Variant classification summary

NM_000546.6:c.833C>T

TP53 · NP_000537.3:p.(Pro278Leu) · NM_000546.6

GRCh37: chr17:7577105 G>A · GRCh38: chr17:7673787 G>A

Gene: TP53 Transcript: NM_000546.6

Final call

Likely Pathogenic

PS3 strong PM2 supporting PP3 moderate

Variant details

Gene

TP53

Transcript

NM_000546.6

Protein

NP_000537.3:p.(Pro278Leu)

gnomAD AF

6.195687058324959e-07 (v4.1)

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PS3 strong: P278L is non-functional in Kato data and loss of function in the majority of additional eligible assays.

2

PM2 supporting: gnomAD v4.1 allele frequency is 6.1957e-07, below the TP53 VCEP threshold.

3

PP3 moderate: the TP53 VCEP assigns PP3_moderate for BayesDel class C65 score 0.583698.

Final determination: Under the TP53 VCEP Version 2.4 point-based framework, PS3 strong contributes 4 points, PM2 supporting 1 point, and PP3 moderate 2 points; the total of 7 points maps to Likely Pathogenic.

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	Not applicable: NM_000546.6:c.833C>T is a missense substitution, whereas the TP53 PVS1 rule addresses initiation-codon, nonsense, frameshift, splice, deletion, and duplication variants.	cspec vcep_pvs1_flowchart vcep_pvs1_splicing_worksheet
PS1	Not assessed	Not assessed: SpliceAI is 0.006, but no differently encoded p.Pro278Leu variant with a VCEP-qualified pathogenic assertion is documented.	cspec PMID:19556618
PS2	Not assessed	Not assessed: the report calls p.Pro278Leu non-confirmed de novo, with the mother untested and insufficient proband cancer details to assign the VCEP PS2 points.	cspec vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application PMID:19556618
PS3	Met	Met, strong: the VCEP row for P278L pre-assigns PS3 after Kato shows non-functional activity and three additional eligible assays show loss of function.	cspec vcep_flowchart_for_application_of_functional_rule_codes vcep_functional_worksheet PMID:12826609
PS4	Not assessed	Not assessed: p.Pro278Leu is reported with multiple cancers, but missing proband ages and LFS-criteria details prevent assigning the required PS4 point total.	vcep_ps4_points_table PMID:19556618
PM1	Not assessed	Not assessed: p.Pro278Leu is not in the six listed codons, and the cancerhotspots.org same-change count required for the alternative PM1 path is unavailable.	cspec
PM2	Met	Met at supporting: gnomAD v4.1 total AF is 6.1957e-07, below the VCEP PM2 threshold of 0.00003, with zero homozygotes.	cspec gnomad_v4
PM3	N/A	Not applicable: the TP53 VCEP explicitly states that PM3 does not apply to TP53/Li-Fraumeni syndrome.	cspec
PM4	N/A	Not applicable: the TP53 VCEP explicitly marks PM4 as Not Applicable for this framework.	cspec
PM5	Not assessed	Not assessed: p.Pro278Ser and p.Pro278Thr are reported at residue 278, but neither has a VCEP-qualified pathogenicity assertion required for PM5.	cspec PMID:15993273 pm5_candidates
PM6	N/A	Not applicable: the TP53 VCEP explicitly marks PM6 as Not Applicable, regardless of the reported non-confirmed de novo observation.	cspec
PP1	Not assessed	Not assessed: the family history lists two sons with multiple tumours but provides no tested-relative variant status or countable cosegregating meioses for PP1.	cspec vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application PMID:19556618
PP2	N/A	Not applicable: the TP53 VCEP explicitly marks PP2 as not applicable.	cspec
PP3	Met	Met at moderate strength: the VCEP table assigns PP3_moderate for BayesDel C65 score 0.583698 for c.833C>T/p.Pro278Leu.	cspec vcep_pp3_bp4_codes spliceai
PP4	Not assessed	Not assessed: no qualifying multigene-panel VAF observations are available for p.Pro278Leu under the VCEP's 5-25% or 5-35% PP4 rules.	cspec
PP5	N/A	Not applicable: the TP53 VCEP explicitly excludes PP5 from use.	cspec
BA1	Not met	Not met: the highest observed frequency is 1.5998e-05 in the VCEP-excluded Remaining group, below the 0.001 BA1 threshold.	cspec gnomad_v4
BS1	Not met	Not met: no eligible ancestry group reaches the 0.0003 BS1 threshold with at least two observed alleles.	cspec gnomad_v4
BS2	Not assessed	Not assessed: gnomAD reports zero homozygotes but lacks the VCEP-required counts of unrelated cancer-free females aged at least 60 years.	cspec gnomad_v4
BS3	Not met	Not met: P278L is non-functional in Kato and shows loss of function in three additional eligible assay columns, contradicting both BS3 rule paths.	cspec vcep_flowchart_for_application_of_functional_rule_codes vcep_functional_worksheet PMID:12826609
BS4	Not assessed	Not assessed: affected relatives are reported, but their p.Pro278Leu testing results are unavailable, so lack of segregation cannot be established.	cspec PMID:19556618
BP1	N/A	Not applicable: the TP53 VCEP excludes BP1 because truncating variants account for only a portion of disease-causing variants.	cspec
BP2	N/A	Not applicable: the TP53 VCEP marks BP2 not applicable despite describing trans-phase and repeated-observation scenarios.	cspec
BP3	N/A	Not applicable: the TP53 VCEP explicitly marks BP3 as Not Applicable for this framework.	cspec
BP4	Not met	Not met: BP4 is excluded for VCEP BayesDel class C65 missense variants despite SpliceAI maximum delta 0.006 below 0.2.	cspec vcep_pp3_bp4_codes spliceai
BP5	N/A	Not applicable: the TP53 VCEP explicitly marks BP5 as not applicable.	cspec
BP6	N/A	Not applicable: the TP53 VCEP explicitly excludes BP6 from use.	cspec
BP7	N/A	Not applicable: BP7 covers synonymous or intronic variants, whereas c.833C>T/p.Pro278Leu is missense.	cspec vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7

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