Hereditary Myeloid Neoplasms Panel, Sequencing

Hereditary Myeloid Neoplasms Panel, Sequencing 3001842

Method

Massively Parallel Sequencing

Use to assess for inherited/germline DNA variants associated with familial myeloid dysplasias and malignancies.
NOT intended to detect somatic variants; for test options to assess somatic DNA variants of diagnostic, prognostic, and/or therapeutic significance, refer to the Laboratory Test Directory.
Cultured skin fibroblasts are the preferred sample type to assess the germline status of patients suspected of a hereditary predisposition to myeloid neoplasms.
Regions of low coverage and reported variants are confirmed by Sanger sequencing as necessary.
ARUP will perform culturing services for skin samples at an additional charge.

If a familial sequence variant has been previously identified, targeted sequencing for that variant may be appropriate; refer to the Laboratory Test Directory for additional information.

While the majority of myelodysplastic syndromes (MDSs), myeloid neoplasms, and malignancies occur sporadically due to somatic mutations, a portion are due to inherited or hereditary predispositions. Identification of an inherited predisposition can affect therapy options and surveillance strategies, as well as lead to testing of biological relatives, and inform stem cell transplant donor selection. Individuals with an inherited predisposition to myeloid neoplasms may present at a younger age, have more than one first-degree relative with MDS/acute myeloid leukemia (AML), and/or a family history of physical findings associated with a known cancer predisposition syndrome. The preferred specimen type to assess the germline status of patients suspected of, or at risk for, a hereditary predisposition to myeloid neoplasms is cultured skin fibroblasts in order to exclude somatic variants and to avoid false negatives due to peripheral blood somatic mosaicism. ARUP will perform culturing services for skin samples at an additional charge.

Disease Overview

Symptoms/Associated Disorders

Pathogenic germline variants in several genes have been associated with familial MDS and acute leukemias.
- Inherited myeloid neoplasm predisposition genes included in this panel that often do NOT present with cytopenia, dysplasia, or other organ dysfunction prior to myeloid malignancy:
  - CEBPA
  - DDX41
- Inherited myeloid neoplasm predisposition genes included in this panel that often DO present with preexisting cytopenia(s) or other organ dysfunction prior to myeloid malignancy:
  - ANKRD26
  - ETV6
  - GATA2
  - RUNX1
  - SAMD9
  - SAMD9L
  - SRP72
- Inherited myeloid neoplasm predisposition genes that also predispose to other solid tumors/cancers or syndromic findings:
  - ATM
  - BLM
  - CBL
  - GATA1
  - KRAS
  - NBN
  - PTPN11
  - TP53
- Inherited bone marrow failure genes:
  - ELANE
  - TERC
  - TERT
For a complete list of genes and associated disorders, please refer to the Genes Tested table.

Epidemiology

In the general population, MDS and AML occur in approximately 4.5 and 3.7 per 100,000 individuals, respectively.
MDS is rare in children and young adults; approximately 50% of childhood MDS is associated with an inherited cause.

Inheritance

Variable, refer to the Genes Tested table

Test Description

Refer to the Genes Tested table for genes included in this panel.

Clinical Sensitivity

Variable, dependent on phenotype/condition

Pathogenic germline genetic variants have been identified in approximately 18% of families with hereditary MDS/acute leukemia or other hematologic malignancy.

Contraindications for Ordering

Should not be ordered to detect somatic variants associated with malignancy because sensitivity for mosaic variants is low with methodology used for germline assays.
Individuals with hematological malignancy and/or a previous allogenic bone marrow transplant should not undergo molecular genetic testing on a peripheral blood specimen. Testing of cultured skin fibroblasts is required for accurate interpretation of test results.

Limitations

A negative result does not exclude a diagnosis of cancer nor a heritable form of myeloid neoplasm.
Diagnostic errors can occur due to rare sequence variations.
Interpretation of the test result may be impacted if the patient has had an allogeneic stem cell transplantation.
This assay is not intended to detect somatic variants associated with hematologic malignancy, although such variants may be detected.
This assay cannot definitively distinguish the germline or somatic origin of detected variants when the patient has a hematologic malignancy, and the assay was performed on blood or other tissue that may be contaminated by malignant cells. In such instances, confirmation of germline variant status by testing of cultured skin fibroblasts is strongly recommended.
The following will not be evaluated:
- Variants outside the coding regions and intron-exon boundaries of targeted gene(s)
- Regulatory region and deep intronic variants, unless specifically targeted for their clinical relevance
- Large deletions/duplications in the targeted genes
- Noncoding transcripts
- The following exons are not sequenced due to technical limitations of the assay:
  - ANKRD26 (NM_014915) exon 19
  - PTPN11 (NM_002834) exon 9
  - SRP72 (NM_006947) exon 19
The following may not be detected:
- Deletions/duplications/insertions of any size by massively parallel sequencing
- Some variants due to technical limitations in the presence of pseudogenes, or repetitive or homologous regions
- Low-level somatic variants, including those that have undergone somatic reversion

