Hereditary Breast and Gynecological Cancer Panel

PLUSbpg-method SEQbpg-method DEL/DUPbpg-method

Test code: ON1801

The Blueprint Genetics Hereditary Breast and Gynecological Cancer Panel analyzes 27 genes associated with inherited susceptibility to breast and gynecological cancer.

Breast cancer is the most common cancer in women. Gynecological cancers are originating in the female reproductive organs and include cervical, ovarian, uterine, vaginal, and vulvar cancers. Breast and gynecological cancers are usually sporadic but 5-10% of the disease onset is caused by pathogenic mutations in cancer susceptibility genes. Inheritance pattern of these genetic cancer predisposition conditions is autosomal dominant. The Hereditary Breast and Gynecological Cancer Panel is suited for detecting heritable germline mutations and may not be used for the detection of somatic mutations in tumor tissue. This Panel includes the Breast Cancer High Risk Panel and is part of the Comprehensive Hereditary Cancer Panel.

About breast and gynecological cancer

The most common hereditary cancer syndromes that are associated with increased risk of breast and gynecological cancers are hereditary breast and ovarian cancer syndrome and Lynch syndrome, also known as hereditary nonpolyposis colon cancer (HNPCC). Carriers of pathogenic mutations in BRCA1 and BRCA2 have an increased risk of breast cancer and, the lifetime risk of having one of the gynecologic cancers is 39-46% and 12-20%, respectively. Lynch syndrome is caused by inherited mutations in DNA mismatch repair genes, most often MSH2 and MLH1, but mutations also occur in MSH6,PMS2, and EPCAM. There is an increased incidence of several types of cancers in HNPCC, most notably of the gynecological cancers, endometrial cancer risk is 40-60%. Several other syndromes and genetic defects have been identified to increase the risk of breast and gynecological cancers. For example, Li-Fraumeni syndrome (TP53), Cowden syndrome (PTEN) and Peutz-Jeghers syndrome (STK11) increase the likelihood of having an inherited predisposition to breast and gynecological cancer. Mutations in DNA repair genes, RAD51C, RAD51D, and BRIP1, have shown clear evidence of an association with ovarian cancer. Protein truncating variants in CHEK2 and ATM have been shown to confer moderate risk for breast cancer.

Availability

Results in 3-4 weeks. We do not offer a maternal cell contamination (MCC) test at the moment. We offer prenatal testing only for cases where the maternal cell contamination studies (MCC) are done by a local genetic laboratory. Read more: http://blueprintgenetics.com/faqs/#prenatal

