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  • Test code: 01105
  • Turnaround time:
    10–21 calendar days (14 days on average)
  • Preferred specimen:
    3mL whole blood in a purple-top tube
  • Alternate specimens:
    DNA or saliva/assisted saliva
  • Sample requirements
  • Request a sample kit
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Invitae Pediatric Hematologic Malignancies Panel

Test description

This test analyzes 16 genes associated with a hereditary predisposition to develop childhood hematologic malignancies. These genes were selected based on the available evidence to date to provide Invitae’s most comprehensive childhood-onset hereditary hematologic malignancies panel. Some of these genes are also associated with an increased risk of other cancer types.

Recent studies of pediatric cancer patients have reported predisposing pathogenic variants in a number of heritable genes. The results show that approximately 10% of children who develop cancer have an underlying cancer predisposing condition. Genetic testing of these genes may confirm a diagnosis and can substantially influence the choice of appropriate screening and medical management options for the child and other relatives. This test is specifically designed for heritable germline mutations and is not appropriate for the detection of somatic mutations in tumor tissue.

If the patient has undergone a bone marrow transplant from a donor (allogenic) prior to genetic testing or has a current hematological malignancy with actively circulating tumor cells, testing a sample type not derived from blood (such as skin biopsy) is recommended. While we do not accept this sample type directly, we can accept gDNA derived from skin or muscle, though deletion/duplication analysis is not guaranteed because the success rate varies based on sample quality. Please see our Sample requirements page for more details.

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Primary panel (16 genes)

ATM BLM CEBPA EPCAM GATA2 HRAS MLH1 MSH2 MSH6 NBN NF1 PMS2 RUNX1 TERC TERT TP53

Alternative tests to consider

Inherited bone marrow failure syndromes (IBMFS) are a group of multisystemic disorders characterized by abnormal bone marrow production (aplastic anemia, thrombocytopenia, neutropenia), other clinical features, and increased risk of hematologic malignancy development. For patients with features suggestive of IBMFS, please see the Invitae Bone Marrow Failure Syndromes Panel for more details.

RASopathies are a class of pediatric developmental disorders that share a common spectrum of symptoms, including congenital heart defects, short stature, distinctive craniofacial features, and a predisposition to malignancies, such as juvenile myelomonocytic leukaemia (JMML) and embryonal rhabdomyosarcoma. For patients with features suggestive of a RASopathies condition, please see the Invitae RASopathies Comprehensive Panel for more details.

Advances in genetic testing and studies of pediatric cancer patients have reported predisposing pathogenic variants in a number of heritable genes. Identification of a hereditary cancer predisposition in childhood or adolescence can substantially influence the choice of appropriate screening and medical management options for the child and other relatives.

Cases of early-onset hematologic malignancies in children or young adults may be associated with underlying hereditary predisposition syndromes. Blood-related cancers may present with other prominent clinical features as part of the spectrum of a particular genetic syndrome. Non-syndromic pure familial myelodysplastic syndrome (MDS)/acute myelogenous leukemia (AML) is characterized by a strong family history of MDS or AML without other apparent phenotypic features. Most cases are caused by inheriting a single pathogenic variant in a gene encoding a transcription factor critical for hematopoiesis. Familial occurrences of MDS/AML appear to be rare, but they may be underdiagnosed.

Determination of an underlying genetic predisposition in an individual with a personal or family history of a hematologic malignancy is critical for the selection of therapy regimens, consideration of bone marrow or stem cell transplant, long-term cancer surveillance and prognosis, and counseling of the individual and their family.

Individuals with a pathogenic variant in one of these genes have an increased risk of malignancy compared to the average person, but not everyone with such a variant will actually develop cancer. Further, the same variant may manifest with different symptoms, even among family members. Because we cannot predict which cancers may develop, additional medical management strategies focused on cancer prevention and early detection may be beneficial. For gene-associated cancer risks, see the tables below.

