Gene Validity Curation

FANCE - Fanconi anemia complementation group E

Gene: FANCE (HGNC:3586)
Classification - 05/14/2020
Disease: Fanconi anemia complementation group E (MONDO_0010953)
Mode of Inheritance: Autosomal recessive inheritance (HP:0000007)
Replication over time: YES Contradictory Evidence: NO
Expert Panel: Hereditary Cancer EP Contributors:
  • Hereditary Cancer GCEP
Evidence Summary: FANCE is one of the 23 FA or FA-like genes known to cause autosomal recessive Fanconi anemia (FA) characterized by bone marrow failure, developmental abnormalities, cancer predisposition, and cellular hypersensitivity to DNA cross-linking agents such as mitomycin C. The first patients with FA complementation group E were reported in 1996 (PMID: 9147877, 7662964). Five homozygous variants in the FANCE gene were observed in individuals with FA complementation group E, and three of these variants were reported to segregate with disease in three small families, suggesting homozygous loss of function is the mechanism of tumorigenesis for this disorder (PMID: 11001585, 17924555). This gene-disease relationship is further supported by rescue cell culture model, protein interaction and functional alteration studies. In summary, FANCE is definitively associated with FA complementation group E. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time.
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
Proband with predicted or proven null variant 1.5 0-2 10
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7
Autosomal Recessive Disease Two variants in trans and at least one de novo or a predicted/proven null variant 2 0-3 12 5
10
10
de Winter JP et al. 2000 Nov (PMID:11001585); Ameziane N et al. 2008 Jan (PMID:17924555);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5
Segregation Evidence   Summed LOD Family Count 0 0  
Candidate gene sequencing 1.33 1
de Winter JP et al. 2000 Nov (PMID:11001585);
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score 1.33    
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) 10
Experimental Evidence
Evidence Category Evidence Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Function Biochemical Function 0.5 0 - 2 2
2
Protein Interaction 0.5 0 - 2 1 2
Taniguchi T et al. 2002 Oct 1 (PMID:12239156);
Expression 0.5 0 - 2
Functional Alteration Patient cells 1 0 - 2 2 2
2
2
Polito D et al. 2014 Mar 7 (PMID:24451376);
Non-patient cells 0.5 0 - 1 1 0.5
Nookala RK et al. 2007 Feb 18 (PMID:17308347);
Models Non-human model organism 2 0 - 4 4 2
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 1 2
Taniguchi T et al. 2002 Oct 1 (PMID:12239156);
Rescue in patient cells 1 0 - 2
Total Experimental Evidence Points (Maximum 6) 6

 


 

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 10 6 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
05/14/2020
EXPERT CURATION (DATE)
Definitive
05/14/2020
EVIDENCE SUMMARY
FANCE is one of the 23 FA or FA-like genes known to cause autosomal recessive Fanconi anemia (FA) characterized by bone marrow failure, developmental abnormalities, cancer predisposition, and cellular hypersensitivity to DNA cross-linking agents such as mitomycin C. The first patients with FA complementation group E were reported in 1996 (PMID: 9147877, 7662964). Five homozygous variants in the FANCE gene were observed in individuals with FA complementation group E, and three of these variants were reported to segregate with disease in three small families, suggesting homozygous loss of function is the mechanism of tumorigenesis for this disorder (PMID: 11001585, 17924555). This gene-disease relationship is further supported by rescue cell culture model, protein interaction and functional alteration studies. In summary, FANCE is definitively associated with FA complementation group E. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time.