Hereditary Cancer Panel

Pathogenic germline variants in multiple genes have been implicated in hereditary cancer. Hereditary cancer predisposition is often characterized by early age of cancer onset (typically before age 50), and multiple, multifocal, and/or related cancers in a single individual or in a closely related family member(s). See Genes Tested table below for more details regarding the genes and syndromes included on the Hereditary Cancer Panel. Genes included on this panel are also included on other related tests (see Related Tests section and Hereditary Cancer Genetic Testing – Germline Testing for Inherited Cancer Syndromes).

Genetics

Genes

See Genes Tested table for genes included in the panel.

Etiology

Approximately 5-10% of cancer is associated with a hereditary cause. 

Inheritance

• All genes tested on this panel are autosomal dominant with the exception of the following:

• Some genes are associated with autosomal recessive childhood cancer predisposition or other syndromes.
• See Genes Tested table for additional details.

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 peripheral blood specimen.
  • Testing of cultured fibroblasts is required for accurate interpretation of test results.

Methodology

This test is performed using the following sequence of steps:

• Selected genomic regions, primarily coding exons and exon-intron boundaries, from the targeted genes are isolated from extracted genomic DNA using a probe-based hybrid capture enrichment workflow.
• Enriched DNA is sequenced by massively parallel sequencing (MPS; also known as next generation sequencing [NGS]) followed by paired-end read alignment and variant calling using a custom bioinformatics pipeline. The pipeline includes an algorithm for detection of large (single exon-level or larger) deletions and duplications.
• Sanger sequencing is performed as necessary to fill in regions of low coverage and, in certain situations, to confirm variant calls.
• Large deletion/duplication calls made using MPS are confirmed by an orthogonal exon-level microarray when sample quality and technical conditions allow.
• Long-range polymerase chain reaction (PCR) followed by nested Sanger sequencing is performed on the following gene and exons:
  • PMS2 (NM_000535) 11, 12, 13, 14, 15
• Bidirectional Sanger sequencing is performed on the following genes and exons:
  • MSH2 (NM_000251) 5
  • PMS2 (NM_000535) 7
  • PTEN (NM_000314) 9
• Multiplex ligation-dependent probe amplification (MLPA) is performed on the following gene to call exon-level deletions and duplications:
  • PMS2 (NM_000535)

Clinical Sensitivity

Variable, dependent on phenotype/condition

Analytic Sensitivity

Limitations

• A negative result does not exclude a heritable form of cancer.
• Diagnostic errors can occur due to rare sequence variations.
• Interpretation of this test result may be impacted if this individual has had an allogeneic stem cell transplantation.
• The following will not be evaluated:
  • Variants outside the coding regions and intron-exon boundaries of the targeted genes
  • Regulatory region variants and deep intronic variants
  • Breakpoints of large deletions/duplications
  • Sequence variants in EPCAM
  • The following exons are not sequenced due to technical limitations of the assay:
    • •  
    • APC (NM_001354896) 12; (NM_001354898, NM_001354904) 2; (NM_001354900) 11
    • BRCA1 (NM_007300) 13
    • CHEK2 (NM_001005735) 3; (NM_001349956) 4
    • FLCN (NM_001353229) 7
    • MEN1 (NM_001370251) 8
    • MITF (NM_001354607) 2
    • PDGFRA (NM_001347827) 17; (NM_001347828) 2; (NM_001347830) 1
    • RECQL (NM_002907) 14,15; (NM_032941) 15,16
    • SDHA (NM_004168) 14; (NM_001294332) 13; (NM_001330758) 12
    • SDHC (NM_001035511) partial exon 5 (Chr1:161332225-161332330); (NM_001278172) partial exon 4 (Chr1:161332225-161332330)
    • SDHD (NM_001276506) 4
    • VHL (NM_001354723) 2
• The following may not be detected:
  • Deletions/duplications/insertions of any size by massively parallel sequencing
  • Large duplications less than 3 exons in size
  • Noncoding transcripts
  • Single exon deletions/duplications may not be detected based on the breakpoints of the rearrangement.
  • Some variants due to technical limitations in the presence of pseudogenes and/or repetitive/homologous regions
  • Low-level somatic variants
  •  
  • The following regions may have reduced sequencing sensitivity due to technical limitations of the assay:
    • RB1 (NM_000321) exon 22
    • SUFU (NM_016169, NM_001178133) exon 1
  • Deletions/duplications in the following exons:

  • Gene	Exon(s)
    APC	(NM_001354896) 12; (NM_001354898, NM_001354904) 2; (NM_001354900) 11
    BMPR1A	(NM_004329) 12-13
    BRCA1	(NM_007294, NM_007299, NM_007300) 2; (NM_007298) 1
    CDH1	(NM_001317185) 10
    CDKN2A	(NM_000077, NM_001195132, NM_001363763, NM_058195) 2
    CHEK2	(NM_007194) 11-15; (NM_001005735) 3,12-16; (NM_001257387) 12-16; (NM_001349956) 4,10-14; (NM_145862) 10-14
    CTNNA1	(NM_001290307) 19; (NM_001324002, NM_001324004) 13; (NM_001324003) 15; (NM_001324005) 16
    FLCN	(NM_001353229) 7
    MEN1	(NM_001370251) 8
    MITF	(NM_001354607) 2
    MLH3	(NM_001040108) 7-8; (NM_014381) 7
    PDGFRA	(NM_001347827) 17; (NM_001347828) 2; (NM_001347830) 1
    PTEN	(NM_000314, NM_001304718) 9; (NM_001304717) 1,10
    RB1	(NM_000321) 22
    RECQL	(NM_002907) 14-15; (NM_032941) 15-16
    SDHA	(NM_004168) 1,10-15; (NM_001294332) 1,9-14; (NM_001330758) 1,10-13
    SDHD	(NM_001276506) 4
    SMARCE1	(NM_003079) 7,10-11
    VHL	(NM_001354723) 2

Genes Tested

To compare directly to other hereditary cancer panels offered by ARUP Laboratories, see the ARUP Hereditary Cancer Panel Comparison table.