Variant classification summary

NM_000546.6:c.587G>T

TP53 · NP_000537.3:p.(Arg196Leu) · NM_000546.6

GRCh37: chr17:7578262 C>A · GRCh38: chr17:7674944 C>A

Gene: TP53 Transcript: NM_000546.6

Final call

VUS

PM2 supporting PP3 moderate BS3 supporting

Variant details

Gene

TP53

Transcript

NM_000546.6

Protein

NP_000537.3:p.(Arg196Leu)

gnomAD AF

ClinVar

OncoKB

Inconclusive

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The TP53 c.587G>T (p.Arg196Leu; p.R196L) variant has been observed in somatic cancers in COSMIC (COSV52667931, n=3) and has been reported in ClinVar as a variant of uncertain significance.

2

This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the TP53 VCEP PM2_Supporting population threshold of 0.00003.

3

In TP53 VCEP-curated functional datasets, Kato transactivation data were partially functional and other eligible assays showed no loss of function, supporting BS3_Supporting rather than PS3.

4

TP53 VCEP in silico criteria assign PP3_Moderate for c.587G>T based on aGVGD Class C65 with BayesDel 0.583489; SpliceAI shows no significant splice effect (max delta 0.14), and REVEL is high at 0.933.

Final determination: Tavtigian et.al., 2020 - Bayesian adaptation of Richards et.al., 2015 v2.4.0 point-based framework yields a total score of 2, 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 variant is a missense substitution and does not fall into the TP53 null-variant or canonical splice categories used for PVS1 application.	cspec pvs1_gene_context pvs1_variant_assessment vcep_pvs1_flowchart
PS1	Not assessed	No established TP53 expert-panel pathogenic or likely pathogenic variant producing the same amino acid change was confirmed from the available records, so PS1 was not assessed.	clinvar cspec
PS2	Not assessed	No confirmed de novo observation with the phenotype-specific TP53 point framework was identified, so PS2 was not assessed.	clinvar cspec vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
PS3	Not met	TP53 VCEP-curated functional data do not support loss of function for this variant. The functional worksheet lists p.Arg196Leu as partially functional in Kato data with no loss of function across other eligible assays, which does not meet TP53 PS3 criteria.	vcep_functional_worksheet vcep_flowchart_for_application_of_functional_rule_codes PMID:12826609 PMID:29979965 PMID:30224644
PS4	Not assessed	Although this variant is rare in population databases, no scored series of independent TP53-associated probands was identified to meet the TP53 PS4 point thresholds, so PS4 was not assessed.	clinvar gnomad_v2 gnomad_v4 cspec vcep_ps4_points_table
PM1	Not met	Codon 196 is not one of the TP53 VCEP predefined hotspot codons, and a qualifying Cancer Hotspots exact-variant recurrence count was not verified. COSMIC shows 3 somatic occurrences, but that does not by itself satisfy the TP53 PM1 rule.	cspec hotspots
PM2	Met	This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the TP53 PM2_Supporting threshold of 0.00003 overall allele frequency and below the single-population threshold of 0.00004.	gnomad_v2 gnomad_v4 cspec
PM3	N/A	PM3 is not applicable for TP53 under this VCEP framework.	cspec
PM4	N/A	PM4 is not applicable for TP53 under this VCEP framework.	cspec
PM5	Not assessed	No verified TP53 expert-panel pathogenic or likely pathogenic missense comparator at codon 196 was confirmed from the available records, so PM5 was not assessed.	pm5_candidates clinvar cspec
PM6	N/A	PM6 is not applicable for TP53 under this VCEP framework.	cspec
PP1	Not assessed	No segregation data with counted informative meioses were identified for this variant, so PP1 was not assessed.	clinvar cspec vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
PP2	N/A	PP2 is not applicable for TP53 under this VCEP framework.	cspec
PP3	Met	TP53 VCEP precomputed in silico assessment assigns PP3_Moderate for c.587G>T. The PP3/BP4 worksheet lists aGVGD Class C65 with BayesDel 0.583489, which is above the TP53 PP3_Moderate BayesDel threshold of 0.16; REVEL is also high at 0.933. SpliceAI shows no significant splice effect with a maximum delta score of 0.14.	vcep_pp3_bp4_codes vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7 bayesdel revel spliceai cspec
PP4	Not assessed	No observation data with variant allele fraction in the TP53 mosaicism range were identified, so PP4 was not assessed.	clinvar cspec
PP5	N/A	PP5 is not applicable under ClinGen SVI and TP53 VCEP recommendations.	cspec
BA1	Not met	This variant is absent from gnomAD v2.1 and gnomAD v4.1 and therefore does not meet the TP53 BA1 stand-alone benign frequency threshold of 0.001.	gnomad_v2 gnomad_v4 cspec
BS1	Not met	This variant is absent from gnomAD v2.1 and gnomAD v4.1 and therefore does not meet the TP53 BS1 benign strong frequency threshold of 0.0003.	gnomad_v2 gnomad_v4 cspec
BS2	Not assessed	No single-source series of unaffected older female carriers was identified, so BS2 was not assessed.	clinvar cspec
BS3	Met	In TP53 VCEP-curated functional datasets, this variant was partially functional in Kato transactivation data and showed no loss of function across other eligible assays. These results support BS3_Supporting and argue against a damaging loss-of-function effect.	vcep_functional_worksheet vcep_flowchart_for_application_of_functional_rule_codes PMID:12826609 PMID:29979965 PMID:30224644
BS4	Not assessed	No non-segregation data in affected relatives were identified for this variant, so BS4 was not assessed.	clinvar cspec
BP1	N/A	BP1 is not applicable for TP53 under this VCEP framework.	cspec
BP2	N/A	BP2 is not applicable for TP53 under this VCEP framework.	cspec
BP3	N/A	BP3 is not applicable for TP53 under this VCEP framework.	cspec
BP4	Not met	Available computational evidence does not support BP4. The TP53 VCEP worksheet assigns PP3_Moderate rather than BP4, with BayesDel 0.583489 well above the benign thresholds and SpliceAI max delta 0.14 showing no major splice effect.	vcep_pp3_bp4_codes vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7 bayesdel spliceai cspec
BP5	N/A	BP5 is not applicable for TP53 under this VCEP framework.	cspec
BP6	N/A	BP6 is not applicable under ClinGen SVI and TP53 VCEP recommendations.	cspec
BP7	N/A	BP7 is a silent or intronic-variant rule and is not applicable to this missense substitution.	cspec vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.