Hereditary Breast and Ovarian Cancer - High Risk and Lynch Syndrome 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
5453 ATM 81408,81479 Add to Order
BRCA1 and BRCA2 81162
BRIP1 81479,81479
CDH1 81406,81479
CHEK2 81479,81479
EPCAM 81479,81403
MLH1 81292,81294
MSH2 81295,81297
MSH6 81298,81300
PALB2 81406,81479
PMS2 81317,81319
PTEN 81321,81323
RAD51C 81479,81479
RAD51D 81479,81479
STK11 81405,81404
TP53 81405,81479
Full Panel Price* $540
Test Code Test Copy Genes Total Price CPT Codes Copy CPT Codes
5453 Genes x (17) $540 81162, 81292, 81294, 81295, 81297, 81298, 81300, 81317, 81319, 81321, 81323, 81403, 81404, 81405(x2), 81406(x2), 81408, 81479(x13) 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) is an inherited disorder that is highly associated with tumors of the breasts and ovaries. HBOC cases tend to arise prior to age 50, tumors often occur bilaterally, consist of multiple affected family members (including males with breast cancer), and occur with a high predisposition in specific ethnic groups. Individuals with Ashkenazi Jewish ancestry have an increased risk for HBOC. There are three specific founder genetic variants that are known to be common in this population: c.68_69delAG (BRCA1), c.5266dupC (BRCA1), and c.5946delT (BRCA2) (Petrucelli et al. 2013. PubMed ID: 20301425). It is estimated that approximately 1:40 individuals with Ashkenazi Jewish ancestry has at least one of these variants; approximately 1:10 women with breast cancer and 1:3 women with ovarian cancer (cancer.net).

Lynch Syndrome, the most prevalent colorectal cancer syndrome, is caused by variations in mismatch repair (MMR) genes, mainly the MSH2 gene. Mismatch repair proteins are involved in numerous cellular functions including repairing DNA synthesis errors, repairing double stranded breaks, and apoptosis. Lynch syndrome is generally early onset, and is characterized by predominantly right-sided colon cancer (Jang et al. 2010. PubMed ID: 20559516). Lynch syndrome is estimated to account for approximately 3-5% of colorectal cancer (Jang et al. 2010. PubMed ID: 20559516; Bonadona et al. 2015. PubMed ID: 21642682). Based on the Amsterdam criteria, families with Lynch syndrome have at least 3 relatives with colorectal cancer, one being a first degree relative, at least 2 successive generations involved, and at least 1 relative with onset of cancer before age 50 (Kohlman et al. 2012. PubMed ID: 20301390; cancer.org).

Genetics

Hereditary breast and ovarian cancer (HBOC) syndrome is a disorder that follows an autosomal dominant pattern of inheritance. It is associated with tumors mainly in the breast and ovaries, and is primarily a result of alterations in high-penetrance genes BRCA1, BRCA2, and TP53 (Seal et al. 2006. PubMed ID: 17033622).

The BRCA1 tumor suppressor gene is associated with hereditary breast and ovarian cancer. Its protein product is essential for processes such as DNA repair, cell cycle checkpoint control, and maintenance of genomic stability (Wang et al. 2009. PubMed ID: 19261749). Women carrying a pathogenic variant in BRCA1 have a 46-65% risk of developing breast cancer, and approximately a 39% risk of developing ovarian cancer by age 70 (Berlinear et al. 2013. PubMed ID: 23188549). Men who have pathogenic variants in the BRCA1 gene have a life time risk of 7-8% of developing breast cancer compared to the average man whose risk is approximately 0.1% (Berlinear et al. 2013. PubMed ID: 23188549).

BRCA2 is a tumor suppressor gene, and along with RAD51 has a major role in DNA damage repair and genome stability (Tan et al. 2008. PubMed ID: 18682420). Women with a pathogenic variant in BRCA2 gene are at a 43-45% risk of developing breast cancer by age 70, and 11% risk of developing ovarian cancer (Berlinear et al. 2013. PubMed ID: 23188549).

Hereditary breast and/or ovarian cancers can sometimes be associated with other hereditary cancer syndromes including Li-Fraumeni, Cowden, Peutz-Jeghers, Hereditary Diffuse Gastric Cancer, and Lynch syndrome (Berlinear et al. 2013. PubMed ID: 23188549). Variants in TP53 have been implicated as the cause of Li-Fraumeni syndrome. Breast cancer appears as a feature of this syndrome, and carriers of TP53 pathogenic variants are at high risk of developing early onset breast cancer (Antoniou et al. 2006. PubMed ID: 16998504).

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).

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).

Other genes that are thought to confer low to moderate risk of breast and ovarian cancer have been identified. Pathogenic variants in CDH1 have been shown to be associated with the development of invasive lobular carcinoma. It is also thought to be a gene that causes intermediate risk of hereditary breast cancer (Masciari et al. 2007. PubMed ID: 17660459). CHEK2 truncating variants have been shown to confer moderate risk of breast cancer development (Meijers-Heijboer et al. 2002. PubMed ID: 11967536; Tan et al. 2008. PubMed ID: 18682420). Variants in ATM that cause ataxia telangiectasia in biallelic carriers confer a two-fold increased risk of breast cancer in monoallelic carriers (Tan et al. 2008. PubMed ID: 18682420). It was estimated that BRIP1 variants confer a relative risk of breast cancer of 2.0, and that inactivating truncating BRIP1 variants cause Fanconi anemia in biallelic carriers and confers susceptibility to breast cancer in monoallelic carriers (Seal et al. 2006. PubMed ID: 17033622). Ovarian tumors from carriers of BRIP1 pathogenic variants show loss of the wild type allele, suggesting its tumor suppressor capabilities. Frameshift pathogenic variants in BRIP1 also lead to an increased risk of invasive ovarian cancer (Rafnar et al. 2011. PubMed ID: 21964575).