Analytic Sensitivity

Variant Class	Analytic Sensitivity (PPA) Estimate^a (%)	Analytic Sensitivity (PPA) 95% Credibility Region^a (%)
SNVs	99.2	96.9-99.4
Deletions 1-10 bp	93.8	84.3-98.2
Deletions 11-44 bp	99.9	87.8-100
Insertions 1-10 bp	94.8	86.8-98.5
Insertions 11-23 bp	99.9	62.1-100
^aGenes included on this test are a subset of a larger methods-based validation from which the PPA values are derived. bp, base pairs; PPA, positive percent agreement; SNVs, single nucleotide variants

Genes Tested

Gene	MIM Number	Inherited Disorder, Hematologic Disease Associations, Cancer Predispositions	Inheritance
ANKRD26	610855	ANKRD26-related thrombocytopenia MDS Leukemia	AD
ATM	607585	Ataxia-telangiectasia Leukemia Lymphoma	AR
ATM	607585	Breast cancer Pancreatic cancer	AD
BLM	604610	Bloom syndrome Leukemia Lymphoma Increased frequency of sister-chromatid exchanges (SCEs)	AR
CBL	165360	Juvenile myelomonocytic leukemia (JMML) Noonan syndrome-like disorder	AD
CEBPA	116897	CEBPA-associated AML	AD
DDX41	608170	Adult onset MDS/AML, with or without macrocytosis or other cytopenias Chronic myeloid leukemia (CML) Non-Hodgkin or Hodgkin lymphoma	AD
ELANE	130130	ELANE-related neutropenia Congenital or cyclic neutropenia Severe or recurrent infections	AD
ETV6	600618	MDS/AML Thrombocytopenia Red cell macrocytosis	AD
GATA1	305371	GATA1-related x-linked cytopenia Thrombocytopenia and/or platelet dysfunction Anemia Mild beta thalassemia Neutropenia Congenital erythropoietic porphyria (CEP)	X-LR
GATA2	137295	MDS/AML Cytopenias Chronic myelomonocytic leukemia (CMML) Frequent infections/immunodeficiency Pulmonary alveolar proteinosis Lymphedema Sensorineural hearing loss	AD
KRAS	190070	Noonan syndrome Cardiofaciocutaneous (CFC) syndrome Costello syndrome JMML	AD
NBN	602667	Nijmegen breakage syndrome (NBS) Aplastic anemia Acute lymphoblastic leukemia (ALL)	AR
NBN	602667	Breast cancer	AD
PTPN11	176876	Noonan syndrome LEOPARD syndrome JMML Metachondromatosis	AD
RUNX1	151385	Familial platelet disorder with associated myeloid malignancy (FPDMM) MDS/AML Thrombocytopenia	AD
SAMD9	610456	MIRAGE Syndrome MDS sometimes accompanied by loss of chromosome 7	AD
SAMD9	610456	Normophosphatemic familial tumoral calcinosis (NFTC)	AR
SAMD9L	611170	SAMD9L-related ataxia-pancytopenia syndrome (ATXPC) MDS/leukemia associated with monosomy 7 Somatic revertant mosaicism associated with milder disease Cerebellar ataxia Immunodeficiency	AD
SRP72	602122	MDS Aplastic anemia/bone marrow failure Hearing loss	AD
TERC	602322	Dyskeratosis congenita Aplastic anemia/bone marrow failure Shortened telomeres Pulmonary fibrosis Somatic revertant mosaicism reported	AD
TERT	187270	Dyskeratosis congenita MDS/AML Aplastic anemia/bone marrow failure Shortened telomeres Cutaneous malignant melanoma Pulmonary fibrosis	AD
TERT	187270	Dyskeratosis congenita (severe)	AR
TP53	191170	Li-Fraumeni syndrome (LFS) Leukemia Multiple solid tumors (sarcoma, breast, brain)	AD
AD, autosomal dominant; AR, autosomal recessive; X-LR, X-linked recessive

References

SEER Cancer Statistics Review, 1975-2016

Howlader N, Noone AM, Krapcho M, et al, eds. SEER cancer statistics review, 1975-2016. National Cancer Institute. Bethesda, MD. Based on November 2018 SEER data submission, posted to the SEER website, April 2019. Updated Apr 2020; accessed Aug 2020.

NCCN - myelodysplastic syndromes v 1.2021

National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Myelodysplastic syndromes. Version 1.2021. Last update Sep 2020; accessed Dec 2020.

27210295

DiNardo CD, Bannon SA, Routbort M, et al. Evaluation of patients and families with concern for predispositions to hematologic malignancies within the Hereditary Hematologic Malignancy Clinic (HHMC). Clin Lymphoma Myeloma Leuk. 2016;16(7):417-428.e2.

