Hereditary Breast and Ovarian Cancer

Hereditary Breast and Ovarian Cancer Panel, Sequencing and Deletion/Duplication 2012026
Method: Massively Parallel Sequencing/Exonic Oligonucleotide-based CGH Microarray

Indication for testing:

  • Recommended test to confirm a diagnosis of hereditary breast and/or ovarian cancer in individuals with a 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).
Breast and Ovarian Hereditary Cancer Syndrome (BRCA1 and BRCA2) Sequencing and Deletion/Duplication 2011949
Method: Polymerase Chain Reaction/Sequencing/Multiplex Ligation-dependent Probe Amplification

Indication for testing:

  • Recommended test to confirm hereditary breast and ovarian cancer (HBOC) syndrome (BRCA1 and BRCA2 genes only).
  • When a relative has a previously identified pathogenic sequence variant, see Familial Mutation, Targeted Sequencing (2001961).

Indication for testing:

  • Acceptable test to confirm HBOC syndrome (BRCA1 and BRCA2 genes only).
  • When a relative has a previously identified pathogenic sequence variant, see Familial Mutation, Targeted Sequencing (2001961).
Familial Mutation, Targeted Sequencing 2001961
Method: Polymerase Chain Reaction/Sequencing

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 onset (typically before age 50) and multiple, multifocal, and/or similar cancers in a single individual or in a closely related family member(s). Pathogenic variants in the genes analyzed by this panel 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 Disorder

BRCA1- and BRCA2-associated HBOC syndrome

  • Individuals with a pathogenic BRCA1 or BRCA2 variant are at increased risk for breast, ovarian, fallopian, peritoneal, pancreatic, prostate, melanoma, and other cancers.

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.
  • 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 not well defined.
  • Some genes are associated with autosomal recessive childhood cancer predisposition 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 (Pruthi, 2010; Meindl, 2011).
    • >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 because sensitivity for mosaic variants is low with methodology used for germline assays.
  • Individuals with 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.
  • When a relative has a previously identified pathogenic variant, see 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

  • For Sanger sequencing and multiplex ligation-dependent probe amplification (MLPA) of BRCA1 and BRCA2: 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

Hereditary breast and ovarian cancer (HBOC) syndrome

Associated cancer(s)/tumor(s): breast, ovarian, prostate, pancreas, melanoma

AD

Fanconi anemia, complementation group S

AR

BRCA2

600185

Hereditary breast and ovarian cancer (HBOC) syndrome

Associated cancer(s)/tumor(s): breast, ovarian, prostate, pancreas, 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/hereditary nonpolyposis colorectal cancer (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/hereditary nonpolyposis colorectal cancer (HNPCC)

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

AD

Constitutional mismatch repair deficiency (CMMRD)

AR

MSH6

600678

Lynch syndrome/hereditary nonpolyposis colorectal cancer (HNPCC)

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

AD

Constitutional mismatch repair deficiency (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/hereditary nonpolyposis colorectal cancer (HNPCC)

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

AD

Constitutional mismatch repair deficiency (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

Peutz-Jeghers syndrome (PJS)

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

AD

TP53

191170

Li-Fraumeni syndrome (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 

BRCA1- and BRCA2-Associated Hereditary Breast and Ovarian Cancer. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews, University of Washington, 1993-2018. Seattle, WA [Last Update: Dec 2016; Accessed: Nov 2018]

Doros L, Schultz K, Stewart D, Bauer A, Williams G, Rossi C, Carr A, Yang J, Dehner L, Messinger Y, Hill D. DICER1-Related Disorders. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews, University of Washington, 1993-2018. Seattle, WA [Accessed: Nov 2018]

Ford D, Easton DF, Stratton M, Narod S, Goldgar D, Devilee P, Bishop DT, Weber B, Lenoir G, Chang-Claude J, Sobol H, Teare MD, Struewing J, Arason A, Scherneck S, Peto J, Rebbeck TR, Tonin P, Neuhausen S, Barkardottir R, Eyfjord J, Lynch H, Ponder BA, Gayther SA, Zelada-Hedman M. Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. The Breast Cancer Linkage Consortium. Am J Hum Genet. 1998; 62(3): 676-89. PubMed

Friedman J. Neurofibromatosis 1. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews, University of Washington, 1993-2018. Seattle, WA [Last Revision: May 2018; Accessed: Nov 2018]

Lalloo F, Evans DG. Familial breast cancer. Clin Genet. 2012; 82(2): 105-14. PubMed

Meindl A, Ditsch N, Kast K, Rhiem K, Schmutzler RK. Hereditary breast and ovarian cancer: new genes, new treatments, new concepts. Dtsch Arztebl Int. 2011; 108(19): 323-30. PubMed

NCCN Clinical Practice Guidelines in Oncology, Genetic/Familial High-Risk Assessment: Breast and Ovarian, Version 2.2019. National Comprehensive Cancer Network. Fort Washington, PA [Last Updated: Jul 2018; Accessed: Nov 2018]

NCCN Clinical Practice Guidelines in Oncology, Genetic/Familial High-Risk Assessment: Colorectal. Version 1.2018. National Comprehensive Cancer Network. Fort Washington, PA [Updated: Jul 2018; Accessed: Jan 2019]

Pruthi S, Gostout BS, Lindor NM. Identification and Management of Women With BRCA Mutations or Hereditary Predisposition for Breast and Ovarian Cancer. Mayo Clin Proc. 2010; 85(12): 1111-20. PubMed

Walsh T, Casadei S, Lee MK, Pennil CC, Nord AS, Thornton AM, Roeb W, Agnew KJ, Stray SM, Wickramanayake A, Norquist B, Pennington KP, Garcia RL, King M, Swisher EM. Mutations in 12 genes for inherited ovarian, fallopian tube, and peritoneal carcinoma identified by massively parallel sequencing. Proc Natl Acad Sci U S A. 2011; 108(44): 18032-7. PubMed

Whittemore AS, Gong G, John EM, McGuire V, Li FP, Ostrow KL, Dicioccio R, Felberg A, West DW. Prevalence of BRCA1 mutation carriers among U.S. non-Hispanic Whites. Cancer Epidemiol Biomarkers Prev. 2004; 13(12): 2078-83. PubMed

Last Update: March 2019