de novo evidence to be evaluated through PS2.	cspec
PP1	Not assessed	Not assessed: no variant-positive affected relatives, obligate carriers, or counted meioses are documented for comparison with the 3-4 meiosis PP1 threshold.	cspec vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
PP2	N/A	Not applicable: the TP53 VCEP designates PP2 as not applicable, and this variant is nonsense rather than missense.	cspec
PP3	N/A	Not applicable: the variant is a nonsense change, so TP53 computational PP3 is outside scope regardless of the available SpliceAI or BayesDel values.	cspec vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7 vcep_pp3_bp4_codes vcep_tp53_single_amino_acid_deletions_bayesdel_scores_1
PP4	Not assessed	Not assessed: TP53 PP4 requires qualifying low-VAF observations, but no VAF or independent low-VAF evidence is available for this variant.	cspec clinvar
PP5	Not met	Not met: the exact ClinVar record has zero Expert Panel submissions, so its laboratory Pathogenic/Likely pathogenic labels cannot trigger PP5.	clinvar cspec
BA1	Not met	Not met: the variant was absent from gnomAD v4.1, far below the TP53 VCEP BA1 threshold of FAF >=0.001 in one eligible ancestry group.	cspec gnomad_v4 gnomad_v2
BS1	Not met	Not met: the variant was absent from gnomAD v4.1, below the TP53 VCEP BS1 threshold of FAF >=0.0003 in one eligible ancestry group.	cspec gnomad_v4 gnomad_v2
BS2	Not assessed	Not assessed: no qualifying unaffected female carriers aged >=60 from a single documented source were available for the TP53 BS2 rule.	cspec
BS3	N/A	Not applicable: TP53 VCEP BS3 covers missense or small in-frame deletions, whereas c.202G>T is a nonsense p.(Glu68Ter) variant with no exact worksheet entry.	cspec vcep_flowchart_for_application_of_functional_rule_codes vcep_functional_worksheet PMID:30224644
BS4	Not assessed	Not assessed: no affected relatives with documented absence of the variant are available to establish lack of segregation for BS4.	cspec vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
BP1	N/A	Not applicable: the TP53 VCEP designates BP1 as not applicable, and this variant is nonsense rather than missense.	cspec
BP2	N/A	Not applicable: the TP53 VCEP Version 2.4 marks BP2 not applicable, regardless of its phase-confirmed trans or three-observation framework.	cspec
BP3	N/A	Not applicable: TP53 VCEP Version 2.4 explicitly excludes BP3, and p.Glu68Ter is a premature-stop variant rather than an in-frame repeat-region deletion.	cspec
BP4	N/A	Not applicable: the variant is a nonsense change, so TP53 computational BP4 is outside scope regardless of the available SpliceAI or BayesDel values.	cspec vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7 vcep_pp3_bp4_codes vcep_tp53_single_amino_acid_deletions_bayesdel_scores_1
BP5	N/A	Not applicable: the TP53 VCEP designates BP5 as not applicable and provides no case-specific benign alternative diagnosis.	cspec
BP6	Not met	Not met: no exact-variant ClinVar Expert Panel Benign or Likely benign classification exists, and all usable laboratory assertions are pathogenic or likely pathogenic.	clinvar cspec
BP7	N/A	Not applicable: the variant is nonsense rather than synonymous or intronic, so TP53 BP7 cannot be applied.	cspec vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7

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