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LYFE SCIENCES
Project: HERA
NM_000546.5:c.1136G>T
p.Arg379Leu  ·  TP53
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Classification rationale
1

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.

clinvar ↗
2

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.

gnomad_v2 ↗ gnomad_v4 ↗ cspec ↗
3

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.

PMID:12826609 ↗ PMID:30224644 ↗
4

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.

spliceai ↗
Applied criteria
Met
Not met
Not assessed
N/A
Very strong
Strong
Moderate
Supporting
Pathogenic evidence
PVS
PVS1
PS
PS1
PS2
PS3
PS4
PM
PM1
PM2
PM3
PM4
PM5
PM6
PP
PP1
PP2
PP3
PP4
PP5
Benign evidence
BA
BA1
BS
BS1
BS2
BS3
BS4
BP
BP1
BP2
BP3
BP4
BP5
BP6
BP7
PVS1
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Rationale
Select a criterion to inspect its explanation.
Evidence used
  • —
Gaps remaining
  • —
Rule
—
Publications
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Research and evidence
gnomAD v2.1 evidence
v2.1
gnomAD v4.1 evidence
v4.1
01
Population
gnomAD v2.1Absent from gnomAD v2.1.
gnomAD v4.1This 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).
gnomAD v2 ↗ gnomAD v4 ↗
ClinVar evidence
02
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).
ClinVar ↗
Functional evidence
03
Functional
OncoKB: 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 ↗
In silico evidence
04
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.10). REVEL score = 0.345. BayesDel score = -0.0781755.
SpliceAI ↗
COSMIC evidence
05
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
COSMIC ↗
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant does not lie in a statistically significant hotspot.
ResidueR379
Hotspots ↗