0%
TP53c.105G>TLikely benign
Print report
Variant interpretation report

TP53 c.105G>T, p.(Leu35Phe)

NM_000546.5:c.105G>T NP_000537.3:p.(Leu35Phe) View identifiers
Classification
Likely benign

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is likely benign. Select a step to read what it means.

Likely benign.A likely benign classification under the recorded framework.

In plain language

Gene-level background from the recorded interpretation.

About TP53

No gene-level summary was recorded for this case.

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.
01The reasoning

How it was classified

The recorded framework is ClinGen TP53 VCEP v2.4.0. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 1 Benign evidence criteria: 2
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting

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.

Benign criteria applied · 2
BS3Strong
BS3 · strong

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.

BP4Moderate
BP4 · moderate

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.

Recorded classification: Likely benign

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

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

No screenshot for this evidence
Computational predictions
Not recorded

No SpliceAI or REVEL score is recorded in the fields used for this tile.

Applied · BP4 →
ClinVar submissions
Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only ClinVar ↗
Functional evidence
Statement recorded

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.

Applied · BS3 → OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
Not assessed

No COSMIC evidence statement is recorded in this case.

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

ACMG/AMP criteria under ClinGen TP53 VCEP v2.4.0, with the data and sources behind each one.

28 criteria with recorded statuses: 3 met · 5 not met · 8 not assessed · 12 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

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.

This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting marked rarity in population databases.

In the TP53 functional evidence framework, p.L35F is listed as functional with no loss of function, supporting BS3 and arguing against PS3.

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.

Met · 3

PM2 SupportingThis 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. Details ▾Hide ▴
Rule
PM2_Supporting: allele frequency <0.00003 overall; if multiple alleles in a population, <0.00004 in that ancestry group.
Evidence considered
  • Absent from gnomAD v2.1
  • Absent from gnomAD v4.1
Sources
cspec ↗gnomad_v2 ↗gnomad_v4 ↗
BS3 StrongAvailable 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. Details ▾Hide ▴
Rule
BS3 applies when TP53 functional evidence shows retained function according to the VCEP framework.
Evidence considered
  • Functional worksheet entry: L35F
  • Functional
  • noLOF
  • Assigned BS3
Sources
vcep_functional_worksheetvcep_flowchart_for_application_of_functional_rule_codes
BP4 ModerateAvailable 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. Details ▾Hide ▴
Rule
BP4_Moderate for missense variants: BayesDel <=-0.008 and no predicted splicing effect with SpliceAI <0.2.
Evidence considered
  • SpliceAI max delta 0.00
  • BayesDel -0.0784713
  • REVEL 0.486
  • TP53 VCEP assignment BP4_moderate
Sources
spliceai ↗bayesdelrevelvcep_pp3_bp4_codesvcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7

Not met · 5 · evaluated, threshold not reached

PS3 Available TP53 functional evidence does not support a damaging loss-of-function effect for this variant. The TP53 functional worksheet lists p.L35F as functional with no loss of function and assigns BS3 rather than PS3. Details ▾Hide ▴
Rule
PS3 requires non-functional or partially functional results meeting TP53 VCEP assay thresholds.
Evidence considered
  • Functional worksheet entry: L35F
  • Functional
  • noLOF
  • Assigned BS3
Sources
vcep_functional_worksheetvcep_flowchart_for_application_of_functional_rule_codes
PM1 Available evidence does not support this variant as occurring in a TP53 mutational hotspot or other critical region qualifying for PM1. Cancer Hotspots did not identify a statistically significant hotspot for this variant, and no residue-level hotspot evidence meeting TP53 VCEP thresholds was identified. Details ▾Hide ▴
Rule
TP53 VCEP PM1 requires canonical hotspot codons or qualifying Cancer Hotspots recurrence.
Evidence considered
  • Cancer Hotspots not significant for L35F
Still missing
  • Cancer Hotspots review was flagged for human review.
  • No qualifying hotspot count for this exact amino acid change was identified.
Sources
cspec ↗hotspots ↗
PP3 Available computational evidence does not support a damaging prediction under the TP53 VCEP framework. SpliceAI predicts no splice effect with a max delta score of 0.00, BayesDel is -0.0784713, and the TP53 VCEP bioinformatic worksheet assigns BP4_moderate rather than PP3 for c.105G>T. REVEL is 0.486, but this does not override the TP53 VCEP-specific in silico assignment. Details ▾Hide ▴
Rule
TP53 VCEP PP3 for missense variants requires qualifying BayesDel/aGVGD evidence or SpliceAI >=0.2 for splice effect.
Evidence considered
  • SpliceAI max delta 0.00
  • BayesDel -0.0784713
  • REVEL 0.486
  • TP53 VCEP assignment BP4_moderate
Sources
spliceai ↗bayesdelrevelvcep_pp3_bp4_codesvcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7
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. Details ▾Hide ▴
Rule
BA1 requires filtering allele frequency >=0.001 in an eligible ancestry group.
Evidence considered
  • Absent from gnomAD v2.1
  • Absent from gnomAD v4.1
Sources
cspec ↗gnomad_v2 ↗gnomad_v4 ↗
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. Details ▾Hide ▴
Rule
BS1 requires filtering allele frequency >=0.0003 and <0.001 in an eligible ancestry group.
Evidence considered
  • Absent from gnomAD v2.1
  • Absent from gnomAD v4.1
Sources
cspec ↗gnomad_v2 ↗gnomad_v4 ↗

