Gene Validity Classification Summary

Gene/Disease Pair:

BAP1 : BAP1-related tumor predisposition syndrome

HGNC:950 | MONDO_0013692
Mode of Inheritance: Autosomal dominant inheritance (HP:0000006)
Expert Panel: Hereditary Cancer EP
SOP: Gene Clinical Validity Standard Operating Procedures (SOP), Version 6

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 7 10.5 10
Wiesner T et al. 2011 Aug 28 (PMID:21874003); Testa JR et al. 2011 Aug 28 (PMID:21874000); Abdel-Rahman MH et al. 2011 Dec (PMID:21941004);
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
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5
Segregation Evidence   Summed LOD Family Count 2.3 2.3  
Candidate gene sequencing 4.22 2
Wiesner T et al. 2011 Aug 28 (PMID:21874003); Abdel-Rahman MH et al. 2011 Dec (PMID:21941004);
Exome/genome or all genes sequenced in linkage region 4.81 2
Testa JR et al. 2011 Aug 28 (PMID:21874000);
Total Summed LOD Score 9.03    
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
1.5
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2 3 1.5
Wiesner T et al. 2011 Aug 28 (PMID:21874003); Testa JR et al. 2011 Aug 28 (PMID:21874000); Abdel-Rahman MH et al. 2011 Dec (PMID:21941004);
Functional Alteration Patient cells 1 0 - 2 2
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4 3 5 4
Dey A et al. 2012 Sep 21 (PMID:22878500); Kadariya Y et al. 2016 May 1 (PMID:26896281); Napolitano A et al. 2016 Apr 14 (PMID:26119930);
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 1
Testa JR et al. 2011 Aug 28 (PMID:21874000);
Rescue in patient cells 1 0 - 2
Total Experimental Evidence Points (Maximum 6) 5.5

 


 

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 5.5 17.5 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
10/12/2018
EXPERT CURATION (DATE)
Definitive
10/12/2018
EVIDENCE SUMMARY
There is abundant published evidence associating the BAP1 gene with BAP1-related tumor predisposition syndrome since the gene-disease relationship was first proposed by Testa et al. (2011). Multiple case level studies have been performed with patients that have variants in the BAP1 gene. Immunohistochemistry on mesotheliomas from multiple families revealed lack of BAP1 nuclear expression. BAP1+/− mice develop more malignant mesotheliomas and spontaneous tumor development was found in three different mouse models with germline heterozygous mutations in Bap1, including two models in which the knock-in mutations are identical to those reported in human BAP1 cancer syndrome families. Re-expression of BAP1 in BAP1-deficient mesothelioma cells markedly decreased colony-forming ability. All of these types of evidence are consistent with a definitive relationship between the BAP1 gene and BAP1-related tumor predisposition syndrome.