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.412G>A (p.Ala138Thr)

CA397842713

1053218 (ClinVar)

Gene: TP53
Condition: Li-Fraumeni syndrome
Inheritance Mode: Autosomal dominant inheritance
UUID: 5cd32b5f-8df0-4db8-9bce-d67d3859a287
Approved on: 2025-06-05
Published on: 2025-07-18

HGVS expressions

NM_000546.6:c.412G>A
NM_000546.6(TP53):c.412G>A (p.Ala138Thr)
NC_000017.11:g.7675200C>T
CM000679.2:g.7675200C>T
NC_000017.10:g.7578518C>T
CM000679.1:g.7578518C>T
NC_000017.9:g.7519243C>T
NG_017013.2:g.17351G>A
ENST00000503591.2:c.412G>A
ENST00000508793.6:c.412G>A
ENST00000509690.6:c.16G>A
ENST00000514944.6:c.133G>A
ENST00000604348.6:c.391G>A
ENST00000269305.9:c.412G>A
ENST00000269305.8:c.412G>A
ENST00000359597.8:c.412G>A
ENST00000413465.6:c.412G>A
ENST00000420246.6:c.412G>A
ENST00000445888.6:c.412G>A
ENST00000455263.6:c.412G>A
ENST00000504290.5:c.16G>A
ENST00000504937.5:c.16G>A
ENST00000505014.5:n.668G>A
ENST00000508793.5:c.412G>A
ENST00000509690.5:c.16G>A
ENST00000510385.5:c.16G>A
ENST00000514944.5:c.133G>A
ENST00000604348.5:c.391G>A
ENST00000610292.4:c.295G>A
ENST00000610538.4:c.295G>A
ENST00000610623.4:c.-66G>A
ENST00000615910.4:c.379G>A
ENST00000617185.4:c.412G>A
ENST00000618944.4:c.-66G>A
ENST00000619186.4:c.-66G>A
ENST00000619485.4:c.295G>A
ENST00000620739.4:c.295G>A
ENST00000622645.4:c.295G>A
ENST00000635293.1:c.295G>A
NM_000546.5:c.412G>A
NM_001126112.2:c.412G>A
NM_001126113.2:c.412G>A
NM_001126114.2:c.412G>A
NM_001126115.1:c.16G>A
NM_001126116.1:c.16G>A
NM_001126117.1:c.16G>A
NM_001126118.1:c.295G>A
NM_001276695.1:c.295G>A
NM_001276696.1:c.295G>A
NM_001276697.1:c.-66G>A
NM_001276698.1:c.-66G>A
NM_001276699.1:c.-66G>A
NM_001276760.1:c.295G>A
NM_001276761.1:c.295G>A
NM_001276695.2:c.295G>A
NM_001276696.2:c.295G>A
NM_001276697.2:c.-66G>A
NM_001276698.2:c.-66G>A
NM_001276699.2:c.-66G>A
NM_001276760.2:c.295G>A
NM_001276761.2:c.295G>A
NM_001126112.3:c.412G>A
NM_001126113.3:c.412G>A
NM_001126114.3:c.412G>A
NM_001126115.2:c.16G>A
NM_001126116.2:c.16G>A
NM_001126117.2:c.16G>A
NM_001126118.2:c.295G>A
NM_001276695.3:c.295G>A
NM_001276696.3:c.295G>A
NM_001276697.3:c.-66G>A
NM_001276698.3:c.-66G>A
NM_001276699.3:c.-66G>A
NM_001276760.3:c.295G>A
NM_001276761.3:c.295G>A
More

Uncertain Significance

Met criteria codes 5
PM5_Supporting BS3_Supporting PM2_Supporting PP4 PP3
Not Met criteria codes 21
PM3 PM1 PM4 PM6 BS2 BS4 BS1 PVS1 PS1 PS2 PS4 PS3 BP2 BP3 BP4 BP1 BP5 BP7 BA1 PP1 PP2

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.412G>A variant in TP53 is a missense variant predicted to cause substitution of alanine by threonine at amino acid 138 (p.Ala138Thr). To our knowledge, this variant has not been reported in individuals meeting classical LFS or Chompret criteria (PS4 not met). 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 retained growth suppression activity indicating that this variant does not impact protein function (BS3_Supporting; PMIDs: 12826609, 29979965, 30224644, [16007150]). Computational predictor scores (BayesDel = 0.4548; 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). 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). At least one individual with this variant was found to have a variant allele fraction of 5-35%, which is a significant predictor of variant pathogenicity (PP4, PMID: 34906512, Internal lab contributor). In summary, this variant meets the criteria to be classified as of uncertain significance for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS3_supporting, PP3, PM2_supporting, PM5_supporting, PP4. (Bayesian Points: 3; VCEP specifications version 2.3)
Met criteria codes
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).
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, [16007150]).
PM2_Supporting
This variant is absent from gnomAD v4.1.0 (PM2_Supporting).
PP4
At least one individual with this variant was found to have a variant allele fraction of 5-35%, which is a significant predictor of variant pathogenicity (PP4, PMID: 34906512, ClinVar GTRs, Internal lab contributors).
PP3
Computational predictor scores (BayesDel = 0.4548; 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).
Not Met criteria codes
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
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
PVS1
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
PS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS4
To our knowledge, this variant has not been reported in individuals meeting classical LFS or Chompret criteria (PS4 not met).
PS3
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
BA1
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
Curation History
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