Not assessed · 8 · no assessment recorded

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. Details ▾Hide ▴
Evidence considered
  • TP53 VCEP PS1 rule requires prior TP53 VCEP pathogenic or likely pathogenic assertion for the same amino acid change
Still missing
  • No same-amino-acid TP53 VCEP pathogenic comparison variant was identified.
Sources
cspec ↗clinvar ↗
PS2 No confirmed de novo occurrence with adequate parental testing and TP53 VCEP point-based scoring was identified for this variant. Details ▾Hide ▴
Evidence considered
  • TP53 VCEP PS2 point framework
Still missing
  • No maternity/paternity-confirmed de novo case was identified.
  • No PS2 point total could be established.
Sources
cspec ↗vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
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. No proband point total could be established for PS4. Details ▾Hide ▴
Evidence considered
  • PM2 prerequisite satisfied by absence from gnomAD
  • No PS4 point evidence identified
Still missing
  • No germline case series or point-scored proband data were identified.
Sources
cspec ↗gnomad_v2 ↗gnomad_v4 ↗vcep_ps4_points_table
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. Details ▾Hide ▴
Evidence considered
  • TP53 VCEP PM5 requires prior TP53 VCEP-classified missense variants at the same residue
Still missing
  • No codon 35 TP53 VCEP pathogenic comparator variants were identified.
Sources
cspec ↗clinvar ↗
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. Details ▾Hide ▴
Evidence considered
  • TP53 VCEP PP1 meiosis thresholds
Still missing
  • No pedigree or meiosis count was identified.
Sources
cspec ↗vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
PP4 No blood variant allele fraction or mosaicism-focused clinical observations were identified to apply the TP53 VCEP PP4 rule. Details ▾Hide ▴
Evidence considered
  • TP53 VCEP PP4 requires blood VAF-based observations
Still missing
  • No VAF-based constitutional mosaicism evidence was identified.
Sources
cspec ↗
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. Details ▾Hide ▴
Evidence considered
  • TP53 VCEP BS2 unaffected carrier thresholds
Still missing
  • No qualifying unaffected carrier count from a single source was identified.
Sources
cspec ↗
BS4 No family data were identified showing lack of segregation with Li-Fraumeni syndrome-associated cancers, so BS4 could not be assessed. Details ▾Hide ▴
Evidence considered
  • TP53 VCEP BS4 requires lack of segregation in affected relatives
Still missing
  • No non-segregation data were identified.
Sources
cspec ↗vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
Not applicable · 12· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a missense variant in TP53, not a nonsense, frameshift, or canonical splice-site variant. SpliceAI predicts no splice effect with a max delta score of 0.00, and the variant-level PVS1 scaffold states that it does not fall into the default null-variant buckets for PVS1 application. Details ▾Hide ▴
Rule
TP53 VCEP PVS1 flowchart applies to null variants and qualifying splice variants, not this missense change.
Evidence considered
  • Missense consequence p.Leu35Phe
  • SpliceAI max delta 0.00
  • TP53-specific PVS1 framework
Sources
spliceai ↗pvs1_gene_contextpvs1_variant_assessmentvcep_pvs1_flowchart
PM3 N/APM3 is not used in the TP53 VCEP framework. Details ▾Hide ▴
Rule
Not applicable in TP53 VCEP.
Evidence considered
  • TP53 VCEP marks PM3 not applicable
Sources
cspec ↗
PM4 N/APM4 is not used for this missense variant in the TP53 VCEP framework. Details ▾Hide ▴
Rule
Not applicable in TP53 VCEP for this variant type.
Evidence considered
  • TP53 VCEP marks PM4 not applicable
Sources
cspec ↗
PM6 N/APM6 is not used in the TP53 VCEP framework. Details ▾Hide ▴
Rule
Not applicable in TP53 VCEP.
Evidence considered
  • TP53 VCEP marks PM6 not applicable
Sources
cspec ↗
PP2 N/APP2 is not used in the TP53 VCEP framework. Details ▾Hide ▴
Rule
Not applicable in TP53 VCEP.
Evidence considered
  • TP53 VCEP marks PP2 not applicable
Sources
cspec ↗
PP5 N/APP5 is not used in the TP53 VCEP framework. Details ▾Hide ▴
Rule
Not applicable in TP53 VCEP.
Evidence considered
  • TP53 VCEP marks PP5 not applicable
Sources
cspec ↗
BP1 N/ABP1 is not used in the TP53 VCEP framework. Details ▾Hide ▴
Rule
Not applicable in TP53 VCEP.
Evidence considered
  • TP53 VCEP marks BP1 not applicable
Sources
cspec ↗
BP2 N/ABP2 is not used in the TP53 VCEP framework. Details ▾Hide ▴
Rule
Not applicable in TP53 VCEP.
Evidence considered
  • TP53 VCEP marks BP2 not applicable
Sources
cspec ↗
BP3 N/ABP3 is not used in the TP53 VCEP framework. Details ▾Hide ▴
Rule
Not applicable in TP53 VCEP.
Evidence considered
  • TP53 VCEP marks BP3 not applicable
Sources
cspec ↗
BP5 N/ABP5 is not used in the TP53 VCEP framework. Details ▾Hide ▴
Rule
Not applicable in TP53 VCEP.
Evidence considered
  • TP53 VCEP marks BP5 not applicable
Sources
cspec ↗
BP6 N/ABP6 is not used in the TP53 VCEP framework. Details ▾Hide ▴
Rule
Not applicable in TP53 VCEP.
Evidence considered
  • TP53 VCEP marks BP6 not applicable
Sources
cspec ↗
BP7 N/ABP7 applies to synonymous or qualifying intronic variants, not to this missense variant. Details ▾Hide ▴
Rule
BP7 is for synonymous or qualifying intronic variants.
Evidence considered
  • Missense consequence p.Leu35Phe
Sources
cspec ↗vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7

