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.472C>T (p.Arg158Cys)

CA000225

127812 (ClinVar)

Gene: TP53 (HGNC:7157)
Condition: Li-Fraumeni syndrome (MONDO:0018875)
Inheritance Mode: Autosomal dominant inheritance
UUID: e0f57545-5b3c-476f-bb86-150cbdaedf7a
Approved on: 2025-12-04
Published on: 2026-01-14

HGVS expressions

NM_000546.6(TP53):c.472C>T (p.Arg158Cys)
NM_000546.6:c.472C>T
NC_000017.11:g.7675140G>A
CM000679.2:g.7675140G>A
NC_000017.10:g.7578458G>A
CM000679.1:g.7578458G>A
NC_000017.9:g.7519183G>A
NG_017013.2:g.17411C>T
ENST00000503591.2:c.472C>T
ENST00000508793.6:c.472C>T
ENST00000509690.6:c.76C>T
ENST00000514944.6:c.193C>T
ENST00000604348.6:c.451C>T
ENST00000269305.9:c.472C>T
ENST00000269305.8:c.472C>T
ENST00000359597.8:c.472C>T
ENST00000413465.6:c.472C>T
ENST00000420246.6:c.472C>T
ENST00000445888.6:c.472C>T
ENST00000455263.6:c.472C>T
ENST00000504290.5:c.76C>T
ENST00000504937.5:c.76C>T
ENST00000505014.5:n.728C>T
ENST00000508793.5:c.472C>T
ENST00000509690.5:c.76C>T
ENST00000510385.5:c.76C>T
ENST00000514944.5:c.193C>T
ENST00000610292.4:c.355C>T
ENST00000610538.4:c.355C>T
ENST00000610623.4:c.-6C>T
ENST00000615910.4:c.439C>T
ENST00000617185.4:c.472C>T
ENST00000618944.4:c.-6C>T
ENST00000619186.4:c.-6C>T
ENST00000619485.4:c.355C>T
ENST00000620739.4:c.355C>T
ENST00000622645.4:c.355C>T
ENST00000635293.1:c.355C>T
NM_000546.5:c.472C>T
NM_001126112.2:c.472C>T
NM_001126113.2:c.472C>T
NM_001126114.2:c.472C>T
NM_001126115.1:c.76C>T
NM_001126116.1:c.76C>T
NM_001126117.1:c.76C>T
NM_001126118.1:c.355C>T
NM_001276695.1:c.355C>T
NM_001276696.1:c.355C>T
NM_001276697.1:c.-6C>T
NM_001276698.1:c.-6C>T
NM_001276699.1:c.-6C>T
NM_001276760.1:c.355C>T
NM_001276761.1:c.355C>T
NM_001276695.2:c.355C>T
NM_001276696.2:c.355C>T
NM_001276697.2:c.-6C>T
NM_001276698.2:c.-6C>T
NM_001276699.2:c.-6C>T
NM_001276760.2:c.355C>T
NM_001276761.2:c.355C>T
NM_001126112.3:c.472C>T
NM_001126113.3:c.472C>T
NM_001126114.3:c.472C>T
NM_001126115.2:c.76C>T
NM_001126116.2:c.76C>T
NM_001126117.2:c.76C>T
NM_001126118.2:c.355C>T
NM_001276695.3:c.355C>T
NM_001276696.3:c.355C>T
NM_001276697.3:c.-6C>T
NM_001276698.3:c.-6C>T
NM_001276699.3:c.-6C>T
NM_001276760.3:c.355C>T
NM_001276761.3:c.355C>T
More

Uncertain Significance

Met criteria codes 3
BS2_Supporting PM2_Supporting PP3_Moderate
Not Met criteria codes 15
PVS1 BS4 BS3 BS1 BP4 PM6 PS2 PS1 PS4 PS3 BA1 PM5 PM1 PP1 PP4

Evidence Links 4

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen TP53 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for TP53 Version 2.4.0

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
TP53 VCEP
The NM_000546.6: c.472C>T variant in TP53 is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 158 (p.Arg158Cys). This variant has been observed in 2-3 heterozygous unrelated females from the same data source with no personal history of cancer prior to age 60 years and no personal history of sarcoma at any age (BS2_Supporting; Internal lab contributor). This variant received a total of 0.5 points across 1 probands. However, PS4 cannot be applied because there there are not enough cases to reach the 1 point minimum to apply PS4_Supporting (PS4 not met; PMID 22170717). In vitro assays performed in yeast and/or human cell lines showed partially functional transactivation and retained growth suppression activity suggesting that this variant does not impact protein function; however, all assays did not agree (BS3_Supporting not met; PMIDs: 12826609, 30224644, 29979965, 39774325). This variant has an allele frequency of 0.000004337 (7/1614070 alleles) across gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00003) for PM2_Supporting and has a subpopulation allele frequency of <0.00004 in all non-bottleneck populations with 2 or more alleles present (PM2_Supporting). Computational predictor scores (BayesDel = 0.51; 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). In summary, this variant meets the criteria to be classified as variant of uncertain significance for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PP3_Moderate, BS2_Supporting, PM2_Supporting. (Bayesian Points: 2; VCEP specifications version 2.4)
Met criteria codes
BS2_Supporting
This variant has been observed in 2-3 heterozygous unrelated females from the same data source with no personal history of cancer prior to age 60 years and no personal history of sarcoma at any age (BS2_Supporting; Internal lab contributor).
PM2_Supporting
This variant has an allele frequency of 0.000004337 (7/1614070 alleles) across gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00003) for PM2_Supporting and has a subpopulation allele frequency of <0.00004 in all non-bottleneck populations with 2 or more alleles present (PM2_Supporting).
PP3_Moderate
Computational predictor scores (BayesDel = 0.51; 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).
Not Met criteria codes
PVS1
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 suggesting that this variant does not impact protein function; however, all assays did not agree (BS3_Supporting not met; PMIDs: 12826609, 30224644, 29979965, 39774325).
LOF PubMed:39774325
No LOF PubMed:29979965
Partially functional PubMed:12826609
No LOF PubMed: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
PM6
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
PS1
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 1 probands. However, PS4 cannot be applied because there there are not enough cases to reach the 1 point minimum to apply PS4_Supporting (PS4 not met; PMID 22170717).
PS3
In vitro assays performed in yeast and/or human cell lines showed partially functional transactivation and retained growth suppression activity suggesting that this variant does not impact protein function; however, all assays did not agree (BS3_Supporting not met; PMIDs: 12826609, 30224644, 29979965, 39774325).
LOF PubMed:39774325
No LOF PubMed:29979965
Partially functional PubMed:12826609
No LOF PubMed:30224644
BA1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM5
2 different missense variants(p.Arg158Leu, p.Arg158Pro) in the same codon have been classified as pathogenic for Li-Fraumeni syndrome by the ClinGen TP53 VCEP’s specifications. However, this variant does not have any applicable functional data while other residues have pathogenic functional data (PM5 Not Met).
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).
PP1
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
Curation History
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