Variant classification summary

NM_000546.5:c.1136G>T

TP53 · NP_000537.3:p.(Arg379Leu) · NM_000546.5

GRCh37: chr17:7572973 C>A · GRCh38: chr17:7669655 C>A

Gene: TP53 Transcript: NM_000546.5

Final call

VUS

PM2 supporting BP4 moderate BP6 supporting benign

Variant details

Gene

TP53

Transcript

NM_000546.5

Protein

NP_000537.3:p.(Arg379Leu)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The TP53 c.1136G>T (p.Arg379Leu) variant has been reported in ClinVar, where the ClinGen TP53 Variant Curation Expert Panel classifies it as Likely Benign, although additional clinical laboratory submissions are uncertain.

2

This variant is absent from gnomAD v2.1 and is present at very low frequency in gnomAD v4.1 (3/1614000 alleles; AF 1.85874e-06), supporting PM2_Supporting and arguing against BS1 or BA1.

3

In the TP53 VCEP functional worksheet, p.Arg379Leu is recorded as partially functional in Kato-class data and noLOF in Giacomelli-class data, with a preassigned interpretation of no functional evidence, so PS3 and BS3 are not supported.

4

TP53-specific in silico assessment lists c.1136G>T as Class C0 with BayesDel -0.0781755 and BP4_moderate, SpliceAI predicts no significant splice impact with max delta score 0.10, and the available REVEL score is 0.345; together these data support BP4_Moderate rather than PP3.

Final determination: Tavtigian et.al., 2020 - Bayesian adaptation of Richards et.al., 2015 v2.4.0 point-based framework yields a total score of -1, which maps to VUS 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 review indicates it does not fall into the null-variant or canonical splice categories used for PVS1. No RNA evidence was identified to show a loss-of-function splicing effect.	cspec pvs1_gene_context pvs1_variant_assessment vcep_pvs1_flowchart
PS1	Not assessed	No reviewed evidence was identified showing that another nucleotide change causing the same TP53 p.Arg379Leu amino acid substitution has already been classified as Pathogenic or Likely Pathogenic under the TP53 VCEP framework.	cspec clinvar
PS2	Not assessed	No confirmed de novo occurrence data with parental confirmation were identified, so PS2 cannot be assessed from the available evidence.	cspec vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
PS3	Not met	Available TP53 functional evidence does not show the level of loss of function required for PS3. In the TP53 functional worksheet, p.Arg379Leu is listed as partially functional in Kato-class data and noLOF in Giacomelli-class data, with a preassigned interpretation of no functional evidence for PS3/BS3.	cspec vcep_functional_worksheet vcep_flowchart_for_application_of_functional_rule_codes PMID:12826609 PMID:30224644
PS4	Not assessed	No proband-count or case-enrichment evidence was identified that would allow scoring this variant under the TP53 PS4 point system.	cspec vcep_ps4_points_table clinvar
PM1	Not met	Available hotspot evidence does not support PM1. This variant is outside the TP53 codons predefined for PM1, and no statistically significant hotspot evidence was identified for p.Arg379Leu.	cspec hotspots
PM2	Met	This variant is absent from gnomAD v2.1 and is extremely rare in gnomAD v4.1, with total AF 1.85874e-06, which is below the TP53 PM2 threshold of 0.00003. Although 2 alleles were observed in the Remaining group, that group frequency was 3.19969e-05, which is below the multiple-allele threshold of 0.00004.	cspec gnomad_v2 gnomad_v4
PM3	N/A	PM3 is not applicable in the TP53 VCEP framework for this condition.	cspec
PM4	N/A	PM4 is not applicable because this variant is a missense substitution, not a protein length-changing in-frame insertion/deletion or stop-loss variant.	cspec
PM5	Not assessed	No reviewed evidence was identified showing that other missense variants at codon 379 have already been classified as Pathogenic or Likely Pathogenic under the TP53 VCEP framework, so PM5 could not be assessed from the available materials.	cspec clinvar
PM6	N/A	PM6 is not applicable in the TP53 VCEP framework.	cspec
PP1	Not assessed	No segregation data were identified to show cosegregation with Li-Fraumeni syndrome-associated cancers, so PP1 cannot be assessed.	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	Not met	Available computational evidence does not meet the TP53 PP3 thresholds. The TP53 VCEP in silico worksheet lists c.1136G>T (p.Arg379Leu) as Class C0 with BayesDel -0.0781755 and a preassigned BP4_moderate call, while SpliceAI predicts no significant splice effect with max delta score 0.10. REVEL was 0.345, but the TP53 VCEP-specific in silico rule set does not support PP3 for this variant.	cspec vcep_pp3_bp4_codes vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7 bayesdel spliceai revel
PP4	Not assessed	No phenotype-specific evidence, blood variant allele fraction data, or repeated low-level observations were identified to support TP53 PP4.	cspec
PP5	N/A	PP5 is not for use in the TP53 VCEP framework.	cspec
BA1	Not met	Population frequency does not meet the TP53 BA1 threshold. The highest observed subpopulation frequency was 3.19969e-05, which is below the BA1 cutoff of 0.001.	cspec gnomad_v4
BS1	Not met	Population frequency does not meet the TP53 BS1 threshold. The highest observed subpopulation frequency was 3.19969e-05, which is below the BS1 cutoff of 0.0003.	cspec gnomad_v4
BS2	Not assessed	No single-source dataset of unaffected older female carriers was identified, so BS2 cannot be assessed.	cspec
BS3	Not met	Available TP53 functional evidence does not support BS3. In the TP53 functional worksheet, p.Arg379Leu is listed as partially functional in Kato-class data and noLOF in Giacomelli-class data, but the preassigned interpretation is no functional evidence rather than BS3 or BS3_Supporting.	cspec vcep_functional_worksheet vcep_flowchart_for_application_of_functional_rule_codes PMID:12826609 PMID:30224644
BS4	Not assessed	No nonsegregation data were identified in affected relatives with Li-Fraumeni syndrome-associated cancers, so BS4 cannot be assessed.	cspec
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	Met	Computational evidence supports a benign effect under the TP53 VCEP rule set. The TP53 in silico worksheet lists c.1136G>T (p.Arg379Leu) as Class C0 with BayesDel -0.0781755 and a preassigned BP4_moderate call, and SpliceAI predicts no significant splice impact with max delta score 0.10, which is below the no-splice-impact threshold of 0.2. REVEL was 0.345 and does not override the TP53 VCEP-specific assignment.	cspec 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	Met	Expert panel ClinGen TP53 Variant Curation Expert Panel, ClinGen classified as Likely benign.	cspec clinvar
BP7	N/A	BP7 is not applicable because this is not a synonymous or qualifying intronic variant.	cspec spliceai

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