Breast Cancer - Comprehensive Risk Panel

Summary and Pricing

Test Method

Sequencing and CNV Detection via NextGen Sequencing using PG-Select Capture Probes
Test Code Test Copy GenesCPT Code Copy CPT Codes
5435 ATM 81408,81479 Add to Order
BARD1 81479,81479
BRCA1 and BRCA2 81162
BRIP1 81479,81479
CDH1 81406,81479
CHEK2 81479,81479
MRE11 81479,81479
MUTYH 81406,81479
NBN 81479,81479
NF1 81408,81479
PALB2 81406,81479
PTEN 81321,81323
RAD51C 81479,81479
RAD51D 81479,81479
RECQL 81479,81479
STK11 81405,81404
TP53 81405,81479
Full Panel Price* $540
Test Code Test Copy Genes Total Price CPT Codes Copy CPT Codes
5435 Genes x (18) $540 81162, 81321, 81323, 81404, 81405(x2), 81406(x3), 81408(x2), 81479(x22) Add to Order

Pricing Comments

We are happy to accommodate requests for testing single genes in this panel or a subset of these genes. The price will remain the list price. If desired, free reflex testing to remaining genes on panel is available.

This test is also offered via our exome backbone with CNV detection (click here). The exome-based test may be higher priced, but permits reflex to the entire exome or to any other set of clinically relevant genes.

Targeted Testing

For ordering sequencing of targeted known variants, go to our Targeted Variants page.

Turnaround Time

The great majority of tests are completed within 20 days.

EMAIL CONTACTS

Genetic Counselors

Geneticist

Clinical Features and Genetics

Clinical Features

Hereditary breast and ovarian cancer (HBOC) syndrome is an inherited disorder involving tumors of the breasts and ovaries. In comparison to sporadic breast and ovarian cancers, HBOC syndrome tends to present at an earlier age (<50 years), occur bilaterally, consist of multiple affected family members (including males with breast cancer), and occur with a higher predisposition in specific ethnicities, such as the Ashkenazi Jewish population (Petrucelli et al. 2016. PubMed ID: 20301425; Pruthi et al. 2010. PubMed ID: 21123638). Other malignancies in HBOC families can also occur, including melanoma, pancreatic, and prostate cancer. Identifying individuals with a high risk for developing HBOC provides the opportunity for early detection of tumors and/or preventive treatments and procedures such as mastectomy and oophorectomy (Smith. 2012. PubMed ID: 23050669).

HBOC syndrome is mainly due to high penetrance pathogenic sequence variants in the BRCA1 and BRCA2 genes. However, pathogenic variants with reasonably high penetrance have been found in other genes. Breast and ovarian cancers can also show familial inheritance due to sequence variants of low penetrance which confer a moderate risk (Berliner et al. 2013. PubMed ID: 23188549). Overall, 5-10% of breast and 10-15% of ovarian cancer cases are the result of genetic predisposition due to gene-specific pathogenic variants that significantly increase an individual's risk of developing these cancers (Marchina et al. 2010. PubMed ID: 21042765).

Higher incidences of breast and/or ovarian cancer have also been observed in several syndromes, albeit with different cancer spectrums. These include, but are not limited to, Li-Fraumeni syndrome, Cowden syndrome, Peutz-Jeghers syndrome, Fanconi anemia, ataxia-telangiectasia, and Nijmegen breakage syndrome caused by pathogenic variants in the TP53, PTEN, STK11, PALB2, ATM, and NBN genes, respectively.

Genetics

Hereditary breast and ovarian cancer is inherited in an autosomal dominant manner and presents with high, although incomplete, penetrance. Pathogenic variants in a number of genes have been reported to significantly increase an individual’s likelihood for developing breast cancer (Tan et al. 2008. PubMed ID: 18682420). Among those, germline pathogenic variants in the most commonly mutated and highly penetrant breast cancer genes, BRCA1 and BRCA2 (Miki et al. 1994. PubMed ID: 7545954; Wooster et al. 1995. PubMed ID: 8524414), appear to provide the highest relative risk, ~10- to 20-fold. Hereditary BRCA1 and BRCA2 pathogenic variants account for approximately 25-60% of inherited breast cancer (Pruthi et al. 2010. PubMed ID: 21123638; Meindl et al. 2011. PubMed ID: 21637635) and 11-39% of inherited ovarian cancer (Berliner et al. 2013. PubMed ID: 23188549). Large rearrangements (deletions, duplications, triplications), including the five most commonly reported BRCA1 CNVs (Hendrickson et al. 2005. PubMed ID: 15846789), can be detected using this test. Other genes have also been implicated in hereditary breast and ovarian cancer, and although individual pathogenic variants in these genes may cause only a small fraction of inherited breast and ovarian cancer, the combination of moderately and mildly penetrant gene variants may be responsible for a significant portion of these hereditary cancers (Turnbull and Rahman. 2008. PubMed ID: 18544032).

