Hereditary Renal Cancer Panel

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

  • 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.
  • Testing for a known familial sequence variant by sequencing gene of interest. A copy of the family member’s test result documenting the familial gene variant is REQUIRED.
  • To determine if the variant(s) of interest are detectable by this assay, contact an ARUP genetic counselor at 800-242-2787.

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 on other related tests (see Related Tests section).

Genetics

Genes

See 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 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) Estimatea (%) and 95% Credibility Region Analytic Specificity (NPA) Estimate (%)

SNVs

>99 (96.9-99.4)

>99.9

Deletions 1-10 bpb

93.8 (84.3-98.2)

>99.9

Insertions 1-10 bpb

94.8 (86.8-98.5)

>99.9

Exon-levelc deletions

97.8 (90.3-99.8) [2 exons or larger]

62.5 (38.3-82.6) [single exon]

>99.9

Exon-levelc 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

    To compare directly to other hereditary cancer panels offered by ARUP Laboratories, see the Hereditary Cancer Panel Comparison table.
    Gene MIM Number Disorder/Associated Cancer(s)/Tumor(s) Inheritance

    BAP1

    603089

    BAP1-TPDS

    BAP1-inactivated melanocytic tumors, basal cell carcinoma, cutaneous melanoma, malignant mesothelioma, renal cell carcinoma, uveal melanoma

    AD

    DICER1

    606241

    DICER1-related disorders

    CNS, cystic nephroma, ovarian sex cord-stromal tumors, pleuropulmonary blastoma, thyroid

    AD

    EPCAM

    (Exon 9 deletions/duplications only)

    185535

    Lynch syndrome/HNPCC

    Brain, colorectal, endometrial, ovarian, pancreas, prostate, renal pelvis and/or ureter, stomach, and others

    AD

    FH

    136850

    FH tumor predisposition syndrome/HLRCC

    Cutaneous and uterine leiomyomata, papillary type 2 renal cancer, paraganglioma, pheochromocytoma

    AD

    Fumarase deficiency

    AR

    FLCN

    607273

    BHDS

    Fibrofolliculomas, pulmonary cysts/history of pneumothorax, renal cancer

    AD

    MET

    164860

    HPRCC

    Papillary type 1 renal cancer

    AD

    MLH1

    120436

    Lynch syndrome/HNPCC

    Brain, colorectal, endometrial, ovarian, pancreas, prostate, renal pelvis and/or ureter, stomach, and others

    AD

    CMMRD

    AR

    MSH2

    609309

    Lynch syndrome/HNPCC

    Brain, colorectal, endometrial, ovarian, pancreas, prostate, renal pelvis and/or ureter, stomach, and others

    AD

    CMMRD

    AR

    MSH6

    600678

    Lynch syndrome/HNPCC

    Brain, colorectal, endometrial, ovarian, pancreas, prostate, renal pelvis and/or ureter, stomach, and others

    AD

    CMMRD

    AR

    PMS2

    600259

    Lynch syndrome/HNPCC

    Brain, colorectal, endometrial, ovarian, pancreas, prostate, renal pelvis and/or ureter, stomach, and others

    AD

    CMMRD

    AR

    PTEN

    601728

    Cowden syndrome/PTEN hamartoma tumor syndrome

    Breast, colorectal, endometrial, Lhermitte-Duclos disease (cerebellar dysplastic gangliocytoma), melanoma, renal cell carcinoma, thyroid, and others

    AD

    SDHA 600857

    HPP syndromes

    GIST, paraganglioma, pheochromocytoma, pulmonary chondroma, renal clear cell carcinoma

    AD

    SDHB

    185470

    HPP syndromes

    GIST, paraganglioma, pheochromocytoma, pulmonary chondroma, renal clear cell carcinoma

    AD

    SDHC

    602413

    HPP syndromes

    GIST, paraganglioma, pheochromocytoma, pulmonary chondroma, renal clear cell carcinoma

    AD

    SDHD

    602690

    HPP syndromes

    GIST, paraganglioma, pheochromocytoma, pulmonary chondroma, renal clear cell carcinoma

    ADa

    SMARCA4

    603254

    Rhabdoid tumor predisposition syndrome

    Associated cancer(s)/tumor(s): rhabdoid tumor

    AD

    SMARCB1

    601607

    Rhabdoid tumor predisposition syndrome

    Associated cancer(s)/tumor(s): rhabdoid tumor

    AD

    TP53

    191170

    LFS

    Adrenocortical carcinoma, breast, choroid plexus carcinoma, CNS, colorectal, melanoma, osteosarcoma, pancreas, prostate, renal, rhabdomyosarcoma, soft tissue sarcoma, stomach, thyroid, and others

    AD

    TSC1

    605284

    TSC

    Cardiac rhabdomyoma, fibromas, renal angiomyolipoma, retinal and other hamartomas, SEGA, and others

    AD

    TSC2

    191092

    TSC

    Cardiac rhabdomyoma, fibromas, renal angiomyolipoma, retinal and other hamartomas, SEGA, and others

    AD

    VHL

    608537

    VHL syndrome

    Endolymphatic sac tumors, epididymal and broad ligament cystadenomas, hemangioblastoma, neuroendocrine tumors, pheochromocytoma, renal cell carcinoma, retinal angioma

    AD

    aPaternal parent-of-origin effect.

    AD, autosomal dominant; AR, autosomal recessive; BAP1-TPDS, BAP1 tumor predisposition syndrome; BHDS, Birt-Hogg-Dube syndrome; CMMRD, constitutional mismatch repair deficiency; CNS, central nervous system; GIST, gastrointestinal stromal tumor; HLRCC, hereditary leiomyomatosis and renal cell cancer; HNPCC, hereditary nonpolyposis colorectal cancer; HPP, hereditary paraganglioma-pheochromocytoma; HPRCC, hereditary papillary renal cell carcinoma; LFS, Li-Fraumeni syndrome; RTPS, rhabdoid tumor predisposition syndrome; SCCOHT, small-cell carcinoma of the ovary, hypercalcemic type; SEGA, subependymal giant cell astrocytoma; TSC, tuberous sclerosis complex; VHL, von Hippel-Lindau

References

Additional Resources