Variant classification summary

NM_000546.5:c.245C>T

TP53 · NP_000537.3:p.(Pro82Leu) · NM_000546.5

GRCh37: chr17:7579442 G>A · GRCh38: chr17:7676124 G>A

Gene: TP53 Transcript: NM_000546.5

Final call

Likely Benign

BS3 BP4 BP6 PM2_Supporting

Variant details

Gene

TP53

Transcript

NM_000546.5

Protein

NP_000537.3:p.(Pro82Leu)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The TP53 c.245C>T (p.Pro82Leu) variant has been reported in ClinVar, where the aggregate classification is Likely Benign with expert panel review.

2

This variant is present at very low frequency in gnomAD v2.1 and v4.1 (overall AF 1.99644e-05 and 1.11599e-05; grpmax FAF 7.03e-06 and 8.76e-06), which is below the TP53 VCEP PM2_Supporting threshold of 0.00003 overall and below 0.00004 in any non-founder ancestry group with multiple alleles.

3

In the TP53 VCEP functional worksheet, p.Pro82Leu (P82L) is assigned BS3 and the summarized assay interpretation is functional with no loss-of-function, supporting retained protein function.

4

Computational assessment under the TP53 VCEP missense framework lists c.245C>T as Class C0 with BayesDel 0.0708215 and BP4, while SpliceAI predicts no splice impact (max delta 0.00); REVEL is 0.57 but does not override the TP53 VCEP benign computational assignment for this variant.

Final determination: BS3_Strong, BP4, and BP6 with PM2_Supporting yield a net -5 Tavtigian points, consistent with a Likely Benign classification under the TP53 VCEP framework.

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	The TP53 VCEP does not use PP5 for variant classification.	cspec
PP4	Not assessed	No blood variant allele fraction or comparable mosaicism data were identified, so the TP53 VCEP PP4 thresholds based on low variant allele fraction observations cannot be evaluated.	cspec
PS4	Not assessed	No countable affected probands or Li-Fraumeni syndrome point total were identified for this variant, so PS4 cannot be applied even though the population frequency is low enough for PM2_Supporting.	cspec vcep_ps4_points_table gnomad_v2 gnomad_v4
BP3	N/A	The TP53 VCEP does not use BP3 for variant classification.	cspec
BP1	N/A	The TP53 VCEP does not use BP1 for variant classification.	cspec
BS1	Not met	The highest observed filtering allele frequency is 7.03e-06 in gnomAD v2.1 and 8.76e-06 in gnomAD v4.1, which is below the TP53 VCEP BS1 threshold of 0.0003, so BS1 is not met.	cspec gnomad_v2 gnomad_v4
BP7	N/A	This is a missense variant, not a synonymous or intronic variant, so BP7 is not applicable.	cspec vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7
PVS1	N/A	This variant is a missense substitution with no predicted splice effect and does not fall into the TP53 or generic PVS1 null-variant categories such as nonsense, frameshift, or canonical splice-site change, so PVS1 is not applicable.	cspec pvs1_gene_context pvs1_variant_assessment spliceai vcep_pvs1_flowchart
PS2	Not assessed	No confirmed de novo observation with the TP53 VCEP point-based evidence required for PS2 was identified.	cspec vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
PP2	N/A	The TP53 VCEP does not use PP2 for variant classification.	cspec
BP2	N/A	The TP53 VCEP does not use BP2 for variant classification.	cspec
PS1	Not assessed	No previously established TP53 VCEP pathogenic or likely pathogenic variant with the same amino acid change was identified in the reviewed evidence, so PS1 cannot be assigned from the available data.	cspec clinvar
PM3	N/A	The TP53 VCEP does not use PM3 for variant classification.	cspec
BA1	Not met	The highest observed filtering allele frequency is 7.03e-06 in gnomAD v2.1 and 8.76e-06 in gnomAD v4.1, which is below the TP53 VCEP BA1 threshold of 0.001, so BA1 is not met.	cspec gnomad_v2 gnomad_v4
PM6	N/A	The TP53 VCEP does not use PM6 for variant classification.	cspec
BS4	Not assessed	No segregation study showing lack of segregation with Li-Fraumeni syndrome-associated cancers was identified, so BS4 cannot be evaluated.	cspec vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
PM5	Not assessed	No reviewed evidence identified previously established TP53 VCEP pathogenic or likely pathogenic missense variants at codon 82 that would support PM5.	cspec clinvar
BS3	Met	In the TP53 VCEP functional worksheet, p.Pro82Leu (P82L) is assigned BS3, and the summarized assay interpretation is functional with no loss-of-function, supporting retained TP53 protein function.	vcep_functional_worksheet vcep_flowchart_for_application_of_functional_rule_codes
PM2	Met	This variant is rare in population databases. The overall allele frequency is 1.99644e-05 in gnomAD v2.1 and 1.11599e-05 in gnomAD v4.1, both below the TP53 VCEP PM2 threshold of 0.00003, and no non-founder ancestry group with multiple alleles exceeds the 0.00004 cutoff, so PM2 is met at supporting strength.	cspec gnomad_v2 gnomad_v4
PP3	Not met	Available computational evidence does not support a damaging effect under the TP53 VCEP in silico framework. The TP53 PP3/BP4 worksheet lists c.245C>T as Class C0 with BayesDel 0.0708215 and BP4, and SpliceAI predicts no splice impact with a max delta score of 0.00. REVEL is available at 0.57, but the TP53 VCEP missense rule for this variant supports BP4 rather than PP3.	vcep_pp3_bp4_codes vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7 bayesdel spliceai revel
BP5	N/A	The TP53 VCEP does not use BP5 for variant classification.	cspec
PP1	Not assessed	No segregation data with countable meioses were identified for this variant, so PP1 cannot be applied.	cspec vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
BP4	Met	Available computational evidence supports a benign interpretation under the TP53 VCEP missense framework. The TP53 PP3/BP4 worksheet lists c.245C>T (p.Pro82Leu) as Class C0 with BayesDel 0.0708215 and assigns BP4, and SpliceAI predicts no splice effect with a max delta score of 0.00. REVEL is 0.57, but the TP53 VCEP precomputed code for this missense change is BP4.	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 a damaging effect. The TP53 VCEP functional worksheet assigns BS3 rather than PS3 for p.Pro82Leu, with summarized results indicating functional activity and no loss-of-function.	vcep_functional_worksheet vcep_flowchart_for_application_of_functional_rule_codes
PM4	N/A	The TP53 VCEP does not use PM4 for variant classification, and this variant is not an in-frame insertion or deletion.	cspec
BS2	Not assessed	No dataset of unrelated females aged 60 years or older without cancer who carry this variant was identified, so BS2 cannot be evaluated.	cspec
BP6	Met	Expert panel ClinGen TP53 Variant Curation Expert Panel, ClinGen classified as Likely benign.	cspec clinvar
PM1	Not met	This missense variant affects codon 82, which is outside the TP53 VCEP codons that qualify directly for PM1 (175, 245, 248, 249, 273, 282), and no verified hotspot evidence showing at least 2 somatic occurrences for this exact amino acid change was identified in the reviewed evidence.	cspec hotspots

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