Variant classification summary

NM_000546.6:c.374C>T

TP53 · NP_000537.3:p.(Thr125Met) · NM_000546.6

GRCh37: chr17:7579313 G>A · GRCh38: chr17:7675995 G>A

Gene: TP53 Transcript: NM_000546.6

Final call

VUS

PM2 supporting PP3 moderate

Variant details

Gene

TP53

Transcript

NM_000546.6

Protein

NP_000537.3:p.(Thr125Met)

gnomAD AF

ClinVar

OncoKB

Inconclusive

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The TP53 c.374C>T (p.Thr125Met) variant has been reported in ClinVar, where most submissions classify it as likely pathogenic or pathogenic.

2

This variant is rare in population databases, with gnomAD v4.1 showing an allele frequency of 1.86088e-06 (3/1612144) and a highest observed African/African American frequency of 1.33568e-05, which is below the TP53 VCEP PM2_Supporting threshold of 0.00003.

3

In the TP53 VCEP functional worksheet, p.Thr125Met is listed as non-functional in Kato et al. but as no loss of function in other eligible assays, leading to a preassigned interpretation of "No evidence" rather than PS3 or BS3.

4

TP53 VCEP computational evidence supports pathogenicity at the PP3_moderate level, with aGVGD Class C65 and BayesDel 0.500232 in the TP53 worksheet; REVEL is 0.925, while SpliceAI predicts no significant splice effect with a maximum 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 3, 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	Not met	This missense variant, NM_000546.6:c.374C>T (p.Thr125Met), is not a nonsense, frameshift, canonical +/-1,2 splice, or other TP53 null variant under the TP53 VCEP PVS1 framework, so PVS1 is not applied.	pvs1_gene_context pvs1_variant_assessment vcep_pvs1_flowchart
PS1	Not assessed	No reviewed evidence identified a different nucleotide change causing the same amino acid substitution with a prior TP53 VCEP pathogenic or likely pathogenic classification, so PS1 was not assessed.	cspec clinvar
PS2	Not assessed	No confirmed de novo observations with parentage and TP53-relevant phenotype documentation were identified, so PS2 was not assessed.	cspec vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
PS3	Not met	In the TP53 VCEP functional worksheet, p.Thr125Met is listed as non-functional in Kato et al. but as no loss of function in other eligible assays, with an overall preassigned interpretation of "No evidence"; therefore the available functional data do not meet TP53 PS3.	vcep_functional_worksheet vcep_flowchart_for_application_of_functional_rule_codes PMID:12826609 PMID:29979965 PMID:30224644
PS4	Not assessed	Although PM2_Supporting is met, no reviewed evidence established the number of unrelated affected individuals needed to score TP53 PS4, so PS4 was not assessed.	cspec vcep_ps4_points_table gnomad_v4
PM1	Not assessed	Codon 125 is not one of the TP53 VCEP predefined PM1 hotspot codons, and the available Cancer Hotspots review for p.Thr125Met was uncertain rather than confirmed at the exact variant level, so PM1 was not assessed.	cspec hotspots
PM2	Met	This variant is rare in population databases. In gnomAD v4.1, the total allele frequency is 1.86088e-06 (3/1612144), which is below the TP53 VCEP PM2 threshold of 0.00003, and no ancestry group shows multiple alleles above 0.00004; PM2_Supporting is met.	cspec gnomad_v4 gnomad_v2
PM3	N/A	PM3 is not applicable in the TP53 VCEP framework for this gene.	cspec
PM4	N/A	PM4 is not applicable for this TP53 missense variant under the TP53 VCEP framework.	cspec
PM5	Not assessed	No reviewed source established one or more different TP53 VCEP-classified pathogenic or likely pathogenic missense variants at residue Thr125, so PM5 was not assessed.	cspec clinvar
PM6	N/A	PM6 is not applicable in the TP53 VCEP framework for this gene.	cspec
PP1	Not assessed	No segregation data were identified for this variant, so PP1 was not 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 for this gene.	cspec
PP3	Met	For this missense variant, the TP53 VCEP bioinformatic worksheet assigns PP3_moderate. The worksheet lists aGVGD Class C65 and BayesDel 0.500232, which is above the TP53 VCEP PP3 threshold of 0.16. REVEL is also high at 0.925, while SpliceAI predicts no significant splice effect (max delta score 0.09).	vcep_pp3_bp4_codes vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7 bayesdel revel spliceai
PP4	Not assessed	No blood variant allele fraction data or phenotype-specific mosaicism evidence were identified, so the TP53-specific PP4 rule was not assessed.	cspec
PP5	N/A	PP5 is not used in the TP53 VCEP framework.	cspec
BA1	Not met	This variant does not meet the TP53 VCEP BA1 threshold. In gnomAD v4.1, the highest observed filtering allele frequency is far below the BA1 cutoff of 0.001, so stand-alone benign evidence is not met.	cspec gnomad_v4
BS1	Not met	This variant does not meet the TP53 VCEP BS1 threshold. The highest observed allele frequency in gnomAD is below the BS1 cutoff of 0.0003, and the available data do not show the required qualifying frequency signal in a continental ancestry group.	cspec gnomad_v4 gnomad_v2
BS2	Not assessed	No single-source cohort data identified 2 or more unrelated women aged 60 years or older without cancer who carry this variant, so BS2 was not assessed.	cspec
BS3	Not met	Available functional evidence does not support retained TP53 function. In the TP53 VCEP functional worksheet, p.Thr125Met is not assigned BS3 and is instead summarized as "No evidence," because the reviewed assays do not provide the consistent retained-function pattern required for BS3.	vcep_functional_worksheet vcep_flowchart_for_application_of_functional_rule_codes PMID:12826609 PMID:29979965 PMID:30224644
BS4	Not assessed	No lack-of-segregation data were identified for this variant, so BS4 was not assessed.	cspec
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 for this TP53 variant under the TP53 VCEP framework.	cspec
BP4	Not met	Benign computational evidence is not met. The TP53 VCEP bioinformatic worksheet assigns PP3_moderate rather than BP4, with BayesDel 0.500232, which is above the benign BP4 range, and REVEL is high at 0.925. SpliceAI predicts no significant splice effect (max delta score 0.09), but the missense prediction profile supports pathogenic rather than benign computational evidence.	vcep_pp3_bp4_codes vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7 bayesdel revel spliceai
BP5	N/A	BP5 is not applicable in the TP53 VCEP framework.	cspec
BP6	N/A	BP6 is not used in the TP53 VCEP framework.	cspec
BP7	N/A	BP7 does not apply because this is a missense variant rather than a synonymous or qualifying intronic change.	cspec spliceai vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7

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