BRCA1- and BRCA2-Associated Hereditary Breast and Ovarian Cancer Syndrome

  • Germline analysis of the BRCA1 and BRCA2 genes in individuals with a suspected diagnosis of HBOC syndrome
  • When a relative has a previously identified pathogenic sequence variant, see Familial Mutation, Targeted Sequencing (2001961).
  • Recommended test for a known familial sequence variant previously identified in a family member
  • A copy of the family member’s test result documenting the familial variant is REQUIRED.
  • Use to assess for large deletion/duplication previously identified in a family member
  • A copy of a relative’s lab report is REQUIRED.

Pathogenic variants in the BRCA1 and BRCA2 genes are associated with hereditary breast and ovarian cancer (HBOC) syndrome. BRCA1- and BRCA2-associated HBOC syndrome is often characterized by 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). Individuals with a single germline BRCA1 or BRCA2 pathogenic variant have an increased risk for breast (female and male), ovarian, fallopian tube, peritoneal, pancreatic, prostate, melanoma, and other cancers. Analysis of the BRCA1 and BRCA2 genes is offered through ARUP's BRCA1 and BRCA2-Associated HBOC Syndrome Panel. For a more comprehensive test of additional hereditary causes of breast and/or ovarian cancer, please see the Hereditary Breast and Ovarian Cancer Panel, which includes analysis of BRCA1 and BRCA2.

Disease Overview

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. 

Lifetime Cancer Risk by Type
Cancer Type Cancer Risk by Gene
BRCA1 BRCA2

Breast cancer (female)

55-72% by 70 yrs of age

45-69%

Breast cancer (male)

1-2%

6-8%

Ovarian cancer (including fallopian tube and peritoneal)

39-44%

11-17%

Pancreatic cancer

1-3%

3-5% by 70 yrs of age

Prostate cancer

29% by 85 yrs of age

60% by 85 yrs of age

Melanoma

1.6% (same as general population)

Elevated risk

Source: Petrucelli, 2022 

Genetics

Genes Tested

  • BRCA1 (NM_007294) and BRCA2 (NM_000059)
  • See Genes Tested table for more information

Etiology

At least 5-10% of all breast cancers and 10-15% of all ovarian cancers are associated with a hereditary cause.   

Prevalence

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

Inheritance

  • Single pathogenic variants in the BRCA1 and BRCA2 genes are inherited in an autosomal dominant manner and are associated with HBOC syndrome.
  • BRCA1 and BRCA2 pathogenic variants are also associated with autosomal recessive Fanconi anemia.

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 (Greenland), and Icelandic populations. 

Test Interpretation

Contraindications for Ordering

  • Should not be ordered to detect somatic variants associated with malignancy because sensitivity for mosaic variants is low with 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, see Familial Mutation, Targeted Sequencing.

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.
  • Sanger sequencing is performed as necessary to fill in regions of low coverage and in certain situations, to confirm variant calls.
  • The pipeline includes an algorithm for detection of large (single exon-level or larger) deletions and duplications.
  • Large deletion/duplication calls made using MPS are confirmed by an orthogonal exon-level microarray when sample quality and technical conditions allow.

Clinical Sensitivity

  • Greater than 98% for BRCA1- and BRCA2-associated HBOC syndrome 
    • BRCA1 variants
      • ~87-89% are detectable by sequencing
      • ~11-13% detectable by deletion/duplication analysis
    • BRCA2 variants
      • ~97-98% are detectable by sequencing
      • ~2-3% are detectable by deletion/duplication analysis
  • BRCA1 and BRCA2 sequencing and deletion/duplication testing detects ~20-60% of hereditary breast and/or ovarian cancers, in general.  

Analytical Sensitivity

Variant Class Analytical Sensitivity (PPA) Estimatea (%) and 95% Credibility Region (%) Analytical Specificity (NPA) (%)

SNVs

>99 (96.9-99.4)

>99.9

Deletions 1-10 bpb

93.8 (84.3-98.2)

>99.9

Insertions 1-10 bpb

94.8 (86.8-98.5)

>99.9

Exon-levelc Deletions

97.8% (90.3-99.8%) [2 exons or larger]

62.5% (38.3%-82.6%) [Single exon]

>99.9

Exon-levelc Duplications

83.3% (56.4%-96.4%) [3 exons or larger]

>99.9

aGenes included on this test are a subset of a larger methods-based validation from which the PPA values are derived. These values do not apply to testing performed by multiplex ligation-dependent probe amplification (MLPA).

bVariants greater than 10 bp may be detected, but the analytical sensitivity may be reduced.

cIn most cases, a single exon deletion or duplication is less than 450 bp and 3 exons span a genomic region larger than 700 bp.

bp, base pairs; NPA, negative percent agreement; PPA, positive percent agreement; SNVs, single nucleotide variants

Results

Result Variant(s) Detected Clinical Significance

Positive

One BRCA1 or BRCA2 pathogenic variant detected

Consistent with a diagnosis of BRCA1/2-associated HBOC syndrome; other genetic/environmental factors may influence the risk of developing cancer

Negative

No BRCA1 or BRCA2 pathogenic variants detected

Diagnosis of BRCA1/2-associated HBOC syndrome is unlikely but not excluded; does not exclude another hereditary cancer syndrome

Inconclusive

BRCA1 or BRCA2 variant of unknown clinical significance detected

Uncertain; it is unknown whether variant is benign or pathogenic

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 and deep intronic variants
    • Breakpoints of large deletions/duplications
    • Single exon deletions/duplications in the following exons:
      • BRCA1 (NM_007294) 2
  • The following may not be detected:
    • Deletions/duplications/insertions of any size by massively parallel sequencing
    • Large duplications less than 3 exons in size
    • Noncoding transcripts
    • Low-level somatic variants
    • Certain other variants due to technical limitations in the presence of pseudogenes and/or repetitive or homologous regions

Genes Tested

Gene MIM Number Disorder Inheritance

BRCA1

113705

HBOC syndrome

Associated cancer(s)/tumor(s): breast, ovarian, fallopian tube, peritoneal, pancreatic, prostate

AD

Fanconi anemia, complementation group S

AR

BRCA2

600185

HBOC syndrome

Associated cancer(s)/tumor(s): breast, ovarian, fallopian tube, peritoneal, pancreatic, prostate, melanoma

AD

Fanconi anemia, complementation group D1

AR

AD, autosomal dominant; AR, autosomal recessive

References