BRCA1 mutation carriers tend to have breast tumors that are estrogen receptor (ER) negative, progesterone receptor (PR) negative, and basal type tumors, whereas BRCA2 mutation carriers have breast tumors that are ER positive, PR positive, and have a luminal phenotype (Pruthi et al. 2010. PubMed ID: 21123638). Individuals with HBOC who have a more severe personal or family history tend to have pathogenic variants in BRCA1 vs. BRCA2 due to generally higher penetrance of pathogenic variants in the BRCA1 gene (Antoniou et al. 2000. PubMed ID: 10642429).

Genes related to other syndromes (Li-Fraumeni syndrome and Cowden syndrome) that are mutated and inherited in a dominant manner may predispose individuals to breast cancer and/or ovarian cancer with moderate penetrance. Early-onset breast cancer is a major component of Li-Fraumeni Syndrome (LFS), and pathogenic variants in the LFS-associated gene TP53 provide a 10- to 20-fold increased risk for developing bilateral mammary carcinomas, in addition to other cancers (ovarian).

Individuals with Cowden syndrome caused by pathogenic variants in PTEN have a lifetime risk of 50% for breast cancer and 5-10% for endometrial cancer (Hearle et al. 2006. PubMed ID: 16707622; Eng. 2000. PubMed ID: 11073535).

Peutz-Jeghers syndrome, caused by pathogenic variants in STK11, can reach a breast cancer incidence of 32% by 60 years of age (Lim et al. 2004. PubMed ID: 15188174).

RAD51C is a tumor suppressor gene that has a role in DNA repair. It is mutated in approximately 1-5% of individuals with a family history of breast and ovarian cancer (Meindl et al. 2011. PubMed ID: 21637635).

CDH1 pathogenic variants predispose individuals to higher rates of breast cancer but not ovarian cancer (Pennington and Swisher. 2012. PubMed ID: 22264603).

The relative risk of breast cancer due to PALB2 pathogenic variants has been estimated at 2.3, with a higher risk for women under 50 years of age (3.0 relative-risk) versus a lower risk in women older than 50 years of age (1.9 relative-risk) (Walsh and King. 2007. PubMed ID: 17292821). A larger recent study has found a higher relative risk (<9) depending on age for PALB2 mutation carriers, and the mean cumulative risk of breast cancer by 70 was 35% (Antoniou et al. 2014. PubMed ID: 25099575).

Individuals with heterozygous pathogenic variants in low to moderately penetrant genes BRIP1 and ATM increase their breast cancer risk from 1.5- to 5-fold (Meindl et al. 2011. PubMed ID: 21637635; Pennington and Swisher. 2012. PubMed ID: 22264603). Others have reported that lifetime risks of BRIP1 and PALB2 pathogenic variants are associated with a 20-50% lifetime risk of breast cancer (Seal et al. 2006. PubMed ID: 17033622; Rahman et al. 2007. PubMed ID: 17200668). Female relatives of individuals with ataxia-telangiectasia who are carriers of an ATM pathogenic variant have a two-to fivefold increased risk of breast cancer (Swift et al. 1987. PubMed ID: 3574400; Thompson et al. 2005. PubMed ID: 15928302). This is an important observation considering that approximately 0.2-1.0% of the general population are heterozygous for an ATM pathogenic variant (Lindor et al. 2008. PubMed ID: 18559331).

Pathogenic variants in CHEK2 have been found in patients who have hereditary breast cancer but do not have detectable BRCA1 or BRCA2 pathogenic variants (Vahteristo et al. 2002. PubMed ID: 12094328; Meijers-Heijboer et al. 2003. PubMed ID: 12690581). CHEK2 pathogenic variants increase the risk of breast cancer two-to threefold, and up to four- to fivefold if there is a family history (Weischer et al. 2008. PubMed ID: 18172190).

NBN pathogenic variants are associated with a twofold increased risk of breast cancer (Walsh and King. 2007. PubMed ID: 17292821).

Pathogenic variants in the MUTYH and RAD51D, genes have also been associated with hereditary breast and/or ovarian cancer (Maxwell et al. 2015. PubMed ID: 25503501; Gutiérrez-Enríquez et al. 2014. PubMed ID: 24130102), although their risk is not well defined.

