Breast Cancer Panel

BRCA1 and BRCA2

Clinical Usage

  • To determine if an individual harbors an increased risk of Hereditary Breast and Ovarian Cancer (HBOC) Syndrome due to inherited mutations in BRCA1 or BRCA2 genes.
  • Individuals should be screened if they have breast or ovarian cancer at an early age, 2 primary breast cancers by the age of 50, triple negative breast cancer by age 60, family members with breast or ovarian cancer, or family members who have pathogenic BRCA1 orBRCA2 mutations.

Cancer Risk for Hereditary Breast and Ovarian Cancer Syndrome

Hereditary Breast and Ovarian Cancer Syndrome can be caused by pathogenic mutations in theBRCA1 or BRCA2 genes. Mutations in these genes predispose women to early onset breast and ovarian cancer, and place men at a higher risk of breast and prostate cancer, as compared to the general population. Women with pathogenic BRCA1 mutations have a 57% to 65% risk of developing breast cancer, and a 39% to 40% risk of developing ovarian cancer by age 70. TheseBRCA1 mutations also lead to a 27% increased risk of developing cancer in the contralateral breast within 5 years off the initial breast cancer diagnosis. Men with pathogenic BRCA1mutations have 1.2% risk of developing breast cancer by age 70 and 1.8-fold increased risk of developing prostate cancer. Women with pathologic BRCA2 mutations have a 45% to 49% risk of developing breast cancer, and an 11% to 18% risk of developing ovarian cancer by age 70. The contralateral breast cancer risk in BRCA2 carriers is 12% within 5 years of the initial breast cancer diagnosis. Men with pathogenic BRCA2 mutations have a 6.0% to 6.8% risk of developing breast cancer by age 70, and a 4.6-fold higher risk of developing prostate cancer. These pathogenic mutations have also been associated with increased risk of developing fallopian tube cancers and peritoneal cancer. No “exact” risk estimate can be applied to all people with these pathogenic mutations; the incidence for individual families and specific variants may differ from these average risk estimates.

Individuals with HBOC have a greater risk of developing cancer; increased monitoring and possible treatments are recommended for these patients.

Background Information

Pathologic mutations in either of these BRCA genes are a major cause of Hereditary Breast and Ovarian Cancer (HBOC) Syndrome, which causes an increased risk for these 2 types of cancers, of prostate cancer in men, and possibly several other types of cancer. Mutations in either of these tumor suppressor genes causing transcription of a malfunctioning protein ultimately results an accumulation of genetic damage that often leads to cancer. These pathologic mutations can be inherited from either parent, and HBOC can affect both genders.

BRCA1 encodes for breast cancer type 1 susceptibility protein, comprised of 1863 amino acids. This protein interacts with several proteins involved in cell cycle progression, gene transcription regulation, DNA damage response, and ubiquitination. Breast cancer type 1 susceptibility protein seems to be a “caretaker” that helps maintain genomic integrity. BRCA1 mutations causing protein loss of function result in defects in DNA repair, defects in transcription, abnormal genetic duplication, defective cell cycle regulation, and chromosome damage.

The BRCA2 gene encodes for the breast cancer type 2 susceptibility protein made of 3418 amino acids. This protein mediates the binding of single-stranded DNA to the recombinase protein RAD51. Cells without BRCA2 are deficient in the repair of double-strand DNA breaks and have hypersensitivity to ionizing radiation. BRCA1 and with BRCA2 both act in the DNA repair process and serve to maintain genomic integrity.

Gene Information

BRAC1 is on the long arm of chromosome 17 at 17q21 and contains 24 coding exons of over 80 kb. It is a tumor suppressor gene. Over 1600 mutations of BRCA1 have been identified.
BRAC2 is a tumor suppressor gene located on the long arm of chromosome 13 at 13q12.3 and contains 27 coding exons. More than 1800 mutations of BRCA2 have been found.
Most pathogenic mutations in BRCA1 and BRCA2 are frameshift deletions, insertions, or nonsense mutations leading to premature truncation of protein transcription with concomitant loss of function.

Population Information

Incidence of deleterious BRCA mutations in the US population and ancestry is based on a few small studies. The current best estimates are shown below.

Ancestry BRCA1 BRCA2
Asian 0.5%
African 1.3% 2.6%
Hispanic 3.5%
Caucasian 2.1%
Caucasian (non-Ashkenazi Jewish) 2%
Ashkenazi Jewish 10.2%

Blanks indicate that no data is available. Ancestry is self-reported.
Interestingly, Hispanics in families at high risk have the same BRCA mutations found in Ashkenazi Jewish populations. Some studies indicate that other Jewish populations also have a high incidence of BRCA mutations.

Test Method

This test utilizes next-generation sequencing technology using an Illumina MiSeqDx instrument. The target region covers all coding exons of BRCA1 and BRCA2 genes and 20bp into each of the introns flanking each of the coding exons. Target enrichment is performed using TruSeq Custom Amplicon chemistry (TSCA) from Illumina. All target sequences are covered at least 100-fold to ensure accuracy. Sequence variants 15 nucleotides or smaller are reliably detected; variants larger than 15 nucleotides are not reliably detected by this methodology. Variants with multiple nucleotide insertions in BRCA1 and BRCA2 genes occur at very low frequency. MDL has not yet demonstrated the accuracy of its test for detection of multiple nucleotide insertions with the BRCA1 or BRCA2 genes.

Specimen

Collection

  • Saliva sample collected in a kit provided by MDL

Rejection Criteria

  • Saliva sample leaked
  • Visible contamination
  • Sample over 4 weeks old
  • Collection kit expired

Interpretation

Three results are possible

  • Positive: An increased risk of cancer specific to the gene mutation. A pathogenic mutation in BRCA1 or BRCA2 was found.
  • Negative: No clinically significant BRCA1 or BRCA2 mutations were detected and the patient has no elevated risk of cancer associated with these genes.
  • Inconclusive: A BRCA1 or 2 mutation was identified, but current medical knowledge cannot predict if the detected mutation is pathologic or benign.