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]
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  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC computer assertion could be determined for this classification!

Variant: NM_000546.6(TP53):c.524G>A (p.Arg175His)

CA000251

12374 (ClinVar)

Gene: TP53
Condition: Li-Fraumeni syndrome
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 7447e408-66fd-43ee-8fc8-6012f43d7ada
Approved on: 2024-09-06
Published on: 2024-09-06

HGVS expressions

NM_000546.6:c.524G>A
NM_000546.6(TP53):c.524G>A (p.Arg175His)
NC_000017.11:g.7675088C>T
CM000679.2:g.7675088C>T
NC_000017.10:g.7578406C>T
CM000679.1:g.7578406C>T
NC_000017.9:g.7519131C>T
NG_017013.2:g.17463G>A
ENST00000503591.2:c.524G>A
ENST00000508793.6:c.524G>A
ENST00000509690.6:c.128G>A
ENST00000514944.6:c.245G>A
ENST00000604348.6:c.503G>A
ENST00000269305.9:c.524G>A
ENST00000269305.8:c.524G>A
ENST00000359597.8:c.524G>A
ENST00000413465.6:c.524G>A
ENST00000420246.6:c.524G>A
ENST00000445888.6:c.524G>A
ENST00000455263.6:c.524G>A
ENST00000504290.5:c.128G>A
ENST00000504937.5:c.128G>A
ENST00000505014.5:n.780G>A
ENST00000509690.5:c.128G>A
ENST00000510385.5:c.128G>A
ENST00000514944.5:c.245G>A
ENST00000574684.1:n.32G>A
ENST00000610292.4:c.407G>A
ENST00000610538.4:c.407G>A
ENST00000610623.4:c.47G>A
ENST00000615910.4:c.491G>A
ENST00000617185.4:c.524G>A
ENST00000618944.4:c.47G>A
ENST00000619186.4:c.47G>A
ENST00000619485.4:c.407G>A
ENST00000620739.4:c.407G>A
ENST00000622645.4:c.407G>A
ENST00000635293.1:c.407G>A
NM_000546.5:c.524G>A
NM_001126112.2:c.524G>A
NM_001126113.2:c.524G>A
NM_001126114.2:c.524G>A
NM_001126115.1:c.128G>A
NM_001126116.1:c.128G>A
NM_001126117.1:c.128G>A
NM_001126118.1:c.407G>A
NM_001276695.1:c.407G>A
NM_001276696.1:c.407G>A
NM_001276697.1:c.47G>A
NM_001276698.1:c.47G>A
NM_001276699.1:c.47G>A
NM_001276760.1:c.407G>A
NM_001276761.1:c.407G>A
NM_001276695.2:c.407G>A
NM_001276696.2:c.407G>A
NM_001276697.2:c.47G>A
NM_001276698.2:c.47G>A
NM_001276699.2:c.47G>A
NM_001276760.2:c.407G>A
NM_001276761.2:c.407G>A
NM_001126112.3:c.524G>A
NM_001126113.3:c.524G>A
NM_001126114.3:c.524G>A
NM_001126115.2:c.128G>A
NM_001126116.2:c.128G>A
NM_001126117.2:c.128G>A
NM_001126118.2:c.407G>A
NM_001276695.3:c.407G>A
NM_001276696.3:c.407G>A
NM_001276697.3:c.47G>A
NM_001276698.3:c.47G>A
NM_001276699.3:c.47G>A
NM_001276760.3:c.407G>A
NM_001276761.3:c.407G>A

Pathogenic

Met criteria codes 6
PS3 PS4_Moderate PP3 PM2_Supporting PP1_Moderate PM1
Not Met criteria codes 9
PS1 PP4 PM5 BA1 BS2 BS4 BS3 BS1 BP4

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.524G>A variant in TP53 is a missense variant predicted to cause substitution of arginine by histidine at amino acid 175 (p.Arg175His). This variant has been reported in 3 unrelated families meeting Classic and Revised Chompret criteria.Based on this evidence, this variant scores 2.5 total points meeting the TP53 VCEP phenotype scoring criteria of 2-3.5 points. (PS4_Moderate: 8825920, 11370630, 8164043). The variant has been reported to segregate with LFS-associated cancers in 5-6 meioses in 1 family (PP1_Moderate; PMID: 8825920). In vitro assays performed in yeast and/or human cell lines showed non-functional transactivation and loss of growth suppression activity indicating that this variant impacts protein function (PS3; PMIDs: 12826609, 30224644, 29979965). 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 = 0.54619; Align GVGD = Class C25) 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). This variant has an allele frequency of 0.000005932 (7/1180032 alleles) in the European (non-Finnish) 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 summary, this variant meets the criteria to be classified as [CLASSIFICATION] for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PS3, PP1_Moderate, PM1, PS4_Moderate, PP3, PM2_Supporting. (Bayesian Points: 12; VCEP specifications version 2.0; 9/6/2024)
Met criteria codes
PS3
In vitro assays performed in yeast and/or human cell lines showed non-functional transactivation and loss of growth suppression activity indicating that this variant impacts protein function (PS3; PMIDs: 12826609, 30224644, 29979965).
PS4_Moderate
This variant has been reported in 3 unrelated families meeting Classic and Revised Chompret criteria.Based on this evidence, this variant scores 2.5 total points meeting the TP53 VCEP phenotype scoring criteria of 2-3.5 points. (PS4_Moderate: 8825920, 11370630, 8164043).
PP3
Computational predictor scores (BayesDel = 0.54619; Align GVGD = Class C25) 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).
PM2_Supporting
This variant has an allele frequency of 0.000005932 (7/1180032 alleles) in the European (non-Finnish) 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).
PP1_Moderate
The variant has been reported to segregate with LFS-associated cancers in 5-6 meioses in 1 family (PP1_Moderate; PMID: 8825920).
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).
Not Met criteria codes
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
PM5
Other residues have worse Grantham scores than this variant
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
BP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
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