Starting

Initialising…

TP53

Final classification

Likely Benign

TP53 c.105G>T · p.Leu35Phe

TP53

The TP53 c.105G>T (p.Leu35Phe, p.L35F) variant has been reported in ClinVar as a variant of uncertain significance by the ClinGen TP53 Variant Curation Expert Panel.

Gene

TP53

Transcript

NM_000546.5

HGVS · transcript:coding

NM_000546.5:c.105G>T

Consequence

N/A

GRCh38

chr17:7676264 C>A

GRCh37

chr17:7579582 C>A

Basis TP53 VCEP v2.4.0 Tavtigian point-based final-classification framework from the official CSPEC/VCEP ruleset ▾

TP53 VCEP v2.4.0 Tavtigian point-based final-classification framework from the official CSPEC/VCEP ruleset

Classification rationale

PM2 BS3BP4 Likely Benign

TP53 c.105G>T

The TP53 c.105G>T (p.Leu35Phe, p.L35F) variant has been reported in ClinVar as a variant of uncertain significance by the ClinGen TP53 Variant Curation Expert Panel.¹ This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting marked rarity in population databases.² In the TP53 functional evidence framework, p.L35F is listed as functional with no loss of function, supporting BS3 and arguing against PS3.³ Computational evidence does not support a damaging effect: SpliceAI predicts no splice impact with a max delta score of 0.00, BayesDel is -0.0784713, REVEL is 0.486, and the TP53 bioinformatic worksheet assigns BP4_moderate.⁴

PM2 + BS3 + BP4 → Likely Benign

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗

3 vcep_functional_worksheetvcep_flowchart_for_application_of_functional_rule_codes

4 spliceai ↗bayesdelrevelvcep_pp3_bp4_codesvcep_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 · 3 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 benign

gnomAD v4.1

gnomAD v2.1

v4.1

Absent from gnomAD v4.1.

v2.1

Absent from gnomAD v2.1.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

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 by ClinGen TP53 Variant Curation Expert Panel, ClinGen (expert panel).

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.486. BayesDel score = -0.0784713.

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. TP53, a tumor suppressor in the DNA damage pathway, is the most frequently mutated gene in cancer.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV53176324, n = 2 times).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

8Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

Cancer hotspots