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

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

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

Put your text here (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.)

Epidemiology/Prevalence

Put your text here

Genetic Abnormalities: Germline

Put your text here and fill in the table (Instructions: Describe germline alteration(s) that cause the syndrome. In the notes, include additional details about most common mutations including founder mutations, mechanisms of molecular pathogenesis, alteration-specific prognosis and any other important genetics-related information. If multiple causes of the syndrome, include relative prevalence of genetic contributions to that syndrome. Please include references throughout the table. Do not delete the table.)

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

Put your text here and fill in the table (Instructions: Describe significant second hit mutations, or somatic variants that present as a germline syndrome. In the notes, include details about most common mutations, mechanisms of molecular pathogenesis, alteration-specific prognosis and any other important genetic-related information. Please include references throughout the table. Do not delete the table.)

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

Put your text here and fill in the table (Instructions: Please include references throughout the table. Do not delete the table.)

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

Genetic Diagnostic Testing Methods

Put your text here (Instructions: Include recommended testing type(s) to identify the clinically significant genetic alterations.)

Additional Information

Put your text here

Links

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

References

(use the "Cite" icon at the top of the page) (Instructions: Add each reference into the text above by clicking where you want to insert the reference, selecting the “Cite” icon at the top of the wiki page, and using the “Automatic” tab option to search by PMID to select the reference to insert. If a PMID is not available, such as for a book, please use the “Cite” icon, select “Manual” and then “Basic Form”, and include the entire reference. To insert the same reference again later in the page, select the “Cite” icon and “Re-use” to find the reference; DO NOT insert the same reference twice using the “Automatic” tab as it will be treated as two separate references. The reference list in this section will be automatically generated and sorted.)

Notes

*Primary authors will typically be those that initially create and complete the content of a page.  If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the Associate Editor or other CCGA representative.  When pages have a major update, the new author will be acknowledged at the beginning of the page, and those who contributed previously will be acknowledged below as a prior author.

Prior Author(s):