NM_000546.5:c.1136G>A

TP53 · NP_000537.3:p.(Arg379His) · NM_000546.5

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

Gene: TP53 Transcript: NM_000546.5

Final call

Likely Benign

BS3 strong BP4 moderate PM2 supporting BP6 supporting benign

Variant details

Gene

TP53

Transcript

NM_000546.5

Protein

NP_000537.3:p.(Arg379His)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

The TP53 c.1136G>A (p.Arg379His) variant has been reported in ClinVar, including a Likely Benign expert-panel assertion from the ClinGen TP53 Variant Curation Expert Panel.

This variant is rare in population databases, with a gnomAD v4.1 total allele frequency of 4.95699e-06 and joint grpmax filtering allele frequency of 4.43e-06, which supports PM2_Supporting and is below the BS1 and BA1 thresholds.

In published TP53 functional studies summarized by the TP53 VCEP functional worksheet, p.Arg379His was functional in the Kato assay set and showed no loss of function in the Giacomelli assay set, supporting BS3 and arguing against PS3.

TP53 VCEP in silico assessment supports a benign computational effect: the variant is assigned BP4_moderate in the TP53 bioinformatic worksheet, BayesDel is -0.0720003, SpliceAI shows no significant splice effect, and REVEL is 0.338.

Final determination: Tavtigian et.al., 2020 - Bayesian adaptation of Richards et.al., 2015 v2.4.0 point-based framework yields a total score of -6, which maps to Likely Benign 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
PP5	N/A	This criterion is not used in the TP53 VCEP framework.	cspec
PP4	Not assessed	No phenotype-specific low-VAF observation data were identified to assess the TP53 VCEP PP4 rules for constitutional mosaicism or related clinical context.	cspec
PS4	Not assessed	This variant meets the TP53 VCEP population prerequisite for PS4 because the gnomAD allele frequency is below the PM2 threshold, but no proband-based Li-Fraumeni syndrome point tally was identified to determine PS4 strength.	cspec gnomad_v4 gnomad_v2 vcep_ps4_points_table
BP3	N/A	This criterion is not applicable in the TP53 VCEP framework.	cspec
BP1	N/A	This criterion is not applicable in the TP53 VCEP framework.	cspec
BS1	Not met	Population data do not meet the TP53 VCEP BS1 threshold. In gnomAD v4.1, the joint grpmax filtering allele frequency is 4.43e-06, which is below the BS1 cutoff of 0.0003, and no eligible non-founder ancestry group shows a qualifying frequency at or above that threshold.	cspec gnomad_v4 gnomad_v2
BP6	Met	Expert panel ClinGen TP53 Variant Curation Expert Panel, ClinGen classified as Likely benign.	cspec clinvar
PM1	Not met	Available evidence does not show that this missense variant is in a TP53 mutational hotspot that meets PM1. Arg379 is not one of the canonical TP53 hotspot codons, and the available Cancer Hotspots review did not identify this variant as lying in a statistically significant hotspot.	cspec hotspots
BP7	N/A	BP7 is intended for synonymous or qualifying intronic variants without splice impact. This variant is a missense substitution, so BP7 does not apply.	cspec vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7
PVS1	Not met	This variant is a missense substitution and does not fall into the TP53 PVS1 null-variant categories. It is not a nonsense, frameshift, initiation-loss, or canonical +/-1,2 splice variant, and SpliceAI does not predict a splice effect (max delta score 0.00).	cspec pvs1_gene_context pvs1_variant_assessment spliceai vcep_pvs1_flowchart
PS2	Not assessed	No confirmed de novo occurrence data with a TP53 VCEP point tally were identified for this variant.	cspec vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
PP2	N/A	This criterion is not applicable in the TP53 VCEP framework.	cspec
BP2	N/A	This criterion is not applicable in the TP53 VCEP framework.	cspec
PS1	Not assessed	No independently established TP53 VCEP pathogenic or likely pathogenic variant causing the same amino acid change was identified from the available evidence, so PS1 was not assessed.	cspec spliceai
PM3	N/A	This criterion is not applicable in the TP53 VCEP framework.	cspec
BA1	Not met	Population data do not meet the TP53 VCEP BA1 threshold. In gnomAD v4.1, the joint grpmax filtering allele frequency is 4.43e-06, which is below the BA1 cutoff of 0.001.	cspec gnomad_v4 gnomad_v2
PM6	N/A	This criterion is not applicable in the TP53 VCEP framework.	cspec
BS4	Not assessed	No family data were identified showing lack of segregation with Li-Fraumeni syndrome-associated cancers, so BS4 was not assessed.	cspec
PM5	Not assessed	No qualifying TP53 VCEP pathogenic or likely pathogenic missense comparator variant at codon 379 was identified from the available evidence, so PM5 was not assessed.	cspec
BS3	Met	Published TP53 functional evidence supports a benign effect. In the TP53 VCEP functional worksheet, p.Arg379His is classified as functional in the Kato assay set and as no loss of function in the Giacomelli assay set, with a pre-assigned BS3 code.	cspec vcep_functional_worksheet vcep_flowchart_for_application_of_functional_rule_codes PMID:12826609 PMID:30224644
PM2	Met	This variant is rare in population databases and meets the TP53 VCEP PM2 threshold. In gnomAD v4.1, the total allele frequency is 4.95699e-06, which is below the PM2 cutoff of 0.00003, and the joint grpmax filtering allele frequency is 4.43e-06. In gnomAD v2.1, the total allele frequency is 7.07234e-06, also below the threshold.	cspec gnomad_v4 gnomad_v2
PP3	Not met	Available computational evidence does not support a damaging effect under the TP53 VCEP missense rules. The TP53 VCEP bioinformatic worksheet assigns BP4_moderate for c.1136G>A, with Align-GVGD class C0, BayesDel -0.0720003, and no predicted splice impact; SpliceAI in the case data also shows no significant splice effect (max delta score 0.00). REVEL is available at 0.338 but does not override the TP53 VCEP rule assignment.	cspec vcep_pp3_bp4_codes vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7 bayesdel spliceai revel
BP5	N/A	This criterion is not applicable in the TP53 VCEP framework.	cspec
PP1	Not assessed	No segregation data were identified to assess co-segregation with Li-Fraumeni syndrome-associated cancers.	cspec vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
BP4	Met	Computational evidence supports a benign effect under the TP53 VCEP missense rules. The TP53 VCEP bioinformatic worksheet assigns BP4_moderate for c.1136G>A with Align-GVGD class C0 and BayesDel -0.0720003, which is below the BP4_moderate cutoff of -0.008, and there is no predicted splice impact (worksheet SpliceAI 0.08; case SpliceAI max delta score 0.00, both below 0.2). REVEL is available at 0.338 and does not contradict the benign VCEP bioinformatic assignment.	cspec vcep_pp3_bp4_codes vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7 bayesdel spliceai revel
PS3	Not met	Available functional evidence does not support loss of function for this variant. In the TP53 VCEP functional worksheet, p.Arg379His is classified as functional in the Kato assay set and as no loss of function in the Giacomelli assay set, so PS3 is not met.	cspec vcep_functional_worksheet vcep_flowchart_for_application_of_functional_rule_codes PMID:12826609 PMID:30224644
PM4	N/A	This criterion is not applicable in the TP53 VCEP framework.	cspec
BS2	Not assessed	No single-source series of unaffected older female carriers was identified to assess BS2 under the TP53 VCEP framework.	cspec

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