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]
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  • 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_000546.5(TP53):c.1093C>T (p.His365Tyr)

CA000035

80708 (ClinVar)

Gene: TP53
Condition: Li-Fraumeni syndrome
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 9285e818-17ae-4db4-83fa-16f6628f6cd6
Approved on: 2024-08-05
Published on: 2024-08-05

HGVS expressions

NM_000546.5:c.1093C>T
NM_000546.5(TP53):c.1093C>T (p.His365Tyr)
NC_000017.11:g.7670616G>A
CM000679.2:g.7670616G>A
NC_000017.10:g.7573934G>A
CM000679.1:g.7573934G>A
NC_000017.9:g.7514659G>A
NG_017013.2:g.21935C>T
ENST00000503591.2:c.1093C>T
ENST00000508793.6:c.1093C>T
ENST00000509690.6:c.697C>T
ENST00000514944.6:c.814C>T
ENST00000604348.6:c.1072C>T
ENST00000269305.9:c.1093C>T
ENST00000269305.8:c.1093C>T
ENST00000359597.8:c.993+2919C>T
ENST00000413465.6:c.782+3565C>T
ENST00000420246.6:c.*200C>T
ENST00000445888.6:c.1093C>T
ENST00000455263.6:c.*112C>T
ENST00000504290.5:c.*112C>T
ENST00000504937.5:c.697C>T
ENST00000510385.5:c.*200C>T
ENST00000576024.1:c.54-926C>T
ENST00000610292.4:c.976C>T
ENST00000610538.4:c.*112C>T
ENST00000610623.4:c.*112C>T
ENST00000615910.4:c.1060C>T
ENST00000617185.4:c.*200C>T
ENST00000618944.4:c.*200C>T
ENST00000619186.4:c.616C>T
ENST00000619485.4:c.976C>T
ENST00000620739.4:c.976C>T
ENST00000622645.4:c.*200C>T
ENST00000635293.1:c.976C>T
NM_001126112.2:c.1093C>T
NM_001126113.2:c.*112C>T
NM_001126114.2:c.*200C>T
NM_001126115.1:c.697C>T
NM_001126116.1:c.*200C>T
NM_001126117.1:c.*112C>T
NM_001126118.1:c.976C>T
NM_001276695.1:c.*112C>T
NM_001276696.1:c.*200C>T
NM_001276697.1:c.616C>T
NM_001276698.1:c.*200C>T
NM_001276699.1:c.*112C>T
NM_001276760.1:c.976C>T
NM_001276761.1:c.976C>T
NM_001276695.2:c.*112C>T
NM_001276696.2:c.*200C>T
NM_001276697.2:c.616C>T
NM_001276698.2:c.*200C>T
NM_001276699.2:c.*112C>T
NM_001276760.2:c.976C>T
NM_001276761.2:c.976C>T
NM_000546.6:c.1093C>T
NM_001126112.3:c.1093C>T
NM_001126113.3:c.*112C>T
NM_001126114.3:c.*200C>T
NM_001126115.2:c.697C>T
NM_001126116.2:c.*200C>T
NM_001126117.2:c.*112C>T
NM_001126118.2:c.976C>T
NM_001276695.3:c.*112C>T
NM_001276696.3:c.*200C>T
NM_001276697.3:c.616C>T
NM_001276698.3:c.*200C>T
NM_001276699.3:c.*112C>T
NM_001276760.3:c.976C>T
NM_001276761.3:c.976C>T

Likely Benign

Met criteria codes 4
PM2_Supporting BS2 BS3 BP4
Not Met criteria codes 13
BS1 BS4 PVS1 BA1 PS2 PS4 PS1 PS3 PP4 PP3 PP1 PM5 PM1

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.1093C>T variant in TP53 is a missense variant predicted to cause substitution of Histidine by Tyrosine at amino acid 365 (p.His365Tyr). 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: SCV000184430.7). This variant has an allele frequency of 0.000006785 (8/1179138 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 = 0.1352; Align GVGD Class C0) are below the recommended thresholds (BayesDel < 0.16 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 Likely Benign for Li Fraumeni Syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2_moderate, PM2_Supporting BS3, BP4. (Bayesian Points: -6; VCEP specifications version 2.0; 7/24/2024).
Met criteria codes
PM2_Supporting
This variant has an allele frequency of 0.000006785 (8/1179138 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 4-7 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: SCV000184430.7).
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)
BP4
Computational predictor scores (BayesDel = 0.1352; Align GVGD Class C0) are below the recommended thresholds (BayesDel < 0.16 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).
Not Met criteria codes
BS1
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
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
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
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
PP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM5
2 different missense variants (c.1094A>C, c.698A>G) 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).
PM1
This variant does not reside within a region of TP53 that is defined as a mutational hotspot by the ClinGen TP53 VCEP.
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