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 computer assertion could be determined for this classification!

Variant: NM_000546.5(TP53):c.818G>A (p.Arg273His)

CA000434

12366 (ClinVar)

Gene: TP53
Condition: Li-Fraumeni syndrome
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 8d32df42-16ac-41f2-9bf1-e2b9ce206190
Approved on: 2024-08-05
Published on: 2024-08-05

HGVS expressions

NM_000546.5:c.818G>A
NM_000546.5(TP53):c.818G>A (p.Arg273His)
NC_000017.11:g.7673802C>T
CM000679.2:g.7673802C>T
NC_000017.10:g.7577120C>T
CM000679.1:g.7577120C>T
NC_000017.9:g.7517845C>T
NG_017013.2:g.18749G>A
ENST00000503591.2:c.818G>A
ENST00000508793.6:c.818G>A
ENST00000509690.6:c.422G>A
ENST00000514944.6:c.539G>A
ENST00000604348.6:c.797G>A
ENST00000269305.9:c.818G>A
ENST00000269305.8:c.818G>A
ENST00000359597.8:c.818G>A
ENST00000413465.6:c.782+379G>A
ENST00000420246.6:c.818G>A
ENST00000445888.6:c.818G>A
ENST00000455263.6:c.818G>A
ENST00000504290.5:c.422G>A
ENST00000504937.5:c.422G>A
ENST00000509690.5:c.422G>A
ENST00000510385.5:c.422G>A
ENST00000610292.4:c.701G>A
ENST00000610538.4:c.701G>A
ENST00000610623.4:c.341G>A
ENST00000615910.4:c.785G>A
ENST00000617185.4:c.818G>A
ENST00000618944.4:c.341G>A
ENST00000619186.4:c.341G>A
ENST00000619485.4:c.701G>A
ENST00000620739.4:c.701G>A
ENST00000622645.4:c.701G>A
ENST00000635293.1:c.701G>A
NM_001126112.2:c.818G>A
NM_001126113.2:c.818G>A
NM_001126114.2:c.818G>A
NM_001126115.1:c.422G>A
NM_001126116.1:c.422G>A
NM_001126117.1:c.422G>A
NM_001126118.1:c.701G>A
NM_001276695.1:c.701G>A
NM_001276696.1:c.701G>A
NM_001276697.1:c.341G>A
NM_001276698.1:c.341G>A
NM_001276699.1:c.341G>A
NM_001276760.1:c.701G>A
NM_001276761.1:c.701G>A
NM_001276695.2:c.701G>A
NM_001276696.2:c.701G>A
NM_001276697.2:c.341G>A
NM_001276698.2:c.341G>A
NM_001276699.2:c.341G>A
NM_001276760.2:c.701G>A
NM_001276761.2:c.701G>A
NM_000546.6:c.818G>A
NM_001126112.3:c.818G>A
NM_001126113.3:c.818G>A
NM_001126114.3:c.818G>A
NM_001126115.2:c.422G>A
NM_001126116.2:c.422G>A
NM_001126117.2:c.422G>A
NM_001126118.2:c.701G>A
NM_001276695.3:c.701G>A
NM_001276696.3:c.701G>A
NM_001276697.3:c.341G>A
NM_001276698.3:c.341G>A
NM_001276699.3:c.341G>A
NM_001276760.3:c.701G>A
NM_001276761.3:c.701G>A
More

Pathogenic

Met criteria codes 7
PP4_Moderate PM2_Supporting PM1 PS4 PS2 PS3 PP3
Not Met criteria codes 7
BA1 PM5 BS2 BS1 BS3 BP4 PS1

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.818G>A variant in TP53 is a missense variant predicted to cause substitution of arginine by histidine at amino acid 273 (p.R273H). This variant has been reported in numerous unrelated probands meeting Classic LFS and Revised Chompret criteria. Based on this evidence, this variant scores 8 total points meeting the TP53 VCEP phenotype scoring criteria of ≥ 8 points. (PS4_Very Strong; PMIDs, 16401470, 15390294, 9242456, 10864200, 1565144, 7732013; SCV000186052.8). This variant has been identified as a de novo occurrence with confirmed parental relationships in 1 individual with an LFS-associated cancer totaling 4 phenotype points (PS2; PMID: 1267231). 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, SCV000186052.8). This variant has an allele frequency of 0.00001186 (14/1179946 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 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: 273) of TP53 that is defined as a mutational hotspot by the ClinGen TP53 VCEP (PM1; PMID: 8023157 ). Computational predictor scores (BayesDel = 0.52; Align GVGD = Class 25) 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). In summary, this variant meets the criteria to be classified as pathogenic for Li Fraumeni Syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PS4_Very Strong, PS2, PM2_Supporting, PS3, PP4_Moderate, PM1, PP3. (Bayesian Points: 22; VCEP specifications version 2.0; 7/24/2024).
Met criteria codes
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, SCV000186052.8).
PM2_Supporting
This variant has an allele frequency of 0.00001186 (14/1179946 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).
PM1
This variant resides within a codon (NM_00546.4: 273) of TP53 that is defined as a mutational hotspot by the ClinGen TP53 VCEP (PM1; PMID: 8023157 )
PS4
PS4_VERY STRONG APPLIED This variant has been reported in numerous unrelated probands meeting Classic LFS and Revised Chompret criteria. Based on this evidence, this variant scores 8 total points meeting the TP53 VCEP phenotype scoring criteria of ≥ 8 points. (PS4_Very Strong; PMIDs, 16401470, 15390294, 9242456, 10864200, 1565144, 7732013; SCV000186052.8)
PS2
This variant has been identified as a de novo occurrence with confirmed parental relationships in 1 individual with an LFS-associated cancer totaling 4 phenotype points (PS2; PMID: 1267231).
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).
PP3
Computational predictor scores (BayesDel = 0.52; Align GVGD = Class 25) 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
BA1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM5
5 different missense variants (p.Arg273Leu; p.Arg273Pro; p.Arg273Gly; p.Arg273Ser; p.Arg273Cys) in the same codon have been reported (ClinVar Variation IDs: 376655, 231060, 634682, 376656, 43594). However, the variants have not yet been curated to determine if they would be classified as pathogenic or likely pathogenic by the ClinGen TP53 VCEP’s specifications (PM5 not evaluated).
BS2
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
BS3
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
PS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Curation History
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