Variant classification summary

NM_000546.5:c.221C>T

TP53 · NP_000537.3:p.(Ala74Val) · NM_000546.5

GRCh37: chr17:7579466 G>A · GRCh38: chr17:7676148 G>A

Gene: TP53 Transcript: NM_000546.5

Final call

Likely Benign

PM2_Supporting BS3 BP4_Moderate BP6_Supporting

Variant details

Gene

TP53

Transcript

NM_000546.5

Protein

NP_000537.3:p.(Ala74Val)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The TP53 c.221C>T (p.Ala74Val) variant has been reported in ClinVar, including a Likely Benign classification from the ClinGen TP53 Variant Curation Expert Panel, and available hotspot review did not identify it as a recurrent TP53 hotspot.

2

This variant is rare in gnomAD v4.1 (11/1613168 alleles; AF 0.00068%; grpmax FAF 2.92e-06) and gnomAD v2.1 (3/281908 alleles; AF 0.00106%), which is below the TP53 PM2 threshold of 0.003% and below the BS1 and BA1 thresholds.

3

In TP53 functional data summarized by the TP53 VCEP, p.Ala74Val was functional and showed no loss of function in the available eligible assay summary, supporting BS3.

4

TP53 VCEP bioinformatic calibration assigns BP4_moderate for c.221C>T; BayesDel is -0.213549, SpliceAI max delta is 0.00, and REVEL is 0.234, which together do not support a damaging computational effect.

Final determination: PM2_Supporting (+1), BS3 (-4), BP4_Moderate (-2), and BP6_Supporting (-1) yield a total of -6 points, which corresponds to Likely Benign under the TP53 VCEP point-based 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
PVS1	N/A	This is a missense variant, not a nonsense, frameshift, or canonical +/-1,2 splice variant, and SpliceAI predicts no significant splice impact (max delta score 0.00). Available evidence does not support a loss-of-function mechanism eligible for PVS1.	cspec vcep_pvs1_flowchart pvs1_gene_context pvs1_variant_assessment spliceai
PS1	Not assessed	No evidence was identified showing that a different nucleotide change produces the same amino acid substitution and has already been classified as pathogenic or likely pathogenic under the TP53 VCEP framework.	cspec
PS2	Not assessed	No confirmed de novo observation with appropriate parental confirmation and Li-Fraumeni syndrome point assignment was identified for this variant.	cspec vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
PS3	Not met	Available TP53 functional evidence does not show loss of function for p.Ala74Val. The TP53 VCEP functional worksheet summarizes this variant as functional with no loss of function, so PS3 is not supported.	vcep_functional_worksheet vcep_flowchart_for_application_of_functional_rule_codes PMID:12826609 PMID:29979965 PMID:30224644
PS4	Not assessed	No case-level evidence was identified to assign TP53 Li-Fraumeni syndrome points for affected probands carrying this variant, so enrichment in affected individuals could not be established.	cspec vcep_ps4_points_table
PM1	Not assessed	Available hotspot review did not identify p.Ala74Val as a statistically significant TP53 hotspot, but the hotspot review was flagged for human confirmation, so PM1 is not assigned at this time.	cspec hotspots
PM2	Met	This variant is rare in population databases. In gnomAD v4.1 it is present at 11/1613168 alleles (AF 0.00068%; grpmax FAF 2.92e-06), and in gnomAD v2.1 at 3/281908 alleles (AF 0.00106%). These values are below the TP53 PM2 threshold of 0.003%, and the higher Finnish frequency is in a founder population excluded by the TP53 VCEP rule.	cspec gnomad_v4 gnomad_v2
PM3	N/A	PM3 is not used for TP53 in this framework because TP53-related disease is not assessed here as a recessive condition requiring trans observations.	cspec
PM4	N/A	PM4 is not applicable because this variant is a missense substitution, not a protein length-changing in-frame insertion/deletion or stop-loss variant.	cspec
PM5	Not assessed	No reviewed evidence was identified showing that other missense substitutions at codon 74 have already been classified as pathogenic or likely pathogenic under the TP53 VCEP framework.	cspec
PM6	N/A	PM6 is not used in this TP53 VCEP framework.	cspec
PP1	Not assessed	No segregation data were identified for this variant, so cosegregation with Li-Fraumeni syndrome-associated cancers could not be assessed.	cspec vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
PP2	N/A	PP2 is not used for TP53 in this framework.	cspec
PP3	Not met	Available computational evidence does not support a damaging effect. The TP53 VCEP bioinformatic worksheet assigns BP4_moderate, not PP3, for c.221C>T; BayesDel is -0.213549, SpliceAI predicts no significant splice impact (max delta 0.00), and REVEL is 0.234.	vcep_pp3_bp4_codes vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7 bayesdel spliceai revel
PP4	Not assessed	No phenotype-specific or low-variant-allele-fraction clinical observation data were identified to support TP53-specific PP4 scoring for this variant.	cspec
PP5	N/A	PP5 is not used in this TP53 VCEP framework.	cspec
BA1	Not met	Population frequency does not meet the TP53 BA1 threshold. The gnomAD v4.1 grpmax FAF is 2.92e-06, which is below the BA1 cutoff of 0.001.	cspec gnomad_v4
BS1	Not met	Population frequency does not meet the TP53 BS1 threshold. The gnomAD v4.1 grpmax FAF is 2.92e-06, which is below the BS1 cutoff of 0.0003.	cspec gnomad_v4
BS2	Not assessed	No single-source dataset of unaffected older female carriers was identified for this variant, so BS2 could not be assessed.	cspec
BS3	Met	In TP53 functional data summarized by the TP53 VCEP, p.Ala74Val was functional and showed no loss of function in the available eligible assay summary. This supports BS3 under the TP53 functional framework.	vcep_functional_worksheet vcep_flowchart_for_application_of_functional_rule_codes PMID:12826609 PMID:29979965 PMID:30224644
BS4	Not assessed	No family data were identified showing lack of segregation with Li-Fraumeni syndrome-associated cancers, so BS4 could not be assessed.	cspec
BP1	N/A	BP1 is not used for TP53 in this framework.	cspec
BP2	N/A	BP2 is not used for TP53 in this framework.	cspec
BP3	N/A	BP3 is not applicable because this variant is not an in-frame insertion or deletion in a repetitive region.	cspec
BP4	Met	Computational evidence supports a benign interpretation. The TP53 VCEP bioinformatic worksheet assigns BP4_moderate for c.221C>T, with BayesDel -0.213549, which is at or below the TP53 BP4_Moderate threshold, and SpliceAI predicts no significant splice impact (max delta 0.00). REVEL is 0.234 and does not provide a strong deleterious signal.	vcep_pp3_bp4_codes vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7 bayesdel spliceai revel
BP5	N/A	BP5 is not used for TP53 in this framework.	cspec
BP6	Met	Expert panel ClinGen TP53 Variant Curation Expert Panel, ClinGen classified as Likely benign.	cspec clinvar
BP7	N/A	BP7 is for synonymous or qualifying intronic variants. This variant is missense, so BP7 does not apply.	cspec vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7

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