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_000546.5(TP53):c.1040C>A (p.Ala347Asp)

CA000022

43587 (ClinVar)

Gene: TP53
Condition: Li-Fraumeni syndrome
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: d4905d59-9322-441b-9ed0-ea2304d97a65
Approved on: 2024-08-05
Published on: 2024-08-05

HGVS expressions

NM_000546.5:c.1040C>A
NM_000546.5(TP53):c.1040C>A (p.Ala347Asp)
NC_000017.11:g.7670669G>T
CM000679.2:g.7670669G>T
NC_000017.10:g.7573987G>T
CM000679.1:g.7573987G>T
NC_000017.9:g.7514712G>T
NG_017013.2:g.21882C>A
ENST00000503591.2:c.1040C>A
ENST00000508793.6:c.1040C>A
ENST00000509690.6:c.644C>A
ENST00000514944.6:c.761C>A
ENST00000604348.6:c.1019C>A
ENST00000269305.9:c.1040C>A
ENST00000269305.8:c.1040C>A
ENST00000359597.8:c.993+2866C>A
ENST00000413465.6:c.782+3512C>A
ENST00000420246.6:c.*147C>A
ENST00000445888.6:c.1040C>A
ENST00000455263.6:c.*59C>A
ENST00000504290.5:c.*59C>A
ENST00000504937.5:c.644C>A
ENST00000510385.5:c.*147C>A
ENST00000576024.1:c.54-979C>A
ENST00000610292.4:c.923C>A
ENST00000610538.4:c.*59C>A
ENST00000610623.4:c.*59C>A
ENST00000615910.4:c.1007C>A
ENST00000617185.4:c.*147C>A
ENST00000618944.4:c.*147C>A
ENST00000619186.4:c.563C>A
ENST00000619485.4:c.923C>A
ENST00000620739.4:c.923C>A
ENST00000622645.4:c.*147C>A
ENST00000635293.1:c.923C>A
NM_001126112.2:c.1040C>A
NM_001126113.2:c.*59C>A
NM_001126114.2:c.*147C>A
NM_001126115.1:c.644C>A
NM_001126116.1:c.*147C>A
NM_001126117.1:c.*59C>A
NM_001126118.1:c.923C>A
NM_001276695.1:c.*59C>A
NM_001276696.1:c.*147C>A
NM_001276697.1:c.563C>A
NM_001276698.1:c.*147C>A
NM_001276699.1:c.*59C>A
NM_001276760.1:c.923C>A
NM_001276761.1:c.923C>A
NM_001276695.2:c.*59C>A
NM_001276696.2:c.*147C>A
NM_001276697.2:c.563C>A
NM_001276698.2:c.*147C>A
NM_001276699.2:c.*59C>A
NM_001276760.2:c.923C>A
NM_001276761.2:c.923C>A
NM_000546.6:c.1040C>A
NM_001126112.3:c.1040C>A
NM_001126113.3:c.*59C>A
NM_001126114.3:c.*147C>A
NM_001126115.2:c.644C>A
NM_001126116.2:c.*147C>A
NM_001126117.2:c.*59C>A
NM_001126118.2:c.923C>A
NM_001276695.3:c.*59C>A
NM_001276696.3:c.*147C>A
NM_001276697.3:c.563C>A
NM_001276698.3:c.*147C>A
NM_001276699.3:c.*59C>A
NM_001276760.3:c.923C>A
NM_001276761.3:c.923C>A
More

Pathogenic

Met criteria codes 4
PM2_Supporting PS4 PS3 PP1_Moderate
Not Met criteria codes 10
BS2 BS1 BP4 PS2 PS1 PP4 PP3 BA1 PM1 PM5

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.1040C>A variant in TP53 is a missense variant predicted to cause substitution of alanine by aspartic acid at amino acid 347 (p.Ala347Asp). This variant has been reported in 4 unrelated families meeting Classic/Revised Chompret criteria reported in 1 individuals under the age of 40 diagnosed with a HER2+ breast cancer. Based on this evidence, this variant scores 4 total points meeting the TP53 VCEP phenotype scoring criteria of 4-7.5 points. (PS4; PMID: 27496084, Internal lab contributors).The variant has been reported to segregate with LFS-associated cancers in 13 meioses in 1 family (PP1_Moderate; Internal contributor: National Cancer Institute). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In vitro assays performed in yeast and/or human cell lines showed non-functional transactivation and loss of growth suppression activity indicating that this variant impacts protein function (PS3; PMIDs: 37067901, 12826609, 30224644, 29979965). In summary, this variant meets the criteria to be classified as Pathogenic for Li Fraumeni Syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PS4, PP1_Moderate, PM2_Supporting, PS3. (Bayesian Points: 11; VCEP specifications version 2.0; 7/24/2024)
Met criteria codes
PM2_Supporting
This variant is absent from gnomAD v4.1.0 (PM2_Supporting).
PS4
This variant has been reported in 4 unrelated families meeting Classic/Revised Chompret criteria reported in 1 individuals under the age of 40 diagnosed with a HER2+ breast cancer. Based on this evidence, this variant scores 4 total points meeting the TP53 VCEP phenotype scoring criteria of 4-7.5 points. (PS4; PMID: 27496084, Internal lab contributors).
PS3
In vitro assays performed in yeast and/or human cell lines showed non-functional transactivation and loss of growth suppression activity indicating that this variant impacts protein function (PS3; PMIDs: 37067901, 12826609, 30224644, 29979965).
PP1_Moderate
The variant has been reported to segregate with LFS-associated cancers in 13 meioses in 1 family (PP1_Moderate; Internal contributor: National Cancer Institute).
Not Met criteria codes
BS2
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 and AlignGVGD do not agree, providing no evidence that correlates with a damaging or benign impact on TP53 function via protein change. Additionally, the computational splicing predictor SpliceAI gives a score of 0.00, predicting 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
PS1
None
PP4
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 and AlignGVGD do not agree, providing no evidence that correlates with a damaging or benign impact on TP53 function via protein change. Additionally, the computational splicing predictor SpliceAI gives a score of 0.00, predicting that the variant has no impact on splicing (score threshold ≤ 0.10) (PP3 and BP4 not met).
BA1
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
3 different missense variants (p.Ala347Val; p.Ala347Ser; p.Ala347Thr) in the same codon have been reported (ClinVar Variation IDs: 422725, 1773570, 662690). However, these variants have not yet met the criteria to be classified as pathogenic or likely pathogenic by the ClinGen TP53 VCEP’s specifications (PM5 not met).
Curation History
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