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Fanconi Anemia via the PALB2/FANCN Gene

Summary and Pricing

Test Method

Sequencing and CNV Detection via NextGen Sequencing using PG-Select Capture Probes
Test Code Test Copy GenesTest CPT Code Gene CPT Codes Copy CPT Codes Base Price
4611 PALB2 81307 81307,81479 $990 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
4611PALB281307 81307,81479 $990 Order Options and Pricing

Pricing Comments

This test is also offered via our exome backbone with CNV detection (click here). The exome-based test may be higher priced, but permits reflex to the entire exome or to any other set of clinically relevant genes.

An additional 25% charge will be applied to STAT orders. STAT orders are prioritized throughout the testing process.

Testing run on PG-Select capture probes does not include exome-wide CNV analysis. Reflex is available to PGxome or an exome-based panel, or you can use this gene list to create a custom panel (click here).

Click here for costs to reflex to whole PGxome.

Turnaround Time

3 weeks on average for standard orders or 2 weeks on average for STAT orders.

Please note: Once the testing process begins, an Estimated Report Date (ERD) range will be displayed in the portal. This is the most accurate prediction of when your report will be complete and may differ from the average TAT published on our website. About 85% of our tests will be reported within or before the ERD range. We will notify you of significant delays or holds which will impact the ERD. Learn more about turnaround times here.

Targeted Testing

For ordering sequencing of targeted known variants, go to our Targeted Variants page.

EMAIL CONTACTS

Genetic Counselors

Geneticist

  • Siwu Peng, PhD

Clinical Features and Genetics

Clinical Features

Fanconi anemia (FA) is considered a blood disorder; however, the clinical features of FA expand well beyond hematologic disorders alone. FA is characterized by a range of physical abnormalities, bone marrow failure (aplastic anemia), pancytopenia, and predisposition to cancers—particularly acute myelogenous leukemia (AML), gynecologic and GI tract cancers, and cancers of the head and neck (Auerbach. Mutat Res 668:4-10, 2009). FA patients are up to 800-fold more susceptible to AML than the general population with a median age of onset of 13 years (Rosenberg et al. Blood 101:822, 2003). Physical abnormalities include radial ray defects (absent thumb or radius), skin pigmentation defects, short stature, microphthalmia, renal and urinary tract defects, genital defects (males in particular), gastrointestinal malformations (atresia), congenital heart disease, hearing and central nervous system defects, and general developmental delay (Tischkowitz and Hodgson. J Med Genet 40:1-10, 2003; Dokal. Baillieres Best Pract Res Clin Haematol 13:407-425, 2000). About one third of FA patients have no obvious physical abnormalities and are diagnosed only after a family member is diagnosed or after developing hematologic anomalies such as thromobocytopenia, leukopenia, and anemia (Giampietro et al. Am J Med Genet 68:58-61, 1997). A hallmark of FA is hypersensitivity of the chromosomes to interstrand cross linking agents such as diepoxybutane (DEB) or mitomycin C (MMC) (Sasaki and Tonomura. Cancer Res 33:1829-1836, 1973). Exposure of primary cell cultures from FA patients to DEB or MMC results in chromosomal aberrations (breaks, radials, rearrangements) due to damaged DNA repair mechanisms that require functional products of the Fanconi anemia genes. For example, the FANCA, -B, -C, -E, -F, -G, -L, and -M proteins are part of a nuclear core complex that regulates monoubiquitination of the FANCD2 and FANCI proteins (ID complex) during S-phase and after exposure to DNA crosslinking agents (Moldovan and D'Andrea. Annu Rev Genet 43:223, 2009). In unaffected individuals, ubiquitination helps localize the ID complex to sites of DNA damage and facilitate repair (Grompe, and van de Vrugt. Developmental Cell 12:661, 2007; Smogorzewska et al. Cell 129:289, 2007), but in FA patients, this mechanism is impaired.

Genetics

FA is a genetically heterogeneous autosomal recessive disorder. To date, 16 FA or FA-like genes have been discovered. Approximately 86% of all cases are attributed to variants in the three genes FANCA (OMIM 607139) (~ 60%), FANCC (OMIM 227645) (~ 16%), and FANCG (OMIM 602956) (~ 10%) (Auerbach. Mutat Res 668:4-10, 2009). Nearly 95% of all cases are attributed to variants in the eight genes, FANCA, -B, -C, -E, -F, -G, -L, and -M, that encode components of a nuclear core complex required for ID complex ubiquitination and facilitation of DNA repair (Grompe, and van de Vrugt. Developmental Cell 12:661, 2007). In the United States, the carrier frequency for FA is estimated at 1 in 181 and the incidence rate of FA is estimated at 1 in 131,000 (http://www.fanconi.org/; Rosenberg et al. Am J Med Genet A 155:1877, 2011). With the exception of FANCD1 and FANCN patients who seem to have more severe clinical symptoms, obvious genotype-phenotype correlations are lacking, and related individuals who harbor a common variant(s) may have drastically different phenotypes. Numerous variants are found throughout the PALB2/FANCN gene and include some missense and splicing variants but primarily include nonsense variants and other small insertions and deletions that result in premature termination (http://www.rockefeller.edu/fanconi/genes/). In relation to other FA patients, FA-N patients often develop leukemia at an earlier age, show increased spontaneous chromosomal breakage, and develop solid tumors (medulloblastoma, astrocytoma, and Wilms Tumors) that are rarely seen in other FA patients (Reid et al. Nat Genet 39:162-164, 2007). In addition, monoallelic variants in PALB2/FANCN predispose to adult cancers, particularly breast cancer, and PALB2/FANCN should be considered among the cancer susceptibility genes (Rahman et al. Nat Genet 39:165, 2007; Tischkowitz et al. PNAS 104:6788, 2007).