Genes in the Hereditary Breast and Gynecological Cancer Panel and their clinical significance
Gene Associated phenotypes Inheritance ClinVar HGMD
ATM Breast cancer, Ataxia-Telangiectasia AD/AR 455 853
BARD1 Breast cancer AD 54 53
BLM Bloom syndrome AR 53 92
BRCA1* Pancreatic cancer, Breast-ovarian cancer, familial AD 2207 2054
BRCA2 Fanconi anemia, Medulloblastoma, Glioma susceptibility, Pancreatic cancer, Wilms tumor, Breast-ovarian cancer, familial AD/AR 2514 1791
BRIP1 Fanconi anemia, Breast cancer AD/AR 87 87
CDH1 CDH1-related cancer AD 66 183
CHEK2* Li-Fraumeni syndrome AD/AR 93 115
DICER1* DICER1 syndrome AD 96 109
EPCAM Diarrhea 5, with tufting enteropathy, congenital, Colorectal cancer, hereditary nonpolyposis AD/AR 15 63
FANCC Fanconi anemia AR 34 34
MLH1 Muir-Torre syndrome, Endometrial cancer, Mismatch repair cancer syndrome, Colorectal cancer, hereditary nonpolyposis AD/AR 670 1084
MRE11A Ataxia-telangiectasia-like disorder-1 AR 25 38
MSH2 Muir-Torre syndrome, Endometrial cancer, Colorectal cancer, hereditary nonpolyposis,, Mismatch repair cancer syndrome AD/AR 646 1089
MSH6 Endometrial cancer, Mismatch repair cancer syndrome, Colorectal cancer, hereditary nonpolyposis AD/AR 308 426
NBN Breast cancer, Nijmegen breakage syndrome AD/AR 57 62
NF1* Watson syndrome, Neurofibromatosis, Neurofibromatosis-Noonan syndrome AD 261 2607
PALB2 Fanconi anemia, Pancreatic cancer, Breast cancer AD/AR 237 223
PMS2* Mismatch repair cancer syndrome, Colorectal cancer, hereditary nonpolyposis AD/AR 151 266
PPM1D Hereditary breast cancer AD 49
PTEN* Bannayan-Riley-Ruvalcaba syndrome, Lhermitte-Duclos syndrome, Cowden syndrome AD 192 564
RAD50 Breast cancer AD 74 40
RAD51C Fanconi anemia, Breast-ovarian cancer, familial AD/AR 49 86
RAD51D Ovarian cancer, familial AD 25 50
STK11 Peutz-Jeghers syndrome AD 69 399
TP53 Colorectal cancer, Li-Fraumeni syndrome, Ependymoma, intracranial, Choroid plexus papilloma, Breast cancer, familial, Adrenocortical carcinoma, Osteogenic sarcoma, Hepatoblastoma, Non-Hodgkin lymphoma AD 148 391
XRCC2 Hereditary breast cancer AD/AR 3 13

*Some regions of the gene are duplicated in the genome leading to limited sensitivity within the regions. Thus, low-quality variants are filtered out from the duplicated regions and only high-quality variants confirmed by other methods are reported out. Read more.

Gene, refers to HGNC approved gene symbol; Inheritance to inheritance patterns such as autosomal dominant (AD), autosomal recessive (AR) and X-linked (XL); ClinVar, refers to a number of variants in the gene classified as pathogenic or likely pathogenic in ClinVar (http://www.ncbi.nlm.nih.gov/clinvar/); HGMD, refers to a number of variants with possible disease association in the gene listed in Human Gene Mutation Database (HGMD, http://www.hgmd.cf.ac.uk/ac/). The list of associated (gene specific) phenotypes are generated from CDG (http://research.nhgri.nih.gov/CGD/) or Orphanet (http://www.orpha.net/) databases.

Blueprint Genetics offers a comprehensive Hereditary Breast and Gynecological Cancer Panel that covers classical genes associated with gynecological cancer. The genes are carefully selected based on the existing scientific evidence, our experience and most current mutation databases. Candidate genes are excluded from this first-line diagnostic test. The test does not recognise balanced translocations or complex inversions, and it may not detect low-level mosaicism. The test should not be used for analysis of sequence repeats or for diagnosis of disorders caused by mutations in the mitochondrial DNA.

Analytical validation is a continuous process at Blueprint Genetics. Our mission is to improve the quality of the sequencing process and each modification is followed by our standardized validation process. Average sensitivity and specificity in Blueprint NGS Panels is 99.3% and 99.9% for detecting SNPs. Sensitivity to for indels vary depending on the size of the alteration: 1-10bps (96.0%), 11-20 bps (88.4%) and 21-30 bps (66.7%). The longest detected indel was 46 bps by sequence analysis. Detection limit for Del/Dup (CNV) analysis varies through the genome depending on exon size, sequencing coverage and sequence content. The sensitivity is 71.5% for single exon deletions and duplications and 99% for three exons’ deletions and duplications. We have validated the assays for different starting materials including EDTA-blood, isolated DNA (no FFPE) and saliva that all provide high-quality results. The diagnostic yield varies substantially depending on the used assay, referring healthcare professional, hospital and country. Blueprint Genetics’ Plus Analysis (Seq+Del/Dup) maximizes the chance to find molecular genetic diagnosis for your patient although Sequence Analysis or Del/Dup Analysis may be cost-effective first line test if your patient’s phenotype is suggestive for a specific mutation profile.