The RECQL gene is a member of the RecQ DNA helicase family, which is involved in DNA repair. RECQL has recently been described as a breast cancer susceptibility gene that is inherited in an autosomal dominant manner (Cybulski et al. 2015. PubMed ID: 25915596; Sun et al. 2015. PubMed ID: 25945795).

The MRE11 (previously MRE11A) gene is involved in homologous recombination, telomere length maintenance, cell cycle checkpoint control, and DNA double-strand break repair (Taylor et al. 2004. PubMed ID: 15279810). The MRE11A protein forms a complex with the RAD50 and NBS1 proteins to form the MRN complex, which is required for proper DNA repair.

See individual gene test descriptions for more information on molecular biology of gene products and mutation spectra.

Testing Strategy

For this Next Generation Sequencing (NGS) test, sequencing is accomplished by capturing specific regions with an optimized solution-based hybridization kit, followed by massively parallel sequencing of the captured DNA fragments.

For Sanger sequencing, polymerase chain reaction (PCR) is used to amplify targeted regions. After purification of the PCR products, cycle sequencing is carried out using the ABI Big Dye Terminator v.3.0 kit. PCR products are resolved by electrophoresis on an ABI 3730xl capillary sequencer. In nearly all cases, cycle sequencing is performed separately in both the forward and reverse directions.

Copy number variants (CNVs) are also detected from NGS data. We utilize a CNV calling algorithm that compares mean read depth and distribution for each target in the test sample against multiple matched controls. Neighboring target read depth and distribution and zygosity of any variants within each target region are used to reinforce CNV calls. All CNVs are confirmed using another technology such as aCGH, MLPA, or PCR before they are reported.

This panel typically provides ≥98% coverage of all coding exons of the genes listed, plus ~10 bases of flanking noncoding DNA. We define coverage as ≥20X NGS reads or Sanger sequencing.

Clinical Sensitivity - Sequencing and CNV

The overall prevalence of germline BRCA1 or BRCA2 pathogenic variants in the general population is 1:400 to 1:800, with higher rates depending on the specific ethnicity, such as 1:40 in the Ashkenazi Jewish population. Nucleotide substitutions and small insertions or deletions are found in about 90% of individuals with an identifiable pathogenic variant. For individuals with pathogenic variants in these genes, BRCA1 variants were observed in 63% and BRCA2 variants in 37% (Petrucelli et al. 2016. PubMed ID: 20301425).

Genes tested in this panel have been implicated in hereditary breast and ovarian cancer, and although individually these genes may be involved in a minority of inherited breast cancer genes, the combination of these variable risk genes may be responsible for a significant portion of these hereditary cancers (Turnbull and Rahman. 2008. PubMed ID: 18544032). A study by Castéra et al. found that around a third of the deleterious variants they identified in their patient cohort were in genes outside of BRCA1/2, including CDH1, CHEK2, PALB2, and TP53 (Castéra et al. 2014. PubMed ID: 24549055).

Copy number variants (CNVs) are found in approximately 10% of individuals with an identifiable BRCA1/2 germline pathogenic variant, with 90% of these in BRCA1 and 10% in BRCA2 (Petrucelli et al. 2016. PubMed ID: 20301425). High-risk patients—individuals with early onset (<50 years of age) invasive or in situ breast cancer, ovarian cancer, or male breast cancer, who also have 2 or more relatives with HBOC—have higher rates of CNVs. Clinical sensitivity for CNVs for the other genes in hereditary breast and ovarian cancer is unknown. However, gross deletions have been reported for the RAD51C (Vuorela et al. 2011. PubMed ID: 21750962), PALB2 (Antoniou et al. 2014. PubMed ID: 25099575), and TP53 (Melhem-Bertrandt et al. 2012. PubMed ID: 21761402) genes. Approximately 1-2% of ataxia-telangiectasia patients have large genomic deletions involving the ATM gene (Gatti. 2010. PubMed ID: 20301790). Deletions in the NF1 gene have been detected in 5% of individuals with neurofibromatosis type 1 (Friedman. 2012. PubMed ID: 20301288). Specific ethnic populations (Latin American/Caribbean) have also been shown to have higher rates of BRCA1/2 CNVs (Judkins et al. 2012. PubMed ID: 22544547). Large deletions have been detected in the CDH1 gene in up to 4% of patients (Kaurah and Huntsman. 2011. PubMed ID: 20301318).

