Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC computed assertion could be determined for this classification!

Variant: NM_001126112.2(TP53):c.1136G>T (p.Arg379Leu)

CA338506

216463 (ClinVar)

Gene: TP53
Condition: Li-Fraumeni syndrome
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: f9be9559-1beb-43e6-a8cf-9eefdd968ba4
Approved on: 2025-01-16
Published on: 2025-01-16

HGVS expressions

NM_001126112.2:c.1136G>T
NM_001126112.2(TP53):c.1136G>T (p.Arg379Leu)
NC_000017.11:g.7669655C>A
CM000679.2:g.7669655C>A
NC_000017.10:g.7572973C>A
CM000679.1:g.7572973C>A
NC_000017.9:g.7513698C>A
NG_017013.2:g.22896G>T
ENST00000503591.2:c.1136G>T
ENST00000508793.6:c.1136G>T
ENST00000509690.6:c.740G>T
ENST00000514944.6:c.857G>T
ENST00000604348.6:c.1115G>T
ENST00000269305.9:c.1136G>T
ENST00000269305.8:c.1136G>T
ENST00000359597.8:c.994-3411G>T
ENST00000413465.6:c.782+4526G>T
ENST00000420246.6:c.*243G>T
ENST00000445888.6:c.1136G>T
ENST00000455263.6:c.*155G>T
ENST00000504290.5:c.*155G>T
ENST00000504937.5:c.740G>T
ENST00000510385.5:c.*243G>T
ENST00000576024.1:c.89G>T
ENST00000610292.4:c.1019G>T
ENST00000610538.4:c.*155G>T
ENST00000610623.4:c.*155G>T
ENST00000615910.4:c.1103G>T
ENST00000617185.4:c.*243G>T
ENST00000618944.4:c.*243G>T
ENST00000619186.4:c.659G>T
ENST00000619485.4:c.1019G>T
ENST00000620739.4:c.1019G>T
ENST00000622645.4:c.*243G>T
ENST00000635293.1:c.983+954G>T
NM_000546.5:c.1136G>T
NM_001126113.2:c.*155G>T
NM_001126114.2:c.*243G>T
NM_001126115.1:c.740G>T
NM_001126116.1:c.*243G>T
NM_001126117.1:c.*155G>T
NM_001126118.1:c.1019G>T
NM_001276695.1:c.*155G>T
NM_001276696.1:c.*243G>T
NM_001276697.1:c.659G>T
NM_001276698.1:c.*243G>T
NM_001276699.1:c.*155G>T
NM_001276760.1:c.1019G>T
NM_001276761.1:c.1019G>T
NM_001276695.2:c.*155G>T
NM_001276696.2:c.*243G>T
NM_001276697.2:c.659G>T
NM_001276698.2:c.*243G>T
NM_001276699.2:c.*155G>T
NM_001276760.2:c.1019G>T
NM_001276761.2:c.1019G>T
NM_000546.6:c.1136G>T
NM_001126112.3:c.1136G>T
NM_001126113.3:c.*155G>T
NM_001126114.3:c.*243G>T
NM_001126115.2:c.740G>T
NM_001126116.2:c.*243G>T
NM_001126117.2:c.*155G>T
NM_001126118.2:c.1019G>T
NM_001276695.3:c.*155G>T
NM_001276696.3:c.*243G>T
NM_001276697.3:c.659G>T
NM_001276698.3:c.*243G>T
NM_001276699.3:c.*155G>T
NM_001276760.3:c.1019G>T
NM_001276761.3:c.1019G>T
More

Likely Benign

Met criteria codes 3
BP4 BS2_Supporting PM2_Supporting
Not Met criteria codes 10
BS4 BS3 PS2 PS4 PS3 PS1 PP4 PP1 PM1 PM5

Evidence Links 2

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen TP53 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for TP53 Version 2.0.0

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
TP53 VCEP
The NM_000546.6: c.1136G>T variant in TP53 is a missense variant predicted to cause substitution of arginine by leucine at amino acid 379 (p.Arg379Leu). This variant has been observed in 2-3 heterozygous unrelated females from the same data source with no personal history of cancer prior to age 60 years and no personal history of sarcoma at any age (BS2_Supporting; Internal lab contributors). This variant has an allele frequency of 0.000001859 (3/1614000 alleles) across gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00003) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). Computational predictor scores (BayesDel = -0.0781755; Align GVGD Class C0) are below the recommended thresholds (BayesDel ≤ -0.008 and an Align GVGD Class ≤ 55), evidence that does not predict a damaging effect on TP53 via protein change. SpliceAI predicts that the variant has no impact on splicing. (BP4_Moderate). In summary, this variant meets the criteria to be classified as Likely Benign for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2_Supporting, PM2_Supporting, BP4_Moderate. (Bayesian Points: -2; VCEP specifications version 2.0; 1/16/2025)
Met criteria codes
BP4
BP4_MODERATE Computational predictor scores (BayesDel = -0.0781755; Align GVGD Class C0) are below the recommended thresholds (BayesDel ≤ -0.008 and an Align GVGD Class ≤ 55), evidence that does not predict a damaging effect on TP53 via protein change. SpliceAI predicts that the variant has no impact on splicing. (BP4_Moderate).
BS2_Supporting
This variant has been observed in 2-3 heterozygous unrelated females from the same data source with no personal history of cancer prior to age 60 years and no personal history of sarcoma at any age (BS2_Supporting; Internal lab contributors).
PM2_Supporting
This variant has an allele frequency of 0.000001859 (3/1614000 alleles) across gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00003) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting).
Not Met criteria codes
BS4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS3
In vitro assays performed in yeast and/or human cell lines showed partially functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function; however a third assay corroborating these findings was not available (BS3 not met; PMIDs: 12826609, 30224644).
noDNE+noLOF PubMed:30224644
partially functional PubMed:12826609
PS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS4
This variant received a total of 0.5 points across 1 proband. (PS4 not met; Internal lab contributor: Invitae).
PS3
In vitro assays performed in yeast and/or human cell lines showed partially functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function; however a third assay corroborating these findings was not available (BS3 not met; PMIDs: 12826609, 30224644).
noDNE+noLOF PubMed:30224644
partially functional PubMed:12826609
PS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM1
This variant does not reside within a region of TP53 that is defined as a mutational hotspot by the ClinGen TP53 VCEP (PM1 not met).
PM5
2 different missense variants (p.Arg379His and p.Arg379Ser are classified as Likely Benign by the TP53 VCEP). Another missense variant (c.1135C>T, p.Arg379Cys) in the same codon has been reported (ClinVar Variation ID: 186611). However, the variants have not yet been curated to determine if they would be classified as pathogenic or likely pathogenic by the ClinGen TP53 VCEP’s specifications (PM5 not evaluated).
Curation History
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