Identifiers

Gene
TP53
Transcript
NM_000546.5
Coding (HGVS c.)
NM_000546.5:c.105G>T
Protein (HGVS p.)
NP_000537.3:p.(Leu35Phe)
GRCh38
chr17:7676264 C>A
GRCh37
chr17:7579582 C>A

Gene diagram

Every interpreted variant in TP53, mapped onto the exon structure of NM_000546.5. Select a row to find it on the plot.

TP53NM_000546.5
Fetching transcript structure from UCSC…
gnomAD v4.1 Allele count data not recorded
gnomAD v2.1 Allele count data not recorded

Statements

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

Other predictors

REVEL
Not available
BayesDel
Not available

How the predictions were used

BP4 ModerateAvailable 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. Details ▾Hide ▴
Rule
BP4_Moderate for missense variants: BayesDel <=-0.008 and no predicted splicing effect with SpliceAI <0.2.
Evidence considered
  • SpliceAI max delta 0.00
  • BayesDel -0.0784713
  • REVEL 0.486
  • TP53 VCEP assignment BP4_moderate
Sources
spliceai ↗bayesdelrevelvcep_pp3_bp4_codesvcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7
PP3 Available computational evidence does not support a damaging prediction under the TP53 VCEP framework. SpliceAI predicts no splice effect with a max delta score of 0.00, BayesDel is -0.0784713, and the TP53 VCEP bioinformatic worksheet assigns BP4_moderate rather than PP3 for c.105G>T. REVEL is 0.486, but this does not override the TP53 VCEP-specific in silico assignment. Details ▾Hide ▴
Rule
TP53 VCEP PP3 for missense variants requires qualifying BayesDel/aGVGD evidence or SpliceAI >=0.2 for splice effect.
Evidence considered
  • SpliceAI max delta 0.00
  • BayesDel -0.0784713
  • REVEL 0.486
  • TP53 VCEP assignment BP4_moderate
Sources
spliceai ↗bayesdelrevelvcep_pp3_bp4_codesvcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7
BP7 N/ABP7 applies to synonymous or qualifying intronic variants, not to this missense variant. Details ▾Hide ▴
Rule
BP7 is for synonymous or qualifying intronic variants.
Evidence considered
  • Missense consequence p.Leu35Phe
Sources
cspec ↗vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7

Statement

In silico

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

0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 Captured gnomAD v4.1 source record Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Captured SpliceAI source record Open source ↗
ClinVar Captured ClinVar source record Open source ↗
COSMIC Captured COSMIC source record Open source ↗
Cancer hotspots Captured Cancer Hotspots source record Open source ↗
OncoKB Captured OncoKB source record Open source ↗
ClinGen CSpec Captured ClinGen CSpec source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

ClinVar

This variant has been reported in ClinVar as Uncertain Significance by ClinGen TP53 Variant Curation Expert Panel, ClinGen (expert panel).

In silico

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

Functional

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.

Somatic

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

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.