Variant classification summary

NM_000546.5:c.743G>T

TP53 · NP_000537.3:p.(Arg248Leu) · NM_000546.5

GRCh37: chr17:7577538 C>A · GRCh38: chr17:7674220 C>A

Gene: TP53 Transcript: NM_000546.5

Final call

Pathogenic

PS3 strong PM1 moderate PM2 supporting PP3 moderate PP5 supporting

Variant details

Gene

TP53

Transcript

NM_000546.5

Protein

NP_000537.3:p.(Arg248Leu)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The TP53 c.743G>T (p.Arg248Leu) variant has been observed in somatic cancers in COSMIC 161 times and has been reported in ClinVar with an expert panel pathogenic classification.

2

This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity under the TP53 VCEP PM2_Supporting threshold.

3

In the TP53 VCEP functional worksheet, p.Arg248Leu is summarized as non-functional with loss-of-function results across eligible assays and is pre-assigned PS3, supporting a damaging effect on p53 function.

4

In the TP53 VCEP bioinformatic worksheet, this missense change is pre-assigned PP3_moderate with Align-GVGD class C65 and BayesDel 0.570318, while SpliceAI predicts no meaningful splice impact with a maximum delta score of 0.01; REVEL is also high at 0.96.

Final determination: Tavtigian et.al., 2020 - Bayesian adaptation of Richards et.al., 2015 v2.4.0 point-based framework yields a total score of 10, which maps to 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	N/A	This variant is a missense substitution, not a nonsense, frameshift, canonical +/-1,2 splice, or other TP53 null variant type eligible for PVS1. SpliceAI also predicts no meaningful splice disruption (max delta score 0.01).	pvs1_variant_assessment vcep_pvs1_flowchart spliceai
PS1	Not assessed	No alternate nucleotide change producing the same TP53 p.Arg248Leu amino acid substitution with a prior TP53 VCEP pathogenic or likely pathogenic assertion was identified in the reviewed evidence.	clinvar cspec
PS2	Not assessed	No confirmed de novo observation with maternity and paternity assessment and the phenotype details required for TP53 point-based scoring was identified.	cspec vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
PS3	Met	In the TP53 functional worksheet, p.Arg248Leu is pre-assigned PS3. The compiled eligible assay results show this variant was non-functional in the Kato transactivation dataset and showed loss of function in the other eligible functional assays summarized for TP53, supporting a damaging effect on protein function.	vcep_functional_worksheet vcep_flowchart_for_application_of_functional_rule_codes PMID:12826609
PS4	Not assessed	This variant meets PM2_Supporting as a population prerequisite for TP53 PS4, but no germline proband-level Li-Fraumeni syndrome cancer observations with enough information to assign TP53 PS4 points were identified.	cspec vcep_ps4_points_table gnomad_v2 gnomad_v4
PM1	Met	This missense variant affects TP53 codon 248, one of the codons explicitly specified by the TP53 VCEP for PM1 at moderate strength. The same amino acid change has also been observed 161 times in COSMIC, consistent with recurrence at this hotspot residue.	cspec
PM2	Met	This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the TP53 VCEP PM2_Supporting threshold of less than 0.00003 overall and below the ancestry-group threshold of less than 0.00004 when multiple alleles are present.	gnomad_v2 gnomad_v4 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	The reviewed evidence confirms that this variant affects codon 248, but it does not document the number of different TP53 VCEP-classified pathogenic or likely pathogenic missense variants already established at this same residue for direct PM5 scoring.	cspec clinvar
PM6	N/A	PM6 is not used in the TP53 VCEP framework.	cspec
PP1	Not assessed	No segregation data with informative meioses across one or more families were identified for this variant.	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, NM_000546.5:c.743G>T (p.Arg248Leu) is pre-assigned PP3_moderate. The entry shows Align-GVGD class C65 and BayesDel 0.570318, which is above the TP53 VCEP PP3_Moderate threshold of 0.16, and SpliceAI predicts no meaningful splice effect (max delta score 0.01). REVEL is also high at 0.96, which is consistent with a damaging missense effect.	vcep_pp3_bp4_codes vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7 bayesdel spliceai revel
PP4	Not assessed	No blood variant allele fraction data or phenotype observations meeting the TP53 VCEP PP4 low-level mosaicism framework were identified.	cspec
PP5	Met	Expert panel ClinGen TP53 Variant Curation Expert Panel, ClinGen classified as Pathogenic.	cspec clinvar
BA1	Not met	This variant is absent from gnomAD v2.1 and gnomAD v4.1 and therefore does not meet the TP53 VCEP BA1 threshold of filtering allele frequency at or above 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 VCEP BS1 threshold of filtering allele frequency at or above 0.0003 and below 0.001.	gnomad_v2 gnomad_v4 cspec
BS2	Not assessed	No single-source dataset showing unrelated females age 60 years or older without cancer who carry this variant was identified.	cspec
BS3	Not met	Available functional evidence does not support retained or near-normal TP53 function. Instead, the TP53 functional worksheet summarizes non-functional and loss-of-function results for p.Arg248Leu, which argues against BS3.	vcep_functional_worksheet vcep_flowchart_for_application_of_functional_rule_codes PMID:12826609
BS4	Not assessed	No family data showing lack of segregation with Li-Fraumeni syndrome-associated cancers were identified.	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 missense effect. In the TP53 VCEP bioinformatic worksheet, this variant is assigned PP3_moderate rather than BP4; BayesDel is 0.570318, which is above the damaging threshold of 0.16, while SpliceAI shows no meaningful splice effect (max delta score 0.01).	vcep_pp3_bp4_codes vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7 bayesdel spliceai
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 and certain intronic variants, whereas this variant is missense.	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.