PALB2 is also considered a gene with moderate risk alleles and can cause a 2 and 4 fold increased risk of breast cancer (Caminsky et al. 2016. PubMed ID: 26898890). RAD51C, essential for homologous recombination repair, has been reported to be a hereditary breast and ovarian cancer susceptibility gene in that several pathogenic variants have been identified in BRCA1/2-negative HBOC families (Clague et al. 2011. PubMed ID: 21980511). RAD51C variants are found in 1-5% of individuals with a family history of breast and ovarian cancer (Meindl et al. 2011. PubMed ID: 21637635). The relative risk of ovarian and breast cancer for RAD51D pathogenic variant carriers was estimated to be 6.3 and 1.3, respectively (Loveday et al. 2011. PubMed ID: 21822267).

Lynch syndrome is an autosomal dominant cancer susceptibility disease that is mainly caused by pathogenic variants in MMR genes: MLH1, MSH2, MSH6, and PMS2. Approximately 90% of causative variants are located in MLH1, and MLH2, and approximately 10% in MSH6 and PMS2. Germline deletions in EPCAM, which is not a mismatch repair gene, inactivates MSH2 in about 1% of individuals with Lynch syndrome (Jang et al. 2010. PubMed ID: 20559516; Bonadona et al. 2015. PubMed ID: 21642682; Kohlman et al. 2012. PubMed ID: 20301390). Germline mutations in the Lynch syndrome genes have also been shown to be associated with ovarian cancer (Watson et al. 2008. PubMed ID: 18398828).

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.

Deletion and duplication testing for STK11 and PMS2 is performed using NGS, but CNVs detected in these genes are confirmed via Multiplex Ligation-dependent Probe Amplification (MLPA).

Clinical Sensitivity - Sequencing and CNV

Current estimates are that less than 1% of the general population have a pathogenic variant in the BRCA1 or BRCA2 genes, and about 10-15% of women diagnosed with breast cancer have a pathogenic variant in one of these genes (Tan et al. 2008. PubMed ID: 18682420). In the German population, CHEK2 is mutated in around 4% of all cases of hereditary breast cancer. The prevalence of PALB2 pathogenic variants in the populations of both Germany and England is approximately 1% (Meindl et al. 2011. PubMed ID: 21637635). All 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 cases, the combination of these high-risk genes may be responsible for a significant portion of these hereditary cancers (Turnbull et al. 2008. PubMed ID: 18544032). Approximately 6% of patients with hereditary ovarian cancers who do not have pathogenic variants in BRCA1 or BRCA2 have causative variants in genes such BRIP1, CHEK2, NBN, PALB2, RAD51C, RAD51D and TP53 (Walsh et al. 2011. PubMed ID: 17292821; Loveday et al. 2011. PubMed ID: 21822267). Highly penetrant pathogenic variants in other genes such as STK11, CDH1 and PTEN account for approximately 1% of all breast cancer cases that aggregate in families. Another 5% of familial breast cancer cases might be explained by causative variants in susceptibility genes of moderate effect such as ATM, CHEK2, NBN, RAD50, RAD51B and RAD51D (Klonowska et al. 2015. PubMed ID: 25994375).

Indications for Test

Individuals with a clinical presentation of Hereditary Breast and Ovarian Cancer syndrome. This test is also suitable for individuals with multifocal, recurrent, and early onset (< 50 years) colorectal tumors or a family history of colorectal tumors. This test is specifically designed for heritable germline mutations and is not appropriate for the detection of somatic mutations in tumor tissue. This is a predictive test and it only provides information regarding the likelihood of breast and/or ovarian cancer. A positive test does not mean that a person will develop any of these diseases and a negative test does not mean that a person will not.

Genes

Official Gene Symbol OMIM ID
ATM 607585
BRCA1 113705
BRCA2 600185
BRIP1 605882
CDH1 192090
CHEK2 604373
EPCAM 185535
MLH1 120436
MSH2 609309
MSH6 600678
PALB2 610355
PMS2 600259
PTEN 601728
RAD51C 602774
RAD51D 602954
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. 2006. PubMed ID: 16998504
  • Berlinear et al. 2013. PubMed ID: 23188549
  • Bonadona et al. 2015. PubMed ID: 21642682
  • Caminsky et al. 2016. PubMed ID: 26898890
  • Cancer.net
  • Cancer.org.
  • Clague et al. 2011. PubMed ID: 21980511
  • Hearle et al. 2006. PubMed ID: 16707622
  • Jang et al. 2010. PubMed ID: 20559516
  • Klonowska et al. 2015. PubMed ID: 25994375
  • Kohlman et al. 2012. PubMed ID: 20301390
  • Lim et al. 2004. PubMed ID: 15188174
  • Loveday et al. 2011. PubMed ID: 21822267
  • Masciari et al. 2007. PubMed ID: 17660459
  • Meijers-Heijboer et al. 2002. PubMed ID: 11967536
  • Meindl et al. 2011. PubMed ID: 21637635
  • Petrucelli et al. 2013. PubMed ID: 20301425
  • Rafnar et al. 2011. PubMed ID: 21964575
  • Seal et al. 2006. PubMed ID: 17033622
  • Tan et al. 2008. PubMed ID: 18682420
  • Turnbull et al. 2008. PubMed ID: 18544032
  • Walsh et al. 2011. PubMed ID: 17292821
  • Wang et al. 2009. PubMed ID: 19261749
  • Watson et al. 2008. PubMed ID: 18398828

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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