Variant: NM_000546.5(TP53):c.1066G>C (p.Gly356Arg)

CA000803

234059 (ClinVar)

Gene: TP53

Condition: Li-Fraumeni syndrome

Inheritance Mode: Autosomal dominant inheritance

UUID: 5e0b5fcb-74ae-405b-ba9f-054ce7b5cd41

Approved on: 2024-09-06

Published on: 2024-09-06

HGVS expressions

NM_000546.5:c.1066G>C
NM_000546.5(TP53):c.1066G>C (p.Gly356Arg)
NC_000017.11:g.7670643C>G
CM000679.2:g.7670643C>G
NC_000017.10:g.7573961C>G
CM000679.1:g.7573961C>G
NC_000017.9:g.7514686C>G
NG_017013.2:g.21908G>C
ENST00000503591.2:c.1066G>C
ENST00000508793.6:c.1066G>C
ENST00000509690.6:c.670G>C
ENST00000514944.6:c.787G>C
ENST00000604348.6:c.1045G>C
ENST00000269305.9:c.1066G>C
ENST00000269305.8:c.1066G>C
ENST00000359597.8:c.993+2892G>C
ENST00000413465.6:c.782+3538G>C
ENST00000420246.6:c.*173G>C
ENST00000445888.6:c.1066G>C
ENST00000455263.6:c.*85G>C
ENST00000504290.5:c.*85G>C
ENST00000504937.5:c.670G>C
ENST00000510385.5:c.*173G>C
ENST00000576024.1:c.54-953G>C
ENST00000610292.4:c.949G>C
ENST00000610538.4:c.*85G>C
ENST00000610623.4:c.*85G>C
ENST00000615910.4:c.1033G>C
ENST00000617185.4:c.*173G>C
ENST00000618944.4:c.*173G>C
ENST00000619186.4:c.589G>C
ENST00000619485.4:c.949G>C
ENST00000620739.4:c.949G>C
ENST00000622645.4:c.*173G>C
ENST00000635293.1:c.949G>C
NM_001126112.2:c.1066G>C
NM_001126113.2:c.*85G>C
NM_001126114.2:c.*173G>C
NM_001126115.1:c.670G>C
NM_001126116.1:c.*173G>C
NM_001126117.1:c.*85G>C
NM_001126118.1:c.949G>C
NM_001276695.1:c.*85G>C
NM_001276696.1:c.*173G>C
NM_001276697.1:c.589G>C
NM_001276698.1:c.*173G>C
NM_001276699.1:c.*85G>C
NM_001276760.1:c.949G>C
NM_001276761.1:c.949G>C
NM_001276695.2:c.*85G>C
NM_001276696.2:c.*173G>C
NM_001276697.2:c.589G>C
NM_001276698.2:c.*173G>C
NM_001276699.2:c.*85G>C
NM_001276760.2:c.949G>C
NM_001276761.2:c.949G>C
NM_000546.6:c.1066G>C
NM_001126112.3:c.1066G>C
NM_001126113.3:c.*85G>C
NM_001126114.3:c.*173G>C
NM_001126115.2:c.670G>C
NM_001126116.2:c.*173G>C
NM_001126117.2:c.*85G>C
NM_001126118.2:c.949G>C
NM_001276695.3:c.*85G>C
NM_001276696.3:c.*173G>C
NM_001276697.3:c.589G>C
NM_001276698.3:c.*173G>C
NM_001276699.3:c.*85G>C
NM_001276760.3:c.949G>C
NM_001276761.3:c.949G>C

Likely Benign

• Met criteria codes: BS3 BS2_Supporting BP4 PM2_Supporting

• Not Met criteria codes: BS4 BS1 BP7 PVS1 PS4 PS2 PS3 PS1 PP1 PP4 PP3 PM1 PM5 BA1

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

Evidence submitted by expert panel

TP53 VCEP

The NM_000546.6: c.1066G>C variant in TP53 is a missense variant predicted to cause substitution of glycine by arginine at amino acid 356 (p.Gly356Arg). This variant has been observed in 2-3 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_Supporting; ClinVar SCV: SCV000278550.7). This variant has an allele frequency of 0.000005932 (7/1179982 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). Computational predictor scores (BayesDel = -0.3473; Align GVGD Class C0) are below the recommended thresholds (BayesDel ≤ -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_Moderate). In summary, this variant meets the criteria to be classified as Likely Benign for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2_Supporting, PM2_Supporting, BS3, BP4_Moderate. (Bayesian Points: -6; VCEP specifications version 2.0; 9/6/2024)

Met criteria codes

• 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).
• BS2_Supporting: This variant has been observed in 2-3 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_Supporting; Internal lab contributor: Ambry).
• BP4: BP4_MODERATE Computational predictor scores (BayesDel = -0.3473; Align GVGD Class C0) are below the recommended thresholds (BayesDel ≤ -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_Moderate).
• PM2_Supporting: This variant has an allele frequency of 0.000005932 (7/1179982 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).

Not Met criteria codes

• 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
• BP7: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PVS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS4: 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
• PS3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS1: The same amino acid change, resulting from a different nucleotide change c.1066G>A, has been reported(ClinVar Variation ID: 2774646). However, this other variant has not yet met the criteria to be classified as pathogenic or likely pathogenic by the ClinGen TP53 VCEP’s specifications (PS1 not evaluated).
• PP1: 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
• 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).
• PM5: 2 different missense variants (p.Gly356Ala, p.Gly356Trp) in the same codon have been reported (ClinVar Variation IDs: 1716142, 1998185). 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).
• BA1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline