Variant classification summary

NM_000546.6:c.373A>C

TP53 · NP_000537.3:p.(Thr125Pro) · NM_000546.6

GRCh37: chr17:7579314 T>G · GRCh38: chr17:7675996 T>G

Gene: TP53 Transcript: NM_000546.6

Final call

Likely Pathogenic

PS3 strong PM2 supporting PP3 supporting

Variant details

Gene

TP53

Transcript

NM_000546.6

Protein

NP_000537.3:p.(Thr125Pro)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The TP53 c.373A>C (p.Thr125Pro) variant has been observed in somatic cancer knowledgebases and has been reported in ClinVar with conflicting germline classifications, including Likely pathogenic and uncertain significance submissions.

2

This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity and meeting the TP53 VCEP PM2_Supporting population threshold of less than 0.00003.

3

TP53 functional data support a damaging effect, with the TP53 VCEP functional worksheet listing p.(Thr125Pro) as non-functional with loss of function across eligible assays and assigning PS3.

4

TP53 in silico evidence also supports deleteriousness: the TP53 VCEP PP3/BP4 worksheet assigns PP3 for c.373A>C with aGVGD Class C35 and BayesDel score 0.576078, while SpliceAI predicts no significant splice impact with a max delta score of 0.09.

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 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, p.(Thr125Pro), and does not fall into the TP53 PVS1 null-variant categories for nonsense, frameshift, canonical +/-1,2 splice, initiation codon, or qualifying exon-level loss. Available evidence does not support application of PVS1.	cspec pvs1_gene_context pvs1_variant_assessment vcep_pvs1_flowchart
PS1	Not met	No alternate nucleotide change producing the same p.(Thr125Pro) amino acid substitution was identified from the reviewed germline database evidence, so PS1 is not met.	clinvar cspec
PS2	Not assessed	No de novo data, confirmed parentage, or proband cancer-point information were identified, so PS2 cannot be assessed.	cspec vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
PS3	Met	TP53 functional evidence supports a damaging effect. In the TP53 VCEP functional worksheet, p.(Thr125Pro) is listed as non-functional in Kato data and loss-of-function in additional eligible assays, with a pre-assigned PS3 code. This is consistent with a deleterious effect on TP53 protein function.	vcep_functional_worksheet vcep_flowchart_for_application_of_functional_rule_codes oncokb PMID:12826609 PMID:29979965 PMID:30224644
PS4	Not assessed	The variant meets the population prerequisite for PS4 because it is absent from gnomAD, but no scored proband observations with Li-Fraumeni syndrome-associated cancers were identified. Available evidence is insufficient to assign a TP53 PS4 point total.	cspec gnomad_v2 gnomad_v4 vcep_ps4_points_table
PM1	Not assessed	Cancer Hotspots review did not confirm the exact variant or residue-level evidence needed to verify TP53 hotspot thresholds. Therefore, the somatic hotspot evidence required for PM1 was not established from the reviewed materials.	cspec hotspots
PM2	Met	This variant is absent from gnomAD v2.1 and gnomAD v4.1. Its observed population frequency is therefore below the TP53 VCEP PM2_Supporting threshold of less than 0.00003 overall and below the per-ancestry multiple-allele threshold of less than 0.00004.	cspec gnomad_v2 gnomad_v4
PM3	N/A	PM3 is not applicable in the TP53 VCEP framework.	cspec
PM4	N/A	PM4 is not applicable in the TP53 VCEP framework.	cspec
PM5	Not assessed	Other missense substitutions at codon 125 are reported in ClinVar, but the reviewed evidence did not establish that these alternate changes were previously classified as Pathogenic or Likely Pathogenic under TP53 VCEP specifications. PM5 therefore remains unassessed.	clinvar cspec
PM6	N/A	PM6 is not applicable in the TP53 VCEP framework.	cspec
PP1	Not assessed	No segregation data were identified, so PP1 cannot be assessed.	cspec vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
PP2	N/A	PP2 is not applicable in the TP53 VCEP framework.	cspec
PP3	Met	TP53 in silico evidence supports a deleterious effect. In the TP53 VCEP PP3/BP4 worksheet, c.373A>C is assigned PP3 with aGVGD Class C35 and BayesDel score 0.576078. SpliceAI predicts no significant splice impact with a max delta score of 0.09, so the evidence supports a missense damaging effect rather than a splice-driven benign interpretation.	vcep_pp3_bp4_codes vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7 spliceai
PP4	Not assessed	No low-variant-allele-fraction blood finding or other qualifying constitutional mosaicism evidence was identified, so PP4 cannot be assessed.	cspec
PP5	N/A	PP5 is not for use in the TP53 VCEP framework.	cspec
BA1	Not met	This variant is absent from gnomAD v2.1 and gnomAD v4.1, so its frequency is below the TP53 VCEP BA1 threshold of at least 0.001 in a qualifying ancestry group. BA1 is not met.	cspec gnomad_v2 gnomad_v4
BS1	Not met	This variant is absent from gnomAD v2.1 and gnomAD v4.1, so its frequency is below the TP53 VCEP BS1 threshold of at least 0.0003 in a qualifying ancestry group. BS1 is not met.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	No source documenting unaffected older female carriers was identified, so BS2 cannot be assessed.	cspec
BS3	Not met	Available functional evidence does not support retained TP53 function. The TP53 VCEP functional worksheet assigns PS3, not BS3, because p.(Thr125Pro) is non-functional and shows loss of function in eligible assays.	vcep_functional_worksheet vcep_flowchart_for_application_of_functional_rule_codes PMID:12826609 PMID:29979965 PMID:30224644
BS4	Not assessed	No lack-of-segregation evidence in affected relatives with Li-Fraumeni syndrome-associated cancers was identified, so BS4 cannot be assessed.	cspec vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
BP1	N/A	BP1 is not applicable in the TP53 VCEP framework.	cspec
BP2	N/A	BP2 is not applicable in the TP53 VCEP framework.	cspec
BP3	N/A	BP3 is not applicable in the TP53 VCEP framework.	cspec
BP4	Not met	Available in silico evidence does not support a benign interpretation. The TP53 VCEP PP3/BP4 worksheet assigns PP3, not BP4, for c.373A>C, and the BayesDel score of 0.576078 is well above the benign thresholds. SpliceAI predicts no significant splice effect, with a max delta score of 0.09.	vcep_pp3_bp4_codes vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7 spliceai
BP5	N/A	BP5 is not applicable in the TP53 VCEP framework.	cspec
BP6	N/A	BP6 is not for use in the TP53 VCEP framework.	cspec
BP7	N/A	BP7 is intended for synonymous or certain intronic variants without predicted splice impact and does not apply to this missense variant.	cspec vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7 spliceai

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