Genes Condition Hematologic malignancy References (PMIDs)
ATM Ataxia-telangiectasia Acute lymphoblastic leukemia (ALL) 3459930, 12673804
BLM Bloom syndrome ALL, acute myeloid leukemia (AML), lymphoma 9062585
CEBPA Familial acute myeloid leukemia (AML) with mutated CEBPA AML 26162409
EPCAM Constitutional mismatch repair deficiency syndrome (CMMR-D) non-Hodgkin’s lymphoma, ALL, AML 18709565, 16341812, 24737826
GATA2 GATA2 deficiency myelodysplastic syndrome (MDS), AML 24227816, 24345756
HRAS Costello syndrome ALL 25742478, 21500339
MLH1 Constitutional mismatch repair deficiency syndrome (CMMR-D) non-Hodgkin’s lymphoma, ALL, AML 18709565, 16341812, 24737826
MSH2 Constitutional mismatch repair deficiency syndrome (CMMR-D) non-Hodgkin’s lymphoma, ALL, AML 18709565, 16341812, 24737826
MSH6 Constitutional mismatch repair deficiency syndrome (CMMR-D) non-Hodgkin’s lymphoma, ALL, AML 18709565, 16341812, 24737826
NBN Nijmegen breakage syndrome ALL 11325820, 16840438
NF1 Neurofibromatosis type 1 Juvenile myelomonocytic leukemia (JMML), MDS 22240541, 23257896
PMS2 Constitutional mismatch repair deficiency syndrome (CMMR-D) non-Hodgkin’s lymphoma, ALL, AML 18709565, 16341812, 24737826
RUNX1 Familial platelet disorder with propensity to myeloid malignancy MDS, AML 18723428
TERC TERC-related dyskeratosis congenita MDS, AML 20507306, 19282459
TERT TERT-related dyskeratosis congenita MDS, AML 20507306, 19282459
TP53 Li-Fraumeni syndrome ALL 23334668, 19204208, 20522432

Most of the genes on this panel have autosomal dominant inheritance. Several other genes have autosomal recessive inheritance, or result in clinically distinct autosomal recessive conditions, as outlined below:

  • ATM is associated with ataxia telangiectasia
  • BLM is associated with Bloom syndrome
  • NBN is associated with Nijmegen breakage syndrome
  • MLH1, MSH2, MSH6 and PMS2 are associated with constitutional mismatch repair deficiency (CMMR-D)

Carriers (heterozygotes) of many of the above autosomal recessive conditions have an increased risk for adult-onset cancers. This information will be included in the test report when a result is present.

This panel may be considered for individuals whose personal and/or family history is suggestive of a hereditary predisposition to hematologic malignancies and includes any of the following:

  • hematologic malignancy occurring at a young age, without prior history of chemotherapy
  • a personal or family history of:
    • low blood counts
    • bleeding diathesis
    • lymphedema
    • immune deficiencies or atypical infections
  • a family history of:
    • MDS/AML/ALL/aplastic anemia
    • early onset cancers of any type
    • several close relatives with cancer
  • additional features that are consistent with the clinical presentation of a genetic syndrome with increased risk of a hematologic malignancy

If the patient has undergone an allogenic bone marrow transplant (using bone marrow from a donor) prior to genetic testing or currently has a hematological malignancy with actively circulating tumor cells, testing a sample type not derived from blood (such as skin biopsy) is warranted. While we do not accept this sample type directly, we can accept gDNA derived from skin or muscle, but deletion/duplication analysis is not guaranteed for gDNA samples because the success rate varies based on sample quality. Please see our Sample requirements page for more details.

