Final classification

Likely Pathogenic

PS3PM2PP3PP5

TP53

c.490A>G

p.Lys164Glu

This variant

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.

Transcript

NM_000546.5

HGVS · transcript:coding

NM_000546.5:c.490A>G

GRCh38

chr17:7675122 T>C

GRCh37

chr17:7578440 T>C

Tavtigian et.al., 2020 - Bayesian adaptation of Richards et.al., 2015 v2.4.0 point-based framework: PS3 strong (+4) + PM2 supporting (+1) + PP3 supporting (+1) + PP5 supporting (+1) = 7 points, which maps to Likely Pathogenic.

Classification rationale

PS3PM2PP3PP5 Likely Pathogenic

TP53 c.490A>G

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.¹ 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 0.00003.² 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.³ 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).⁴

PS3 + PM2 + PP3 + PP5 → Likely Pathogenic

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗cspec ↗

3 PMID:12826609 ↗PMID:29979965 ↗PMID:30224644 ↗vcep_functional_worksheetvcep_flowchart_for_application_of_functional_rule_codes

4 vcep_pp3_bp4_codesbayesdelrevelspliceai ↗vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.

Gene diagram · NM_000546.5 · variants mapped to exon structure

TP53 NM_000546.5

Fetching transcript structure from UCSC…

Applied criteria · 4 applied · 13 assessed

MetEvidence satisfies this criterion.

Not metEvaluated against available evidence; threshold not reached.

Not assessedApplies in principle, but no evidence was found to evaluate it.

N/ADoesn't apply to this variant type.

Applied · 4

Strength Supporting Moderate Strong Very strong

PS3 strong Pathogenic

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.

TP53 VCEP functional worksheet row for K164E: NA / Non-functional / LOF / LOF / LOF / NA / PS3.ClinVar cites the core TP53 functional studies.

PMID:12826609 ↗PMID:29979965 ↗PMID:30224644 ↗

PM2 supporting Pathogenic

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 v2.1: absent.gnomAD v4.1: 1 allele totalAF 6.195118989650434e-07.

gnomad_v2 ↗gnomad_v4 ↗cspec ↗

PP3 supporting Pathogenic

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).

TP53 VCEP PP3-BP4 spreadsheet row: c.490A>G / p.Lys164Glu / Class C55 / 0.557217 / PP3.REVEL score 0.875.SpliceAI max delta score 0.00.

spliceai ↗

PP5 supporting Pathogenic

Expert panel ClinGen TP53 Variant Curation Expert Panel, ClinGen classified as Pathogenic.

TP53 VCEP marks PP5 as not applicable.ClinVar expert panel classification

cspec ↗clinvar ↗

Assessed · not applied · 6 not met · 7 not assessed

Pathogenic

PS1 No different nucleotide change producing the same p.Lys164Glu amino acid substitution was identified in the reviewed ClinVar evidence, so PS1 is not met.

PS2 No confirmed de novo observation with the TP53 VCEP point-based case information was identified, so PS2 cannot be assessed.

PS4 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.

PM1 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.

PM5 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.

PP1 No segregation data were identified to count informative meioses, so PP1 cannot be assessed.

PP4 No qualifying low-VAF constitutional mosaic observation data were identified, so the TP53-specific PP4 rule cannot be assessed.

Benign

BA1 Available population data do not show a qualifying founder-excluded continental frequency at or above the TP53 BA1 threshold of 0.001.

BS1 Available population data do not show a qualifying founder-excluded continental frequency at or above the TP53 BS1 threshold of 0.0003.

BS2 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.

BS3 Available TP53 functional evidence does not show retained or partially retained wild-type function.

BS4 No lack-of-segregation data were identified in affected family members, so BS4 cannot be assessed.

BP4 Benign computational evidence is not supported.

N/A · 11 PVS1 · PM3 · PM4 · PM6 · PP2 · BP1 · BP2 · BP3 · BP5 · BP6 · BP7

Research & evidence

Population frequency · supports pathogenic

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 6.19512e-07; MAF= 0.00006%, 1/1614174 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 3.37815e-05; MAF= 0.00338%, 1/29602 alleles, homozygotes = 0).

v2.1

Absent from gnomAD v2.1.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

6.2e-05% · 1 / 1,614,174
0 hom

Ashkenazi Jewish

1 / 29,602

0.0034%

+ 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, African/African American, European (non-Finnish))

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant has been reported in ClinVar as Uncertain significance (3 clinical laboratories) and as Likely pathogenic (1 clinical laboratory) and as Pathogenic (1 clinical laboratory) and as Pathogenic by ClinGen TP53 Variant Curation Expert Panel, ClinGen (expert panel). (ClinVarID = 246416)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.875. BayesDel score = 0.557217.

SpliceAI ↗

Functional Likely Oncogenic

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV52728094, n = 34 times).

Hotspots

This variant lies in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Literature · how each cited paper was used

3papers cited

Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why. 3 further PMIDs triaged but not cited — see Sources & references.

Understanding the function-structure and function-mutation relationships of p53 tumor suppressor protein by high-resolution missense mutation analysis.

PMID 12826609 ↗ · Kato S et al. · 2003 Jul 8 ONCOKB · functional

Found

Structured finding pending for this record — see source link.

Applied to

→PS3 strong

A Systematic p53 Mutation Library Links Differential Functional Impact to Cancer Mutation Pattern and Evolutionary Conservation.

PMID 29979965 ↗ · Kotler E et al. · 2018 Jul 5 ONCOKB · functional

Found

Structured finding pending for this record — see source link.

Applied to

→PS3 strong

Mutational processes shape the landscape of TP53 mutations in human cancer.

PMID 30224644 ↗ · Giacomelli AO et al. · 2018 Oct ONCOKB · functional

Found

Structured finding pending for this record — see source link.

Applied to

→PS3 strong

Sources & reference links

8Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 3 PMIDs not cited in assessment

27328919 ↗ TP53 Variations in Human Cancers: New Lessons from the IARC TP53 Database and Genomics Data. ONCOKB

9699640 ↗ Molecular genetic characterization of BRCA1- and BRCA2-linked hereditary ovarian cancers. ONCOKB

28492532 ↗ Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. CLINVAR

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