LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-09-28
Case ID: NM_000546.5_c.309C_A_20260928_151354
Framework: ACMG/AMP 2015
Variant classification summary

NM_000546.5:c.309C>A

TP53  · NP_000537.3:p.(Tyr103Ter)  · NM_000546.5
GRCh37: chr17:7579378 G>T  ·  GRCh38: chr17:7676060 G>T
Gene: TP53 Transcript: NM_000546.5
Final call
Likely Pathogenic
PVS1 very strong PM2 supporting
All criteria require review: For research and educational purposes only.
Variant details
Gene
TP53
Transcript
NM_000546.5
Protein
NP_000537.3:p.(Tyr103Ter)
gnomAD AF
ClinVar
Pathogenic
OncoKB
Likely Oncogenic
Classification rationale
Interpretation summary
Generated evidence synthesis
1
PVS1 very strong: p.Tyr103Ter is an upstream nonsense variant predicted to undergo nonsense-mediated decay.
2
PM2 supporting: the variant is absent from the reported gnomAD population datasets.
Final determination: Under the TP53 VCEP Version 2.4 point-based rule, PVS1 very strong (8 points) plus PM2 supporting (1 point) gives 9 points, which 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 at very strong strength: p.Tyr103Ter is a nonsense variant upstream of TP53 p.Lys351, satisfying the VCEP NMD PVS1 rule.
cspec vcep_pvs1_flowchart PMID:17224268
PS1 N/A Not applicable: c.309C>A is a nonsense change producing p.Tyr103Ter, not an amino-acid substitution eligible for same-amino-acid PS1.
cspec
PS2 Not assessed Not assessed: the exact variant was reported in one LFS-like family, but confirmed parental testing and de novo status required for PS2 are not documented.
cspec vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application PMID:17224268
PS3 N/A Not applicable: TP53 VCEP functional rules cover missense variants and small in-frame deletions, whereas this variant is a nonsense p.(Tyr103Ter).
cspec vcep_flowchart_for_application_of_functional_rule_codes vcep_functional_worksheet
PS4 Not assessed Not assessed: one family reports p.Y103X, but the VCEP PS4 point total for the proband is not explicitly established.
cspec vcep_ps4_points_table PMID:17224268
PM1 N/A Not applicable: p.Tyr103Ter is nonsense at codon 103, outside the VCEP PM1 missense codons 175, 245, 248, 249, 273, and 282.
cspec vcep_output
PM2 Met Met at supporting: the variant is absent from all reported gnomAD datasets, consistent with an allele frequency below the TP53 VCEP PM2 threshold of 0.00003.
cspec gnomad_v2 gnomad_v4
PM3 N/A Not applicable: TP53 VCEP version 2.4 explicitly designates PM3 as not applicable.
cspec
PM4 N/A Not applicable: the TP53 VCEP explicitly excludes PM4, and this variant is a nonsense loss-of-function change rather than an in-frame length-altering variant.
cspec
PM5 N/A Not applicable: p.Tyr103Ter is a nonsense variant, whereas the TP53 VCEP PM5 rule requires a missense variant at the same residue.
cspec pm5_candidates
PM6 N/A Not applicable: the TP53 VCEP explicitly dropped PM6 and requires all de novo evidence to be evaluated through PS2.
cspec
PP1 Not assessed Not assessed: one family report documents the variant and cancer history, but no variant-positive affected relatives or countable cosegregating meioses are provided.
cspec vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application PMID:17224268
PP2 N/A Not applicable: the governing TP53 VCEP explicitly designates PP2 as not applicable.
cspec
PP3 N/A Not applicable: p.(Y103*) is a nonsense variant, outside TP53 VCEP PP3 scope for missense, splice-region, intronic, or synonymous variants.
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: the VCEP PP4 VAF rule requires blood multigene-panel evidence, but no VAF or testing-context data are available.
cspec
PP5 N/A Not applicable: the TP53 VCEP prohibits PP5, and ClinVar has no exact-variant expert-panel classification.
cspec clinvar
BA1 Not met Not met: the variant is absent from gnomAD v2.1 and v4.1, with no ancestry-specific FAF meeting the TP53 VCEP BA1 threshold of 0.001.
cspec gnomad_v2 gnomad_v4
BS1 Not met Not met: the variant is absent from gnomAD v2.1 and v4.1, rather than showing the TP53 VCEP BS1 FAF interval of 0.0003 to below 0.001.
cspec gnomad_v2 gnomad_v4
BS2 Not assessed Not assessed: no qualifying unrelated female carriers aged 60 or older without cancer were reported for comparison with the TP53 VCEP BS2 thresholds.
cspec gnomad_v2 gnomad_v4
BS3 N/A Not applicable: TP53 VCEP benign functional rules cover missense variants and small in-frame deletions, whereas this variant is a nonsense p.(Tyr103Ter).
cspec vcep_flowchart_for_application_of_functional_rule_codes vcep_functional_worksheet
BS4 Not assessed Not assessed: no tested affected family member is documented as lacking the exact TP53 variant, so non-segregation cannot be demonstrated.
cspec vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application PMID:17224268
BP1 N/A Not applicable: the governing TP53 VCEP explicitly designates BP1 as not applicable.
cspec
BP2 N/A Not applicable: TP53 VCEP version 2.4 explicitly designates BP2 as not applicable.
cspec
BP3 N/A Not applicable: the TP53 VCEP explicitly excludes BP3, and p.Tyr103Ter is a truncating nonsense variant rather than a benign repeat-region in-frame change.
cspec
BP4 N/A Not applicable: p.(Y103*) is a nonsense variant, outside TP53 VCEP BP4 scope for missense, splice-region, intronic, or synonymous variants.
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 explicitly marks BP5 as not applicable for this gene.
cspec
BP6 N/A Not applicable: the TP53 VCEP prohibits BP6, and ClinVar has no exact-variant benign expert-panel classification.
cspec clinvar
BP7 N/A Not applicable: p.(Y103*) is a nonsense variant, whereas TP53 VCEP BP7 is limited to synonymous or qualifying intronic variants.
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
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