LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-04-30
Case ID: NM_000546.5_c.581T_G_20260430_163515
Framework: ACMG/AMP 2015
Variant classification summary

NM_000546.5:c.581T>G

TP53  · NP_000537.3:p.(Leu194Arg)  · NM_000546.5
GRCh37: chr17:7578268 A>C  ·  GRCh38: chr17:7674950 A>C
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.(Leu194Arg)
gnomAD AF
ClinVar
OncoKB
Likely Oncogenic
Classification rationale
Interpretation summary
Generated evidence synthesis
1
The TP53 c.581T>G (p.Leu194Arg; p.L194R) variant has curated somatic cancer literature in OncoKB and is reported in ClinVar as Pathogenic, including by the ClinGen TP53 Variant Curation Expert Panel.
2
This variant is rare in population databases, with 1/1614188 alleles in gnomAD v4.1 (AF 6.20e-07) and 1/251486 alleles in gnomAD v2.1 (AF 3.98e-06), which is below the TP53 PM2 threshold of 0.00003.
3
In the TP53 VCEP functional worksheet, p.Leu194Arg is listed as non-functional in the Kato assay and as loss-of-function in the other eligible assay categories reviewed, supporting PS3.
4
In the TP53 VCEP bioinformatic worksheet, c.581T>G is assigned PP3_moderate; BayesDel is 0.582962, REVEL is 0.933, and SpliceAI shows no significant predicted splice effect (max delta score 0.13), supporting a damaging missense effect without evidence for a splice-based mechanism.
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 Not met This missense variant is not a nonsense, frameshift, canonical +/-1,2 splice, or other null variant, and SpliceAI does not predict a splice-disrupting effect (max delta score 0.13). Available evidence does not support applying TP53-specific PVS1 to this variant.
pvs1_gene_context pvs1_variant_assessment vcep_pvs1_flowchart spliceai cspec
PS1 Not assessed PS1 requires a different nucleotide change that results in the same amino acid substitution and has a TP53 VCEP pathogenic assertion. Such evidence was not identified in the reviewed sources, so PS1 was not assessed.
clinvar cspec
PS2 Not assessed No confirmed de novo observation with the TP53-specific point-based cancer criteria was identified, so PS2 was not assessed.
cspec vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
PS3 Met In the TP53 VCEP functional worksheet, p.Leu194Arg is listed as non-functional in the Kato assay and as loss-of-function in the other eligible assay categories reviewed, with a pre-assigned PS3 code. This supports a damaging effect on TP53 protein function.
vcep_functional_worksheet vcep_flowchart_for_application_of_functional_rule_codes PMID:12826609 PMID:29979965 PMID:30224644
PS4 Not assessed The population data support PM2_Supporting, but no proband-level Li-Fraumeni syndrome point data or affected-case series were identified to score PS4 under the TP53 VCEP framework, so PS4 was not assessed.
cspec vcep_ps4_points_table gnomad_v4 gnomad_v2 clinvar
PM1 Not met Although this variant has curated somatic cancer literature and recurrent somatic observation in cancer resources, a verified TP53 Cancer Hotspots hotspot assignment for codon 194 or for p.Leu194Arg was not established from the reviewed hotspot evidence. Available evidence does not support applying PM1 under the TP53 VCEP rule.
hotspots oncokb cspec
PM2 Met This variant is rare in population databases. In gnomAD v4.1 it is present in 1/1,614,188 alleles (AF 6.20e-07), and in gnomAD v2.1 it is present in 1/251,486 alleles (AF 3.98e-06), both below the TP53 PM2 threshold of 0.00003.
gnomad_v4 gnomad_v2 cspec
PM3 N/A PM3 is not used in the TP53 VCEP framework.
cspec
PM4 N/A PM4 is not used in the TP53 VCEP framework.
cspec
PM5 Not assessed PM5 requires a different missense change at the same residue with a prior TP53 VCEP pathogenic or likely pathogenic assertion. Such residue-level evidence was not identified in the reviewed sources, so PM5 was not assessed.
clinvar cspec
PM6 N/A PM6 is not used in the TP53 VCEP framework.
cspec
PP1 Not assessed No segregation data with informative meioses were identified for this variant, so PP1 was not assessed.
cspec vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
PP2 N/A PP2 is not used in the TP53 VCEP framework.
cspec
PP3 Met In the TP53 VCEP bioinformatic worksheet, c.581T>G is assigned PP3_moderate. BayesDel is 0.582962, which is above the TP53 pathogenic threshold of 0.16, REVEL is 0.933, and SpliceAI shows no significant predicted splice effect (max delta score 0.13), supporting 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 cspec
PP4 Not assessed TP53 PP4 is based on low-variant-allele-fraction observations in the appropriate clinical context. No proband-specific variant allele fraction or mosaicism-focused clinical evidence was identified, so PP4 was not assessed.
cspec
PP5 Met Expert panel ClinGen TP53 Variant Curation Expert Panel, ClinGen classified as Pathogenic.
cspec clinvar
BA1 Not met This variant is far below the TP53 BA1 threshold of 0.001. In gnomAD v4.1 the total allele frequency is 6.20e-07, so BA1 is not met.
gnomad_v4 cspec
BS1 Not met This variant is below the TP53 BS1 threshold. In gnomAD v4.1 the total allele frequency is 6.20e-07, and the highest observed subgroup frequency is 3.38e-05 from a single Ashkenazi Jewish allele, which does not meet the BS1 threshold of >=0.0003.
gnomad_v4 gnomad_v2 cspec
BS2 Not assessed No single-source cohort showing unaffected women age 60 years or older carrying this variant was identified, so BS2 was not assessed.
cspec
BS3 Not met Available functional evidence does not support retained TP53 function. The TP53 VCEP functional worksheet lists p.Leu194Arg as non-functional and loss-of-function across eligible assay categories, 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 family data showing lack of segregation with Li-Fraumeni syndrome-associated cancers were identified, so BS4 was not assessed.
cspec vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
BP1 N/A BP1 is not used in the TP53 VCEP framework.
cspec
BP2 N/A BP2 is not used in the TP53 VCEP framework.
cspec
BP3 N/A BP3 is not used in the TP53 VCEP framework.
cspec
BP4 Not met Available computational evidence does not support a benign prediction. In the TP53 VCEP bioinformatic worksheet, c.581T>G is assigned PP3_moderate rather than BP4; BayesDel is 0.582962, which is well above the benign ranges, and REVEL is 0.933. SpliceAI shows no significant splice effect (max delta score 0.13), but the missense prediction remains damaging overall.
vcep_pp3_bp4_codes vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7 bayesdel revel spliceai cspec
BP5 N/A BP5 is not used in the TP53 VCEP framework.
cspec
BP6 N/A BP6 is not used in the TP53 VCEP framework.
cspec
BP7 N/A BP7 is intended for synonymous or relevant intronic variants without splice impact. This is a missense variant, so BP7 is not applicable.
cspec vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7
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