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Breast and Ovarian Hereditary Cancer Panel,
Sequencing and Deletion/Duplication, 20 Genes
Indications for Ordering
Based on symptoms
• For women with any of the following
o Breast cancer diagnosed by age 45
o Ovarian cancer
o Two primary breast cancers, first diagnosed by age 50
o Breast cancer diagnosed by age 50 with one or more
family members with breast cancer
o Triple negative breast cancer diagnosed by age 60
o Breast cancer at any age with one or more family
members with breast cancer diagnosed by age 50
o Breast cancer diagnosed at any age with two or more
family members from the same side diagnosed with
breast cancer at any age
o Breast cancer at any age with one or more family
members with ovarian cancer
o Breast cancer diagnosed at any age with two or more
family members with pancreatic or prostate cancer
o Breast cancer diagnosed at any age and male family
member with breast cancer
o Breast cancer at any age and Ashkenazi Jewish ancestry
• For men with any of the following
o Breast cancer at any age
o Pancreatic cancer or prostate cancer at any age with
two or more family members with breast, ovarian,
pancreatic, and/or prostate cancer at any age
Based on family history (in asymptomatic patient)
• For women with no Ashkenazi Jewish ancestry and family
history of any of the following on the same side of the
family
o Two first-degree relatives diagnosed with breast cancer,
one diagnosed at age 50 or younger
o Three or more first-degree or second-degree relatives
diagnosed with breast cancer regardless of their age
o A combination of first- and second-degree relatives
diagnosed with breast cancer and ovarian cancer (one
cancer type per person)
o A first-degree relative with bilateral breast cancer
o A combination of two or more first- or second-degree
relatives diagnosed with ovarian cancer regardless of
age at diagnosis
o A first- or second-degree relative diagnosed with both
breast and ovarian cancer regardless of age at diagnosis
o Breast cancer diagnosed in a male relative
• For women with Ashkenazi Jewish ancestry and family
history of any of the following
o First-degree relative diagnosed with breast or ovarian
cancer
o Two second-degree relatives on the same side of the
family diagnosed with breast or ovarian cancer
• For individuals with a family history of a known
pathogenic mutation, previously identified in a relative, in
one of the genes on the Breast and Ovarian Hereditary
Cancer Panel, order targeted mutation testing
Test Description
• Targeted capture of all coding exons and exon-intron
junctions, including the PTEN promoter region, followed
by massively parallel sequencing
• Sanger sequencing of CHEK2 c.1100delC mutation
• Deletion/duplication analysis by tiled, custom-designed
comparative genomic hybridization (CGH) array
Tests to Consider
Primary tests
Breast and Ovarian Hereditary Cancer Panel, Sequencing
and Deletion/Duplication, 20 Genes 2012026
• Preferred first-tier genetic test for confirmation of
hereditary breast and ovarian cancer (HBOC) syndrome
• Highest detection rate for HBOC syndrome but also
highest likelihood of identifying variants of unknown
significance
Breast and Ovarian Hereditary Cancer Syndrome (BRCA1 and
BRCA2) Sequencing and Deletion/Duplication 2011949
• Acceptable first-tier genetic test for confirmation of HBOC
• ~20-60% sensitivity for HBOC syndrome
o Only the BRCA1 and BRCA2 genes are assayed
Breast and Ovarian Hereditary Cancer Syndrome (BRCA1 and
BRCA2) Sequencing 2011954
• ~Up to 90% sensitivity for BRCA1 and BRCA2 mutations
Breast and Ovarian Hereditary Cancer Syndrome (BRCA1 and
BRCA2) Deletion/Duplication 2011915
• Use if no mutation detected by sequencing
