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

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 · 3 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 · 3

Strength Supporting Moderate Strong Very strong

PM2 supporting Pathogenic

This variant is absent from gnomAD v2.1 and gnomAD v4.1, corresponding to an observed allele frequency of 0, which is below the TP53 VCEP PM2 threshold of less than 0.00003 overall and below the per-ancestry threshold of less than 0.00004.

Absent from gnomAD v2.1Absent from gnomAD v4.1

cspec ↗gnomad_v2 ↗gnomad_v4 ↗

BS3 strong Benign

Available TP53 functional evidence supports retained function rather than loss of function. The TP53 functional worksheet lists p.L35F as functional with no loss of function and assigns BS3.

Functional worksheet entry: L35FFunctionalnoLOF

BP4 moderate Benign

Available computational evidence supports a benign prediction under the TP53 VCEP framework. SpliceAI predicts no splice effect with a max delta score of 0.00, BayesDel is -0.0784713, which is at or below the TP53 VCEP BP4_Moderate threshold of -0.008, and the TP53 bioinformatic worksheet assigns BP4_moderate for c.105G>T. REVEL is 0.486 and does not change the TP53 VCEP-specific BP4 assignment.

SpliceAI max delta 0.00BayesDel -0.0784713REVEL 0.486

spliceai ↗

Assessed · not applied · 5 not met · 8 not assessed

Pathogenic

PS1 No reviewed evidence was identified showing that another nucleotide change causing the same amino acid substitution has already been classified as pathogenic or likely pathogenic under the TP53 VCEP framework.

PS2 No confirmed de novo occurrence with adequate parental testing and TP53 VCEP point-based scoring was identified for this variant.

PS3 Available TP53 functional evidence does not support a damaging loss-of-function effect for this variant.

PS4 The variant meets PM2_Supporting based on population rarity, but no TP53 VCEP case-point evidence was identified to show enrichment in affected individuals.

PM1 Available evidence does not support this variant as occurring in a TP53 mutational hotspot or other critical region qualifying for PM1.

PM5 No reviewed evidence was identified showing that other missense variants at codon 35 have already been classified as pathogenic or likely pathogenic under the TP53 VCEP framework at the strengths required for PM5.

PP1 No segregation data were identified for this variant, so the number of informative meioses required for TP53 VCEP PP1 scoring could not be determined.

PP3 Available computational evidence does not support a damaging prediction under the TP53 VCEP framework.

PP4 No blood variant allele fraction or mosaicism-focused clinical observations were identified to apply the TP53 VCEP PP4 rule.

Benign

BA1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, so its observed allele frequency of 0 is below the TP53 VCEP BA1 threshold of at least 0.001.

BS1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, so its observed allele frequency of 0 is below the TP53 VCEP BS1 threshold of at least 0.0003.

BS2 No source was identified showing the number of unrelated females aged 60 years or older without cancer who carry this variant, so BS2 could not be assessed.

BS4 No family data were identified showing lack of segregation with Li-Fraumeni syndrome-associated cancers, so BS4 could not be assessed.

N/A · 12 PVS1 · PM3 · PM4 · PM6 · PP2 · PP5 · BP1 · BP2 · BP3 · BP5 · BP6 · BP7

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

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