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>T (p.Ala138Val)

CA000168

184863 (ClinVar)

Gene: TP53
Condition: Li-Fraumeni syndrome
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 17f94fab-129d-4993-9e05-77c0d0aaac1e
Approved on: 2025-06-05
Published on: 2025-07-18

HGVS expressions

NM_000546.6:c.413C>T
NM_000546.6(TP53):c.413C>T (p.Ala138Val)
NC_000017.11:g.7675199G>A
CM000679.2:g.7675199G>A
NC_000017.10:g.7578517G>A
CM000679.1:g.7578517G>A
NC_000017.9:g.7519242G>A
NG_017013.2:g.17352C>T
ENST00000503591.2:c.413C>T
ENST00000508793.6:c.413C>T
ENST00000509690.6:c.17C>T
ENST00000514944.6:c.134C>T
ENST00000604348.6:c.392C>T
ENST00000269305.9:c.413C>T
ENST00000269305.8:c.413C>T
ENST00000359597.8:c.413C>T
ENST00000413465.6:c.413C>T
ENST00000420246.6:c.413C>T
ENST00000445888.6:c.413C>T
ENST00000455263.6:c.413C>T
ENST00000504290.5:c.17C>T
ENST00000504937.5:c.17C>T
ENST00000505014.5:n.669C>T
ENST00000508793.5:c.413C>T
ENST00000509690.5:c.17C>T
ENST00000510385.5:c.17C>T
ENST00000514944.5:c.134C>T
ENST00000604348.5:c.392C>T
ENST00000610292.4:c.296C>T
ENST00000610538.4:c.296C>T
ENST00000610623.4:c.-65C>T
ENST00000615910.4:c.380C>T
ENST00000617185.4:c.413C>T
ENST00000618944.4:c.-65C>T
ENST00000619186.4:c.-65C>T
ENST00000619485.4:c.296C>T
ENST00000620739.4:c.296C>T
ENST00000622645.4:c.296C>T
ENST00000635293.1:c.296C>T
NM_000546.5:c.413C>T
NM_001126112.2:c.413C>T
NM_001126113.2:c.413C>T
NM_001126114.2:c.413C>T
NM_001126115.1:c.17C>T
NM_001126116.1:c.17C>T
NM_001126117.1:c.17C>T
NM_001126118.1:c.296C>T
NM_001276695.1:c.296C>T
NM_001276696.1:c.296C>T
NM_001276697.1:c.-65C>T
NM_001276698.1:c.-65C>T
NM_001276699.1:c.-65C>T
NM_001276760.1:c.296C>T
NM_001276761.1:c.296C>T
NM_001276695.2:c.296C>T
NM_001276696.2:c.296C>T
NM_001276697.2:c.-65C>T
NM_001276698.2:c.-65C>T
NM_001276699.2:c.-65C>T
NM_001276760.2:c.296C>T
NM_001276761.2:c.296C>T
NM_001126112.3:c.413C>T
NM_001126113.3:c.413C>T
NM_001126114.3:c.413C>T
NM_001126115.2:c.17C>T
NM_001126116.2:c.17C>T
NM_001126117.2:c.17C>T
NM_001126118.2:c.296C>T
NM_001276695.3:c.296C>T
NM_001276696.3:c.296C>T
NM_001276697.3:c.-65C>T
NM_001276698.3:c.-65C>T
NM_001276699.3:c.-65C>T
NM_001276760.3:c.296C>T
NM_001276761.3:c.296C>T
More

Likely Pathogenic

Met criteria codes 6
PS4_Supporting PS3_Moderate PP3 PM5_Supporting PP4_Moderate PM2_Supporting
Not Met criteria codes 19
BA1 BS2 BS4 BS3 BS1 BP2 BP3 BP4 BP1 BP5 BP7 PS2 PP1 PP2 PM3 PM1 PM4 PM6 PVS1

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>T variant in TP53 is a missense variant predicted to cause substitution of alanine by valine at amino acid 138 (p.Ala138Val). This variant has been reported in one proband/family meeting Classic criteria. Based on this evidence, this variant scores 1 total points meeting the TP53 VCEP phenotype scoring criteria of 1-1.5 points. (PS4_Supporting; PMID: 22507745). At least two individuals with this variant were found to have a variant allele fraction of 5-25%, which is a significant predictor of variant pathogenicity (PP4_Moderate, PMID: 34906512, ClinVar GTRs, Internal lab contributors). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In vitro assays performed in yeast and/or human cell lines showed partially functional transactivation and loss of growth suppression activity indicating that this variant impacts protein function (PS3_Moderate; PMIDs: 12826609, 30224644, 29979965). 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). Computational predictor scores (BayesDel = 0.5174; Align GVGD = Class 55) are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of > 15), evidence that correlates with impact to TP53 via protein change (PP3). In summary, this variant meets the criteria to be classified as likely pathogenic for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PS3_moderate, PP3, PM2_supporting, PS4_supporting, PP4_moderate, PM5_supporting. (Bayesian Points: 8; VCEP specifications version 2.3)
Met criteria codes
PS4_Supporting
This variant has been reported in one unrelated probands/families meeting Classic criteria. Based on this evidence, this variant scores 1 total points meeting the TP53 VCEP phenotype scoring criteria of 1-1.5 points. (PS4_Supporting; PMID: 22507745).
PS3_Moderate
In vitro assays performed in yeast and/or human cell lines showed partially functional transactivation and loss of growth suppression activity indicating that this variant impacts protein function (PS3_Moderate; PMIDs: 12826609, 30224644, 29979965).
PP3
Computational predictor scores (BayesDel = 0.5174; Align GVGD = Class 55) are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of > 15), evidence that correlates with impact to TP53 via protein change (PP3).
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).
PP4_Moderate
At least two individuals with this variant were found to have a variant allele fraction of 5-25%, which is a significant predictor of variant pathogenicity (PP4_Moderate, PMID: 34906512, Internal lab contributors).
PM2_Supporting
This variant is absent from gnomAD v4.1.0 (PM2_Supporting).
Not Met criteria codes
BA1
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
BS3
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
BP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
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
BP5
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
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
PM3
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
PM6
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
Curation History
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