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_000546.6(TP53):c.413C>A (p.Ala138Asp)

CA397842699

528270 (ClinVar)

Gene: TP53
Condition: Li-Fraumeni syndrome
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 13274ad3-33eb-4e3f-a51e-b8200de80394
Approved on: 2025-06-05
Published on: 2025-07-18

HGVS expressions

NM_000546.6:c.413C>A
NM_000546.6(TP53):c.413C>A (p.Ala138Asp)
NC_000017.11:g.7675199G>T
CM000679.2:g.7675199G>T
NC_000017.10:g.7578517G>T
CM000679.1:g.7578517G>T
NC_000017.9:g.7519242G>T
NG_017013.2:g.17352C>A
ENST00000503591.2:c.413C>A
ENST00000508793.6:c.413C>A
ENST00000509690.6:c.17C>A
ENST00000514944.6:c.134C>A
ENST00000604348.6:c.392C>A
ENST00000269305.9:c.413C>A
ENST00000269305.8:c.413C>A
ENST00000359597.8:c.413C>A
ENST00000413465.6:c.413C>A
ENST00000420246.6:c.413C>A
ENST00000445888.6:c.413C>A
ENST00000455263.6:c.413C>A
ENST00000504290.5:c.17C>A
ENST00000504937.5:c.17C>A
ENST00000505014.5:n.669C>A
ENST00000508793.5:c.413C>A
ENST00000509690.5:c.17C>A
ENST00000510385.5:c.17C>A
ENST00000514944.5:c.134C>A
ENST00000604348.5:c.392C>A
ENST00000610292.4:c.296C>A
ENST00000610538.4:c.296C>A
ENST00000610623.4:c.-65C>A
ENST00000615910.4:c.380C>A
ENST00000617185.4:c.413C>A
ENST00000618944.4:c.-65C>A
ENST00000619186.4:c.-65C>A
ENST00000619485.4:c.296C>A
ENST00000620739.4:c.296C>A
ENST00000622645.4:c.296C>A
ENST00000635293.1:c.296C>A
NM_000546.5:c.413C>A
NM_001126112.2:c.413C>A
NM_001126113.2:c.413C>A
NM_001126114.2:c.413C>A
NM_001126115.1:c.17C>A
NM_001126116.1:c.17C>A
NM_001126117.1:c.17C>A
NM_001126118.1:c.296C>A
NM_001276695.1:c.296C>A
NM_001276696.1:c.296C>A
NM_001276697.1:c.-65C>A
NM_001276698.1:c.-65C>A
NM_001276699.1:c.-65C>A
NM_001276760.1:c.296C>A
NM_001276761.1:c.296C>A
NM_001276695.2:c.296C>A
NM_001276696.2:c.296C>A
NM_001276697.2:c.-65C>A
NM_001276698.2:c.-65C>A
NM_001276699.2:c.-65C>A
NM_001276760.2:c.296C>A
NM_001276761.2:c.296C>A
NM_001126112.3:c.413C>A
NM_001126113.3:c.413C>A
NM_001126114.3:c.413C>A
NM_001126115.2:c.17C>A
NM_001126116.2:c.17C>A
NM_001126117.2:c.17C>A
NM_001126118.2:c.296C>A
NM_001276695.3:c.296C>A
NM_001276696.3:c.296C>A
NM_001276697.3:c.-65C>A
NM_001276698.3:c.-65C>A
NM_001276699.3:c.-65C>A
NM_001276760.3:c.296C>A
NM_001276761.3:c.296C>A
More

Uncertain Significance

Met criteria codes 4
PP3_Moderate PM2_Supporting BS3_Supporting PM5_Supporting
Not Met criteria codes 18
BP3 BP4 BP1 BP7 PS2 PS4 PS3 PS1 PP4 PP1 PP2 PM1 PM4 BA1 PVS1 BS2 BS4 BS1

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 2.3.0

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
TP53 VCEP
The NM_000546.6: c.413C>A variant in TP53 is a missense variant predicted to cause substitution of alanine by asparginine at amino acid 138 (p.Ala138Asp). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant received a total of 0.5 points across one proband. (PS4 not met; Internal lab contributor). 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 (BS3_Supporting; PMIDs: 12826609, 29979965, 30224644). Computational predictor scores (BayesDel = 0.5405; Align GVGD = Class 65) are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of 65), evidence that correlates with impact to TP53 via protein change (PP3_Moderate). Another missense variant (c.412G>C (p.Ala138Pro)) (ClinVar Variation ID: 12376), in the same codon has been classified as likely pathogenic for Li-Fraumeni syndrome by the ClinGen TP53 VCEP’s specifications (PM5_Supporting). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PM2_supporting, BS3_supporting, PP3_moderate, PM5_Supporting. (Bayesian Points: 3; VCEP specifications version 2.3)
Met criteria codes
PP3_Moderate
Computational predictor scores (BayesDel = 0.5405; Align GVGD = Class 65) are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of 65), evidence that correlates with impact to TP53 via protein change (PP3_Moderate).
PM2_Supporting
This variant is absent from gnomAD v4.1.0 (PM2_Supporting).
BS3_Supporting
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 (BS3_Supporting; PMIDs: 12826609, 29979965, 30224644).
PM5_Supporting
Another missense variant (c.412G>C (p.Ala138Pro)) (ClinVar Variation ID: 12376), in the same codon have been classified as likely pathogenic for Li-Fraumeni syndrome by the ClinGen TP53 VCEP’s specifications (PM5_Supporting).
Not Met criteria codes
BP3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP7
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
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 one proband. (PS4 not met; Internal lab contributor).
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
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
PP2
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).
PM4
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
PVS1
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
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
Curation History
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