LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-05-09
Case ID: NM_000546.5_c.840A_T_20260509_221147
Framework: ACMG/AMP 2015
Variant classification summary

NM_000546.5:c.840A>T

TP53  · NP_000537.3:p.(Arg280Ser)  · NM_000546.5
GRCh37: chr17:7577098 T>A  ·  GRCh38: chr17:7673780 T>A
Gene: TP53 Transcript: NM_000546.5
Final call
Likely Pathogenic
PS3 strong PM2 supporting PP3 moderate PP5 supporting
All criteria require review: For research and educational purposes only.
Variant details
Gene
TP53
Transcript
NM_000546.5
Protein
NP_000537.3:p.(Arg280Ser)
gnomAD AF
ClinVar
OncoKB
Likely Oncogenic
Classification rationale
Interpretation summary
Generated evidence synthesis
1
The TP53 c.840A>T (p.Arg280Ser) variant has been observed in somatic cancer resources and has been reported in ClinVar, where the ClinGen TP53 Variant Curation Expert Panel classifies it as pathogenic.
2
This variant is absent from gnomAD v2.1 and is present only once in gnomAD v4.1 (1/1,613,914 alleles; AF 6.19612e-07), which is below the TP53 PM2 threshold of 0.00003.
3
In the TP53 VCEP functional worksheet, p.Arg280Ser is non-functional in the Kato assay and shows loss of function across additional eligible assays, supporting PS3.
4
TP53 VCEP in silico resources assign PP3_Moderate for c.840A>T based on aGVGD Class C65 and BayesDel 0.519515; local computational data are concordant with BayesDel 0.471463 and REVEL 0.878, while SpliceAI predicts no significant splice impact (max delta score 0.01).
Final determination: Tavtigian et.al., 2020 - Bayesian adaptation of Richards et.al., 2015 v2.4.0 point-based framework yields a total score of 8, 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 This is a missense variant, and available TP53-specific PVS1 materials do not support applying a null-variant criterion to p.(Arg280Ser). SpliceAI also predicts no meaningful splice disruption (max delta score 0.01), so available evidence does not support a PVS1 mechanism.
cspec pvs1_gene_context pvs1_variant_assessment spliceai vcep_pvs1_flowchart
PS1 Not assessed No independently verified TP53 VCEP-qualified alternate nucleotide change encoding the same amino acid substitution was identified in the reviewed evidence, so PS1 was not applied.
cspec clinvar
PS2 Not assessed No de novo observations with the phenotype-specific point framework, parental confirmation, or case-level scoring data were identified, so PS2 was not applied.
cspec vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
PS3 Met In the TP53 VCEP functional worksheet, p.(Arg280Ser) is listed as non-functional in the Kato transactivation assay and as loss of function across additional eligible assays, which supports PS3 at strong strength.
vcep_functional_worksheet vcep_flowchart_for_application_of_functional_rule_codes PMID:12826609 PMID:29979965 PMID:30224644
PS4 Not assessed This variant is very rare in population databases, satisfying the population prerequisite for TP53 PS4 review, but no countable set of germline probands with TP53 VCEP point totals was identified, so PS4 was not applied.
cspec gnomad_v2 gnomad_v4 vcep_ps4_points_table
PM1 Not assessed Codon 280 is not one of the TP53 VCEP codons that automatically qualify for PM1, and the available Cancer Hotspots capture for exact-variant recurrence was inconclusive and flagged for human review, so PM1 was not applied.
cspec hotspots
PM2 Met This variant is absent from gnomAD v2.1 and present only once in gnomAD v4.1 (1/1,613,914 alleles; AF 6.19612e-07; highest non-founder subpopulation AF 8.47432e-07 in non-Finnish Europeans), which is below the TP53 VCEP PM2 threshold of 0.00003 and below the multi-allele ancestry threshold of 0.00004.
cspec gnomad_v2 gnomad_v4
PM3 N/A PM3 is not applicable in the TP53 VCEP framework.
cspec
PM4 N/A PM4 is not applicable in the TP53 VCEP framework.
cspec
PM5 Not assessed A verified TP53 VCEP-qualified same-residue pathogenic comparator was not established from the reviewed evidence, so PM5 was not applied.
cspec pm5_candidates
PM6 N/A PM6 is not applicable in the TP53 VCEP framework.
cspec
PP1 Not assessed No segregation data with meiosis counts in families affected by Li-Fraumeni syndrome-associated cancers were identified, so PP1 was not applied.
cspec vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
PP2 N/A PP2 is not applicable in the TP53 VCEP framework.
cspec
PP3 Met The TP53 VCEP PP3/BP4 worksheet assigns PP3_Moderate to c.840A>T based on aGVGD Class C65 and BayesDel 0.519515. Local computational data are concordant, with BayesDel 0.471463 and REVEL 0.878, while SpliceAI predicts no meaningful splice effect (max delta score 0.01). These findings support a damaging missense effect rather than a splicing mechanism.
vcep_pp3_bp4_codes vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7 bayesdel revel spliceai
PP4 Not assessed No case-level blood variant allele fraction data or repeat observations meeting the TP53 mosaicism-focused PP4 framework were identified, so PP4 was not applied.
cspec
PP5 Met Expert panel ClinGen TP53 Variant Curation Expert Panel, ClinGen classified as Pathogenic.
cspec clinvar
BA1 Not met The observed population frequency is far below the TP53 VCEP BA1 threshold of 0.001. In gnomAD v4.1, this variant is present only once (AF 6.19612e-07), and it is absent from gnomAD v2.1.
cspec gnomad_v2 gnomad_v4
BS1 Not met The observed population frequency does not reach the TP53 VCEP BS1 threshold of 0.0003. In gnomAD v4.1, this variant is present once (AF 6.19612e-07), and no qualifying subpopulation frequency above threshold was identified.
cspec gnomad_v4
BS2 Not assessed No single-source dataset demonstrating unaffected females at age 60 years or older with this variant was identified, so BS2 was not applied.
cspec
BS3 Not met Available functional evidence does not support retained TP53 function. In the TP53 VCEP functional worksheet, p.(Arg280Ser) is non-functional in Kato data and shows loss of function across other eligible assays, which argues against BS3.
vcep_functional_worksheet vcep_flowchart_for_application_of_functional_rule_codes PMID:12826609 PMID:29979965 PMID:30224644
BS4 Not assessed No non-segregation evidence in relatives affected with Li-Fraumeni syndrome-associated cancers was identified, so BS4 was not applied.
cspec vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
BP1 N/A BP1 is not applicable in the TP53 VCEP framework.
cspec
BP2 N/A BP2 is not applicable in the TP53 VCEP framework.
cspec
BP3 N/A BP3 is not applicable in the TP53 VCEP framework.
cspec
BP4 Not met Available computational evidence does not support a benign interpretation. The TP53 VCEP PP3/BP4 worksheet assigns PP3_Moderate rather than BP4, with aGVGD Class C65 and BayesDel 0.519515; local BayesDel is also elevated at 0.471463. Although SpliceAI predicts no meaningful splice effect (max delta score 0.01), the missense prediction data support deleteriousness rather than BP4.
vcep_pp3_bp4_codes vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7 bayesdel spliceai revel
BP5 N/A BP5 is not applicable in the TP53 VCEP framework.
cspec
BP6 N/A BP6 is not for use in the TP53 VCEP framework.
cspec
BP7 N/A BP7 is a synonymous or intronic rule and does not apply to this missense variant.
cspec vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7
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