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
TP53
Final classification
VUS
TP53 c.1136G>T · p.Arg379Leu
TP53
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
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
PS
PM
PP
Benign evidence
BA
BS
BP
—
—
—
Rationale
Select a criterion.
Sources
Evidence used
Gaps remaining
Rule
—
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