Variant classification summary

NM_000546.5:c.476C>T

TP53 · NP_000537.3:p.(Ala159Val) · NM_000546.5

GRCh37: chr17:7578454 G>A · GRCh38: chr17:7675136 G>A

Gene: TP53 Transcript: NM_000546.5

Final call

VUS

PS3 strong PM2 supporting

Variant details

Gene

TP53

Transcript

NM_000546.5

Protein

NP_000537.3:p.(Ala159Val)

gnomAD AF

ClinVar

Likely pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PS3 strong: A159V is non-functional in Kato data and loss of function in most additional eligible assays.

2

PM2 supporting: c.476C>T is absent from gnomAD v2.1 and v4.1.

Final determination: Under the TP53 VCEP point-based framework, PS3 strong contributes 4 points and PM2 supporting contributes 1 point; the total of 5 points maps to VUS.

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: c.476C>T is a missense substitution retaining protein length, while TP53 PVS1 is restricted to specified null-variant classes.	cspec pvs1_variant_assessment vcep_pvs1_flowchart vcep_pvs1_splicing_worksheet
PS1	Not assessed	Not assessed: no qualifying alternate-nucleotide variant producing the same p.Ala159Val change was identified for comparison under the VCEP rule.	cspec clinvar spliceai PMID:12826609 PMID:30224644
PS2	Not assessed	Not assessed: no variant-specific de novo observation, parental confirmation, or proband cancer-point tally is available to reach the VCEP's 1-point PS2 threshold.	cspec vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
PS3	Met	Met, strong: the VCEP worksheet assigns PS3 because A159V is non-functional by Kato and LOF in three additional eligible assays.	cspec vcep_flowchart_for_application_of_functional_rule_codes vcep_functional_worksheet PMID:12826609 PMID:29979965 PMID:30224644
PS4	Not assessed	Not assessed: no proband phenotype or case-control enrichment is available to assign the VCEP's PS4 point thresholds of 1-1.5, 2-3.5, 4-7.5, or ≥8.	cspec vcep_ps4_points_table
PM1	Not assessed	Not assessed: A159 is a reported hotspot, but the required cancerhotspots same-amino-acid count of at least 10 is unavailable.	cspec
PM2	Met	Met at supporting strength: the variant is absent from gnomAD v2.1 and v4.1, consistent with allele frequency 0 below the VCEP's 0.00003 threshold.	cspec gnomad_v2 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: c.476C>T changes Ala159 to Val without changing protein length, and the TP53 VCEP marks PM4 not applicable.	cspec pvs1_variant_assessment
PM5	Not assessed	Not assessed: zero same-residue comparator variants were available for TP53 residue 159 under the VCEP PM5 requirements.	cspec pm5_candidates PMID:12826609 PMID:30224644
PM6	N/A	Not applicable: the TP53 VCEP dropped PM6 and requires all de novo evidence to be evaluated under PS2.	cspec
PP1	Not assessed	Not assessed: no variant-positive relatives with LFS-associated cancer or countable meioses are documented against the VCEP's minimum 3-meiosis supporting threshold.	cspec vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
PP2	N/A	Not applicable: the TP53 VCEP explicitly marks PP2 as not applicable for this gene.	cspec
PP3	Not met	Not met: TP53 Supplementary Table S2 pre-assigns c.476C>T (BayesDel 0.272813, Class C0) as ‘No evidence’ for PP3.	cspec vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7 vcep_pp3_bp4_codes spliceai
PP4	Not assessed	Not assessed: no qualifying multigene-panel VAF observation is available for the VCEP PP4 thresholds of 5-35% or at least two observations at 5-25%.	cspec
PP5	N/A	Not applicable: the TP53 VCEP explicitly prohibits PP5 use, regardless of external pathogenic classifications.	cspec
BA1	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, rather than reaching the VCEP's FAF threshold of at least 0.001.	cspec gnomad_v2 gnomad_v4
BS1	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, rather than reaching the VCEP's FAF interval of at least 0.0003 but below 0.001.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: no qualifying count of unrelated female carriers aged at least 60 years without cancer is available from a single source.	cspec
BS3	Not met	Not met: the VCEP worksheet assigns PS3, with Kato non-functional and LOF classifications in three additional eligible assays, not benign functional evidence.	cspec vcep_flowchart_for_application_of_functional_rule_codes vcep_functional_worksheet PMID:12826609 PMID:29979965 PMID:30224644
BS4	Not assessed	Not assessed: no affected family members with variant-negative testing are documented to demonstrate the VCEP's required lack of segregation.	cspec vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
BP1	N/A	Not applicable: the TP53 VCEP states BP1 does not apply because truncating variants cause only a portion of TP53 disease.	cspec
BP2	N/A	Not applicable: the TP53 VCEP marks BP2 as not applicable at every strength level, regardless of phase or pathogenic-variant observations.	cspec
BP3	N/A	Not applicable: c.476C>T is a missense substitution, not an in-frame indel in a repetitive region, and the TP53 VCEP marks BP3 not applicable.	cspec pvs1_variant_assessment
BP4	Not met	Not met: BayesDel 0.272813 exceeds the TP53 BP4 Supporting cutoff of <0.16, despite SpliceAI max delta 0.003 being below 0.2.	cspec vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7 vcep_pp3_bp4_codes spliceai
BP5	N/A	Not applicable: the TP53 VCEP marks BP5 as Not applicable and provides no BP5 rule for this gene.	cspec
BP6	N/A	Not applicable: the TP53 VCEP explicitly prohibits BP6 use, regardless of external benign classifications.	cspec
BP7	N/A	Not applicable: c.476C>T is an exonic missense variant, whereas TP53 BP7 covers only synonymous or intronic variants.	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.