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.460G>C (p.Gly154Arg)

CA397842125

482229 (ClinVar)

Gene: TP53
Condition: Li-Fraumeni syndrome
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: eb31ed0c-9eea-44f5-a877-6ff90b047927
Approved on: 2025-06-05
Published on: 2025-07-18

HGVS expressions

NM_000546.6:c.460G>C
NM_000546.6(TP53):c.460G>C (p.Gly154Arg)
NC_000017.11:g.7675152C>G
CM000679.2:g.7675152C>G
NC_000017.10:g.7578470C>G
CM000679.1:g.7578470C>G
NC_000017.9:g.7519195C>G
NG_017013.2:g.17399G>C
ENST00000503591.2:c.460G>C
ENST00000508793.6:c.460G>C
ENST00000509690.6:c.64G>C
ENST00000514944.6:c.181G>C
ENST00000604348.6:c.439G>C
ENST00000269305.9:c.460G>C
ENST00000269305.8:c.460G>C
ENST00000359597.8:c.460G>C
ENST00000413465.6:c.460G>C
ENST00000420246.6:c.460G>C
ENST00000445888.6:c.460G>C
ENST00000455263.6:c.460G>C
ENST00000504290.5:c.64G>C
ENST00000504937.5:c.64G>C
ENST00000505014.5:n.716G>C
ENST00000508793.5:c.460G>C
ENST00000509690.5:c.64G>C
ENST00000510385.5:c.64G>C
ENST00000514944.5:c.181G>C
ENST00000610292.4:c.343G>C
ENST00000610538.4:c.343G>C
ENST00000610623.4:c.-18G>C
ENST00000615910.4:c.427G>C
ENST00000617185.4:c.460G>C
ENST00000618944.4:c.-18G>C
ENST00000619186.4:c.-18G>C
ENST00000619485.4:c.343G>C
ENST00000620739.4:c.343G>C
ENST00000622645.4:c.343G>C
ENST00000635293.1:c.343G>C
NM_000546.5:c.460G>C
NM_001126112.2:c.460G>C
NM_001126113.2:c.460G>C
NM_001126114.2:c.460G>C
NM_001126115.1:c.64G>C
NM_001126116.1:c.64G>C
NM_001126117.1:c.64G>C
NM_001126118.1:c.343G>C
NM_001276695.1:c.343G>C
NM_001276696.1:c.343G>C
NM_001276697.1:c.-18G>C
NM_001276698.1:c.-18G>C
NM_001276699.1:c.-18G>C
NM_001276760.1:c.343G>C
NM_001276761.1:c.343G>C
NM_001276695.2:c.343G>C
NM_001276696.2:c.343G>C
NM_001276697.2:c.-18G>C
NM_001276698.2:c.-18G>C
NM_001276699.2:c.-18G>C
NM_001276760.2:c.343G>C
NM_001276761.2:c.343G>C
NM_001126112.3:c.460G>C
NM_001126113.3:c.460G>C
NM_001126114.3:c.460G>C
NM_001126115.2:c.64G>C
NM_001126116.2:c.64G>C
NM_001126117.2:c.64G>C
NM_001126118.2:c.343G>C
NM_001276695.3:c.343G>C
NM_001276696.3:c.343G>C
NM_001276697.3:c.-18G>C
NM_001276698.3:c.-18G>C
NM_001276699.3:c.-18G>C
NM_001276760.3:c.343G>C
NM_001276761.3:c.343G>C
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Uncertain Significance

Met criteria codes 2
PM2_Supporting PP3_Moderate
Not Met criteria codes 14
PM1 PM5 BA1 BS2 BS4 BS3 BS1 BP4 PS2 PS4 PS3 PS1 PP4 PP1

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.460G>C variant in TP53 is a missense variant predicted to cause substitution of Glycine by Arginine at amino acid 154 (p.Gly154Arg). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). Although this variant has been observed in germline cases, to our knowledge, this variant has not been reported in individuals meeting classical LFS or Chompret criteria (PS4 not met; Internal lab contributors). Computational predictor scores (BayesDel = 0.3308; Align GVGD = Class C65) 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). 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; however a third assay corroborating these findings was not available (BS3_Supporting not met; PMIDs: 12826609, 30224644). In summary, this variant meets the criteria to be classified as variant of uncertain clinical significance for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PP3_Moderate, PM2_Supporting. (Bayesian Points: 3; VCEP specifications version 2.3)
Met criteria codes
PM2_Supporting
This variant is absent from gnomAD v4.1.0 (PM2_Supporting)
PP3_Moderate
Computational predictor scores (BayesDel = 0.3308; Align GVGD = Class C65) 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).
Not Met criteria codes
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.460G>A (p.Gly154Ser) in the same codon has been reported (ClinVar Variation ID: 133284). However, this variant does not meet criteria for PM5 code application (PM5 not met).
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
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; however a third assay corroborating these findings was not available (BS3_Supporting not met; PMIDs: 12826609, 30224644).
BS1
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
PS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS4
Although this variant has been observed in germline cases, to our knowledge, this variant has not been reported in individuals meeting classical LFS or Chompret criteria (PS4 not met; Internal lab contributors).
PS3
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; however a third assay corroborating these findings was not available (BS3_Supporting not met; PMIDs: 12826609, 30224644).
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
Curation History
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