Other conditions to consider:

  • Inherited bone marrow failure syndromes (IBMFS) are a group of multisystemic disorders characterized by abnormal bone marrow production (aplastic anemia, thrombocytopenia, neutropenia), other clinical features, and increased risk of hematologic malignancy development. For patients with features suggestive of IBMFS, please see the Invitae Bone Marrow Failure Syndromes Panel for more details.
  • RASopathies are a class of pediatric developmental disorders that share a common spectrum of symptoms, including congenital heart defects, short stature, distinctive craniofacial features, and a predisposition to malignancies, such as juvenile myelomonocytic leukaemia (JMML) and embryonal rhabdomyosarcoma. For patients with features suggestive of a RASopathies condition, please see the Invitae RASopathies Comprehensive Panel for more details.

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  2. Gonzalez, KD, et al. Beyond Li Fraumeni Syndrome: clinical characteristics of families with p53 germline mutations. J. Clin. Oncol. 2009; 27(8):1250-6. doi: 10.1200/JCO.2008.16.6959. PMID: 19204208
  3. Ruijs, MW, et al. TP53 germline mutation testing in 180 families suspected of Li-Fraumeni syndrome: mutation detection rate and relative frequency of cancers in different familial phenotypes. J. Med. Genet. 2010; 47(6):421-8. PMID: 20522432
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  17. Tawana, K, et al. Disease evolution and outcomes in familial AML with germline CEBPA mutations. Blood. 2015; 126(10):1214-23. PMID: 26162409
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  19. Krüger, L, et al. Cancer incidence in Nijmegen breakage syndrome is modulated by the amount of a variant NBS protein. Carcinogenesis. 2007; 28(1):107-11. PMID: 16840438
  20. Gumy, Pause, F, et al. ATM gene alterations in childhood acute lymphoblastic leukemias. Hum. Mutat. 2003; 21(5):554. PMID: 12673804
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Assay and technical information

Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).

Our sequence analysis covers clinically important regions of each gene, including coding exons, +/- 10 base pairs of adjacent intronic sequence in the transcript listed below. In addition, analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any specific limitations in the analysis of these genes are also listed in the table below.

Based on validation study results, this assay achieves >99% analytical sensitivity and specificity for single nucleotide variants, insertions and deletions <15bp in length, and exon-level deletions and duplications. Invitae's methods also detect insertions and deletions larger than 15bp but smaller than a full exon but sensitivity for these may be marginally reduced. Invitae’s deletion/duplication analysis determines copy number at a single exon resolution at virtually all targeted exons. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. Certain types of variants, such as structural rearrangements (e.g. inversions, gene conversion events, translocations, etc.) or variants embedded in sequence with complex architecture (e.g. short tandem repeats or segmental duplications), may not be detected. Additionally, it may not be possible to fully resolve certain details about variants, such as mosaicism, phasing, or mapping ambiguity. Unless explicitly guaranteed, sequence changes in the promoter, non-coding exons, and other non-coding regions are not covered by this assay. Please consult the test definition on our website for details regarding regions or types of variants that are covered or excluded for this test. This report reflects the analysis of an extracted genomic DNA sample. In very rare cases, (circulating hematolymphoid neoplasm, bone marrow transplant, recent blood transfusion) the analyzed DNA may not represent the patient's constitutional genome.

Gene Transcript reference Sequencing analysis Deletion/Duplication analysis
ATM NM_000051.3
BLM NM_000057.3
CEBPA NM_004364.4
EPCAM* NM_002354.2
GATA2 NM_032638.4
HRAS NM_005343.2
MLH1* NM_000249.3
MSH2* NM_000251.2
MSH6 NM_000179.2
NBN NM_002485.4
NF1 NM_000267.3
PMS2 NM_000535.5
RUNX1 NM_001754.4
TERC NR_001566.1
TERT NM_198253.2
TP53* NM_000546.5

EPCAM: Analysis is limited to deletion/duplication analysis.
MLH1: Deletion/duplication analysis covers the promoter region.
MSH2: Analysis includes the exon 1-7 inversion (Boland mutation).
TP53: Deletion/duplication analysis covers the promoter region.