Hereditary Breast and Ovarian Cancer BRCA1/2 Panel

Hereditary breast and ovarian cancer (HBOC) syndrome is an inherited disorder that is highly associated with tumors of the breasts and ovaries. Other malignancies in HBOC families can occur, including melanoma, pancreatic and prostate cancer. In comparison to sporadic breast and ovarian cancers, HBOC syndrome tumors tend to occur at an earlier age (< 50 years), to occur bilaterally, to occur in multiple family members, to include males with breast cancer, and to occur with a higher predisposition in specific ethnicities, such as the Ashkenazi Jewish population (Petrucelli et al. 2016. PubMed ID: 20301425; Pruthi et al. 2010. PubMed ID: 21123638). Identifying individuals with a high-risk for developing HBOC may allow for early detection of tumor growth and allow for prophylactic mastectomy and/or oophorectomy or other treatments (Smith 2012. PubMed ID: 23050669). The majority of breast and ovarian cancers occur sporadically. However, approximately 5-10% of breast, and 10-15% of ovarian cancer cases are due to pathogenic variants in specific genes, particularly BRCA1 and BRCA2, that significantly increase an individual's risk of developing these cancers (Marchina et al. 2010. PubMed ID: 21042765). In addition, HBOC syndrome may also be the result of lower penetrance variants in other genes, which confer a moderate risk (Berliner et al. 2013. PubMed ID: 23188549).

Hereditary breast and ovarian cancer is inherited in an autosomal dominant manner and presents with high, although incomplete, penetrance. Pathogenic variants in a number of genes have been reported to significantly increase an individual’s likelihood for developing breast cancer (Tan et al. 2008. PubMed ID: 18682420). Among those, germline pathogenic variants in the most common highly penetrant mutated breast cancer genes, BRCA1 and BRCA2 (Miki et al. 1994. PubMed ID: 7545954; Wooster et al. 1995. PubMed ID: 8524414), appear to provide the highest relative risk with lifetime prevalence up to 40%-85% for breast cancer (Rebbeck et al. 2009. PubMed ID: 19141781; Pruthi et al. 2010. PubMed ID: 21123638), and 10-46% for ovarian cancer depending on the gene mutated (Smith 2012. PubMed ID: 23050669; Pruthi et al. 2010. PubMed ID: 21123638). Hereditary BRCA1 and BRCA2 variants account for approximately 25-60% of inherited breast cancer (Pruthi et al. 2010. PubMed ID: 21123638; Meindl et al. 2011. PubMed ID: 21637635) and 11-39% for ovarian cancer (Berliner et al. 2013. PubMed ID: 23188549).

BRCA1 mutation carriers tend to have breast tumors that are estrogen receptor (ER) negative, progesterone receptor (PR) negative and basal type tumors, whereas BRCA2 mutation carriers have breast tumors that are ER positive, PR positive, and have a luminal phenotype (Pruthi et al. 2010. PubMed ID: 21123638). Individuals with HBOC with a more severe personal or family history tend to have pathogenic variants in BRCA1 vs. BRCA2 due to higher penetrance of pathogenic variants in the BRCA1 gene (Antoniou et al. 2000. PubMed ID: 10642429).

BRCA1 is a tumor suppressor gene that is involved in cellular processes including DNA damage repair, cell cycle progression, gene transcription and ubiquitination. BRCA2 is a tumor suppressor gene that along with RAD51 has a large role in DNA repair processes and genome stability. Most pathogenic variants of the BRCA1 and BRCA2 genes are private variants which are observed in a single family or in a small number of families. Three pathogenic variants in the BRCA genes are commonly found in Ashkenazi Jewish individuals: c.68_69delAG (BRCA1), c.5266dupC (BRCA1), and c.5946delT (BRCA2), and the coexistence of more than one founder mutation has been reported in some Ashkenazi Jewish families. Most BRCA pathogenic variants are inherited from a parent who may or may not have been affected with HBOC due to incomplete penetrance of the mutation, gender, and other factors (Petrucelli et al. 2016. PubMed ID: 20301425). Most pathogenic variants in these genes are chain termination (nonsense, frameshift or splicing).

Large rearrangements (deletions, duplications, triplications), including the five most commonly reported BRCA1 CNVs (Hendrickson et al. 2005. PubMed ID: 15846789), can be detected using this test.

The overall prevalence of germline BRCA1 or BRCA2 pathogenic variants in the general population is 1:400 to 1:800, with higher rates depending on the specific ethnicity, such as 1:40 in the Ashkenazi Jewish population. Nucleotide substitutions and small insertions/deletions are found in about 90% of individuals with an identifiable pathogenic variant. For individuals with pathogenic variants in these genes, BRCA1 variants were observed in 63% and BRCA2 variants in 37% (Petrucelli et al. 2016. PubMed ID: 20301425).

Copy Number Variants (CNVs) are found in approximately 10% of individuals with an identifiable germline pathogenic variant, with 90% of these in BRCA1 and 10% in BRCA2 (Petrucelli et al. 2013. PubMed ID: 20301425). High-risk patients, defined as individuals with early onset (<50 years of age) invasive or in situ breast cancer or ovarian cancer or male breast cancer, and with 2 or more relatives with HBOC have higher rates of CNVs. Specific ethnic populations (Latin American/Caribbean) have also been shown to have higher rates of CNVs (Judkins et al. 2012. PubMed ID: 22544547).

This panel provides 100% coverage of all coding exons of the genes listed, plus ~10 bases of flanking noncoding DNA. We define coverage as ≥20X NGS reads or Sanger sequencing.