BRCA2 Gene Curation
- Andrea Oza
Gene-disease assertions not curated here (add link or write note):
Disease | Hereditary breast and ovarian cancer |
|---|---|
Inheritance | Autosomal dominant |
Prevalence | 1:70 (common) Source: Orphanet (ORPHA:145) |
Rapid or full curation? | Rapid Full |
Breast/Ovarian Cancer GCEP, accessed 06.26.2023 | |
Clinical Validity Scoring Notes and points | Not provided Source: Breast/Ovarian Cancer GCEP, accessed 06.26.2023 |
Clinical Validity Points Total | 18 Source: Breast/Ovarian Cancer GCEP, accessed 06.26.2023 |
Clinical Validity Classification Definitive (12pts) Strong (12pts) Moderate (7-11pts) Limited (0.1-6pts) No genetic evidence Refuted Disputed | Definitive Source: |
Molecular Mechanism Loss of function Gain of function Dominant negative Unknown Other | Loss of function Source: ClinGen dosage sensitivity: Haploinsufficiency score = 3, loss of function described in summary, accessed 06.26.2023
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Penetrance Complete (100%) High (≥90%) Reduced (<90% and >10%) Low (≤10%) (list source/PMID) | Reduced |
Age of Onset Congenital Pediatric Adolescent Adulthood Late adulthood (list source/PMID) | Adulthood |
Severity | Moderate |
Clinical Features | Breast (male and female), ovarian, prostate, and pancreatic cancers, as well as melanoma (cutaneous & ocular) Sources: |
Gene SOPs & Notes | PVS1: Most 3' pathogenic variant reported by ENIGMA rules is c.9924C>G (p.Tyr3308Ter) - (Vallee et al., 2016) A downstream variant, c.9976A>T p.Lys3326Ter does not confer a high risk of cancer (ENIGMA rules, (Meeks et al., 2016). Splicing - Exon 12 skipping. BRCA2 Δ12 is a naturally occurring in-frame splicing event (Fackenthal et al., 2016). BRCA2 exon12 is functionally redundant (Li et al., 2009). Therefore, the following positions should have PVS1 downgraded or not applied: c.6842-1, c.6842-2, c.6937 to non-G, c.6937+1, c.6937+1 |
Curation Summary: | The BRCA2 gene is associated with autosomal dominant hereditary breast and ovarian cancer, which is characterised by increased risk of breast (male and female), ovarian, prostate, and pancreatic cancers, as well as melanoma (cutaneous & ocular). The National Comprehensive Cancer Network (NCCN) provides risk management guidelines for individuals with a pathogenic variant in this gene. In addition, the BRCA2 gene is associated with autosomal recessive Fanconi Anemia. |
Case ID, Curator name, Date, Jira ticket link | Andrea Oza 06.26.2023 https://broadinstitute.atlassian.net/browse/CIT-130 |
Disease | Fanconi Anemia |
|---|---|
Inheritance | Autosomal recessive |
Prevalence | 1-9 / 1 000 000 Source: Orphanet (ORPHA:84) |
Rapid or full curation? | Rapid Full |
Hereditary Cancer GCEP, accessed 06.26.2023 | |
Clinical Validity Scoring Notes and points | 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. Source: Breast/Ovarian Cancer GCEP, accessed 06.26.2023 |
Clinical Validity Points Total | 18 Source: Hereditary Cancer GCEP, accessed 06.26.2023 |
Clinical Validity Classification | Definitive Source: Hereditary Cancer GCEP, accessed 06.26.2023 |
Molecular Mechanism | Loss of function Source: Hereditary Cancer GCEP, accessed 06.26.2023 c.7464_7465insTA (p.Asp2489Terfs) - EXON 15, NMD+ c.5609_5610delTCinsAG (p.Phe1870Ter) - exon 11, NMD+ c.8219T>A (p.Leu2740Ter) - exon 18, NMD+
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Penetrance (list source/PMID) | Complete Source: No sources of reduced penetrance found in literature review |
Age of Onset (list source/PMID) | Childhood https://rarediseases.info.nih.gov/diseases/6425/fanconi-anemia |
Severity | Moderate
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Clinical Features | Cellular phenotype: BRCA2- and PALB2-related FA have similar and distinguishing cellular phenotype from other FA subtypes. Elevated spontaneous chromosome breakage rates, markedly reduced lymphocyte survival, increased chromosome breakage on exposure to MMC. No formation of RAD51 loci in PALB2- deficient fibroblasts after ionizing radiation (PMID: 17200671). Bone marrow failure - aplastic anemia, neutropenia, thrombocytopenia, myelodysplastic syndrome Cancer susceptibility - acute myeloid leukemia, solid tumors (head and neck; skin, GU, liver). High risk of solid tumors compared to other Fanconi anemia subtypes due to variants in other genes (PMID: 17200671) Physical anomalies -
Developmental delay and/or intellectual disability Sources: NCBI - WWW Error Blocked Diagnostic |
Gene SOPs & Notes | SEE HBOC SOP/NOTES ABOVE |
Curation Summary: | The BRCA2 gene is associated with autosomal recessive Fanconi anemia, which is characterized by bone marrow failure, cancer susceptibility, physical anomalies, developmental delay and/or intellectual disability. This gene is also associated with autosomal dominant hereditary breast and ovarian cancer, which is characterised by increased risk of breast (male and female), ovarian, prostate, and pancreatic cancers, as well as melanoma (cutaneous & ocular). The National Comprehensive Cancer Network (NCCN) provides risk management guidelines for individuals with a heterozygous pathogenic variant in this gene. |
Case ID, Curator name, Date, Jira ticket link | Andrea Oza 06.26.2023 https://broadinstitute.atlassian.net/browse/CIT-130 |