Hereditary Leukemia Panel

  • bpg-method PLUS
  • bpg-method SEQ
  • bpg-method DEL/DUP

Test code: ON0101

The Blueprint Genetics Hereditary Leukemia Panel analyzes 25 genes associated with inherited suscebtibility to leukemia.

This Panel covers genes associated with hereditary syndromes that also confer an increased risk of leukemia. The Hereditary Leukemia Panel is suited for detecting heritable germline mutations and may not be used for the detection of somatic mutations in tumor tissue. This Panel is part of the Comprehensive Hereditary Cancer Panel, Bone Marrow Failure Syndrome Panel and Comprehensive Hematology Panel.

About Hereditary Leukemia

Inherited predisposition to hematological malignancies, namely acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), and bone marrow myelodysplastic syndrome (MDS) may be associated with syndromic features, or occur as principal clinical features. MDSs and AML can occur in the context of syndromic bone marrow failure (eg. dyskeratosis congenita, severe congenital neutropenia, Fanconi anemia). Other hereditary syndromes with increased risk of leukemia include Li-Fraumeni syndrome (TP53), ataxia telangiectasia (ATM), Bloom syndrome (BLM), neurofibromatosis type 1 (NF1) and less frequently Noonan syndrome (PTPN11). Some reports have also shown an association of biallelic germline mutations in constitutional mismatch repair-deficiency syndrome genes, MLH1, MSH2, MSH6, and PMS2 with development of ALL. Isolated hematological malignancies are associated with germline mutations in RUNX1 (Familial platelet syndrome with predisposition to acute myelogenous leukemia), CEBPA (familial AML) and GATA2 (GATA2-associated syndromes). Many different genetic defects associated with development of leukemia have been described but the common underlying mechanism is dysfunctional DNA damage response. Based on a recent study, pathogenic variants in the known predisposition genes explain approximately 29% of families with inherited susceptibility to MDS/AML (PMID: 26492932).

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 Leukemia Panel and their clinical significance
Gene Associated phenotypes Inheritance ClinVar HGMD
ATM Breast cancer, Ataxia-Telangiectasia AD/AR 455 853
BLM Bloom syndrome AR 53 92
BRCA2 Fanconi anemia, Medulloblastoma, Glioma susceptibility, Pancreatic cancer, Wilms tumor, Breast-ovarian cancer, familial AD/AR 2514 1791
CDKN2A Melanoma, familial, Melanoma-pancreatic cancer syndrome AD 37 217
CEBPA Acute myeloid leukemia, familial AD 12 9
DKC1 Hoyeraal-Hreidarsson syndrome, Dyskeratosis congenita XL 45 69
ELANE Neutropenia AD 30 213
FANCA Fanconi anemia AR 33 474
GATA2 Myelodysplastic syndrome, Chronic neutropenia associated with monocytopenia, evolving to myelodysplasia and acute myeloid leukemia, Acute myeloid leukemia, Emberger syndrome, Immunodeficiency AD 19 76
HRAS Costello syndrome, Congenital myopathy with excess of muscle spindles AD 30 26
KRAS* Noonan syndrome, Cardiofaciocutaneous syndrome AD 46 38
MLH1 Muir-Torre syndrome, Endometrial cancer, Mismatch repair cancer syndrome, Colorectal cancer, hereditary nonpolyposis AD/AR 670 1084
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
NRAS Noonan syndrome AD 17 8
PMS2* Mismatch repair cancer syndrome, Colorectal cancer, hereditary nonpolyposis AD/AR 151 266
PTPN11 LEOPARD syndrome, Noonan syndrome, Metachondromatosis AD 122 129
RUNX1 Platelet disorder, familial, with associated myeloid malignancy AD 13 74
SBDS* Aplastic anemia, Shwachman-Diamond syndrome, Severe spondylometaphyseal dysplasia AD/AR 12 88
TERC Aplastic anemia, Pulmonary fibrosis and/or bone marrow failure, telomere-related, Dyskeratosis congenita AD 36 60
TERT Aplastic anemia, Pulmonary fibrosis and/or bone marrow failure, telomere-related, Dyskeratosis congenita AD/AR 39 133
TINF2 Revesz syndrome, Dyskeratosis congenita AD 20 33
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

*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.

Gene Genomic location HG19 HGVS RefSeq RS-number Comment Reference
ATM Chr11:108098321 c.-30-1G>T NM_000051.3 rs869312754
ATM Chr11:108141209 c.2839-579_2839-576delAAGT NM_000051.3
ATM Chr11:108179837 c.5763-1050A>G NM_000051.3 rs774925473
CDKN2A Chr9:21974860 c.-34G>T NM_000077.4 rs1800586
DKC1 ChrX:153991099 c.-142C>G NM_001363.3 rs199422241
MLH1 Chr3:37035012 c.-27C>A NM_000249.3 rs587779001
MSH2 Chr2:47630251 c.-78_-77delTG NM_000251.2 rs587779182
MSH2 Chr2:47635062 c.212-478T>G NM_000251.2 rs587779138
NF1 Chr17:29577934 c.4110+1802delA NM_001042492.2 rs863224944
NF1 Chr17:29657848 c.5812+332A>G NM_001042492.2 rs863224491

Blueprint Genetics offers a comprehensive Hereditary Leukemia Panel that covers classical genes associated with ataxia telangiectasia, Bloom syndrome, Costello syndrome, dyskeratosis congenital, familial acute myeloid leukemia caused by CEBPA mutations, familial platelet syndrome with predisposition to acute myelogenous leukemia, Fanconi anemia, leukemia, Li-Fraumeni syndrome, lynch syndrome, monocytopenia with susceptibility to infections, neurofibromatosis type 1, Noonan syndrome, severe congenital neutropenia and shwachman-Diamond syndrome. 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 81479
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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