• ~10% sensitivity for BRCA1 and BRCA2 mutations
• Use to test for known familial BRCA1 or BRCA2 large
deletions/ duplications
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Genetics
Related tests
Ashkenazi Jewish (BRCA1 and BRCA2) 3 Mutations 2011958
• For individuals of Ashkenazi Jewish descent only
• 97% sensitivity for BRCA1 and BRCA2 mutations in
Ashkenazi Jewish individuals
Familial Mutation, Targeted Sequencing 2001961
• Useful when a familial mutation identifiable by
sequencing is known
Disease Overview
HBOC syndrome
Prevalence – 1:500 individuals from general population and
1:40 Ashkenazi Jewish individuals has a BRCA1 or BRCA2
mutation
• BRCA1 and BRCA2 mutations are believed to cause
20-60% of hereditary breast cancer
• 5-10% of all breast cancers and 10-15% of ovarian cancers
are caused by BRCA1 or BRCA2 mutations
Age of onset
• Sporadic breast cancer usually occurs after age 50
• Breast cancer commonly occurs before age 50 in BRCA1
and BRCA2 mutation carriers
Symptoms
• BRCA1 mutation carriers are at increased risk for HBOC
and may also be at increased risk for fallopian, peritoneal,
cervical, uterine, pancreatic, and colorectal cancers
• BRCA2 mutation carriers are at increased risk for HBOC
and may also be at increased risk for pancreatic, stomach,
gallbladder, bile duct, and melanoma cancers
• Men with BRCA1 mutations are at increased risk for
breast cancer and possibly pancreatic, prostate, and
testicular cancers
• Men with BRCA2 mutations are at increased risk for
breast, pancreatic, and prostate cancers
Diagnostic issues
• Diagnostic testing may allow one to learn if they have a
predisposition to develop HBOC and other associated
cancers to optimize screening/medical management
• Allows asymptomatic family members to learn who is at
increased risk
Prevention of primary manifestations for BRCA1 and BRCA2
mutation carriers
• Prophylactic mastectomy and/or oophorectomy and
chemoprevention using tamoxifen
• Surveillance for breast cancer screening is a combination
of monthly breast self-examinations, annual or
semiannual clinical breast examinations, annual
mammography, and breast MRI
• Ovarian cancer screening is a combination of annual or
semiannual pelvic examinations, transvaginal ultrasounds,
and measurement of CA-125 concentration
• Prostate cancer screening involves annual digital rectal
exam and prostate specific antigen testing
Genes – see table
• Penetrance – female mutation carriers have cumulative
cancer risks
o For breast cancer – 57% for BRCA1 and 49% for BRCA2
by age 70
o For ovarian cancer – 40% for BRCA1 and 18% for BRCA2
by age 70
Structure/function
• BRCA1 and BRCA2 genes function as tumor suppressors
that ensure the stability of the cell’s DNA and help
prevent uncontrolled cell growth
Mutations
• Up to 90% of BRCA1 and BRCA2 mutations are detectable
by sequencing
• Approximately 10% of BRCA1 and BRCA2 mutations are
detectable by large deletion/duplication analysis
Test Interpretation
Sensitivity/specificity
• Clinical sensitivity – unknown for the HBOC 20 gene panel
• BRCA1 and BRCA2 sequencing and deletion/duplication
testing alone detects 20-60% of HBOC (Pruthi, et al, 2010;
Meindl, et al, 2011)Analytical sensitivity and specificity of
sequencing – 99% and 96%, respectively
• Analytical sensitivity and specificity of CGH – 99%
Test results
• Positive
o One pathogenic mutation identified in a gene with
autosomal dominant inheritance confirms a diagnosis of
HBOC syndrome
o Individuals with a pathogenic dominant germ line
mutation have a 50% chance of passing the mutation on
to their offspring
o Two pathogenic mutations located on opposite
chromosomes in an autosomal recessively inherited
gene confirm a diagnosis of HBOC syndrome
