Hereditary Breast Cancer Panels (Including BRCA1 and BRCA2)

Pathogenic germline variants in multiple genes have been implicated in hereditary breast cancer. Hereditary cancer syndromes are often characterized by an early age of cancer onset (typically before 50 years of age) and multiple, multifocal, and/or similar cancers in a single individual or in a closely related family member(s). Pathogenic variants in the BRCA1 and BRCA2 genes are associated with the most common cause of hereditary breast cancer, known as BRCA1- and BRCA2-associated hereditary breast and ovarian cancer (HBOC) syndrome. Other inherited causes of hereditary breast cancer have been identified. Additional screening, and in some cases, risk-reducing options have been recommended for individuals with pathogenic variants in moderate to high-risk hereditary breast cancer genes. Expanded testing for hereditary causes of breast and/or gynecological cancers is also available. For more information, refer to the ARUP Hereditary Cancer Panel Comparison table or visit the Laboratory Test Directory.

Disease Overview

BRCA1- and BRCA2-Associated HBOC Syndrome

BRCA1- and BRCA2-associated HBOC syndrome is caused by a single germline BRCA1 or BRCA2 pathogenic variant and results in an increased lifetime risk of certain cancers. 

Others

See the Genes Tested table for more information about the other syndromes included in the Hereditary Breast Cancer High-Risk Panel and the Hereditary Breast Cancer Guidelines-Based Panel.

Genetics

Genes Tested by Panel

See Genes Tested table for more information regarding the genes included in all three panels.

Etiology

At least 5-10% of all breast cancers are associated with a hereditary cause. ^, 

Prevalence

BRCA1 and BRCA2 genes

• One in 400 individuals from the general population or 1 in 40 Ashkenazi Jewish individuals have a BRCA1 or BRCA2 pathogenic variant. ^, 

Inheritance

• Autosomal dominant for all genes on the three described panels
• Additionally, some genes are associated with autosomal recessive childhood cancer predisposition or other syndromes.

BRCA1 and BRCA2 Pathogenic Founder Variants

• The following three founder variants are estimated to make up 99% of pathogenic variants in individuals of Ashkenazi Jewish descent :
  • BRCA1 c.68_69delAG (also known as 185delAG)
  • BRCA1 c.5266dupC (also known as 5382insC)
  • BRCA2 c.5946delT (also known as 6174delT)
• Additional founder variants have been identified in other populations, including African, Amish, Ammassalik (Greenlandic), and Icelandic populations. 

Test Interpretation

Contraindications for Ordering

• These tests should not be ordered to detect somatic variants associated with malignancy because sensitivity for mosaic variants is low with the methodology used for germline assays.
• Individuals with hematologic malignancy and/or a previous allogeneic bone marrow transplantation should not undergo molecular genetic testing on a peripheral blood specimen.
  • Testing of cultured fibroblasts is required for accurate interpretation of test results.
• When a relative has a previously identified pathogenic variant, targeted sequencing for that variant may be appropriate; refer to the Laboratory Test Directory for additional information.

Methodology

This test is performed using the following sequence of steps:

• Selected genomic regions, primarily coding exons and exon-intron boundaries, from the targeted genes are isolated from extracted genomic DNA using a probe-based hybrid capture enrichment workflow.
• Enriched DNA is sequenced by massively parallel sequencing (MPS; also known as next generation sequencing [NGS]) followed by paired-end read alignment and variant calling using a custom bioinformatics pipeline. The pipeline includes an algorithm for the detection of large (single exon-level or larger) deletions and duplications.
• Sanger sequencing is performed as necessary to fill in regions of low coverage and in certain situations, to confirm variant calls.
• Large deletion/duplication calls made using MPS are confirmed by an orthogonal exon-level microarray when sample quality and technical conditions allow.
• Bidirectional Sanger sequencing is performed on the following gene and exon:
  • PTEN (NM_000314) 9

Clinical Sensitivity

BRCA1 and BRCA2-Associated HBOC Syndrome Panel, Sequencing and Deletion/Duplication (3001855)

• Greater than 98% for BRCA1- and BRCA2-associated hereditary breast and ovarian cancer syndrome 
  • BRCA1 variants:
    • Approximately 87-89% are detectable by sequencing
    • Approximately 11-13% detectable by deletion/duplication analysis
  • BRCA2 variants:
    • Approximately 97-98% are detectable by sequencing
    • Approximately 2-3% are detectable by deletion/duplication analysis

Hereditary Breast Cancer High-Risk Panel, Sequencing and Deletion/Duplication (3005632) and Hereditary Breast Cancer Guidelines-Based Panel, Sequencing and Deletion/Duplication (3005654)

• BRCA1 and BRCA2 sequencing and deletion/duplication testing detects approximately 20-60% of hereditary breast and/or ovarian cancers, in general. ^, 
• Clinical sensitivity of additional genes is largely unknown.

Analytic Sensitivity

Limitations

• A negative result does not exclude a heritable form of cancer.
• Diagnostic errors can occur due to rare sequence variations.
• Interpretation of this test result may be impacted if this individual has had an allogeneic stem cell transplantation.
• The following will not be evaluated:
  • Variants outside the coding regions and intron-exon boundaries of the targeted genes
  • Regulatory region variants and deep intronic variants
  • Breakpoints of large deletions/duplications
  • The following exons are not sequenced due to technical limitations of the assay:
    • BRCA1 (NM_007300) 13
    • CHEK2 (NM_001005735) 3; (NM_001349956) 4
• The following may not be detected:
  • Deletions/duplications/insertions of any size by massively parallel sequencing
  • Large duplications less than 3 exons in size
  • Deletions/duplications in the following exons:
    • BRCA1 (NM_007294, NM_007299, NM_007300) 2; (NM_007298) 1
    • CDH1 (NM_001317185) 10
    • CHEK2 (NM_007194) 11-15; (NM_001005735) 3,12-16; (NM_001257387) 12-16; (NM_001349956) 4,10-14; (NM_145862) 10-14;
    • PTEN (NM_000314, NM_001304718) 9; (NM_001304717) 1,10
  • Noncoding transcripts
  • Some variants due to technical limitations in the presence of pseudogenes and/or repetitive or homologous regions
  • Low-level somatic variants

Genes Tested

The following genes are included on one or more of the panels described in this document. For a list of genes tested by each panel, see the Genes Tested by Panel section.

To compare directly to other hereditary cancer panels offered by ARUP Laboratories, see the ARUP Hereditary Cancer Panel Comparison table.