Invitae Pediatric Hematologic Malignancies Panel

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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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Test description

This test analyzes 16 genes that are associated with a hereditary predisposition to the development of 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 cohorts of pediatric cancer patients have reported predisposing gene mutations for several childhood cancers. 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 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, though 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.

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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 cohorts of pediatric cancer patients have reported predisposing gene mutations for several childhood cancers. 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 genetic 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 MDS/AML is characterized by a strong family history of MDS or AML without other apparent phenotypic features. Interestingly, 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 can present differently, even among individuals within the same family.

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

The following genes confer an increased risk of malignancies in an autosomal dominant inheritance pattern: CEBPA, GATA2, HRAS, NF1, RUNX1, TERC, TERT, and TP53.

The following genes confer an increased risk of malignancies in an autosomal recessive inheritance pattern: ATM (ataxia telangiectasia), BLM (Bloom syndrome), EPCAM, MLH1, MSH2, MSH6, PMS2 (CMMR-D), and NBN (Nijmegen breakage syndrome).

Carriers (heterozygotes) of any 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 a bone marrow transplant 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. Alter, BP, et al. Malignancies and survival patterns in the National Cancer Institute inherited bone marrow failure syndromes cohort study. Br. J. Haematol. 2010; 150(2):179-88. doi: 10.1111/j.1365-2141.2010.08212.x. PMID: 20507306
  3. Babushok, DV, Bessler, M. Genetic predisposition syndromes: when should they be considered in the work-up of MDS?. Best Pract Res Clin Haematol. 2015; 28(1):55-68. PMID: 25659730
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  10. 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
  11. Gumy, Pause, F, et al. ATM gene alterations in childhood acute lymphoblastic leukemias. Hum. Mutat. 2003; 21(5):554. PMID: 12673804
  12. Holme, H, et al. Marked genetic heterogeneity in familial myelodysplasia/acute myeloid leukaemia. Br. J. Haematol. 2012; 158(2):242-8. PMID: 22533337
  13. Klein, RD, Marcucci, G. Familial Acute Myeloid Leukemia (AML) with Mutated CEBPA. 2010 Oct 21. In: Pagon, RA, et al, editors. GeneReviews(®) (Internet). University of Washington, Seattle. PMID: 20963938
  14. Knapke, S, et al. Identification, management, and evaluation of children with cancer-predisposition syndromes. Am Soc Clin Oncol Educ Book. 2012; :576-84. PMID: 24451799
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  18. Liew, E, Owen, C. Familial myelodysplastic syndromes: a review of the literature. Haematologica. 2011; 96(10):1536-42. PMID: 21606161
  19. Malkin, D, et al. Predisposition to pediatric and hematologic cancers: a moving target. Am Soc Clin Oncol Educ Book. 2014; :e44-55. PMID: 24857136
  20. Mody, RJ, et al. Integrative Clinical Sequencing in the Management of Refractory or Relapsed Cancer in Youth. JAMA. 2015; 314(9):913-25. PMID: 26325560
  21. Morrell, D, et al. Mortality and cancer incidence in 263 patients with ataxia-telangiectasia. J. Natl. Cancer Inst. 1986; 77(1):89-92. PMID: 3459930
  22. Nanri, T, et al. A family harboring a germ-line N-terminal C/EBPalpha mutation and development of acute myeloid leukemia with an additional somatic C-terminal C/EBPalpha mutation. Genes Chromosomes Cancer. 2010; 49(3):237-41. PMID: 19953636
  23. Owen, C, et al. Familial myelodysplasia and acute myeloid leukaemia--a review. Br. J. Haematol. 2008; 140(2):123-32. PMID: 18173751
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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, and select noncoding variants. Our assay provides a Q30 quality-adjusted mean coverage depth of 350x (50x minimum, or supplemented with additional analysis). Variants classified as pathogenic or likely pathogenic are confirmed with orthogonal methods, except individual variants that have high quality scores and previously validated in at least ten unrelated samples.

Our analysis detects most intragenic deletions and duplications at single exon resolution. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. If you are requesting the detection of a specific single-exon copy number variation, please contact Client Services before placing your order.

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
GATA2: Analysis includes the intronic variant NM_032638:c.1017+572C>T.
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.