GTS5:BRCA-related cancer predisposition syndrome (BRCA1, BRCA2)

Genetic Tumour Syndromes (Who Classification, 5th ed.)

Primary Author(s)*

Parisa Kargaran, Ph.D.

WHO Classification of Disease

Structure	Disease
Book	Genetic Tumour Syndromes (5th ed.)
Category	DNA repair and genomic stability
Family	Homologous recombination
Type	BRCA-related cancer predisposition syndrome (BRCA1, BRCA2)
Subtype(s)	N/A

Related Terminology

Acceptable	Hereditary breast and ovarian cancer syndrome
Not Recommended	N/A

Definition/Description of Disease

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Epidemiology/Prevalence

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Genetic Abnormalities: Germline

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Gene	Genetic Variant or Variant Type	Molecular Pathogenesis	Inheritance, Penetrance, Expressivity	Notes
BRCA1	SNVs (frameshift, nonsense, pathogenic missense, canonical splice-site, synonymous splice-altering variants); CNVs (inactivating multi-exon deletions or duplications)	Multiple variant types lead to loss of BRCA1 function, resulting in impaired homologous recombination–mediated DNA double-strand break repair, defective DNA damage response, and genomic instability	Autosomal dominant cancer predisposition with incomplete penetrance and variable expressivity; rare biallelic pathogenic variants associated with Fanconi anemia–like phenotypes	Heterozygous pathogenic variants confer increased lifetime risk of female and male breast cancer, ovarian cancer, prostate cancer, and pancreatic cancer. Estimated lifetime breast cancer risk ~60–80% and ovarian cancer risk ~35–45% in women . Founder mutations reported in multiple populations, including c.68_69delAG (185delAG) and c.5266dupC (5382insC) . Large genomic rearrangements represent a clinically significant subset of pathogenic BRCA1 variants and require copy-number–sensitive testing methods. Molecular pathogenesis reflects failure of homologous recombination repair .
BRCA2	SNVs (frameshift, nonsense, pathogenic missense, canonical splice-site, synonymous splice-altering variants); CNVs (inactivating multi-exon deletions or duplications)	Multiple variant types leading to loss of BRCA2 function, resulting in defective homologous recombination–mediated DNA double-strand break repair, genomic instability, and cancer susceptibility	Autosomal dominant cancer predisposition with incomplete penetrance and variable expressivity; autosomal recessive when biallelic, causing Fanconi anemia subtype D1 (FA-D1)	Heterozygous pathogenic variants confer increased lifetime risk of female and male breast, ovarian, pancreatic, prostate, and melanoma cancers. Estimated female breast cancer risk ~45–70%, ovarian cancer ~10–30% . Founder mutations include c.5946delT (6174delT) in Ashkenazi Jewish populations . Large genomic rearrangements represent a clinically significant subset of pathogenic variants and may be missed by sequencing-only assays . Biallelic pathogenic variants result in FA-D1, characterized by congenital anomalies, bone marrow failure, and early-onset malignancies

Genetic Abnormalities: Somatic

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Gene	Genetic Variant or Variant Type	Molecular Pathogenesis	Inheritance, Penetrance, Expressivity	Notes
BRCA1	Biallelic inactivation (second hit) including somatic SNVs/indels, copy-neutral LOH, focal or arm-level deletion, promoter hypermethylation, or complex structural rearrangements	In individuals with a germline pathogenic BRCA1 variant, tumor development follows a two-hit mechanism. Somatic loss of the remaining wild-type allele results in complete BRCA1 deficiency, impaired homologous recombination DNA repair, genomic instability, and carcinogenesis	Somatic, tumor-specific event; not inherited. Results in a homologous recombination–deficient (HRD) tumor phenotype	Common in BRCA1-associated breast and ovarian cancers. Biallelic loss is associated with increased sensitivity to platinum chemotherapy and PARP inhibitors . Promoter hypermethylation represents a frequent non-sequence–based second hit in BRCA1-driven tumors
BRCA1	Somatic reversion mutations (frameshift correction, splice rescue, deletion of pathogenic allele restoring open reading frame)	Under selective pressure from PARP inhibitors or platinum therapy, secondary somatic mutations may restore BRCA1 function, re-establish homologous recombination, and confer therapeutic resistance	Acquired resistance mechanism; tumor-specific; not inherited	Documented in ovarian and breast cancers and associated with acquired resistance to PARP inhibitors and platinum agents and disease progression [4,5]
BRCA2	Biallelic inactivation (second hit) including somatic SNVs/indels, copy-neutral LOH, focal or whole-arm deletion, or complex structural rearrangements	In individuals with a germline pathogenic BRCA2 variant, tumorigenesis follows a two-hit mechanism. Somatic loss of the remaining wild-type allele leads to complete loss of BRCA2 function, defective homologous recombination repair, genomic instability, and tumor development	Somatic event occurs in tumor tissue only; not inherited. Tumor phenotype shows homologous recombination deficiency (HRD)	Common mechanism in BRCA2-associated breast, ovarian, pancreatic, and prostate cancers. Presence of biallelic loss predicts sensitivity to platinum chemotherapy and PARP inhibitors
BRCA2	Somatic reversion mutations (frameshift/nonsense “correction,” splice rescue, or deletion of pathogenic allele restoring reading frame)	Under selective pressure from PARP inhibitors or platinum therapy, secondary somatic mutations can restore partial or full BRCA2 function, re-establish homologous recombination, and confer therapy resistance	Acquired, tumor-specific resistance mechanism; not inherited	Well-described in ovarian, breast, pancreatic, and prostate cancers. Associated with acquired resistance to PARP inhibitors and platinum agents and disease progression

Genes and Main Pathways Involved

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Gene; Genetic Alteration	Pathway	Pathophysiologic Outcome
BRCA1; Loss-of-function germline or somatic mutations	Homologous recombination (HR) DNA double-strand break repair; DNA damage response	Defective DNA repair leading to genomic instability and chromosomal aberrations; increased cancer susceptibility. Tumors demonstrate homologous recombination deficiency (HRD) and sensitivity to platinum agents and PARP inhibitors
BRCA2; Loss-of-function germline or somatic mutations	Homologous recombination DNA repair (RAD51 loading and stabilization)	Impaired repair of DNA double-strand breaks, genomic instability, and tumorigenesis; HRD phenotype with therapeutic vulnerability to PARP inhibition
PALB2; Inactivating mutations	BRCA1–BRCA2–PALB2 DNA repair complex (HR pathway)	Disruption of BRCA1–BRCA2 interaction, defective homologous recombination, and increased cancer risk similar to BRCA2-associated tumors
ATM; Inactivating mutations	DNA damage sensing and signaling (ATM–CHK2 pathway)	Impaired activation of DNA damage checkpoints, defective response to double-strand breaks, accumulation of genomic damage, and cancer predisposition
CHEK2; Inactivating mutations	Cell-cycle checkpoint control and DNA damage response	Failure of G1/S and G2/M checkpoint arrest following DNA damage, allowing propagation of genomic instability
TP53; Inactivating or dominant-negative mutations	Cell-cycle regulation, apoptosis, genome integrity	Loss of DNA damage–induced cell-cycle arrest and apoptosis, enabling survival and expansion of genetically unstable cells
RAD51C / RAD51D; Inactivating mutations	Homologous recombination DNA repair	mpaired strand invasion and repair of DNA double-strand breaks, contributing to HRD and hereditary cancer susceptibility

Genetic Diagnostic Testing Methods

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Additional Information

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Links

https://clinicalgenome.org/affiliation/50087/

References

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Notes

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