Hereditary Cancer Panel

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

2012032

Hereditary Cancer Panel, Sequencing and Deletion/Duplication 2012032

Method

Massively Parallel Sequencing/Sequencing/Multiplex Ligation-Dependent Probe Amplification (MLPA)

Recommended test to confirm a diagnosis of a hereditary cancer syndrome in individuals with personal or family history consistent with features of more than one cancer syndrome
Testing minors for adult-onset conditions is not recommended and testing will not be performed on minors without prior approval; for additional information, please contact an ARUP genetic counselor (800-242-2787).

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.

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 in other ARUP hereditary cancer tests. For more information, refer to the ARUP Hereditary Cancer Panel Comparison table.

Genetics

Genes

Refer to the 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 except for the following:

Gene	Inheritance Pattern
SDHAF2	Autosomal dominant with paternal parent-of-origin effect
SDHD	Autosomal dominant with paternal parent-of-origin effect
MAX	Autosomal dominant with possible paternal parent-of-origin effect
MUTYH	Autosomal recessive but may also have autosomal dominant risks that are not well-defined
MLH3	Autosomal recessive
MSH3	Autosomal recessive
NTHL1	Autosomal recessive
TERT	Both autosomal dominant and autosomal recessive

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

Test Interpretation

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

Variant Class	Analytic Sensitivity (PPA) Estimate^a (%) and 95% Credibility Region (%)	Analytic Specificity (NPA) Estimate (%)
SNVs	>99 (96.9-99.4)	>99.9
Deletions 1-10 bp^b	93.8 (84.3-98.2)	>99.9
Insertions 1-10 bp^b	94.8 (86.8-98.5)	>99.9
Exon-level^c deletions	97.8 (90.3-99.8) [2 exons or larger] 62.5 (38.3-82.6) [single exon]	>99.9
Exon-level^c duplications	83.3 (56.4-96.4) [3 exons or larger]	>99.9
Exon-level deletions/duplications (MLPA)	>99	>99
^aPPA values are derived from larger methods-based MPS and/or Sanger validations. These values do not apply to testing performed by multiplex ligation-dependent probe amplification (MLPA) unless otherwise indicated. ^bVariants greater than 10 bp may be detected, but the analytical sensitivity may be reduced. ^cIn most cases, a single exon deletion or duplication is less than 450 bp and 3 exons span a genomic region larger than 700 bp. bp, base pairs; NPA, negative percent agreement; PPA, positive percent agreement; SNVs, single nucleotide variants

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