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Hereditary Renal Cancer Panel

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

2010214

Hereditary Renal Cancer Panel, Sequencing and Deletion/Duplication 2010214

Method

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

Use to confirm a diagnosis of a hereditary renal cancer syndrome in individuals with a personal or family history of renal cancer
Testing minors for adult-onset conditions is not recommended and will not be performed on minors without prior approval. For additional information, please contact an ARUP genetic counselor at 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 renal cancer. Hereditary cancer predisposition is often characterized by early age of onset (typically before age 50) and multiple, multifocal, and/or related cancers in a single individual or in a closely related family member(s). Pathogenic variants in the genes analyzed by this panel cause variable phenotypes and cancer risks, including nonrenal cancers. See Genes Tested table below for more details regarding the genes and syndromes included on the Hereditary Renal 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

See the Genes Tested table for genes included in the panel.

Etiology

Approximately 3-5% of renal cancers are associated with a hereditary cause.

Inheritance

All genes tested on the hereditary renal cancer panel are autosomal dominant with the exception of the SDHD gene, which is autosomal dominant with paternal parent-of-origin effect.
Some genes are also associated with autosomal recessive childhood cancer predisposition or other syndromes.
See the Genes Tested table for additional details.

Test Interpretation

Contraindications for Ordering

Should not be ordered to detect somatic variants associated with malignancy as sensitivity for mosaic variants is low with methodology used for germline assays
Individuals with hematological malignancy and/or a previous allogeneic 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 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 analytic 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; PPA, positive percent agreement; NPA, negative 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:
  - FLCN (NM_001353229) 7
  - 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 MPS
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
Deletions/duplications in the following exons:
- FLCN (NM_001353229) 7
- PTEN (NM_000314, NM_001304718) 9; (NM_001304717) 1,10
- SDHA (NM_004168) 1,10-15; (NM_001294332) 1,9-14; (NM_001330758) 1,10-13
- SDHD (NM_001276506) 4
- VHL (NM_001354723) 2

Genes Tested