Clinical Sensitivity - Sequencing with CNV PG-Select

Variants in FA genes account for >95% of all patients with FA.

Testing Strategy

This test provides full coverage of all coding exons of the PALB2 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.

Indications for Test

Patients with clinical features of FA or who develop aplastic anemia at any age (even if they present no other physical abnormalities) and patients with a family history of FA or cancer, characteristic birth defects, or spontaneous chromosome breakage. This test may also be considered for the reproductive partners of individuals who carry pathogenic variants in PALB2.

Gene

Official Gene Symbol OMIM ID
PALB2 610355
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

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Citations

  • Auerbach AD. 2009. Fanconi anemia and its diagnosis. Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis 668: 4–10. PubMed ID: 19622403
  • Dokal I. 2000. The genetics of Fanconi’s anaemia. Baillieres Best Pract. Res. Clin. Haematol. 13: 407–425. PubMed ID: 11030042
  • Fanconi Anemia Research Fund, Inc.
  • Giampietro PF, Verlander PC, Davis JG, Auerbach AD. 1997. Diagnosis of Fanconi anemia in patients without congenital malformations: an international Fanconi Anemia Registry Study. Am. J. Med. Genet. 68: 58–61. PubMed ID: 8986277
  • Grompe M, and Van de Vrugt, H. 2007. The Fanconi Family Adds a Fraternal Twin. Developmental Cell 12: 661–662. PubMed ID: 17488615
  • Moldovan G-L, D’Andrea AD. 2009. How the Fanconi Anemia Pathway Guards the Genome. Annual Review of Genetics 43: 223–249. PubMed ID: 19686080
  • Rahman, N., et al., (2007). "PALB2, which encodes a BRCA2-interacting protein, is a breast cancer susceptibility gene". Nat Genet 39(2):165-7. PubMed ID: 17200668
  • Reid, S., et.al. (2007). "Biallelic mutations in PALB2 cause Fanconi anemia subtype FA-N and predispose to childhood cancer." Nat Genet 39(2): 162-4. PubMed ID: 17200671
  • Rosenberg PS, Greene MH, Alter BP. 2003. Cancer incidence in persons with Fanconi anemia. Blood 101: 822–826. PubMed ID: 12393424
  • Rosenberg PS, Tamary H, Alter BP. 2011. How high are carrier frequencies of rare recessive syndromes? Contemporary estimates for Fanconi Anemia in the United States and Israel. American Journal of Medical Genetics Part A 155: 1877–1883. PubMed ID: 21739583
  • Sasaki MS, Tonomura A. 1973. A high susceptibility of Fanconi’s anemia to chromosome breakage by DNA cross-linking agents. Cancer Research 33: 1829–1836. PubMed ID: 4352739
  • Smogorzewska A, Matsuoka S, Vinciguerra P, McDonald ER, Hurov KE, Luo J, Ballif BA, Gygi SP, Hofmann K, D’Andrea AD, Elledge SJ. 2007. Identification of the FANCI Protein, a Monoubiquitinated FANCD2 Paralog Required for DNA Repair. Cell 129: 289–301. PubMed ID: 17412408
  • The Rockefeller University Fanconi Anemia Mutation Database
  • Tischkowitz MD, Hodgson SV. 2003. Fanconi anaemia. Journal of medical genetics 40: 1–10. PubMed ID: 12525534
  • Tischkowitz, M. et al., (2007). "Analysis of PALB2/FANCN-associated breast cancer families". PNAS 104(16):6788-93.
    PubMed ID: 17420451

Ordering/Specimens

Ordering Options

We offer several options when ordering sequencing tests. For more information on these options, see our Ordering Instructions page. To view available options, click on the Order Options button within the test description.

myPrevent - Online Ordering

  • The test can be added to your online orders in the Summary and Pricing section.
  • Once the test has been added log in to myPrevent to fill out an online requisition form.
  • PGnome sequencing panels can be ordered via the myPrevent portal only at this time.

Requisition Form

  • A completed requisition form must accompany all specimens.
  • Billing information along with specimen and shipping instructions are within the requisition form.
  • All testing must be ordered by a qualified healthcare provider.

For Requisition Forms, visit our Forms page

If ordering a Duo or Trio test, the proband and all comparator samples are required to initiate testing. If we do not receive all required samples for the test ordered within 21 days, we will convert the order to the most effective testing strategy with the samples available. Prior authorization and/or billing in place may be impacted by a change in test code.


Specimen Types

Specimen Requirements and Shipping Details

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STAT and Prenatal Test Options are not available with Patient Plus.

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Note: acceptable specimen types are whole blood and DNA from whole blood only.
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