Gene Validity Curation

BRCA1 - Fanconi anemia, complementation group S

Gene: BRCA1 (HGNC:1100)
Classification - 05/14/2020
Disease: Fanconi anemia, complementation group S (MONDO_0054748)
Mode of Inheritance: Autosomal recessive inheritance (HP:0000007)
Replication over time: YES Contradictory Evidence: NO
Expert Panel: Hereditary Cancer EP
Evidence Summary: Fanconi anemia complementation group S (FANCS, OMIM:617883) is an autosomal recessive disorder characterized by developmental delay apparent from infancy, short stature, microcephaly, and coarse dysmorphic features. Homozygous or compound heterozygous pathogenic variants in BRCA1 have been reported to be associated with FANCS. In total, eight affected individuals with FANCS from six unrelated families were curated here. All three adult probands have breast or ovarian cancer diagnosed before age of 30 (PMID: 23269703; 25472942; 31347298). Two out of five younger probands were diagnosed with cancer: one with T-cell acute lymphoblastic leukemia at age 5 and one with neuroblastoma at age 2 (PMID:29712865). BRCA1, BRIP1, RAD51C, PALB2 have also been established as FA genes in the FA/BRCA DNA repair pathway. Multiple reports of functional assays using patients cells have consistent/similar results. For example, Sawyer SL, et al., 2015 (PMID: 25472942) indicated patient primary skin fibroblast cells showed reduced BRCA1 and Rad51 foci formation at IR induced damage sites and exhibited deficiency in DSB recognition. Rescue studies of PARP inhibition by Olaparib were also reported. In summary, BRCA1 is definitively associated with the autosomal recessive FANCS disorder. This has been 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
11
11.5
Domchek SM et al. 2013 Apr (PMID:23269703); Sawyer SL et al. 2015 Feb (PMID:25472942); Freire BL et al. 2018 Mar (PMID:29133208); Seo A et al. 2018 May 15 (PMID:29712865);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 1
0.5
Keupp K et al. 2019 Sep (PMID:31347298);
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) 11.5
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 8
8
2
Sawyer SL et al. 2015 Feb (PMID:25472942); Freire BL et al. 2018 Mar (PMID:29133208); Keupp K et al. 2019 Sep (PMID:31347298);
Non-patient cells 0.5 0 - 1 2 1
Domchek SM et al. 2013 Apr (PMID:23269703);
Models Non-human model organism 2 0 - 4 4 1
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
Sawyer SL et al. 2015 Feb (PMID:25472942);
Total Experimental Evidence Points (Maximum 6) 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 11.5 5 16.5 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
05/14/2020
EXPERT CURATION (DATE)
Definitive
05/14/2020
EVIDENCE SUMMARY
Fanconi anemia complementation group S (FANCS, OMIM:617883) is an autosomal recessive disorder characterized by developmental delay apparent from infancy, short stature, microcephaly, and coarse dysmorphic features. Homozygous or compound heterozygous pathogenic variants in BRCA1 have been reported to be associated with FANCS. In total, eight affected individuals with FANCS from six unrelated families were curated here. All three adult probands have breast or ovarian cancer diagnosed before age of 30 (PMID: 23269703; 25472942; 31347298). Two out of five younger probands were diagnosed with cancer: one with T-cell acute lymphoblastic leukemia at age 5 and one with neuroblastoma at age 2 (PMID:29712865). BRCA1, BRIP1, RAD51C, PALB2 have also been established as FA genes in the FA/BRCA DNA repair pathway. Multiple reports of functional assays using patients cells have consistent/similar results. For example, Sawyer SL, et al., 2015 (PMID: 25472942) indicated patient primary skin fibroblast cells showed reduced BRCA1 and Rad51 foci formation at IR induced damage sites and exhibited deficiency in DSB recognition. Rescue studies of PARP inhibition by Olaparib were also reported. In summary, BRCA1 is definitively associated with the autosomal recessive FANCS disorder. This has been demonstrated in both the research and clinical diagnostic settings and has been upheld over time.