Gene Validity Curation

CEBPA - acute myeloid leukemia

Gene: CEBPA (HGNC:1833)
Classification - 08/18/2019
Disease: acute myeloid leukemia (MONDO_0018874)
Mode of Inheritance: Autosomal dominant inheritance (HP:0000006)
Replication over time: YES Contradictory Evidence: NO
Expert Panel: Hereditary Cancer EP
Evidence Summary: CEBPA was first reported in relation to autosomal dominant acute myeloid leukemia in 2004 (Smith et al., 2004 PMID: 15575056). At least 16 unique variants (primarily frameshift but also missense and nonsense) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. Summary of Case Level Data: 12 points Variants in this gene have been reported in at least 16 probands in 11 publications (PMIDs: 21455213, 30563700, 23716546, 21177436, 26162409, 19953636, 18946494, 18768433, 15902292, 15575056, 26721895). Variants in this gene segregated with disease in 15 additional family members. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism for disease is primarily through a dominant negative effect. N-terminal frameshift mutations cause truncation of the 42-kD CEBPA protein and overproduction of a 30-kD which functions in a dominant negative fashion (Pabst et al., 2001 PMID: 11242107). A small set of variants have also been identified near the C-terminal end, in the basic leucine zipper region, which is predicted to disrupt the DNA binding and dimerization of CEBPA. EXPERIMENTAL EVIDENCE: 4 points This gene-disease association is supported by functional alteration of its biochemical function, its expression, and animal models. CEBPA functions as a myeloid transcription factor, acting as an important mediator of granulocytic maturation (Wang et al., 1999 PMID: 10397723). This is supported by the expression of CEBPA both in normal development and during malignancy (Scott et al., 1992 PMID: 1391942). This role in granulocytic maturation is disrupted by N-terminal frameshift mutations, as observed in non-patient H1299 cells (Pabst et al., 2008 PMID: 18768433). This is supported by mice carrying engineered Cebpa alleles, that specifically disrupt the 42-kDa wild-type protein while allowing expression of the dominant-negative 30-kDa form, which led to development of AML with complete penetrance (Kirstetter et al., 2008 PMID: 18394553).
Genetic Evidence
Case-Level Data
Evidence Type Case Information Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Variant Evidence
Autosomal Dominant or X-linked Disorder Variant is de novo 2 0-3 12 1
2
2
Stelljes M et al. 2011 Jul (PMID:21455213);
Proband with predicted or proven null variant 1.5 0-2 10 13 8.5 8.5
Smith ML et al. 2004 Dec 2 (PMID:15575056); Sellick GS et al. 2005 Jul (PMID:15902292); Pabst T et al. 2008 Nov 1 (PMID:18768433); Renneville A et al. 2009 Apr (PMID:18946494); Nanri T et al. 2010 Mar (PMID:19953636); Tawana K et al. 2015 Sep 3 (PMID:26162409); Taskesen E et al. 2011 Feb 24 (PMID:21177436); Debeljak M et al. 2013 Jul (PMID:23716546); Kim HS et al. 2019 Jan (PMID:30563700);
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7 2
0.75
0.75
Pathak A et al. 2016 July (PMID:26721895); Kim HS et al. 2019 Jan (PMID:30563700);
Autosomal Recessive Disease Two variants in trans and at least one de novo or a predicted/proven null variant 2 0-3 12
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5
Segregation Evidence   Summed LOD Family Count 1 1  
Candidate gene sequencing
Exome/genome or all genes sequenced in linkage region 2.71 1
Pathak A et al. 2016 July (PMID:26721895);
Total Summed LOD Score 2.71    
Case-Control Data
Case-Control Study Type Case-Control Quality Criteria Guidelines Points PMIDs/Notes
Points/Study Max Count Points Counted
Single Variant Analysis 1. Variant Detection Methodology
2. Power
3. Bias and confounding
4. Statistical Significance
0-6 12
Aggregate Variant Analysis 0-6
Total Genetic Evidence Points (Maximum 12) 12
Experimental Evidence
Evidence Category Evidence Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Function Biochemical Function 0.5 0 - 2 2 1
0.5
1.5
Wang X et al. 1999 Jul 15 (PMID:10397723);
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2 1 1
Scott LM et al. 1992 Oct 1 (PMID:1391942);
Functional Alteration Patient cells 1 0 - 2 2
0.5
Non-patient cells 0.5 0 - 1 1 0.5
Pabst T et al. 2008 Nov 1 (PMID:18768433);
Models Non-human model organism 2 0 - 4 4 1 2 2
Kirstetter P et al. 2008 Apr (PMID:18394553);
Cell culture model 1 0 - 2
Rescue Rescue in human 2 0 - 4
Rescue in non-human model organism 2 0 - 4
Rescue in cell culture model 1 0 - 2
Rescue in patient cells 1 0 - 2
Total Experimental Evidence Points (Maximum 6) 4

 


 

Assertion criteria Genetic Evidence (0-12 points) Experimental Evidence
(0-6 points)
Total Points
(0-18)
Replication Over Time (Y/N)
Description Case-level, family segregation, or case-control data that support the gene-disease association Gene-level experimental evidence that support the gene-disease association Sum of Genetic & Experimental
Evidence
> 2 pubs w/ convincing evidence over time (>3 yrs)
Assigned Points 12 4 16 YES
CALCULATED CLASSIFICATION LIMITED 1-6
MODERATE 7-11
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
NO
CALCULATED CLASSIFICATION (DATE)
Definitive
06/19/2019
EXPERT CURATION (DATE)
Definitive
08/18/2019
EVIDENCE SUMMARY
CEBPA was first reported in relation to autosomal dominant acute myeloid leukemia in 2004 (Smith et al., 2004 PMID: 15575056). At least 16 unique variants (primarily frameshift but also missense and nonsense) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. Summary of Case Level Data: 12 points Variants in this gene have been reported in at least 16 probands in 11 publications (PMIDs: 21455213, 30563700, 23716546, 21177436, 26162409, 19953636, 18946494, 18768433, 15902292, 15575056, 26721895). Variants in this gene segregated with disease in 15 additional family members. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism for disease is primarily through a dominant negative effect. N-terminal frameshift mutations cause truncation of the 42-kD CEBPA protein and overproduction of a 30-kD which functions in a dominant negative fashion (Pabst et al., 2001 PMID: 11242107). A small set of variants have also been identified near the C-terminal end, in the basic leucine zipper region, which is predicted to disrupt the DNA binding and dimerization of CEBPA. EXPERIMENTAL EVIDENCE: 4 points This gene-disease association is supported by functional alteration of its biochemical function, its expression, and animal models. CEBPA functions as a myeloid transcription factor, acting as an important mediator of granulocytic maturation (Wang et al., 1999 PMID: 10397723). This is supported by the expression of CEBPA both in normal development and during malignancy (Scott et al., 1992 PMID: 1391942). This role in granulocytic maturation is disrupted by N-terminal frameshift mutations, as observed in non-patient H1299 cells (Pabst et al., 2008 PMID: 18768433). This is supported by mice carrying engineered Cebpa alleles, that specifically disrupt the 42-kDa wild-type protein while allowing expression of the dominant-negative 30-kDa form, which led to development of AML with complete penetrance (Kirstetter et al., 2008 PMID: 18394553).