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.523C>T (p.Arg175Cys)

CA002442

245851 (ClinVar)

Gene: TP53
Condition: Li-Fraumeni syndrome
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 3699ed0e-e5f6-4457-bee4-961ef507dd2c
Approved on: 2025-01-16
Published on: 2025-01-16

HGVS expressions

NM_000546.6:c.523C>T
NM_000546.6(TP53):c.523C>T (p.Arg175Cys)
NC_000017.11:g.7675089G>A
CM000679.2:g.7675089G>A
NC_000017.10:g.7578407G>A
CM000679.1:g.7578407G>A
NC_000017.9:g.7519132G>A
NG_017013.2:g.17462C>T
ENST00000503591.2:c.523C>T
ENST00000508793.6:c.523C>T
ENST00000509690.6:c.127C>T
ENST00000514944.6:c.244C>T
ENST00000604348.6:c.502C>T
ENST00000269305.9:c.523C>T
ENST00000269305.8:c.523C>T
ENST00000359597.8:c.523C>T
ENST00000413465.6:c.523C>T
ENST00000420246.6:c.523C>T
ENST00000445888.6:c.523C>T
ENST00000455263.6:c.523C>T
ENST00000504290.5:c.127C>T
ENST00000504937.5:c.127C>T
ENST00000505014.5:n.779C>T
ENST00000509690.5:c.127C>T
ENST00000510385.5:c.127C>T
ENST00000514944.5:c.244C>T
ENST00000574684.1:n.31C>T
ENST00000610292.4:c.406C>T
ENST00000610538.4:c.406C>T
ENST00000610623.4:c.46C>T
ENST00000615910.4:c.490C>T
ENST00000617185.4:c.523C>T
ENST00000618944.4:c.46C>T
ENST00000619186.4:c.46C>T
ENST00000619485.4:c.406C>T
ENST00000620739.4:c.406C>T
ENST00000622645.4:c.406C>T
ENST00000635293.1:c.406C>T
NM_000546.5:c.523C>T
NM_001126112.2:c.523C>T
NM_001126113.2:c.523C>T
NM_001126114.2:c.523C>T
NM_001126115.1:c.127C>T
NM_001126116.1:c.127C>T
NM_001126117.1:c.127C>T
NM_001126118.1:c.406C>T
NM_001276695.1:c.406C>T
NM_001276696.1:c.406C>T
NM_001276697.1:c.46C>T
NM_001276698.1:c.46C>T
NM_001276699.1:c.46C>T
NM_001276760.1:c.406C>T
NM_001276761.1:c.406C>T
NM_001276695.2:c.406C>T
NM_001276696.2:c.406C>T
NM_001276697.2:c.46C>T
NM_001276698.2:c.46C>T
NM_001276699.2:c.46C>T
NM_001276760.2:c.406C>T
NM_001276761.2:c.406C>T
NM_001126112.3:c.523C>T
NM_001126113.3:c.523C>T
NM_001126114.3:c.523C>T
NM_001126115.2:c.127C>T
NM_001126116.2:c.127C>T
NM_001126117.2:c.127C>T
NM_001126118.2:c.406C>T
NM_001276695.3:c.406C>T
NM_001276696.3:c.406C>T
NM_001276697.3:c.46C>T
NM_001276698.3:c.46C>T
NM_001276699.3:c.46C>T
NM_001276760.3:c.406C>T
NM_001276761.3:c.406C>T
More

Uncertain Significance

Met criteria codes 7
BS3_Supporting PM2_Supporting PM1 PP3_Moderate BS2 PS4_Supporting PP4_Moderate
Not Met criteria codes 13
PS2 PS3 PS1 PP1 PVS1 PM6 PM5 BA1 BS4 BS1 BP2 BP4 BP7

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 2.0.0

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
TP53 VCEP
The NM_000546.6: c.523C>T variant in TP53 is a missense variant predicted to cause substitution of arginine by cystindine at amino acid 175 (p.Arg175Cys). This variant has been reported in 2 unrelated probands meeting Revised Chompret criteria. Based on this evidence, this variant scores 1 total point meeting the TP53 VCEP phenotype scoring criteria of 1-1.5 points. (PS4_Supporting; PMID: 31119730; Internal lab contributor: Color). This variant has an allele frequency of 0.00003293 (3/91090 alleles) in the South Asian population in gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00004) for PM2_Supporting, and therefore meets this criterion (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). This variant resides within a codon (NM_00546.4: 175, 245, 248, 249, 273, 282) of TP53 that is defined as a mutational hotspot by the ClinGen TP53 VCEP (PM1; PMID: 8023157). Computational predictor scores (BayesDel = 0.5443; 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). This variant has been observed in 4-7 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_Moderate; Internal lab contributors: Ambry). 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 contributor: Invitae). 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: PS4_Supporting, PM2_Supporting, BS3_Supporting, PM1, PP3_Moderate, BS2_Moderate, PP4_Moderate. (Bayesian Points: 5; VCEP specifications version 2.0; 1/16/2025)
Met criteria codes
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).
PM2_Supporting
This variant has an allele frequency of 0.00003293 (3/91090 alleles) in the South Asian population in gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00004) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting).
PM1
This variant resides within a codon (NM_00546.4: 175, 245, 248, 249, 273, 282) of TP53 that is defined as a mutational hotspot by the ClinGen TP53 VCEP (PM1; PMID: 8023157).
PP3_Moderate
Computational predictor scores (BayesDel = 0.5443; 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).
BS2
BS2_MODERATE This variant has been observed in 4-7 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_Moderate; Internal lab contributors: Invitae).
PS4_Supporting
This variant has been reported in 2 unrelated probands meeting Revised Chompret criteria. Based on this evidence, this variant scores 1 total point meeting the TP53 VCEP phenotype scoring criteria of 1-1.5 points. (PS4_Supporting; PMID: 31119730; Internal lab contributor: Color).
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 contributor: Invitae).
Not Met criteria codes
PS2
No enough evidence
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
PP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PVS1
Variant is not a null variant
PM6
No enough evidence
PM5
Code not applied as this variant has benign functional data and the other residues being compared have pathogenic functional data. This indicates this variant does not have the same impact as these other residues. 2 different missense variants (p.Arg175His and p.Arg175Gly) (ClinVar Variation ID: 12374, 376649), in the same codon have been classified as pathogenic for Li-Fraumeni syndrome by the ClinGen TP53 VCEP’s specifications. (PM5_Strong).
BA1
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
BP2
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
BP7
Variant is not synonymous
Curation History
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