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.144C>A (p.Asp48Glu)

CA000055

141056 (ClinVar)

Gene: TP53
Condition: Li-Fraumeni syndrome
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: a73c7ac4-5d9a-4c83-8aab-e4fea34cea32
Approved on: 2025-01-16
Published on: 2025-01-16

HGVS expressions

NM_000546.5:c.144C>A
NM_000546.5(TP53):c.144C>A (p.Asp48Glu)
NC_000017.11:g.7676225G>T
CM000679.2:g.7676225G>T
NC_000017.10:g.7579543G>T
CM000679.1:g.7579543G>T
NC_000017.9:g.7520268G>T
NG_017013.2:g.16326C>A
ENST00000503591.2:c.144C>A
ENST00000508793.6:c.144C>A
ENST00000509690.6:c.-21-989C>A
ENST00000514944.6:c.96+157C>A
ENST00000604348.6:c.144C>A
ENST00000269305.9:c.144C>A
ENST00000269305.8:c.144C>A
ENST00000359597.8:c.144C>A
ENST00000413465.6:c.144C>A
ENST00000420246.6:c.144C>A
ENST00000445888.6:c.144C>A
ENST00000455263.6:c.144C>A
ENST00000503591.1:c.144C>A
ENST00000505014.5:n.400C>A
ENST00000508793.5:c.144C>A
ENST00000509690.5:c.-21-989C>A
ENST00000514944.5:c.96+157C>A
ENST00000604348.5:c.144C>A
ENST00000610292.4:c.27C>A
ENST00000610538.4:c.27C>A
ENST00000615910.4:c.144C>A
ENST00000617185.4:c.144C>A
ENST00000619485.4:c.27C>A
ENST00000620739.4:c.27C>A
ENST00000622645.4:c.27C>A
ENST00000635293.1:c.27C>A
NM_001126112.2:c.144C>A
NM_001126113.2:c.144C>A
NM_001126114.2:c.144C>A
NM_001126118.1:c.27C>A
NM_001276695.1:c.27C>A
NM_001276696.1:c.27C>A
NM_001276760.1:c.27C>A
NM_001276761.1:c.27C>A
NM_001276695.2:c.27C>A
NM_001276696.2:c.27C>A
NM_001276760.2:c.27C>A
NM_001276761.2:c.27C>A
NM_000546.6:c.144C>A
NM_001126112.3:c.144C>A
NM_001126113.3:c.144C>A
NM_001126114.3:c.144C>A
NM_001126118.2:c.27C>A
NM_001276695.3:c.27C>A
NM_001276696.3:c.27C>A
NM_001276760.3:c.27C>A
NM_001276761.3:c.27C>A
More

Likely Benign

Met criteria codes 3
PM2_Supporting BS3 BP4
Not Met criteria codes 15
PS2 PS4 PS3 PS1 BA1 PP4 PP1 PP3 PM1 PM5 PM6 BS2 BS4 BS1 BP2

Evidence Links 3

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.144C>A variant in TP53 is a missense variant predicted to cause substitution of aspartic acid by glutamic acid at amino acid 48 (p.Asp48Glu). This variant has an allele frequency of 0.000001695 (2/1180034 alleles) in the European (non-Finnish) 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 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). Computational predictor scores (BayesDel = -0.224; 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: BS3, BP4_Moderate, PM2_Supporting. (Bayesian Points: -5; VCEP specifications version 2.0; 1/16/2025).
Met criteria codes
PM2_Supporting
This variant has an allele frequency of 0.000001695 (2/1180034 alleles) in the European (non-Finnish) 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).
noLOF PubMed:12826609
Non-functional PubMed:30224644
N/A PubMed:29979965
BP4
BP4_MODERATE Computational predictor scores (BayesDel = -0.224; 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).
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 literature. Did not request internal lab data.
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 literature. Did not request internal lab data.
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
Another missense variant(c.143A>G, p.aAsp8Gly) in the same codon has been reported (ClinVar Variation ID: 2795844). However, this variant has not yet met the criteria to be classified as pathogenic or likely pathogenic by the ClinGen TP53 VCEP’s specifications (PM5 not met).
PM6
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS2
No literature. Did not request internal lab data.
BS4
No literature. Did not request internal lab data.
BS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Curation History
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