The TP53 c.1136G>T (p.Arg379Leu) variant has been reported in ClinVar, where the ClinGen TP53 Variant Curation Expert Panel classifies it as Likely Benign, although additional clinical laboratory submissions are uncertain.1 This variant is absent from gnomAD v2.1 and is present at very low frequency in gnomAD v4.1 (3/1614000 alleles; AF 1.85874e-06), supporting PM2_Supporting and arguing against BS1 or BA1.2 In the TP53 VCEP functional worksheet, p.Arg379Leu is recorded as partially functional in Kato-class data and noLOF in Giacomelli-class data, with a preassigned interpretation of no functional evidence, so PS3 and BS3 are not supported.3 TP53-specific in silico assessment lists c.1136G>T as Class C0 with BayesDel -0.0781755 and BP4_moderate, SpliceAI predicts no significant splice impact with max delta score 0.10, and the available REVEL score is 0.345; together these data support BP4_Moderate rather than PP3.4
Final classification
VUS
PM2BP4BP6
TP53
c.1136G>T
p.Arg379Leu
This variant
The TP53 c.1136G>T (p.Arg379Leu) variant has been reported in ClinVar, where the ClinGen TP53 Variant Curation Expert Panel classifies it as Likely Benign, although additional clinical laboratory submissions are uncertain.
Tavtigian et.al., 2020 - Bayesian adaptation of Richards et.al., 2015 v2.4.0 point-based framework: PM2 supporting (+1) + BP4 moderate (-2) = -1 points, which maps to VUS.
Classification rationale
PM2
BP4BP6
VUS
TP53 c.1136G>T
PM2 + BP4 + BP6
→
VUS
3
vcep_functional_worksheetvcep_flowchart_for_application_of_functional_rule_codesPMID:12826609 ↗PMID:30224644 ↗
4
vcep_pp3_bp4_codesvcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7bayesdelspliceai ↗revel
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 · 14 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 is extremely rare in gnomAD v4.1, with total AF 1.85874e-06, which is below the TP53 PM2 threshold of 0.00003. Although 2 alleles were observed in the Remaining group, that group frequency was 3.19969e-05, which is below the multiple-allele threshold of 0.00004.
gnomAD v2.1: absent.gnomAD v4.1: 3/1614000 allelestotal AF 1.858736059479554e-06
BP4
moderate
Benign
Computational evidence supports a benign effect under the TP53 VCEP rule set. The TP53 in silico worksheet lists c.1136G>T (p.Arg379Leu) as Class C0 with BayesDel -0.0781755 and a preassigned BP4_moderate call, and SpliceAI predicts no significant splice impact with max delta score 0.10, which is below the no-splice-impact threshold of 0.2. REVEL was 0.345 and does not override the TP53 VCEP-specific assignment.
PP3-BP4 worksheet row: c.1136G>T / p.Arg379Leu / Class C0 / BayesDel -0.0781755 / BP4_moderate / SpliceAI 0.1.SpliceAI max delta score: 0.10.REVEL score: 0.345.
Assessed · not applied
· 6 not met · 8 not assessed
Pathogenic
PS1
No reviewed evidence was identified showing that another nucleotide change causing the same TP53 p.Arg379Leu amino acid substitution has already been classified as Pathogenic or Likely Pathogenic under the TP53 VCEP framework.
PS2
No confirmed de novo occurrence data with parental confirmation were identified, so PS2 cannot be assessed from the available evidence.
PS3
Available TP53 functional evidence does not show the level of loss of function required for PS3.
PS4
No proband-count or case-enrichment evidence was identified that would allow scoring this variant under the TP53 PS4 point system.
PM1
Available hotspot evidence does not support PM1.
PM5
No reviewed evidence was identified showing that other missense variants at codon 379 have already been classified as Pathogenic or Likely Pathogenic under the TP53 VCEP framework, so PM5 could not be assessed from the available materials.
PP1
No segregation data were identified to show cosegregation with Li-Fraumeni syndrome-associated cancers, so PP1 cannot be assessed.
PP3
Available computational evidence does not meet the TP53 PP3 thresholds.
PP4
No phenotype-specific evidence, blood variant allele fraction data, or repeated low-level observations were identified to support TP53 PP4.
Benign
BA1
Population frequency does not meet the TP53 BA1 threshold.
BS1
Population frequency does not meet the TP53 BS1 threshold.
BS2
No single-source dataset of unaffected older female carriers was identified, so BS2 cannot be assessed.
BS3
Available TP53 functional evidence does not support BS3.
BS4
No nonsegregation data were identified in affected relatives with Li-Fraumeni syndrome-associated cancers, so BS4 cannot be assessed.
N/A · 11
PVS1 · PM3 · PM4 · PM6 · PP2 · PP5 · BP1 · BP2 · BP3 · BP5 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 1.85874e-06; MAF= 0.00019%, 3/1614000 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 3.19969e-05; MAF= 0.00320%, 2/62506 alleles, homozygotes = 0).
v2.1
Absent from gnomAD v2.1.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.00019%
· 3 / 1,614,000
0 hom
0 hom
Remaining individuals 2 / 62,506 |
0.0032% |
East Asian 1 / 44,876 |
0.0022% |
+ 8 not observed (Admixed American, European (Finnish), Amish, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American, European (non-Finnish))
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (7 clinical laboratories) and as Likely Benign by ClinGen TP53 Variant Curation Expert Panel, ClinGen (expert panel).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.10). REVEL score = 0.345. BayesDel score = -0.0781755.
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.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links