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_000546.6(TP53):c.1079G>C (p.Gly360Ala)

CA000029

142003 (ClinVar)

Gene: TP53
Condition: Li-Fraumeni syndrome
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 69d5e5bf-2cb9-4c24-b1ee-e092cce3c5d6
Approved on: 2024-08-05
Published on: 2024-08-05

HGVS expressions

NM_000546.6:c.1079G>C
NM_000546.6(TP53):c.1079G>C (p.Gly360Ala)
NC_000017.11:g.7670630C>G
CM000679.2:g.7670630C>G
NC_000017.10:g.7573948C>G
CM000679.1:g.7573948C>G
NC_000017.9:g.7514673C>G
NG_017013.2:g.21921G>C
ENST00000503591.2:c.1079G>C
ENST00000508793.6:c.1079G>C
ENST00000509690.6:c.683G>C
ENST00000514944.6:c.800G>C
ENST00000604348.6:c.1058G>C
ENST00000269305.9:c.1079G>C
ENST00000269305.8:c.1079G>C
ENST00000359597.8:c.993+2905G>C
ENST00000413465.6:c.782+3551G>C
ENST00000420246.6:c.*186G>C
ENST00000445888.6:c.1079G>C
ENST00000455263.6:c.*98G>C
ENST00000504290.5:c.*98G>C
ENST00000504937.5:c.683G>C
ENST00000510385.5:c.*186G>C
ENST00000576024.1:c.54-940G>C
ENST00000610292.4:c.962G>C
ENST00000610538.4:c.*98G>C
ENST00000610623.4:c.*98G>C
ENST00000615910.4:c.1046G>C
ENST00000617185.4:c.*186G>C
ENST00000618944.4:c.*186G>C
ENST00000619186.4:c.602G>C
ENST00000619485.4:c.962G>C
ENST00000620739.4:c.962G>C
ENST00000622645.4:c.*186G>C
ENST00000635293.1:c.962G>C
NM_000546.5:c.1079G>C
NM_001126112.2:c.1079G>C
NM_001126113.2:c.*98G>C
NM_001126114.2:c.*186G>C
NM_001126115.1:c.683G>C
NM_001126116.1:c.*186G>C
NM_001126117.1:c.*98G>C
NM_001126118.1:c.962G>C
NM_001276695.1:c.*98G>C
NM_001276696.1:c.*186G>C
NM_001276697.1:c.602G>C
NM_001276698.1:c.*186G>C
NM_001276699.1:c.*98G>C
NM_001276760.1:c.962G>C
NM_001276761.1:c.962G>C
NM_001276695.2:c.*98G>C
NM_001276696.2:c.*186G>C
NM_001276697.2:c.602G>C
NM_001276698.2:c.*186G>C
NM_001276699.2:c.*98G>C
NM_001276760.2:c.962G>C
NM_001276761.2:c.962G>C
NM_001126112.3:c.1079G>C
NM_001126113.3:c.*98G>C
NM_001126114.3:c.*186G>C
NM_001126115.2:c.683G>C
NM_001126116.2:c.*186G>C
NM_001126117.2:c.*98G>C
NM_001126118.2:c.962G>C
NM_001276695.3:c.*98G>C
NM_001276696.3:c.*186G>C
NM_001276697.3:c.602G>C
NM_001276698.3:c.*186G>C
NM_001276699.3:c.*98G>C
NM_001276760.3:c.962G>C
NM_001276761.3:c.962G>C
More

Benign

Met criteria codes 3
BS1 BS2 BP4
Not Met criteria codes 13
PM2 PM1 PM5 BA1 BS4 BS3 PS2 PS4 PS1 PS3 PP4 PP1 PP3

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.1079G>C variant in TP53 is a missense variant predicted to cause substitution of glycine by alanine at amino acid 360 (p.Gly360Ala). This variant has been observed in at least 8 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, Internal lab contributor: SCV000185669.8). The filtering allele frequency is 0.0005306 in the African/African American population in gnomAD v4.1.0, which is higher than the ClinGen TP53 VCEP threshold (≥0.0003 but <0.001) for BS1, and therefore meets this criterion (BS1). Computational predictor scores (BayesDel = -0.3336; 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 Benign for Li Fraumeni Syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2, BS1 BP4_Moderate. (Bayesian Points: -10; VCEP specifications version 2.0; 7/24/2024)
Met criteria codes
BS1
The filtering allele frequency is 0.0005306 in the African/African American population in gnomAD v4.1.0, which is higher than the ClinGen TP53 VCEP threshold (≥0.0003 but <0.001) for BS1, and therefore meets this criterion (BS1).
BS2
This variant has been observed in at least 8 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, Internal lab contributor: SCV000185669.8).
BP4
BP4_MODERATE Computational predictor scores (BayesDel = -0.3336; 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).
Not Met criteria codes
PM2
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
5 different missense variants (c.1079G>A, c.1079G>T, c.1078G>C, c.1078G>T, c.1078G>A) in the same codon have been reported. 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
BS4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS3
In vitro assays performed in yeast and/or human cell lines showed conflicting results with respect to transactivation, growth suppression activity, and/or tetramer formation (PS3/BS3 not met; PMIDs: 12826609, 16007150, 29979965, 30224644)
PS2
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
PS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS3
In vitro assays performed in yeast and/or human cell lines showed conflicting results with respect to transactivation, growth suppression activity, and/or tetramer formation (PS3/BS3 not met; PMIDs: 12826609, 16007150, 29979965, 30224644)
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
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Curation History
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