GTS5:BRCA-related cancer predisposition syndrome (BRCA1, BRCA2): Difference between revisions
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==Definition/Description of Disease== | ==Definition/Description of Disease== | ||
Put your text here <span style="color:#0070C0">(''Instructions: Include a brief general clinical description, diagnostic criteria, and differential diagnosis if applicable. Include disease context relative to other WHO classification categories, i.e. describe any information relevant to the genetic aspects of the disease from all WHO classification books in which the syndrome is described.'')</span> | Put your text here <span style="color:#0070C0">(''Instructions: Include a brief general clinical description, diagnostic criteria, and differential diagnosis if applicable. Include disease context relative to other WHO classification categories, i.e. describe any information relevant to the genetic aspects of the disease from all WHO classification books in which the syndrome is described.'')</span> | ||
'''BRCA1 and BRCA2 Associated Hereditary Cancer Predisposition''' | |||
''BRCA1'' (17q21.31) and ''BRCA2'' (13q13.1) are tumor-suppressor genes that encode key components of the homologous recombination (HR) DNA double-strand break repair pathway. BRCA1 plays a central role in DNA damage sensing, checkpoint activation, and repair pathway choice, while ''BRCA2'' is essential for ''RAD51'' loading and stabilization at sites of DNA damage. Together, ''BRCA1'' and ''BRCA2'' maintain genomic stability and prevent accumulation of chromosomal aberrations. In the heterozygous state, germline pathogenic variants in ''BRCA1'' or ''BRCA2'' cause autosomal dominant hereditary breast and ovarian cancer (HBOC) syndrome with incomplete penetrance and variable expressivity. Affected individuals have substantially increased lifetime risks for female breast and ovarian cancers, with additional risks for male breast, prostate, pancreatic, and melanoma cancers, particularly in ''BRCA2'' carriers. Disease onset is often earlier than sporadic counterparts, and tumors frequently demonstrate a homologous recombination deficient (HRD) molecular phenotype. This syndrome is classified across multiple WHO Tumour Classification volumes under hereditary cancer predisposition syndromes affecting breast, ovary, prostate, and pancreas. In the biallelic state, pathogenic variants in ''BRCA2'' (also known as FANCD1) cause Fanconi anemia subtype D1, a rare autosomal recessive chromosomal instability disorder characterized by congenital anomalies, growth retardation, progressive bone marrow failure, and early onset malignancies, including acute leukemia and solid tumors in childhood. Biallelic pathogenic variants in ''BRCA1'' are exceedingly rare and have been associated with Fanconi anemia like phenotypes with developmental abnormalities and pediatric cancer susceptibility. These conditions fall within the WHO classification of inherited bone marrow failure and genomic instability syndromes. Diagnosis of ''BRCA1/BRCA2'' associated hereditary cancer predisposition is established through germline molecular genetic testing, typically using sequencing with deletion/duplication analysis. Tumor testing may reveal secondary somatic inactivation or reversion mutations, which have therapeutic implications. Differential diagnosis includes other hereditary breast and ovarian cancer syndromes involving genes in the HR and DNA damage response pathways (e.g., ''PALB2, ATM, CHEK2, RAD51C/D''), as well as sporadic cancers with somatic HR deficiency. | |||
==Epidemiology/Prevalence== | ==Epidemiology/Prevalence== | ||
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