Variant classification summary

NM_000546.5:c.105G>T

TP53 · NP_000537.3:p.(Leu35Phe) · NM_000546.5

GRCh37: chr17:7579582 C>A · GRCh38: chr17:7676264 C>A

Gene: TP53 Transcript: NM_000546.5

Final call

Likely Benign

PM2_Supporting BS3 BP4_Moderate

Variant details

Gene

TP53

Transcript

NM_000546.5

Protein

NP_000537.3:p.(Leu35Phe)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The TP53 c.105G>T (p.Leu35Phe, p.L35F) variant has been reported in ClinVar as a variant of uncertain significance by the ClinGen TP53 Variant Curation Expert Panel.

2

This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting marked rarity in population databases.

3

In the TP53 functional evidence framework, p.L35F is listed as functional with no loss of function, supporting BS3 and arguing against PS3.

4

Computational evidence does not support a damaging effect: SpliceAI predicts no splice impact with a max delta score of 0.00, BayesDel is -0.0784713, REVEL is 0.486, and the TP53 bioinformatic worksheet assigns BP4_moderate.

Final determination: Using the TP53 VCEP Tavtigian point-based framework, PM2_Supporting (+1), BS3 (-4), and BP4_Moderate (-2) yield a total of -5 points, which corresponds to Likely Benign.

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 in TP53, not a nonsense, frameshift, or canonical splice-site variant. SpliceAI predicts no splice effect with a max delta score of 0.00, and the variant-level PVS1 scaffold states that it does not fall into the default null-variant buckets for PVS1 application.	spliceai 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 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 with adequate parental testing and TP53 VCEP point-based scoring was identified for this variant.	cspec vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
PS3	Not met	Available TP53 functional evidence does not support a damaging loss-of-function effect for this variant. The TP53 functional worksheet lists p.L35F as functional with no loss of function and assigns BS3 rather than PS3.	vcep_functional_worksheet vcep_flowchart_for_application_of_functional_rule_codes
PS4	Not assessed	The variant meets PM2_Supporting based on population rarity, but no TP53 VCEP case-point evidence was identified to show enrichment in affected individuals. No proband point total could be established for PS4.	cspec gnomad_v2 gnomad_v4 vcep_ps4_points_table
PM1	Not met	Available evidence does not support this variant as occurring in a TP53 mutational hotspot or other critical region qualifying for PM1. Cancer Hotspots did not identify a statistically significant hotspot for this variant, and no residue-level hotspot evidence meeting TP53 VCEP thresholds was identified.	cspec hotspots
PM2	Met	This variant is absent from gnomAD v2.1 and gnomAD v4.1, corresponding to an observed allele frequency of 0, which is below the TP53 VCEP PM2 threshold of less than 0.00003 overall and below the per-ancestry threshold of less than 0.00004.	cspec gnomad_v2 gnomad_v4
PM3	N/A	PM3 is not used in the TP53 VCEP framework.	cspec
PM4	N/A	PM4 is not used for this missense variant in the TP53 VCEP framework.	cspec
PM5	Not assessed	No reviewed evidence was identified showing that other missense variants at codon 35 have already been classified as pathogenic or likely pathogenic under the TP53 VCEP framework at the strengths required for PM5.	cspec clinvar
PM6	N/A	PM6 is not used in the TP53 VCEP framework.	cspec
PP1	Not assessed	No segregation data were identified for this variant, so the number of informative meioses required for TP53 VCEP PP1 scoring could not be determined.	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	Not met	Available computational evidence does not support a damaging prediction under the TP53 VCEP framework. SpliceAI predicts no splice effect with a max delta score of 0.00, BayesDel is -0.0784713, and the TP53 VCEP bioinformatic worksheet assigns BP4_moderate rather than PP3 for c.105G>T. REVEL is 0.486, but this does not override the TP53 VCEP-specific in silico assignment.	spliceai bayesdel revel vcep_pp3_bp4_codes vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7
PP4	Not assessed	No blood variant allele fraction or mosaicism-focused clinical observations were identified to apply the TP53 VCEP PP4 rule.	cspec
PP5	N/A	PP5 is not used in the TP53 VCEP framework.	cspec
BA1	Not met	This variant is absent from gnomAD v2.1 and gnomAD v4.1, so its observed allele frequency of 0 is below the TP53 VCEP BA1 threshold of at least 0.001.	cspec gnomad_v2 gnomad_v4
BS1	Not met	This variant is absent from gnomAD v2.1 and gnomAD v4.1, so its observed allele frequency of 0 is below the TP53 VCEP BS1 threshold of at least 0.0003.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	No source was identified showing the number of unrelated females aged 60 years or older without cancer who carry this variant, so BS2 could not be assessed.	cspec
BS3	Met	Available TP53 functional evidence supports retained function rather than loss of function. The TP53 functional worksheet lists p.L35F as functional with no loss of function and assigns BS3.	vcep_functional_worksheet vcep_flowchart_for_application_of_functional_rule_codes
BS4	Not assessed	No family data were identified showing lack of segregation with Li-Fraumeni syndrome-associated cancers, so BS4 could not be 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	Met	Available computational evidence supports a benign prediction under the TP53 VCEP framework. SpliceAI predicts no splice effect with a max delta score of 0.00, BayesDel is -0.0784713, which is at or below the TP53 VCEP BP4_Moderate threshold of -0.008, and the TP53 bioinformatic worksheet assigns BP4_moderate for c.105G>T. REVEL is 0.486 and does not change the TP53 VCEP-specific BP4 assignment.	spliceai bayesdel revel vcep_pp3_bp4_codes vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7
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 applies to synonymous or qualifying intronic variants, not to this missense variant.	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.