28104920

Guidugli L, Johnson AK, Alkorta-Aranburu G, et al. Clinical utility of gene panel-based testing for hereditary myelodysplastic syndrome/acute leukemia predisposition syndromes. Leukemia. 2017;31(5):1226-1229.

GeneReviews - ANKRD26-related thrombocytopenia

Perez Botero J, Dugan SN, Anderson MW. ANKRD26-related thrombocytopenia. In: Adam MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews. University of Washington, Seattle. Posted Jan 2018; accessed Aug 2020.

GeneReviews Ataxia-Telangiectasia - Tcell

Gatti R, Perlman S. Ataxia-telangiectasia. In: Adam MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews. University of Washington, Seattle. Updated Oct 2016; accessed Feb 2020.

NCCN - genetic/familial high-risk assessment: breast, ovarian, and pancreatic v 2.2021

National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: genetic/familial high-risk assessment—breast, ovarian, and pancreatic. Version 2.2021. Updated Nov 2020; accessed Aug 2021.

GeneReviews - Bloom Syndrome

Flanagan M, Cunniff CM. Bloom syndrome. In: Adam MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews. University of Washington, Seattle. Last update Feb 2019; accessed May 2020.

GeneReviews - CEBPA-Associated Familial Acute Myeloid Leukemia

Tawana K, Fitzgibbon J. CEBPA-associated familial acute myeloid leukemia (AML). In: Adam MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews. University of Washington, Seattle. Last update Apr 2016; accessed Aug 2020.

26712909

Lewinsohn M, Brown AL, Weinel LM, et al. Novel germ line DDX41 mutations define families with a lower age of MDS/AML onset and lymphoid malignancies. Blood. 2016;127(8):1017-1023.

GeneReviews - ELANE-Related Neutropenia

Dale DC, Makaryan V. ELANE-related neutropenia. In: Adam MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews. University of Washington, Seattle. Last update Aug 2018; accessed Feb 2020.

25807284

Noetzli L, Lo RW, Lee-Sherick AB, et al. Germline mutations in ETV6 are associated with thrombocytopenia, red cell macrocytosis and predisposition to lymphoblastic leukemia. Nat Genet. 2015;47(5):535-538.

25581430

Zhang MY, Churpek JE, Keel SB, et al. Germline ETV6 mutations in familial thrombocytopenia and hematologic malignancy. Nat Genet. 2015;47(2):180-185.

GeneReviews - GATA1-Related X-Linked Cytopenia

Chou ST, Kacena MA, Weiss MJ, et al. GATA1-related X-linked cytopenia. In: Adam MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews. University of Washington, Seattle. Last update May 2017; accessed Aug 2020.

25397911

Hsu AP, McReynolds LJ, Holland SM. GATA2 deficiency. Curr Opin Allergy Clin Immunol. 2015;15(1):104-109.

28637621

Wlodarski MW, Collin M, Horwitz MS. GATA2 deficiency and related myeloid neoplasms. Semin Hematol. 2017;54(2):81-86.

16474405

Schubbert S, Zenker M, Rowe SL, et al. Germline KRAS mutations cause Noonan syndrome. Nat Genet. 2006;38(3):331-336.

GeneReviews - Noonan syndrome

Allanson JE, Roberts AE. Noonan syndrome. In: Adam MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews. University of Washington, Seattle. Last revision Aug 2019; accessed Aug 2020.

GeneReviews - Nijmegen Breakage Syndrome

Varon R, Demuth I, Chrzanowska KH. Nijmegen breakage syndrome. In: Adam MP, Ardinger HH, Pagon RA, et al, editors. GeneReviews, University of Washington; 1993-2020. [Last update: Feb 2017; Accessed: Aug 2020]

GeneReviews - SAMD9L-Related Ataxia-Pancytopenia Syndrome

Phowthongkum P, Chen DH, Raskind WH, et al. SAMD9L-related ataxia-pancytopenia syndrome. In: Adam MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews. University of Washington, Seattle. Posted Jun 2017; accessed Aug 2020.

28202457

Tesi B, Davidsson J, Voss M, et al. Gain-of-function SAMD9L mutations cause a syndrome of cytopenia, immunodeficiency, MDS, and neurological symptoms. Blood. 2017;129(16):2266-2279.

GeneReviews - Dyskeratosis congenita

Savage SA. Dyskeratosis congenita. In: Adam MP, Ardinger HH, Pagon RA, et al., eds. GeneReviews. University of Washington, Seattle. Last revision Nov 2019; accessed Aug 2020.

GeneReviews - Li-Fraumeni Syndrome

Schneider K, Zelley K, Nichols KE, et al. Li-Fraumeni syndrome. In: Adam MP, Everman DB, Mirzaa GM, et al, eds. GeneReviews, University of Washington; 1993-2022. Last update Nov 2019; accessed Dec 2022.

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