Hereditary Breast and Ovarian Cancer Panel

Indication for testing:

  • Multigene panel to confirm a hereditary cause of breast and/or ovarian cancer in individuals with a complex personal or family history of breast and/or ovarian cancer
  • When a relative has a previously identified pathogenic sequence variant, see Familial Mutation, Targeted Sequencing (2001961)

Indication for testing:

  • 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

Pathogenic variants in multiple genes have been implicated in hereditary breast and/or ovarian cancer (HBOC). Hereditary cancer predisposition is often characterized by early age of cancer onset (typically before age 50) and multiple, multifocal, and/or similar cancers in a single individual or in a closely related family member(s). The HBOC panel includes analysis of several genes associated with hereditary breast and/or ovarian cancer that cause variable phenotypes and cancer risks, including nonbreast/nonovarian cancers. Pathogenic variants in the BRCA1 and BRCA2 genes are associated with HBOC syndrome.

Disease Overview

Associated Disorders

  • BRCA1 and BRCA2-associated HBOC syndrome  
    • Caused by a single pathogenic BRCA1 or BRCA2 variant
    • Individuals are at increased risk for breast, ovarian, fallopian tube, peritoneal, pancreatic, prostate, melanoma, and other cancers
  • Lynch syndrome 
    • Caused by a single pathogenic variant in one of the mismatch repair (MMR) genes (MLH1, MSH2, MSH6, PMS2) or EPCAM exon 9 deletions
    • Individuals are at an increased risk for colorectal, uterine, ovarian, and other cancers
  • Other associated disorders on this panel include: Cowden syndrome, Li-Fraumeni syndrome (LFS), Peutz-Jeghers syndrome (PJS), and others. Please 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

  • 1/400 individuals from general population or 1/40 Ashkenazi Jews have a BRCA1 or BRCA2 pathogenic variant  
  • Lynch syndrome occurs in approximately 1/440 individuals in the general population 
  • Prevalence of pathogenic variants in the additional genes on this panel is largely unknown

Inheritance

  • All genes tested on the HBOC panel are autosomal dominant with the exception of the MUTYH gene, which is autosomal recessive, but may also have autosomal dominant risks that are currently not well defined
  • Some genes are associated with a predisposition to autosomal recessive childhood cancer or other syndromes

Test Description

See Genes Tested table for genes included in the panel.

Clinical Sensitivity

Variable, dependent on phenotype/condition

  • BRCA1 and BRCA2 sequencing and deletion/duplication testing alone detects 20-60% of HBOCs, in general   
    • >80% of BRCA1 and BRCA2 variants are detectable by sequencing
    • ~10% of BRCA1 and BRCA2 variants are detectable by large deletion/duplication analysis

Testing Strategy

Contraindications for Ordering

  • Should not be ordered to detect somatic variants associated with malignancy as sensitivity for mosaic variants is low with the methodology used for germline assays
  • Individuals with a hematological malignancy and/or a previous allogenic bone marrow transplant should not undergo molecular genetic testing on a peripheral blood specimen
    • Testing of cultured fibroblasts is required for accurate interpretation of test results for these individuals
  • When a relative has a previously identified pathogenic variant, order Familial Mutation, Targeted Sequencing (2001961).

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
    • Deletions/duplications in NF1, RECQL
    • Sequence variants in EPCAM
    • Noncoding transcripts
    • The following exons are not sequenced due to technical limitations of the assay:
      • CHEK2 (NM_001349956) 4; (NM_001005735) 3; (NM_007194) 10,12,13,14,15
      • RECQL (NM_002907) 14, 15
  • The following may not be detected:
    • Deletions/duplications/insertions of any size by massively parallel sequencing
    • Deletions/duplications less than 1kb in the targeted genes by array
    • Some variants due to technical limitations in the presence of pseudogenes, repetitive, or homologous regions
    • Low-level somatic variants
    • Single exon deletions/duplications in the following exons:
    • Gene Exon(s)

      BARD1

      (NM_000465) 1

      BRCA1

      (NM_007300) 13

      CDH1

      (NM_004360) 1

      CHEK2

      (NM_001005735) 3; (NM_007194) 11, 12, 14, 15

      MRE11

      (NM_005591) 2

      MSH2

      (NM_000251) 1; (NM_001258281) 2

      MSH6

      (NM_000179) 10

      MUTYH

      (NM_001128425) 1

      PALB2

      (NM_024675) 1

      PTEN

      (NM_000314) 8, 9; (NM_001304717) 1

      RAD51D

      (NM_002878) 1

      TP53

      (NM_001126113) 10; (NM_001126114) 1

Analytical Sensitivity

  • Sanger sequencing and multiplex ligation-dependent probe amplification (MLPA) of PMS2: 99%
  • For massively parallel sequencing:
  • Variant Class Analytical Sensitivity (PPA) Estimatea (%) Analytical Sensitivity (PPA) 95% Credibility Regiona (%)

