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Please note this is a beta version of the ClinGen Evidence Repository. This resource is intended to provide access to variant level evidence used and applied by ClinGen Variant Curation Expert Panels in the classification of variants. In this beta version, the evidence is limited to curation notes and referenced literature (PMIDs).

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Criteria Specification: CSpec Registry PDF

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

CA000022

43587 (ClinVar)

Gene: TP53
Condition: Li-Fraumeni syndrome
Inheritance Mode: Autosomal dominant inheritance

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
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
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

Likely Pathogenic

Met criteria codes 4
PP1_Moderate PS4_Supporting PS3 PM2_Supporting
Unmet criteria codes 1
PP3

Expert Panel

Evidence Links 2

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
PP1_Moderate
Variant segregates in large family submitted by EP member.
PS4_Supporting
One proband meeting LFS criteria from EP submitter that is referenced in PMID: 27496084 = 1 pt

PS3
T-A assay shows non-functional allele plus abnl tetramer formation as 2nd study.
PM2_Supporting
Absent in population databases
Unmet criteria codes
PP3
Conflicting predictions between BayesDel and AGVGD
Approved on: 2019-08-28
Published on: 2020-01-24
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