Starting

Initialising…

TP53

Final classification

Likely Pathogenic

TP53 c.490A>G · p.Lys164Glu

TP53

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.

Gene

TP53

Transcript

NM_000546.5

HGVS · transcript:coding

NM_000546.5:c.490A>G

Consequence

N/A

GRCh38

chr17:7675122 T>C

GRCh37

chr17:7578440 T>C

Basis 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. ▾

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

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

TP53 NM_000546.5

Fetching transcript structure from UCSC…

Applied criteria · 4 met · select any tile

Met

Not met

Not assessed

N/A

Strength very strong supporting

Pathogenic evidence

PVS

Benign evidence

—

Rationale

Select a criterion.

Sources

Evidence used

Gaps remaining

Rule

—

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. 6 further PMIDs triaged but not cited — see Sources & References.

PMID PMID:12826609

PMID PMID:12826609 ↗

Found

Structured finding pending for this record — see source link.

Applied to

→PS3 supports · met

PMID PMID:29979965

PMID PMID:29979965 ↗

Found

Structured finding pending for this record — see source link.

Applied to

→PS3 supports · met

PMID PMID:30224644

PMID PMID:30224644 ↗

Found

Structured finding pending for this record — see source link.

Applied to

→PS3 supports · met

Sources & reference links

8Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 6 PMIDs not cited in assessment

12826609 ↗ Understanding the function-structure and function-mutation relationships of p53 tumor suppressor protein by high-resolution missense mutation analysis. ONCOKB

29979965 ↗ A Systematic p53 Mutation Library Links Differential Functional Impact to Cancer Mutation Pattern and Evolutionary Conservation. ONCOKB

30224644 ↗ Mutational processes shape the landscape of TP53 mutations in human cancer. ONCOKB

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