Hereditary breast and ovarian cancer (HBOC)

HBOC presents as breast and ovarian cancer occurring at younger ages, or in multiple relatives across generations. In BRCA1 and BRCA2 carriers, lifetime female breast cancer risk reaches roughly 55 to 72% and 45 to 69% respectively, and ovarian cancer risk roughly 39 to 44% and 11 to 17% respectively, by age 80. Breast cancer is frequently pre-menopausal. BRCA1-related breast tumours are more often high-grade and triple-negative, whereas ovarian tumours are usually high-grade serous carcinomas. Carriers of a pathogenic variant in these genes also have an increased risk of pancreatic cancer, which affects women and men alike, while male carriers have raised risks of male breast cancer and prostate cancer; these additional risks are generally more pronounced for BRCA2 than for BRCA1. Beyond BRCA1 and BRCA2, the panel covers further breast- and ovarian-cancer risk genes (for example ATM, CHEK2 and PALB2) that generally confer more moderate risks and, for some, distinct syndromic features, detailed under Causes. Expressivity is variable within and between families.

A pathogenic BRCA1 or BRCA2 variant is carried by an estimated 1/200 to 1/400 individuals, rising to about 1/40 in people of Ashkenazi Jewish descent.

HBOC is caused by germline pathogenic variants in genes that maintain genome integrity, several of them acting in homologous-recombination repair of DNA double-strand breaks. BRCA1 and BRCA2 account for the majority of identified pathogenic variants, in roughly comparable proportions. The panel also covers further high- and moderate-penetrance risk genes: variants in ATM, CHEK2, PALB2, BARD1, RAD51C and RAD51D are associated with breast cancer risk in large population analyses, and BRIP1, RAD51C, and RAD51D are moderate-penetrance ovarian-cancer risk genes. PTEN, STK11, CDH1, and TP53 underlie Cowden, , and respectively, each of which includes breast cancer among its features. Loss of function impairs DNA repair and produces the genomic instability that drives tumour development

The cancer predisposition associated with the panel genes is inherited in an autosomal dominant (monoallelic) manner. Each child of an affected individual has a 50% probability of having inherited the familial pathogenic variant. The proportion of probands with a de novo pathogenic variant is low. Prenatal molecular testing is technically possible once the familial pathogenic variant has been identified.

The diagnosis is established by identifying a heterozygous germline pathogenic variant in one of the panel genes through molecular genetic testing. Clinical and family-history criteria support the indication for testing but do not establish the diagnosis without a molecular result. Multigene panel analysis allows several risk genes to be assessed in parallel rather than testing BRCA1 and BRCA2 alone.

Biallelic pathogenic variants in several panel genes cause distinct recessive disorders:

• : biallelic BRCA2, BRIP1, PALB2 or RAD51C variants cause a recessive childhood bone-marrow-failure and cancer syndrome.
• Ataxia-telangiectasia: biallelic ATM variants cause a recessive neurodegenerative and cancer-predisposition syndrome.

Main differential diagnoses include:

• : predominantly colorectal and endometrial cancer with elevated ovarian-cancer risk; family pattern is bowel- and endometrium-dominant rather than breast-dominant; EPCAM, MLH1, MSH2, MSH6, PMS2

• Genetic testing supports establishing the diagnosis by identifying the underlying pathogenic variant, clarifying the genetic aetiology and providing a basis for genetic counselling.
• A confirmed result supports condition-specific surveillance and discussion of preventive management options with the treating physicians, which they decide together with the affected individual.
• A known familial variant supports predictive testing of at-risk relatives, so they can clarify their personal risk and access surveillance and counselling where indicated.

• Kuchenbaecker KB, Hopper JL, Barnes DR, Phillips KA, Mooij TM, Roos-Blom MJ, et al. Risks of Breast, Ovarian, and Contralateral Breast Cancer for BRCA1 and BRCA2 Mutation Carriers. JAMA. 2017;317(23):2402-2416. doi: 10.1001/jama.2017.7112. PMID: .
• Petrucelli N, Daly MB, Pal T. BRCA1- and BRCA2-Associated Hereditary Breast and Ovarian Cancer. 1998 Sep 4 [Updated 2026 Mar 25]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews. Seattle (WA): University of Washington, Seattle; 1993-2026. PMID: 20301425.
• Dorling L, Carvalho S, Allen J, Gonzalez-Neira A, Luccarini C, Wahlstrom C, et al. Breast Cancer Risk Genes – Association Analysis in More than 113,000 Women. N Engl J Med. 2021;384(5):428-439. doi: 10.1056/NEJMoa1913948. PMID: .
• Cummings S, Roman SS, Saam J, Bernhisel R, Brown K, Lancaster JM, et al. Age of ovarian cancer diagnosis among BRIP1, RAD51C, and RAD51D mutation carriers identified through multi-gene panel testing. J Ovarian Res. 2021;14(1):61. doi: 10.1186/s13048-021-00809-w. PMID: .