This test is predicted to detect causative PTEN deletions in ~11% of patients with BRRS, but the rate is not known for other PTEN related disorders (Eng. 2000. PubMed ID: 11073535). Approximately 45% of patients with a positive family history or 21% of patients with no family history of Peutz-Jeghers syndrome will have a pathogenic variant in STK11 by deletion analysis (McGarrity et al. 2013. PubMed ID: 20301443). Deletions in the TP53 gene have been detected in 1% of Li-Fraumeni cases (Schneider et al. 2013. PubMed ID: 20301488). To our knowledge, no CNVs have been reported in the literature for MRE11 and RECQL.

Indications for Test

Individuals with a clinical presentation of hereditary breast cancer are candidates. Clinical presentation includes family history, early-onset of breast cancer (<50 years), and bilateral breast tumors, with multiple affected family members (including males with breast cancer). Members of a high-risk ethnicity, such as the Ashkenazi Jewish population, are also candidates (Petrucelli et al. 2016. PubMed ID: 20301425; Pruthi et al. 2010. PubMed ID: 21123638). This is a predictive test which only provides information regarding the likelihood of breast cancer. A positive test does not mean that a person will develop breast cancer, and a negative test does not mean that a person will not. This test is specifically designed for heritable germline mutations and is not appropriate for the detection of somatic mutations in tumor tissue.

Genes

Official Gene Symbol OMIM ID
ATM 607585
BARD1 601593
BRCA1 113705
BRCA2 600185
BRIP1 605882
CDH1 192090
CHEK2 604373
MRE11 600814
MUTYH 604933
NBN 602667
NF1 613113
PALB2 610355
PTEN 601728
RAD51C 602774
RAD51D 602954
RECQL 600537
STK11 602216
TP53 191170
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Related Test

Name
PGxome®

Citations

  • Antoniou et al. 2000. PubMed ID: 10642429
  • Antoniou et al. 2014. PubMed ID: 25099575
  • Berliner et al. 2013. PubMed ID: 23188549
  • Castéra et al. 2014. PubMed ID: 24549055
  • Cybulski et al. 2015. PubMed ID: 25915596
  • Eng. 2000. PubMed ID: 11073535
  • Friedman. 2012. PubMed ID: 20301288
  • Gatti. 2010. PubMed ID: 20301790
  • Gutiérrez-Enríquez et al. 2014. PubMed ID: 24130102
  • Hearle et al. 2006. PubMed ID: 16707622
  • Hendrickson et al. 2005. PubMed ID: 15846789
  • Judkins et al. 2012. PubMed ID: 22544547
  • Kaurah and Huntsman. 2011. PubMed ID: 20301318
  • Lim et al. 2004. PubMed ID: 15188174
  • Lindor et al. 2008. PubMed ID: 18559331
  • Marchina et al. 2010. PubMed ID: 21042765
  • Maxwell et al. 2015. PubMed ID: 25503501
  • McGarrity et al. 2013. PubMed ID: 20301443
  • Meijers-Heijboer et al. 2003. PubMed ID: 12690581
  • Meindl et al. 2011. PubMed ID: 21637635
  • Melhem-Bertrandt et al. 2012. PubMed ID: 21761402
  • Miki et al. 1994. PubMed ID: 7545954
  • Pennington and Swisher. 2012. PubMed ID: 22264603
  • Petrucelli et al. 2016. PubMed ID: 20301425
  • Pruthi et al. 2010. PubMed ID: 21123638
  • Rahman et al. 2007. PubMed ID: 17200668
  • Schneider et al. 2013. PubMed ID: 20301488
  • Seal et al. 2006. PubMed ID: 17033622
  • Smith. 2012. PubMed ID: 23050669
  • Sun et al. 2015. PubMed ID: 25945795
  • Swift et al. 1987. PubMed ID: 3574400
  • Tan et al. 2008. PubMed ID: 18682420
  • Taylor et al. 2004. PubMed ID: 15279810
  • Thompson et al. 2005. PubMed ID: 15928302
  • Turnbull and Rahman. 2008. PubMed ID: 18544032
  • Vahteristo et al. 2002. PubMed ID: 12094328
  • Vuorela et al. 2011. PubMed ID: 21750962
  • Walsh and King. 2007. PubMed ID: 17292821
  • Weischer et al. 2008. PubMed ID: 18172190
  • Wooster et al. 1995. PubMed ID: 8524414

Ordering/Specimens

Ordering Options

myPrevent - Online Ordering

  • The test can be added to your online orders in the Summary and Pricing section.
  • Once the test has been added log in to myPrevent to fill out an online requisition form.

Requisition Form

  • A completed requisition form must accompany all specimens.
  • Billing information along with specimen and shipping instructions are within the requisition form.
  • All testing must be ordered by a qualified healthcare provider.

Specimen Types

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