Evidence Repository - Clinical Genome Resources

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

Variant: NM_000546.5(TP53):c.1163A>C (p.Glu388Ala)

Curation Version - 1.2
Curation History
JSON LD for Version 1.2

CA000047

141425 (ClinVar)

Gene: TP53

Condition: Li-Fraumeni syndrome

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 4ef47921-0407-4ece-a6d2-91823363a565

Approved on: 2022-01-10

Published on: 2022-01-10

HGVS expressions

NM_000546.5:c.1163A>C

NM_000546.5(TP53):c.1163A>C (p.Glu388Ala)

NC_000017.11:g.7669628T>G

CM000679.2:g.7669628T>G

NC_000017.10:g.7572946T>G

CM000679.1:g.7572946T>G

NC_000017.9:g.7513671T>G

NG_017013.2:g.22923A>C

ENST00000269305.9:c.1163A>C

ENST00000269305.8:c.1163A>C

ENST00000359597.8:n.994-3384A>C

ENST00000413465.6:n.782+4553A>C

ENST00000420246.6:c.*270A>C

ENST00000445888.6:c.1163A>C

ENST00000455263.6:c.*182A>C

ENST00000504290.5:c.*182A>C

ENST00000504937.5:c.767A>C

ENST00000510385.5:c.*270A>C

ENST00000576024.1:n.116A>C

ENST00000610292.4:c.1046A>C

ENST00000610538.4:c.*182A>C

ENST00000610623.4:c.*182A>C

ENST00000615910.4:n.1130A>C

ENST00000617185.4:c.*270A>C

ENST00000618944.4:c.*270A>C

ENST00000619186.4:c.686A>C

ENST00000619485.4:c.1046A>C

ENST00000620739.4:c.1046A>C

ENST00000622645.4:c.*270A>C

ENST00000635293.1:c.983+981A>C

NM_001126112.2:c.1163A>C

NM_001126113.2:c.*182A>C

NM_001126114.2:c.*270A>C

NM_001126115.1:c.767A>C

NM_001126116.1:c.*270A>C

NM_001126117.1:c.*182A>C

NM_001126118.1:c.1046A>C

NM_001276695.1:c.*182A>C

NM_001276696.1:c.*270A>C

NM_001276697.1:c.686A>C

NM_001276698.1:c.*270A>C

NM_001276699.1:c.*182A>C

NM_001276760.1:c.1046A>C

NM_001276761.1:c.1046A>C

NM_001276695.2:c.*182A>C

NM_001276696.2:c.*270A>C

NM_001276697.2:c.686A>C

NM_001276698.2:c.*270A>C

NM_001276699.2:c.*182A>C

NM_001276760.2:c.1046A>C

NM_001276761.2:c.1046A>C

NM_000546.6:c.1163A>C

NM_001126112.3:c.1163A>C

NM_001126113.3:c.*182A>C

NM_001126114.3:c.*270A>C

NM_001126115.2:c.767A>C

NM_001126116.2:c.*270A>C

NM_001126117.2:c.*182A>C

NM_001126118.2:c.1046A>C

NM_001276695.3:c.*182A>C

NM_001276696.3:c.*270A>C

NM_001276697.3:c.686A>C

NM_001276698.3:c.*270A>C

NM_001276699.3:c.*182A>C

NM_001276760.3:c.1046A>C

NM_001276761.3:c.1046A>C

NM_000546.6(TP53):c.1163A>C (p.Glu388Ala)

Likely Benign

BS3 BP4 BS2_Supporting

PM6 PM2 PM1 PM5 PVS1 BA1 BS4 BS1 BP2 PS2 PS3 PS1 PP1 PP3

Evidence Links 3

Expert Panel

TP53 VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

TP53 VCEP

Transactivation assays show retained function according to Kato, et al. and there is no evidence of a dominant negative effect or loss of function according to Giacomelli, et al. (BS3; PMID: 12826609, 30224644). This variant has a BayesDel score < 0.16 and Align GVGD (Zebrafish) is Class C0 (BP4). This variant has been observed in 2-7 60+ year old females without a cancer diagnosis (BS2_Supporting; Internal laboratory contributor). In summary, TP53 c.1163A>C (p.Glu388Ala) meets criteria to be classified as likely benign for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: BS3, BP4, BS2_Supporting.

BS3

Functional (Kato et al 2003, 100% mean transactivation activity (>75%)) noDNE+noLOF (Giacomelli et al. 2018, p53WTNutlin3 Z-score -0.248 (< 0.61) and Etoposide Z-score 1.239 (> -0.21 ))

noDNE+noLOF (p53WTNutlin3 Z-score -0.248 (< 0.61) and Etoposide Z-score 1.239 (> -0.21 )) PubMed:30224644

nuclear localization not affected but mutation of the SUMO consensus as E388A p53 would prevent both SUMO-1 and SUMO-2/3 conjugation onto p53, but our experiments were performed under conditions where SUMO-2/3 conjugation of p53 was detectable, while SUMO-1 modification was not. PubMed:21900752

Functional (100% mean transactivation activity (>75%)) PubMed:12826609

BP4

Bayesdel is -0.0336 and AGVGD is C0

BS2_Supporting

Ambry labs 2 female cases cancer free at age 60 (SCV000184752.5).

PM6

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PM2

1 allele in gnomAD

PM1

Not selected hotspot codon or seen in cancerhotspots.org

PM5

The current variant is the only variant found in this codon in ClinVar.

PVS1

missense variant

BA1

Absent from ExAC, 1000 Genomes, ESP, 1 allele in gnomAD

BS4

Li et al. 2016 (PMID: 26534844): Figure 1, family 71, 2 individuals with a personal history of BC (no LFS criteria or Chompret ), in 4 unaffected individuals, and absent in 1 individual with a personal history of BC

BS1

<0.03%

BP2

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

PS3

Stindt et al. 2011 (21900752): nuclear localization not affected but mutation of the SUMO consensus as E388A p53 would prevent both SUMO-1 and SUMO-2/3 conjugation onto p53, but our experiments were performed under conditions where SUMO-2/3 conjugation of p53 was detectable, while SUMO-1 modification was not. (conflicting evidence but overruled by Kato-Functional)

PS1

The current variant is the only variant found in this codon in ClinVar.

PP1

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PP3

Bayesdel is -0.0336 and AGVGD is C0

Curation History

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.