BRCA1 Gene Curation
- Andrea Oza
Gene-disease assertions not curated here (add link or write note):
Disease | Hereditary breast and ovarian cancer |
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Inheritance | Autosomal dominant |
Prevalence | 1:70 (common) Source: Orphanet |
Rapid or full curation? | Rapid Full |
ClinGen Breast/Ovarian Cancer GCEP, accessed 06.23.2023 | |
Clinical Validity Scoring Notes and points | Not published by GCEP |
Clinical Validity Points Total | N/A Source: ClinGen Breast/Ovarian Cancer GCEP, accessed 06.23.2023 |
Clinical Validity Classification Definitive (12pts) Strong (12pts) Moderate (7-11pts) Limited (0.1-6pts) No genetic evidence Refuted Disputed | Definitive Source: ClinGen Breast/Ovarian Cancer GCEP, accessed 06.23.2023 |
Molecular Mechanism Loss of function Gain of function Dominant negative Unknown Other | Loss of function (with Caveats, see SOP)
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Penetrance Complete (100%) High (≥90%) Reduced (<90% and >10%) Low (≤10%) (list source/PMID) | Reduced (may vary by variant) |
Age of Onset Congenital Pediatric Adolescent Adulthood Late adulthood (list source/PMID) | Adulthood |
Severity | Moderate |
Clinical Features | female and male breast cancer, ovarian cancer (including fallopian tube and primary peritoneal cancers), and to a lesser extent other cancers such as prostate cancer, pancreatic cancer, and melanoma primarily in individuals with a BRCA2 pathogenic variant Sources: |
Gene SOPs & Notes | See full list of ENGIMA guidance here https://docs.google.com/document/d/1Y1pOVN_q2L4Muvz40esgOeqP8kg9c_hR/edit?usp=drive_link&ouid=112394273326480266110&rtpof=true&sd=true PVS1 downgrade flags. Make sure to fully review and appropriately downgrade PVS1 for the following canonical splice site locations: https://broadinstitute.atlassian.net/browse/CIT-141
Most 3' Pathogenic variant - According to ENIGMA, the most 3' pathogenic variant in eon 24 is Y1863X (c.5559C>G p.Tyr1853Ter. Please fully curate if needed. PS4: Proband counting is not currently allowed |
Curation Summary: | The BRCA1 gene is associated with autosomal dominant hereditary breast and ovarian cancer syndrome, which is characterized by increased risk for female and male breast cancer, ovarian cancer, pancreatic cancer, and prostate cancer. The National Comprehensive Cancer Network provides management guidelines for individuals with a pathogenic variant in this gene. The BRCA1 gene is also associated with autosomal dominant Fanconi anemia. |
Case ID, Curator name, Date, Jira ticket link | https://broadinstitute.atlassian.net/browse/CIT-141 https://broadinstitute.atlassian.net/browse/CIT-130 Andrea Oza 06.23.2023 |
Disease | Fanconi anemia |
|---|---|
Inheritance | Autosomal recessive |
Prevalence |
Source: |
Rapid or full curation? | Rapid Full |
Hereditary Cancer GCEP accessed 6.23.2023 | |
Clinical Validity Scoring Notes and points | 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. Source: Hereditary Cancer GCEP accessed 6.23.2023 |
Clinical Validity Points Total | 16.5 Source: Hereditary Cancer GCEP accessed 6.23.2023 |
Clinical Validity Classification | Definitive Source: Hereditary Cancer GCEP accessed 6.23.2023 |
Molecular Mechanism | Unknown, potentially LOF with caveats - Complete biallelic loss of BRCA1 was thought to be embryonic lethal. However, several truncating variants reported to date located in exon 11 have been reported in individuals with FA. It is thought this is due to a naturally occuring alternative splice donor in exon 11 that lies 5' to the variants and produces 2 short isoforms that lack the residues affected by tehe mutations (PMID: 29712865) |
Penetrance (list source/PMID) |
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Age of Onset (list source/PMID) |
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Severity |
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Clinical Features |
Sources: |
Gene SOPs & Notes | SEE NOTES ABOVE UNDER HBOC |
Curation Summary: |
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Case ID, Curator name, Date, Jira ticket link | Andrea Oza 06.23.2023 https://broadinstitute.atlassian.net/browse/CIT-141 https://broadinstitute.atlassian.net/browse/CIT-130 |