Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

BRCA2 : Fanconi anemia complementation group D1

HGNC:1101 | MONDO_0011584
Mode of Inheritance: Autosomal recessive inheritance (HP:0000007)
Expert Panel: Hereditary Cancer
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
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 6
12
12
Howlett NG et al. 2002 Jul 26 (PMID:12065746); Hirsch B et al. 2004 Apr 1 (PMID:14670928); Wagner JE et al. 2004 Apr 15 (PMID:15070707);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 1
1.5
Howlett NG et al. 2002 Jul 26 (PMID:12065746);
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
2
2
Nalepa G et al. 2018 Mar (PMID:29376519);
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2
Functional Alteration Patient cells 1 0 - 2 2
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4 2 3 4
Navarro S et al. 2006 Oct (PMID:16859999); McAllister KA et al. 2002 Feb 15 (PMID:11861370);
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 1 1
Howlett NG et al. 2002 Jul 26 (PMID:12065746);
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
04/19/2019
EXPERT CURATION (DATE)
Definitive
04/19/2019
EVIDENCE SUMMARY
There is abundant evidence published associating the BRCA2 gene with Fanconi anemia complementation group D1, since the gene-disease relationship was first proposed by Howlett et al. (2002). Multiple case level studies have been performed with FA patients that have variants in the BRCA2 gene. BRCA1, BRIP1, RAD51C, PALB2 have also been established as FA genes in the FA/BRCA DNA repair pathway. Multiple Brca2 deficient mouse models have been established to show consistent phenotypes with FA patients including increased overall tumor incidence, decreased survival and hematopoietic dysfunction. Wildtype BRCA2 cDNA restored mitomycin C (MMC) resistance in patient derived fibroblasts. All of these types of evidence are consistent with a definitive relationship between the BRCA2 gene and Fanconi anemia complementation group D1.