Variant: NM_000546.5(TP53):c.877G>T (p.Gly293Trp)

CA000470

127826 (ClinVar)

Gene: TP53

Condition: Li-Fraumeni syndrome

Inheritance Mode: Autosomal dominant inheritance

UUID: fcf81c41-2ef5-4155-8668-25fc599a1d42

Approved on: 2025-01-16

Published on: 2025-01-16

HGVS expressions

NM_000546.5:c.877G>T
NM_000546.5(TP53):c.877G>T (p.Gly293Trp)
NC_000017.11:g.7673743C>A
CM000679.2:g.7673743C>A
NC_000017.10:g.7577061C>A
CM000679.1:g.7577061C>A
NC_000017.9:g.7517786C>A
NG_017013.2:g.18808G>T
ENST00000503591.2:c.877G>T
ENST00000508793.6:c.877G>T
ENST00000509690.6:c.481G>T
ENST00000514944.6:c.598G>T
ENST00000604348.6:c.856G>T
ENST00000269305.9:c.877G>T
ENST00000269305.8:c.877G>T
ENST00000359597.8:c.877G>T
ENST00000413465.6:c.782+438G>T
ENST00000420246.6:c.877G>T
ENST00000445888.6:c.877G>T
ENST00000455263.6:c.877G>T
ENST00000504290.5:c.481G>T
ENST00000504937.5:c.481G>T
ENST00000509690.5:c.481G>T
ENST00000510385.5:c.481G>T
ENST00000610292.4:c.760G>T
ENST00000610538.4:c.760G>T
ENST00000610623.4:c.400G>T
ENST00000615910.4:c.844G>T
ENST00000617185.4:c.877G>T
ENST00000618944.4:c.400G>T
ENST00000619186.4:c.400G>T
ENST00000619485.4:c.760G>T
ENST00000620739.4:c.760G>T
ENST00000622645.4:c.760G>T
ENST00000635293.1:c.760G>T
NM_001126112.2:c.877G>T
NM_001126113.2:c.877G>T
NM_001126114.2:c.877G>T
NM_001126115.1:c.481G>T
NM_001126116.1:c.481G>T
NM_001126117.1:c.481G>T
NM_001126118.1:c.760G>T
NM_001276695.1:c.760G>T
NM_001276696.1:c.760G>T
NM_001276697.1:c.400G>T
NM_001276698.1:c.400G>T
NM_001276699.1:c.400G>T
NM_001276760.1:c.760G>T
NM_001276761.1:c.760G>T
NM_001276695.2:c.760G>T
NM_001276696.2:c.760G>T
NM_001276697.2:c.400G>T
NM_001276698.2:c.400G>T
NM_001276699.2:c.400G>T
NM_001276760.2:c.760G>T
NM_001276761.2:c.760G>T
NM_000546.6:c.877G>T
NM_001126112.3:c.877G>T
NM_001126113.3:c.877G>T
NM_001126114.3:c.877G>T
NM_001126115.2:c.481G>T
NM_001126116.2:c.481G>T
NM_001126117.2:c.481G>T
NM_001126118.2:c.760G>T
NM_001276695.3:c.760G>T
NM_001276696.3:c.760G>T
NM_001276697.3:c.400G>T
NM_001276698.3:c.400G>T
NM_001276699.3:c.400G>T
NM_001276760.3:c.760G>T
NM_001276761.3:c.760G>T

Likely Benign

• Met criteria codes: PM2_Supporting BS2 BS3

• Not Met criteria codes: BA1 PM5 PM1 BS4 BS1 BP4 PS2 PS4 PS3 PS1 PP4 PP1 PP3

Expert Panel

TP53 VCEP

Criteria Specification Information

Criteria Specification: ClinGen TP53 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for TP53 Version 2.2.0

Evidence submitted by expert panel

TP53 VCEP

The NM_000546.6:c.877G>T variant in TP53 is a missense variant predicted to cause substitution of glycine by tryptophan at amino acid 293 (p.Gly293Trp). This variant has been observed in 4 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, SCV000187101.5). This variant has an allele frequency of 0.00003305 (39/1180036 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 functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function(BS3; PMIDs: 12826609, 29979965, 30224644). In summary, TP53 c.877G>T (p.Gly293Trp) meets criteria to be classified as likely benign for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Expert Panel: BS2_Moderate, PM2_Supporting, BS3. (Bayesian Points: -5; VCEP specifications version 2.2, 1/16/2025).

Met criteria codes

• PM2_Supporting: This variant has an allele frequency of 0.00003305 (39/1180036 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).
• BS2: BS2_MODERATE This variant has been observed in 4 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, SCV000187101.5).
• BS3: In vitro assays performed in yeast and/or human cell lines showed functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function(BS3; PMIDs: 12826609, 29979965, 30224644).

Not Met criteria codes

• BA1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM5: 2 different missense variants (c.877G>A and c.877G>C, p.Gly293Arg) in the same codon have been reported (ClinVar Variation IDs: 1365220, 230208). 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).
• 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).
• 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
• BP4: The results from the computational predictors BayesDel (>0.16) and AlignGVGD (Class C0) do not agree, providing no evidence that correlates with a damaging or benign impact on TP53 function via protein change. Additionally, SpliceAI predicts that the variant has no impact on splicing (score threshold ≤ 0.10) (PP3 and BP4 not met).
• PS2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS4: This variant received a total of 0.5 points across 1 unrelated proband from an individual laboratory, and therefore PS4 cannot be applied. (PS4 not met; SCV000149650.14).
• 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
• PP4: 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
• PP3: The results from the computational predictors BayesDel (>0.16) and AlignGVGD (Class C0) do not agree, providing no evidence that correlates with a damaging or benign impact on TP53 function via protein change. Additionally, SpliceAI predicts that the variant has no impact on splicing (score threshold ≤ 0.10) (PP3 and BP4 not met).