    SNVs

    99.2

    96.9-99.4

    Deletions 1-10 bp

    93.8

    84.3-98.2

    Deletions 11-44 bp

    100

    87.8-100

    Insertions 1-10 bp

    94.8

    86.8-98.5

    Insertions 11-23 bp

    100

    62.1-100

    aGenes included on this test are a subset of a larger methods-based validation from which the PPA values are derived.

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

Genes Tested

Gene MIM Number Disorder Inheritance

ATM

607585

Associated cancer(s)/tumor(s): breast, ovarian,a colorectal a

AD

Ataxia-telangiectasia (AT)

Associated cancer(s)/tumor(s): leukemia and lymphoma

AR

BARD1

601593

Associated cancer(s)/tumor(s): breast a

AD

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

BRIP1

605882

Associated cancer(s)/tumor(s): ovarian, breast a

AD

Fanconi anemia, complementation group J

AR

CDH1

192090

Hereditary diffuse gastric cancer (HDGC)

Associated cancer(s)/tumor(s): diffuse gastric, lobular breast

AD

CHEK2

604373

Associated cancer(s)/tumor(s): breast, colorectal,a  prostate,a thyroid a

AD

DICER1

606241

DICER1-related disorders

Associated cancer(s)/tumor(s): pleuropulmonary blastoma, ovarian sex cord-stromal tumors, cystic nephroma, thyroid

AD

EPCAM

185535

Lynch syndrome/hereditary nonpolyposis colorectal cancer (HNPCC)

Associated cancer(s)/tumor(s): colorectal, endometrial, stomach, ovarian, and others

AD

MLH1

120436

Lynch syndrome/HNPCC

Associated cancer(s)/tumor(s): colorectal, endometrial, stomach, ovarian, and others

AD

Constitutional mismatch repair deficiency (CMMRD)

AR

MRE11/MRE11A

600814

Associated cancer(s)/tumor(s): breast a

AD

Ataxia-telangiectasia-like disorder

AR

MSH2

609309

Lynch syndrome/HNPCC

Associated cancer(s)/tumor(s): colorectal, endometrial, stomach, ovarian, and others

AD

CMMRD

AR

MSH6

600678

Lynch syndrome/HNPCC

Associated cancer(s)/tumor(s): colorectal, endometrial, stomach, ovarian, and others

AD

CMMRD

AR

MUTYH

604933

Associated cancer(s)/tumor(s): breast a

AD

MUTYH-associated polyposis (MAP)

Associated cancer(s)/tumor(s): colon, duodenal

AR

NBN

602667

Associated cancer(s)/tumor(s): breast

AD

Nijmegan breakage syndrome (NBS)

AR

NF1

613113

Neurofibromatosis type 1 (NF1)

Associated cancer(s)/tumor(s): breast, neurofibromas, gliomas, malignant peripheral nerve sheath tumors, gastrointestinal stromal tumor (GIST), leukemia

AD

PALB2

610355

Associated cancer(s)/tumor(s): breast, pancreatic a

AD

Fanconi anemia, complementation group N

AR

PMS2

600259

Lynch syndrome/HNPCC

Associated cancer(s)/tumor(s): colorectal, endometrial, stomach, ovarian, and others

AD

CMMRD

AR

PTEN

601728

Cowden syndrome/PTEN hamartoma tumor syndrome

Associated cancer(s)/tumor(s): breast, endometrial, thyroid, colon, renal cell carcinoma

AD

RAD51C

602774

Associated cancer(s)/tumor(s): ovarian

AD

Fanconi anemia, complementation group O

AR

RAD51D

602954

Associated cancer(s)/tumor(s): ovarian 

AD

RECQL

600537

Associated cancer(s)/tumor(s): breast a

AD

STK11

602216

PJS

Associated cancer(s)/tumor(s): breast, colon, stomach, small intestine, pancreas, ovary, testes, lung

AD

TP53

191170

LFS

Associated cancer(s)/tumor(s): soft tissue sarcoma, osteosarcoma, central nervous system (CNS) tumor, breast, adrenocortical carcinoma, choroid plexus carcinoma, rhabdomyosarcoma

AD

aAssociation is suggested but not well-established at this time.

AD, autosomal dominant; AR, autosomal recessive

References

Additional Resources