The sequencing data generated in our laboratory is analyzed with our proprietary data analysis and annotation pipeline, integrating state-of-the art algorithms and industry-standard software solutions. Incorporation of rigorous quality control steps throughout the workflow of the pipeline ensures the consistency, validity and accuracy of results. The highest relevance in the reported variants is achieved through elimination of false positive findings based on variability data for thousands of publicly available human reference sequences and validation against our in-house curated mutation database as well as the most current and relevant human mutation databases. Reference databases currently used are the 1000 Genomes Project (http://www.1000genomes.org), the NHLBI GO Exome Sequencing Project (ESP; http://evs.gs.washington.edu/EVS), the Exome Aggregation Consortium (ExAC; http://exac.broadinstitute.org), ClinVar database of genotype-phenotype associations (http://www.ncbi.nlm.nih.gov/clinvar) and the Human Gene Mutation Database (http://www.hgmd.cf.ac.uk). The consequence of variants in coding and splice regions are estimated using the following in silico variant prediction tools: SIFT (http://sift.jcvi.org), Polyphen (http://genetics.bwh.harvard.edu/pph2/), and Mutation Taster (http://www.mutationtaster.org).

Through our online ordering and statement reporting system, Nucleus, the customer can access specific details of the analysis of the patient. This includes coverage and quality specifications and other relevant information on the analysis. This represents our mission to build fully transparent diagnostics where the customer gains easy access to crucial details of the analysis process.

In addition to our cutting-edge patented sequencing technology and proprietary bioinformatics pipeline, we also provide the customers with the best-informed clinical report on the market. Clinical interpretation requires fundamental clinical and genetic understanding. At Blueprint Genetics our geneticists and clinicians, who together evaluate the results from the sequence analysis pipeline in the context of phenotype information provided in the requisition form, prepare the clinical statement. Our goal is to provide clinically meaningful statements that are understandable for all medical professionals, even without training in genetics.

Variants reported in the statement are always classified using the Blueprint Genetics Variant Classification Scheme modified from the ACMG guidelines (Richards et al. 2015), which has been developed by evaluating existing literature, databases and with thousands of clinical cases analyzed in our laboratory. Variant classification forms the corner stone of clinical interpretation and following patient management decisions. Our statement also includes allele frequencies in reference populations and in silico predictions. We also provide PubMed IDs to the articles or submission numbers to public databases that have been used in the interpretation of the detected variants. In our conclusion, we summarize all the existing information and provide our rationale for the classification of the variant.

A final component of the analysis is the Sanger confirmation of the variants classified as likely pathogenic or pathogenic. This does not only bring confidence to the results obtained by our NGS solution but establishes the mutation specific test for family members. Sanger sequencing is also used occasionally with other variants reported in the statement. In the case of variant of uncertain significance (VUS) we do not recommend risk stratification based on the genetic finding. Furthermore, in the case VUS we do not recommend use of genetic information in patient management or genetic counseling. For some cases Blueprint Genetics offers a special free of charge service to investigate the role of identified VUS.

We constantly follow genetic literature adapting new relevant information and findings to our diagnostics. Relevant novel discoveries can be rapidly translated and adopted into our diagnostics without delay. These processes ensure that our diagnostic panels and clinical statements remain the most up-to-date on the market.

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ICD & CPT codes

CPT codes

SEQ 81432
DEL/DUP 81479

Accepted sample types

  • EDTA blood, min. 1 ml
  • Purified DNA, min. 5μg
  • Saliva (Oragene DNA OG-500 kit)

Label the sample tube with your patient’s name, date of birth and the date of sample collection.

Note that we do not accept DNA samples isolated from formalin-fixed paraffin-embedded (FFPE) tissue.

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