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

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 are associated with autosomal dominant hereditary breast and ovarian cancer (HBOC) syndrome, with incomplete penetrance and variable expressivity observed. 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 for 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 the 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. Genetic testing of tumors post therapy (particularly PARP inhibitor therapy) 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

BRCA1

• Incidence / Carrier frequency: Germline pathogenic variants in BRCA1 occur in approximately 1 in 400–500 individuals in the general population, with higher prevalence in certain founder populations (e.g., ~1 in 40 in Ashkenazi Jewish individuals).
• Cancer risk (heterozygous carriers): Heterozygous pathogenic variants in BRCA1 are associated with a high lifetime risk of breast and ovarian cancer, with incomplete penetrance and variable expressivity.
• Lifetime cancer risks:
  • Female breast cancer: ~60–80% lifetime risk (relative risk ~7–10 fold compared with the general population)
  • Ovarian cancer: ~35–45% lifetime risk
  • Male breast cancer: Increased risk, though substantially lower than in females
  • Other cancers: Increased risk of prostate and pancreatic cancers
• Tumor characteristics: BRCA1 associated breast cancers are enriched for triple negative breast cancer (TNBC) and frequently display a homologous recombination deficient (HRD) phenotype.

BRCA2

• Incidence / Carrier frequency: Germline pathogenic variants in BRCA2 are present in approximately 1 in 400–500 individuals in the general population, with increased prevalence in founder populations (e.g., Ashkenazi Jewish).
• Cancer risk (heterozygous carriers): Heterozygous pathogenic variants in BRCA2 confer substantially increased risks for breast, ovarian, pancreatic, prostate, and male breast cancers, with incomplete penetrance.
• Lifetime cancer risks:
  • Female breast cancer: ~45–70% lifetime risk (relative risk ~5–7-fold)
  • Ovarian cancer: ~10–30% lifetime risk
  • Male breast cancer: Significantly increased compared with the general population
  • Prostate cancer: Elevated risk, often with earlier onset and aggressive features
  • Pancreatic cancer: Moderately increased risk
• Tumor characteristics: BRCA2 associated breast cancers are more often hormone receptor positive, though HRD remains a defining molecular feature.

Genetic Abnormalities: Germline

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

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
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

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

Germline diagnosis of BRCA1 and BRCA2 associated hereditary cancer predisposition is established by molecular genetic testing performed on constitutional DNA (e.g., blood or saliva). Testing strategies must detect both sequence variants and copy number alterations, as pathogenic variants span multiple variant classes.

Primary testing approaches: Next-generation sequencing (NGS), including multigene hereditary cancer panels or genome/exome sequencing, is the first-line method for detection of single-nucleotide variants (SNVs), small insertions/deletions, and splice-site variants in BRCA1 and BRCA2. Copy-number variant (CNV) analysis, performed using NGS-based CNV calling, multiplex ligation-dependent probe amplification (MLPA), or array-based methods, is required to detect large genomic rearrangements, including multi-exon deletions or duplications, which represent a clinically significant subset of pathogenic variants.

Supplementary and confirmatory methods: MLPA or other targeted deletion/duplication assays are commonly used to confirm suspected CNVs or when sequencing-only approaches are insufficient. Sanger sequencing may be employed for targeted variant confirmation or cascade testing in at-risk relatives once a familial pathogenic variant has been identified.

Tumor testing: Tumor sequencing may identify somatic BRCA1/BRCA2 alterations, loss of heterozygosity, or reversion mutations, which have implications for therapeutic selection and resistance, particularly in the context of PARP inhibitor therapy. Identification of a pathogenic BRCA1/BRCA2 variant in tumor tissue should prompt confirmatory germline testing to distinguish hereditary from purely somatic events.

Additional Information BRCA1 and BRCA2

• Founder mutations: Multiple recurrent pathogenic variants demonstrate strong population specific founder effects, most notably c.68_69delAG (185delAG) and c.5266dupC (5382insC) in BRCA1, and c.5946delT (6174delT) in BRCA2, particularly among individuals of Ashkenazi Jewish ancestry. Additional founder variants have been reported in Icelandic, Dutch, and other geographically or ethnically defined populations, underscoring the importance of ancestry-informed testing strategies.

• Genotype–phenotype correlations: Although penetrance is variable, BRCA1 pathogenic variants are disproportionately associated with triple-negative breast cancer, whereas BRCA2 pathogenic variants are more commonly linked to hormone receptor–positive breast cancer and confer a higher risk of male breast and prostate cancers. These genotype-phenotype differences have implications for clinical presentation, surveillance, and therapeutic decision-making.

• Therapeutic implications: Tumors with biallelic inactivation of BRCA1 or BRCA2 exhibit homologous recombination deficiency (HRD), resulting in increased sensitivity to platinum-based chemotherapy and PARP inhibitors. However, acquisition of secondary somatic reversion mutations that restore gene function represents a well-established mechanism of acquired therapeutic resistance, particularly following prolonged treatment exposure.

• Risk management considerations: Identification of germline pathogenic variants in BRCA1 or BRCA2 has substantial implications for personalized cancer risk assessment, implementation of enhanced surveillance protocols, consideration of risk-reducing surgical interventions, and cascade testing of at risk relatives.

• Overlap with other syndromes: BRCA1 and BRCA2 associated hereditary cancer predisposition shares molecular and clinical features with other DNA damage response and homologous recombination repair disorders, including syndromes caused by pathogenic variants in PALB2, ATM, CHEK2, and RAD51C/D. These genes should be considered in differential diagnosis and comprehensive hereditary cancer panel testing.

Links

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

https://www.ncbi.nlm.nih.gov/clinvar/?term=%22BRCA1%22%5BGENE%5D

https://www.ncbi.nlm.nih.gov/clinvar/?term=%22BRCA2%22%5BGENE%5D

Notes

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