Variant: NM_000546.6(TP53):c.436T>G (p.Trp146Gly)

CA000190

186587 (ClinVar)

Gene: TP53

Condition: Li-Fraumeni syndrome

Inheritance Mode: Autosomal dominant inheritance

UUID: 4e4e51a2-bf4a-44a4-9fb7-5d5816cdfb92

Approved on: 2025-03-04

Published on: 2025-06-23

HGVS expressions

NM_000546.6:c.436T>G
NM_000546.6(TP53):c.436T>G (p.Trp146Gly)
NC_000017.11:g.7675176A>C
CM000679.2:g.7675176A>C
NC_000017.10:g.7578494A>C
CM000679.1:g.7578494A>C
NC_000017.9:g.7519219A>C
NG_017013.2:g.17375T>G
ENST00000503591.2:c.436T>G
ENST00000508793.6:c.436T>G
ENST00000509690.6:c.40T>G
ENST00000514944.6:c.157T>G
ENST00000604348.6:c.415T>G
ENST00000269305.9:c.436T>G
ENST00000269305.8:c.436T>G
ENST00000359597.8:c.436T>G
ENST00000413465.6:c.436T>G
ENST00000420246.6:c.436T>G
ENST00000445888.6:c.436T>G
ENST00000455263.6:c.436T>G
ENST00000504290.5:c.40T>G
ENST00000504937.5:c.40T>G
ENST00000505014.5:n.692T>G
ENST00000508793.5:c.436T>G
ENST00000509690.5:c.40T>G
ENST00000510385.5:c.40T>G
ENST00000514944.5:c.157T>G
ENST00000604348.5:c.415T>G
ENST00000610292.4:c.319T>G
ENST00000610538.4:c.319T>G
ENST00000610623.4:c.-42T>G
ENST00000615910.4:c.403T>G
ENST00000617185.4:c.436T>G
ENST00000618944.4:c.-42T>G
ENST00000619186.4:c.-42T>G
ENST00000619485.4:c.319T>G
ENST00000620739.4:c.319T>G
ENST00000622645.4:c.319T>G
ENST00000635293.1:c.319T>G
NM_000546.5:c.436T>G
NM_001126112.2:c.436T>G
NM_001126113.2:c.436T>G
NM_001126114.2:c.436T>G
NM_001126115.1:c.40T>G
NM_001126116.1:c.40T>G
NM_001126117.1:c.40T>G
NM_001126118.1:c.319T>G
NM_001276695.1:c.319T>G
NM_001276696.1:c.319T>G
NM_001276697.1:c.-42T>G
NM_001276698.1:c.-42T>G
NM_001276699.1:c.-42T>G
NM_001276760.1:c.319T>G
NM_001276761.1:c.319T>G
NM_001276695.2:c.319T>G
NM_001276696.2:c.319T>G
NM_001276697.2:c.-42T>G
NM_001276698.2:c.-42T>G
NM_001276699.2:c.-42T>G
NM_001276760.2:c.319T>G
NM_001276761.2:c.319T>G
NM_001126112.3:c.436T>G
NM_001126113.3:c.436T>G
NM_001126114.3:c.436T>G
NM_001126115.2:c.40T>G
NM_001126116.2:c.40T>G
NM_001126117.2:c.40T>G
NM_001126118.2:c.319T>G
NM_001276695.3:c.319T>G
NM_001276696.3:c.319T>G
NM_001276697.3:c.-42T>G
NM_001276698.3:c.-42T>G
NM_001276699.3:c.-42T>G
NM_001276760.3:c.319T>G
NM_001276761.3:c.319T>G

Uncertain Significance

• Met criteria codes: PS4_Supporting PM2_Supporting BP4 PS3

• Not Met criteria codes: BS2 BS4 BS3 BS1 PS2 PS1 BA1 PP1 PP4 PP3 PM1 PM5

Expert Panel

TP53 VCEP

Criteria Specification Information

Criteria Specification: ClinGen TP53 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for TP53 Version 2.3.0

Evidence submitted by expert panel

TP53 VCEP

The NM_000546.6: c.436T>G variant in TP53 is a missense variant predicted to cause substitution of tryptophan by glycine at amino acid 146 (p.Trp146Gly). This variant has been reported in 2 families, one meeting Classic and one Revised Chompret criteria. Based on this evidence, this variant scores 1.5 total points meeting the TP53 VCEP phenotype scoring criteria of 1-1.5 points. (PS4_Supporting; Internal lab contributors). 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; PMIDs: 12826609, 30224644). Computational predictor scores (BayesDel = 0.0351; Align GVGD Class 0) are below the recommended thresholds (BayesDel < 0.16 and > -0.008 and an Align GVGD Class ≤ 55), evidence that does not predict a damaging effect on TP53 via protein change. SpliceAI predicts that the variant has no impact on splicing (BP4). In summary, this variant meets the criteria to be classified as Uncertain Significance for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PS4_Supporting, PM2_Supporting, PS3, BP4. (Bayesian Points: 5; VCEP specifications version 2.3)

Met criteria codes

• PS4_Supporting: This variant has been reported in 2 families, one meeting Classic and one Revised Chompret criteria. Based on this evidence, this variant scores 1.5 total points meeting the TP53 VCEP phenotype scoring criteria of 1-1.5 points. (PS4_Supporting; Internal lab contributors).
• PM2_Supporting: This variant is absent from gnomAD v4.1.0 (PM2_Supporting).
• BP4: Computational predictor scores (BayesDel = 0.0351; Align GVGD Class 0) are below the recommended thresholds (BayesDel < 0.16 and > -0.008 and an Align GVGD Class ≤ 55), evidence that does not predict a damaging effect on TP53 via protein change. SpliceAI predicts that the variant has no impact on splicing (BP4).
• 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). Non-functional (Kato); LOF but not DNE (Giacomelli); not LOF (Kotler)

Not Met criteria codes

• BS2: Not seen in FLOSSIES. Internal lab data not reviewed
• 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
• 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
• BA1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PP1: 2 meioses; insufficient for code
• PP4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PP3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• 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). 1/27 on cancerhotspots.com
• PM5: Two different missense variants (c.438G>C (p.Trp146Cys); c.438G>T (p.Trp146Cys)) in the same codon have been reported (ClinVar Variation IDs: 1740219; 824855). However, these variants do not meet criteria for PM5 code application (PM5 not met). Grantham score for W->G is less than score for W->C.