Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Variant: NM_000546.5(TP53):c.403T>G (p.Cys135Gly)

Curation Version - 2.0
Curation History
JSON LD for Version 2.0

CA16602989

376563 (ClinVar)

Gene: TP53

Condition: Li-Fraumeni syndrome

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: c4a27155-9f6f-4586-8a08-70b96d281243

Approved on: 2024-08-05

Published on: 2024-08-05

HGVS expressions

NM_000546.5:c.403T>G

NM_000546.5(TP53):c.403T>G (p.Cys135Gly)

NC_000017.11:g.7675209A>C

CM000679.2:g.7675209A>C

NC_000017.10:g.7578527A>C

CM000679.1:g.7578527A>C

NC_000017.9:g.7519252A>C

NG_017013.2:g.17342T>G

ENST00000503591.2:c.403T>G

ENST00000508793.6:c.403T>G

ENST00000509690.6:c.7T>G

ENST00000514944.6:c.124T>G

ENST00000604348.6:c.382T>G

ENST00000269305.9:c.403T>G

ENST00000269305.8:c.403T>G

ENST00000359597.8:c.403T>G

ENST00000413465.6:c.403T>G

ENST00000420246.6:c.403T>G

ENST00000445888.6:c.403T>G

ENST00000455263.6:c.403T>G

ENST00000504290.5:c.7T>G

ENST00000504937.5:c.7T>G

ENST00000505014.5:n.659T>G

ENST00000508793.5:c.403T>G

ENST00000509690.5:c.7T>G

ENST00000510385.5:c.7T>G

ENST00000514944.5:c.124T>G

ENST00000604348.5:c.382T>G

ENST00000610292.4:c.286T>G

ENST00000610538.4:c.286T>G

ENST00000610623.4:c.-75T>G

ENST00000615910.4:c.370T>G

ENST00000617185.4:c.403T>G

ENST00000618944.4:c.-75T>G

ENST00000619186.4:c.-75T>G

ENST00000619485.4:c.286T>G

ENST00000620739.4:c.286T>G

ENST00000622645.4:c.286T>G

ENST00000635293.1:c.286T>G

NM_001126112.2:c.403T>G

NM_001126113.2:c.403T>G

NM_001126114.2:c.403T>G

NM_001126115.1:c.7T>G

NM_001126116.1:c.7T>G

NM_001126117.1:c.7T>G

NM_001126118.1:c.286T>G

NM_001276695.1:c.286T>G

NM_001276696.1:c.286T>G

NM_001276697.1:c.-75T>G

NM_001276698.1:c.-75T>G

NM_001276699.1:c.-75T>G

NM_001276760.1:c.286T>G

NM_001276761.1:c.286T>G

NM_001276695.2:c.286T>G

NM_001276696.2:c.286T>G

NM_001276697.2:c.-75T>G

NM_001276698.2:c.-75T>G

NM_001276699.2:c.-75T>G

NM_001276760.2:c.286T>G

NM_001276761.2:c.286T>G

NM_000546.6:c.403T>G

NM_001126112.3:c.403T>G

NM_001126113.3:c.403T>G

NM_001126114.3:c.403T>G

NM_001126115.2:c.7T>G

NM_001126116.2:c.7T>G

NM_001126117.2:c.7T>G

NM_001126118.2:c.286T>G

NM_001276695.3:c.286T>G

NM_001276696.3:c.286T>G

NM_001276697.3:c.-75T>G

NM_001276698.3:c.-75T>G

NM_001276699.3:c.-75T>G

NM_001276760.3:c.286T>G

NM_001276761.3:c.286T>G

Pathogenic

PP4_Moderate PP3_Moderate PS3 PM1_Supporting PM2_Supporting

PM5 PS2 PS4 PS1 BA1 PP1 PVS1 BS4 BS3 BS1 BS2 BP4

Evidence Links 0

Expert Panel

TP53 VCEP

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.403T>G variant in TP53 is a missense variant predicted to cause substitution of Cysteine by Glycine at amino acid 135 (p.Cys135Gly). 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, Internal lab contributors: SCV000664432.4). This variant is absent from gnomAD v4.1.0 (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; PMID: 12826609, 30224644, 29979965). Computational predictor scores (BayesDel = 0.5991; 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). This variant has 2 somatic occurrences for the same amino acid change in cancerhotspots.org (v2) sufficient to be defined as a mutational hotspot by the Clingen TP53 VCEP (2-9 somatic occurrences, PMID: 30311369) (PM1_Supporting). 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: PP4_Moderate, PM2_Supporting, PS3, PP3_Moderate, PM1_Supporting. (Bayesian Points: 10; VCEP specifications version 2.0; 7/24/2024).

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, Internal lab contributors: SCV000664432.4).

PP3_Moderate

Computational predictor scores (BayesDel = 0.5991; 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).

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 (PMID: 12826609, 30224644, 29979965) (PS3).

PM1_Supporting

This variant has 2 somatic occurrences for the same amino acid change in cancerhotspots.org (v2) sufficient to be defined as a mutational hotspot by the Clingen TP53 VCEP (2-9 somatic occurrences, PMID: 30311369) (PM1_Supporting).

PM2_Supporting

This variant is absent from gnomAD v4.1.0 (PM2_Supporting).

PM5

5 different missense variants (c.403T>A, p.Cys135Ser;c.403T>C, p.Cys135Arg; c.404G>A, p.Cys135Tyr; c.404G>T, p.Cys135Phe; c.405C>G, p.Cys135Trp) in the same codon have been reported (ClinVar Variation ID 376561, 376559, 141762, 376562, 376560). 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).

PS2