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	Many	EXAMPLE: Multiple variant types leading to loss of function	EXAMPLE: Autosomal recessive, ~30% penetrant for carriers
BRCA2	EXAMPLE: List the specific mutation

Genetic Abnormalities: Somatic

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Gene	Genetic Variant or Variant Type	Molecular Pathogenesis	Inheritance, Penetrance, Expressivity	Notes
EXAMPLE: BRCA1	EXAMPLE: Biallelic inactivation variants	EXAMPLE: Second hit mutation can occur as copy neutral LOH, inactivating mutation, deletion, promoter hypermethylation, or a structural abnormality disrupting the gene.
EXAMPLE: BRCA1	EXAMPLE: Reversion mutation	EXAMPLE: After exposure to certain therapies (e.g. PARP inhibitors), a second mutation may restore gene function as a resistance mechanism.

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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Prior Author(s):