Clinical Guidance

BRCA1 and BRCA2 genotype-phenotype correlations have been identified. Such correlations are not currently used in individual risk assessment and management but may be in the future with appropriate validation.

BRCA1

p.Arg1699Gln is a reduced-penetrance allele that was determined to be associated with intermediate risk; the estimated cumulative risk to age 70 for breast or ovarian cancer was 24% .

BRCA2

Source: GeneReviews — "BRCA1- and BRCA2-Associated Hereditary Breast and Ovarian Cancer"

Penetrance

The penetrance of breast, ovarian, and other cancers associated with pathogenic variants in BRCA1 and BRCA2 is less than 100% .

Source: GeneReviews — "BRCA1- and BRCA2-Associated Hereditary Breast and Ovarian Cancer"

Diagnostic Criteria

Suggestive Findings

BRCA1- and BRCA2-associated hereditary breast and ovarian cancer (HBOC) should be suspected in individuals with a personal or family history (first-, second-, or third-degree relative in either lineage) of any of the following:

Source: GeneReviews — "BRCA1- and BRCA2-Associated Hereditary Breast and Ovarian Cancer"

Differential Diagnosis

Syndromic breast cancer. Individuals with the following cancer susceptibility syndromes have an elevated breast cancer risk. In many instances, BRCA1- and BRCA2-associated hereditary breast and ovarian cancer (HBOC) can be distinguished from these other disorders based on the constellation of tumors present in the family; however, in some cases, molecular genetic testing may be necessary to differentiate the disorders. Table 3. Genes Associated with Cancer Susceptibility to Consider in the Differential Diagnosis of BRCA1- and BRCA2-Associated Hereditary Breast and Ovarian Cancer

Management Guidelines

Evaluations Following Initial Diagnosis

Individuals who have a germline pathogenic variant in BRCA1 or BRCA2 are counseled at the time of disclosure of molecular genetic test results about their options for and .

Treatment of Manifestations

Breast cancer. National Comprehensive Cancer Network (NCCN) guidelines suggest that women with a BRCA1 or BRCA2 pathogenic variant could consider bilateral mastectomy as a primary surgical treatment of breast cancer because of their elevated rate of ipsilateral and contralateral breast cancer (NCCN Guidelines; no-fee registration and login required). PARP inhibitors have emerged as a promising treatment in individuals with BRCA1- and BRCA2-associated breast cancer, given their role in DNA repair. Because BRCA1, BRCA2, and PARP participate in DNA repair, their mutual disruption could lead to "synergistic lethality" of tumor cells. PARP inhibitors were first studied in women with BRCA1- and BRCA2-associated metastatic breast cancer. Significant improvement was seen in in progression-free survival, leading to FDA approval of olaparib for women with locally advanced metastatic breast cancer in 2017 . In a recent randomized, double-blind Phase III trial, olaparib also improved progression-free survival in individuals with early, high-risk, human epidermal growth factor receptor 2-negative BRCA1- and BRCA2-associated breast cancer in the adjuvant setting . Ovarian cancer.

Source: GeneReviews — "BRCA1- and BRCA2-Associated Hereditary Breast and Ovarian Cancer"

Clinical Guidance

No data specific to individuals with BRCA1 or BRCA2 pathogenic variants are available.

Source: GeneReviews — "BRCA1- and BRCA2-Associated Hereditary Breast and Ovarian Cancer"

Therapies Under Investigation

Several ongoing studies are investigating novel approaches to the treatment of BRCA1- and BRCA2-associated breast and ovarian cancer. The majority of these studies involve PARP inhibitors. Several prospective and randomized clinical trials are investigating PARP inhibitor treatment of metastatic pancreatic cancer . Studies to identify biomarkers of disease resistance and expected treatment toxicity are also under way . Additional clinical trials are exploring the use of other PARP inhibitors alone or in combination with other systemic treatments. Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information on clinical studies.

Source: GeneReviews — "BRCA1- and BRCA2-Associated Hereditary Breast and Ovarian Cancer"

Surveillance Guidelines

Table 4.

Recommended Surveillance for Women with BRCA1- and BRCA2-Associated Hereditary Breast and Ovarian Cancer

System/Concern | Evaluation | Frequency

Breast cancer

| Breast self-exam | Monthly

Clinical breast exam | Every 6-12 mos beginning at age 25 yrs

Mammogram | Annually beginning at age 30 yrs

Breast MRI | Annually beginning at age 25 yrs or earlier if breast cancer was diagnosed in family member age 30 yrs

Ovarian cancer

| Screening not recommended1 |

Melanoma

| Skin exam w/dermatologist | Individualized based on family history

Pancreatic

cancer | In asymptomatic persons who meet criteria based on mutation status family history, contrast-enhanced MRI/MRCP /or EUS may be considered in a research setting to better delineate the risks benefits of pancreatic cancer screening. |

EUS = endoscopic ultrasound; MRCP = magnetic resonance cholangiopancreatography

1. For women who have not elected to undergo prophylactic bilateral salpingo-oophorectomy: while some clinicians conduct annual transvaginal ultrasound and/or CA-125 concentration, these modalities have not been effective in detecting early-stage ovarian cancer, either in high-risk or in average-risk women.

Table 5.

Recommended Surveillance for Men with BRCA1- and BRCA2-Associated Hereditary Breast and Ovarian Cancer

System/Concern | Evaluation | Frequency

Breast cancer

| Breast self-exam training | At the time of identification of a BRCA1 or BRCA2 pathogenic variant

Breast self-exam | Monthly beginning at age 35 yrs

Source: GeneReviews — "BRCA1- and BRCA2-Associated Hereditary Breast and Ovarian Cancer"