Variant classification summary

NM_000546.5:c.490A>G

TP53 · NP_000537.3:p.(Lys164Glu) · NM_000546.5

GRCh37: chr17:7578440 T>C · GRCh38: chr17:7675122 T>C

Gene: TP53 Transcript: NM_000546.5

Final call

Likely Pathogenic

PS3 strong PM2 supporting PP3 supporting PP5 supporting

Variant details

Gene

TP53

Transcript

NM_000546.5

Protein

NP_000537.3:p.(Lys164Glu)

gnomAD AF

6.195118989650434e-07 (v4.1)

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The TP53 c.490A>G (p.Lys164Glu) variant has been reported in ClinVar, including a Pathogenic expert-panel classification by the ClinGen TP53 Variant Curation Expert Panel.

2

This variant is absent from gnomAD v2.1 and present once in gnomAD v4.1 (1/1614174 alleles; AF 6.20e-07), which is below the TP53 PM2 threshold of 0.00003.

3

In published TP53 functional studies summarized by the TP53 VCEP, this variant was non-functional in the Kato assay and showed loss of function across other eligible assays, supporting PS3 at strong strength.

4

TP53 VCEP computational tables assign PP3 to this missense change; BayesDel is 0.557217 and REVEL is 0.875, while SpliceAI predicts no significant splice impact (max delta score 0.00).

Final determination: Tavtigian et.al., 2020 - Bayesian adaptation of Richards et.al., 2015 v2.4.0 point-based framework yields a total score of 7, 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 is a missense substitution, p.(Lys164Glu), rather than a nonsense, frameshift, canonical +/-1,2 splice, or copy-number loss variant, and SpliceAI predicts no splice effect (max delta score 0.00). The TP53-specific PVS1 framework therefore does not apply.	cspec pvs1_gene_context pvs1_variant_assessment spliceai vcep_pvs1_flowchart
PS1	Not met	No different nucleotide change producing the same p.Lys164Glu amino acid substitution was identified in the reviewed ClinVar evidence, so PS1 is not met.	clinvar cspec
PS2	Not assessed	No confirmed de novo observation with the TP53 VCEP point-based case information was identified, so PS2 cannot be assessed.	clinvar cspec vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
PS3	Met	In TP53 functional studies, this variant was non-functional in the Kato transactivation assay and showed loss of function across other eligible assays in the TP53 VCEP functional worksheet, supporting PS3 at strong strength.	PMID:12826609 PMID:29979965 PMID:30224644 vcep_functional_worksheet vcep_flowchart_for_application_of_functional_rule_codes clinvar
PS4	Not assessed	Although this variant has been reported in ClinVar, no proband-level Li-Fraumeni syndrome point data were identified to calculate the TP53 PS4 score, so PS4 cannot be assessed.	clinvar cspec vcep_ps4_points_table
PM1	Not assessed	Cancer Hotspots review for residue Lys164 was flagged as uncertain and did not verify a residue-specific or exact amino-acid-change count in cancerhotspots.org, so the TP53 PM1 threshold cannot be confirmed.	hotspots cspec
PM2	Met	This variant is absent from gnomAD v2.1 and present once in gnomAD v4.1 (1/1614174 alleles; AF 6.20e-07), which is below the TP53 PM2 threshold of 0.00003. The single observed allele is in Ashkenazi Jewish, a founder-influenced population excluded by the TP53 VCEP population rule.	gnomad_v2 gnomad_v4 cspec
PM3	N/A	PM3 is not applicable in the TP53 VCEP framework for this disorder context.	cspec
PM4	N/A	PM4 is not applicable because this variant is a missense substitution and the TP53 VCEP does not use PM4 for this context.	cspec
PM5	Not met	A review of same-residue comparator evidence did not identify a different TP53 missense variant at Lys164 previously established as pathogenic or likely pathogenic under the TP53 framework, so PM5 is not met.	pm5_candidates clinvar cspec
PM6	N/A	PM6 is not applicable in the TP53 VCEP framework.	cspec
PP1	Not assessed	No segregation data were identified to count informative meioses, so PP1 cannot be assessed.	clinvar 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 VCEP bioinformatic tables assign PP3 to c.490A>G. BayesDel is 0.557217, above the TP53 pathogenic threshold of 0.16, and REVEL is 0.875, supporting a damaging effect; SpliceAI shows no splice impact (max delta score 0.00).	vcep_pp3_bp4_codes vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7 bayesdel revel spliceai cspec
PP4	Not assessed	No qualifying low-VAF constitutional mosaic observation data were identified, so the TP53-specific PP4 rule cannot be assessed.	cspec
PP5	Met	Expert panel ClinGen TP53 Variant Curation Expert Panel, ClinGen classified as Pathogenic.	cspec clinvar
BA1	Not met	Available population data do not show a qualifying founder-excluded continental frequency at or above the TP53 BA1 threshold of 0.001. The only observed gnomAD v4.1 allele yields a total AF of 6.20e-07.	gnomad_v4 cspec
BS1	Not met	Available population data do not show a qualifying founder-excluded continental frequency at or above the TP53 BS1 threshold of 0.0003. The observed gnomAD v4.1 total AF is 6.20e-07.	gnomad_v4 cspec
BS2	Not assessed	No data were identified showing unrelated cancer-free females aged at least 60 years from a single source who carry this variant, so BS2 cannot be assessed.	cspec
BS3	Not met	Available TP53 functional evidence does not show retained or partially retained wild-type function. Instead, the TP53 VCEP functional worksheet classifies p.K164E as PS3 based on non-functional and loss-of-function assay results, so BS3 is not met.	PMID:12826609 PMID:29979965 PMID:30224644 vcep_functional_worksheet vcep_flowchart_for_application_of_functional_rule_codes
BS4	Not assessed	No lack-of-segregation data were identified in affected family members, so BS4 cannot be assessed.	clinvar 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 because this is not an in-frame indel in a repetitive region and the TP53 VCEP does not use BP3 here.	cspec
BP4	Not met	Benign computational evidence is not supported. BayesDel is 0.557217, which is not below the TP53 BP4 thresholds, the TP53 VCEP precomputed assignment for this variant is PP3 rather than BP4, and SpliceAI predicts no splice impact (max delta score 0.00).	vcep_pp3_bp4_codes vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7 bayesdel spliceai cspec
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 variant is missense rather than synonymous or qualifying intronic.	cspec vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7

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