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_000546.5(TP53):c.1136G>A (p.Arg379His)

CA10584584

246221 (ClinVar)

Gene: TP53
Condition: Li-Fraumeni syndrome
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 9bd50b93-5f12-44c4-81f6-e1a9ced34840
Approved on: 2025-01-16
Published on: 2025-01-16

HGVS expressions

NM_000546.5:c.1136G>A
NM_000546.5(TP53):c.1136G>A (p.Arg379His)
NC_000017.11:g.7669655C>T
CM000679.2:g.7669655C>T
NC_000017.10:g.7572973C>T
CM000679.1:g.7572973C>T
NC_000017.9:g.7513698C>T
NG_017013.2:g.22896G>A
ENST00000503591.2:c.1136G>A
ENST00000508793.6:c.1136G>A
ENST00000509690.6:c.740G>A
ENST00000514944.6:c.857G>A
ENST00000604348.6:c.1115G>A
ENST00000269305.9:c.1136G>A
ENST00000269305.8:c.1136G>A
ENST00000359597.8:c.994-3411G>A
ENST00000413465.6:c.782+4526G>A
ENST00000420246.6:c.*243G>A
ENST00000445888.6:c.1136G>A
ENST00000455263.6:c.*155G>A
ENST00000504290.5:c.*155G>A
ENST00000504937.5:c.740G>A
ENST00000510385.5:c.*243G>A
ENST00000576024.1:c.89G>A
ENST00000610292.4:c.1019G>A
ENST00000610538.4:c.*155G>A
ENST00000610623.4:c.*155G>A
ENST00000615910.4:c.1103G>A
ENST00000617185.4:c.*243G>A
ENST00000618944.4:c.*243G>A
ENST00000619186.4:c.659G>A
ENST00000619485.4:c.1019G>A
ENST00000620739.4:c.1019G>A
ENST00000622645.4:c.*243G>A
ENST00000635293.1:c.983+954G>A
NM_001126112.2:c.1136G>A
NM_001126113.2:c.*155G>A
NM_001126114.2:c.*243G>A
NM_001126115.1:c.740G>A
NM_001126116.1:c.*243G>A
NM_001126117.1:c.*155G>A
NM_001126118.1:c.1019G>A
NM_001276695.1:c.*155G>A
NM_001276696.1:c.*243G>A
NM_001276697.1:c.659G>A
NM_001276698.1:c.*243G>A
NM_001276699.1:c.*155G>A
NM_001276760.1:c.1019G>A
NM_001276761.1:c.1019G>A
NM_001276695.2:c.*155G>A
NM_001276696.2:c.*243G>A
NM_001276697.2:c.659G>A
NM_001276698.2:c.*243G>A
NM_001276699.2:c.*155G>A
NM_001276760.2:c.1019G>A
NM_001276761.2:c.1019G>A
NM_000546.6:c.1136G>A
NM_001126112.3:c.1136G>A
NM_001126113.3:c.*155G>A
NM_001126114.3:c.*243G>A
NM_001126115.2:c.740G>A
NM_001126116.2:c.*243G>A
NM_001126117.2:c.*155G>A
NM_001126118.2:c.1019G>A
NM_001276695.3:c.*155G>A
NM_001276696.3:c.*243G>A
NM_001276697.3:c.659G>A
NM_001276698.3:c.*243G>A
NM_001276699.3:c.*155G>A
NM_001276760.3:c.1019G>A
NM_001276761.3:c.1019G>A
More

Likely Benign

Met criteria codes 3
PM2_Supporting BS3 BP4
Not Met criteria codes 13
PS2 PS4 PS3 PS1 BA1 PP4 PP1 PP3 PM1 PM5 BS4 BS1 BS2

Evidence Links 0

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_000546.5:c.1136G>A variant in TP53 is a missense variant predicted to cause substitution of arginine by histidine at amino acid 379 (p.Arg379His). In vitro assays performed in yeast and/or human cell lines showed functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function (BS3; PMIDs: 12826609, 29979965, 30224644). This variant has a BayesDel score ≤ -0.008 and Align GVGD (Zebrafish) is Class C0 (BP4_moderate). This variant has an allele frequency of 0.00002671 (2/74876 alleles) in the African/African American population in gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00004) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). 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: PM2_supporting, BP4_moderate, BS3. (Bayesian Points: -5; VCEP specifications version 2.0, Date of Approval: 1/16/2025).
Met criteria codes
PM2_Supporting
This variant has an allele frequency of 0.00002671 (2/74876 alleles) in the African/African American population in gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00004) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting).
BS3
In vitro assays performed in yeast and/or human cell lines showed functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function (BS3; PMIDs: 12826609, 29979965, 30224644).
BP4
BP4_MODERATE Computational predictor scores (BayesDel = -0.072; Align GVGD Class 0) 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).
Not Met criteria codes
PS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BA1
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
PP3
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
3 different missense variants (p.Arg379Leu, p.Arg379Ser, p.Arg379Cys) in the same codon have been reported. However, these variants have not yet met the criteria to be classified as pathogenic or likely pathogenic by the ClinGen TP53 VCEP’s specifications (PM5 not met).
BS4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Curation History
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