The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

  • See Evidence submitted by expert panel for details.

Variant: NM_000546.5(TP53):c.1040C>A (p.Ala347Asp)

CA000022

43587 (ClinVar)

Gene: TP53
Condition: Li-Fraumeni syndrome
Inheritance Mode: Autosomal dominant inheritance
UUID: d4905d59-9322-441b-9ed0-ea2304d97a65

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
ENST00000269305.9:c.1040C>A
ENST00000269305.8:c.1040C>A
ENST00000359597.8:n.993+2866C>A
ENST00000413465.6:n.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:n.54-979C>A
ENST00000610292.4:c.923C>A
ENST00000610538.4:c.*59C>A
ENST00000610623.4:c.*59C>A
ENST00000615910.4:n.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
NM_000546.6(TP53):c.1040C>A (p.Ala347Asp)

Likely Pathogenic

Met criteria codes 4
PM2_Supporting PS3 PS4_Supporting PP1_Moderate
Not Met criteria codes 1
PP3

Evidence Links 2

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
TP53 VCEP
This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). Transactivation assays show a low functioning allele according to Kato, et al. and there is a tetramerization assay demonstrating a mutant protein that only forms dimers (PS3; PMID: 12826609, PMID: 16007150). This variant has been reported in 1 proband meeting Classic Li-Fraumeni syndrome criteria (PS4_Supporting; PMID: 27496084). The variant was found to co-segregation with disease in this proband’s family, with 5 or 6 meioses observed (PP1_Moderate; PMID: 27496084). In summary, TP53 c.1040C>A; p.Ala347Asp meets criteria to be classified as likely pathogenic for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: PM2_Supporting, PS3, PS4_Supporting, PP1_Moderate.
Met criteria codes
PM2_Supporting
Absent in population databases
PS3
T-A assay shows non-functional allele plus abnl tetramer formation as 2nd study.
PS4_Supporting
One proband meeting LFS criteria from EP submitter that is referenced in PMID: 27496084 = 1 pt

PP1_Moderate
Variant segregates in large family submitted by EP member.
Not Met criteria codes
PP3
Conflicting predictions between BayesDel and AGVGD
Approved on: 2022-03-18
Published on: 2022-03-18
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