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 computed assertion could be determined for this classification!

Variant: NM_000546.5(TP53):c.480G>A (p.Met160Ile)

CA002482

230758 (ClinVar)

Gene: TP53
Condition: Li-Fraumeni syndrome
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 569b4177-6cd9-4d9e-9c08-6feaf795f9dc
Approved on: 2025-01-16
Published on: 2025-01-16

HGVS expressions

NM_000546.5:c.480G>A
NM_000546.5(TP53):c.480G>A (p.Met160Ile)
NC_000017.11:g.7675132C>T
CM000679.2:g.7675132C>T
NC_000017.10:g.7578450C>T
CM000679.1:g.7578450C>T
NC_000017.9:g.7519175C>T
NG_017013.2:g.17419G>A
ENST00000503591.2:c.480G>A
ENST00000508793.6:c.480G>A
ENST00000509690.6:c.84G>A
ENST00000514944.6:c.201G>A
ENST00000604348.6:c.459G>A
ENST00000269305.9:c.480G>A
ENST00000269305.8:c.480G>A
ENST00000359597.8:c.480G>A
ENST00000413465.6:c.480G>A
ENST00000420246.6:c.480G>A
ENST00000445888.6:c.480G>A
ENST00000455263.6:c.480G>A
ENST00000504290.5:c.84G>A
ENST00000504937.5:c.84G>A
ENST00000505014.5:n.736G>A
ENST00000508793.5:c.480G>A
ENST00000509690.5:c.84G>A
ENST00000510385.5:c.84G>A
ENST00000514944.5:c.201G>A
ENST00000610292.4:c.363G>A
ENST00000610538.4:c.363G>A
ENST00000610623.4:c.3G>A
ENST00000615910.4:c.447G>A
ENST00000617185.4:c.480G>A
ENST00000618944.4:c.3G>A
ENST00000619186.4:c.3G>A
ENST00000619485.4:c.363G>A
ENST00000620739.4:c.363G>A
ENST00000622645.4:c.363G>A
ENST00000635293.1:c.363G>A
NM_001126112.2:c.480G>A
NM_001126113.2:c.480G>A
NM_001126114.2:c.480G>A
NM_001126115.1:c.84G>A
NM_001126116.1:c.84G>A
NM_001126117.1:c.84G>A
NM_001126118.1:c.363G>A
NM_001276695.1:c.363G>A
NM_001276696.1:c.363G>A
NM_001276697.1:c.3G>A
NM_001276698.1:c.3G>A
NM_001276699.1:c.3G>A
NM_001276760.1:c.363G>A
NM_001276761.1:c.363G>A
NM_001276695.2:c.363G>A
NM_001276696.2:c.363G>A
NM_001276697.2:c.3G>A
NM_001276698.2:c.3G>A
NM_001276699.2:c.3G>A
NM_001276760.2:c.363G>A
NM_001276761.2:c.363G>A
NM_000546.6:c.480G>A
NM_001126112.3:c.480G>A
NM_001126113.3:c.480G>A
NM_001126114.3:c.480G>A
NM_001126115.2:c.84G>A
NM_001126116.2:c.84G>A
NM_001126117.2:c.84G>A
NM_001126118.2:c.363G>A
NM_001276695.3:c.363G>A
NM_001276696.3:c.363G>A
NM_001276697.3:c.3G>A
NM_001276698.3:c.3G>A
NM_001276699.3:c.3G>A
NM_001276760.3:c.363G>A
NM_001276761.3:c.363G>A
More

Likely Benign

Met criteria codes 3
BS3_Supporting BS2_Supporting PM2_Supporting
Not Met criteria codes 16
BS4 BS1 BP7 BP2 BP4 PS2 PS4 PS3 PS1 PVS1 BA1 PP1 PP3 PM1 PM5 PM6

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 2.1.0

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
TP53 VCEP
The NM_000546.6: c.480G>A variant in TP53 is a missense variant predicted to cause substitution of methionine by isoleucine at amino acid 160 (p.Met160Ile). This variant has been observed in 4-7 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). In vitro assays performed in yeast and/or human cell lines showed partially functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function (BS3_Supporting; PMIDs: 12826609, 29979965, 30224644). This variant has an allele frequency of 0.000003390 (4/1180050 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 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_Moderate, BS3_Supporting, PM2_Supporting. (Bayesian Points: -2; VCEP specifications version 2.1; 1/16/2025).
Met criteria codes
BS3_Supporting
In vitro assays performed in yeast and/or human cell lines showed partially functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function (BS3_Supporting; PMIDs: 12826609, 29979965, 30224644).
BS2_Supporting
BS2_MODERATE This variant has been observed in 4-7 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).
PM2_Supporting
This variant has an allele frequency of 0.000003390 (4/1180050 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
BP2
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 and AlignGVGD 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). Bayesdel = 0.2, aGVGD=C0; No splice effect by in silico predictors
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
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
PVS1
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
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 (c.479T>C p.Met160Thr and c.478A>G p.Met160Val) in the same codon have been reported (PMIDs, ClinVar Variation ID: 2915501 and 444396). However, the variants have not yet met the criteria to be classified as pathogenic or likely pathogenic by the ClinGen TP53 VCEP’s specifications (PM5 not evaluated).
PM6
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Curation History
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