Gene Validity Curation

BRIP1 - Fanconi anemia complementation group j

Gene: BRIP1 (HGNC:20473)
Classification - 08/18/2019
Disease: Fanconi anemia complementation group j (MONDO_0012187)
Mode of Inheritance: Autosomal recessive inheritance (HP:0000007)
Replication over time: YES Contradictory Evidence: NO
Expert Panel: Hereditary Cancer EP
Evidence Summary: BRIP1 gene, the BRCA1-interacting helicase, has been associated with Fanconi anemia of complementation group J (FANCJ) (#609054). At least 27 variants have reported in unrelated families/groups. Here we record 5 individuals in 4 families (3 Innuit individuals and 2 Hispanic individuals) and 6 individuals in a group of 18 FA cases of unassigned FA complementation group from IFAR [Livran O et al., PubMed: 16116424]; 6 individuals from various backgrounds, many with reported consanguinity (Iran, Canada, UK and Kuwait) from EUFA [Levitus M et al., PMID: 16116423]. Most of these FA individuals either have homozygous or compound heterozygous mutations in BRIP1 gene. The most common one, 2533C>T (R798X), may be a hot spot or an ancient mutation. Immunoblotting showed no BRIP1 protein in lymphoblastoid cells line from individuals who were homozygous or heterozygous with respect to 2533C-T/R798X (R798X/8003A>T and R798X/Y800X) (Levran O et al., 2005.). Western blot using antibody against BRIP1 showed the absence of a full-length BRIP1 protein band in nuclear extracts from cell lines carrying truncating mutations, whereas an attenuated band was observed in the cell line from individual EUFA776 with two missense mutations (1941G>C/W647C and 2119C>T/R707C) (Levitus M et al,. 2005.). Purified recombinant A349P allele protein had reduced iron and was defective in coupling adenosine triphosphate (ATP) hydrolysis and translocase activity to unwinding forked duplex or G-quadruplex DNA substrates or disrupting protein-DNA complexes. The FANCJ-A349P allele failed to rescue cisplatin or telomestatin sensitivity of a FA-J null cell line. Experimental evidences are replicably showed its DNA repair function. Mutations in this gene abolish its DNA helicase activity in cellular levels and animal models.
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 15
30
12
Levran O et al. 2005 Sep (PMID:16116424); Levitus M et al. 2005 Sep (PMID:16116423);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 1
1
Levitus M et al. 2005 Sep (PMID:16116423);
Segregation Evidence   Summed LOD Family Count  
Candidate gene sequencing
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score    
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
Wu Y et al. 2010 Nov 11 (PMID:20639400);
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2 1 0.5
Levran O et al. 2005 Sep (PMID:16116424);
Functional Alteration Patient cells 1 0 - 2 2 1
1
1.5
Litman R et al. 2005 Sep (PMID:16153896);
Non-patient cells 0.5 0 - 1 1 0.5
Wu Y et al. 2010 Nov 11 (PMID:20639400);
Models Non-human model organism 2 0 - 4 4 2 3 4
Sun X et al. 2016 Jun (PMID:26490168); Matsuzaki K et al. 2015 Dec 15 (PMID:26637282);
Cell culture model 1 0 - 2 3 3
Bridge WL et al. 2005 Sep (PMID:16116421); Litman R et al. 2005 Sep (PMID:16153896);
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) 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 12 6 18 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
08/18/2019
EXPERT CURATION (DATE)
Definitive
08/18/2019
EVIDENCE SUMMARY
BRIP1 gene, the BRCA1-interacting helicase, has been associated with Fanconi anemia of complementation group J (FANCJ) (#609054). At least 27 variants have reported in unrelated families/groups. Here we record 5 individuals in 4 families (3 Innuit individuals and 2 Hispanic individuals) and 6 individuals in a group of 18 FA cases of unassigned FA complementation group from IFAR [Livran O et al., PubMed: 16116424]; 6 individuals from various backgrounds, many with reported consanguinity (Iran, Canada, UK and Kuwait) from EUFA [Levitus M et al., PMID: 16116423]. Most of these FA individuals either have homozygous or compound heterozygous mutations in BRIP1 gene. The most common one, 2533C>T (R798X), may be a hot spot or an ancient mutation. Immunoblotting showed no BRIP1 protein in lymphoblastoid cells line from individuals who were homozygous or heterozygous with respect to 2533C-T/R798X (R798X/8003A>T and R798X/Y800X) (Levran O et al., 2005.). Western blot using antibody against BRIP1 showed the absence of a full-length BRIP1 protein band in nuclear extracts from cell lines carrying truncating mutations, whereas an attenuated band was observed in the cell line from individual EUFA776 with two missense mutations (1941G>C/W647C and 2119C>T/R707C) (Levitus M et al,. 2005.). Purified recombinant A349P allele protein had reduced iron and was defective in coupling adenosine triphosphate (ATP) hydrolysis and translocase activity to unwinding forked duplex or G-quadruplex DNA substrates or disrupting protein-DNA complexes. The FANCJ-A349P allele failed to rescue cisplatin or telomestatin sensitivity of a FA-J null cell line. Experimental evidences are replicably showed its DNA repair function. Mutations in this gene abolish its DNA helicase activity in cellular levels and animal models.