o One pathogenic mutation in an autosomal recessively
inherited gene confirms carrier status for HBOC
syndrome
• Negative
o No pathogenic mutations detected in any of the genes
tested reduces the likelihood of, but does not exclude, a
diagnosis of HBOC syndrome as not all mutations in the
tested genes are identified and not all predisposing
genes are interrogated
• Inconclusive
o Variants of unknown clinical significance may be
identified
APRIL 2015 | © 2013 ARUP LABORATORIES
Limitations
• The following will not be determined or evaluated
o Deep intronic and regulatory mutations
o Breakpoints for large deletions/duplications
o Sequence changes in EPCAM
o Exons 11-15 of CHEK2 will not be evaluated with the
exception of the c.1100delC mutation
o Deletions/duplications
 Exon 1 in CDH1, MSH2, and RAD51D
 Exons 4,6, and 7 in STK11
 Exon 8 in PTEN
 Exon 12 in ATM
• Small deletions or insertions may not be detected
• Diagnostic errors can occur due to rare sequence
variations
Gene
Symbol
ATM
Gene Name
NM #
References
• Ford D, et al. 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 Mar;62(3):676-89
• Lalloo F, Evans DG. Familial breast cancer. Clin Genet
2012; 82:105
• Meindl A, Ditsch N, Kast K, et al. Hereditary breast and
ovarian cancer: new genes, new treatments, new
concepts. Dtsch Arztebl Int. 2011 May;108(19):323-30
• 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 Dec;85(12):1111-20
• Walsh T, Casadei S, Lee MK, et al. Mutations in 12 genes
for inherited ovarian cancer, fallopian tube, and
peritoneal carcinoma identified by massively parallel
sequencing. PNAS 2011;108:18032
OMIM #
Inheritance
Cancer Association
000051.3
607585
AD
Breast
BARD1
BRCA1
Ataxia telangiectasia mutated (includes
complementation groups A, C and D)
BRCA1- associated RING domain gene 1
Breast cancer 1
000465.2
007294.3
601593
113705
AD
AD
BRCA2
Breast cancer 2
000059.3
600185
AD
BRIP1
BRCA1 interacting protein C-terminal,
helicase 1
Cadherin 1, E-cadherin (epithelial)
CHK2 checkpoint homologue (S. pombe
RAD53)
Epithelial cell adhesion molecule
Multiple endocrine neoplasia 1
032043.2
605882
AD
Breast, neuroblastoma
Breast, ovarian, fallopian, peritoneal,
pancreatic, prostate
Breast, ovarian, fallopian, peritoneal,
pancreatic, prostate, gallbladder, gastric,
melanoma
Breast, ovarian
004360.3
007194.3
192090
604373
AD
AD
Gastric, breast, prostate
Breast, colorectal, prostate
002354.2
130799.2
185535
613733
AD
AD
000249.3
120436
AD
000251.2
609309
AD
MSH6
MutL homologue 1, colorectal cancer,
nonpolyposis type 2 (E. coli)
MutS homologue 2, colorectal cancer,
nonpolyposis type 1 (E coli)
MutS (E.coli) homologue 6
000179.2
600678
AD
MUTYH
MutY homologue (E.coli)
001128425.1
604933
AR, AD
NBN
PALB2
PTEN
Nibrin (NBS1)
Partner and localizer of BRCA2
Phosphatase and tensin homolog
002485.4
024675.3
000314.4
602667
610335
601728
AD
AD
AD
Colorectal, ovarian
Glucagonomas, gastrinomas, VIPomas,
thymic, bronchial, gastric, breast
Ovarian, colorectal, endometrial, bladder,
kidney
Ovarian, colorectal, endometrium, bladder,
kidney
Ovarian, colorectal , endometrium, bladder,
kidney
Colorectal (AR), gastric, breast, duodenal,
endometrium (AD)
Breast, ovarian
Breast, pancreatic
Thyroid, breast, endometrial
RAD51C
RAD51D
STK11
TP53
RAD51 homolog (S. cerevisiae)
RAD51D homolog D (S. cerevisiae)
Serine/threonine kinase 11 (LKB1)
Tumor protein 53
058216.1
002878.3
000455.4
000546.5
602774
602954
602216
191170
AD
AD
AD
AD
CDH1
CHEK2
EPCAM
MEN1
MLH1
MSH2
AD = autosomal dominant ; AR = autosomal recessive
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Breast, ovarian
Breast, ovarian
Colorectal, pancreatic, breast, ovarian
Breast, ovarian, brain, soft tissue and
osteosarcomas, gastrointestinal, leukemia,
lymphoma, adrenocortical carcinoma