Hereditary Renal Cancer Panel

Hereditary Renal Cancer Panel, Sequencing and Deletion/Duplication 2010214
Method: Massively Parallel Sequencing/Exonic Oligonucleotide-based CGH Microarray

Indication for testing:

  • Recommended test to confirm a diagnosis of a hereditary renal cancer syndrome in individuals with a personal or family history of renal cancer.
  • When a relative has a previously identified pathogenic sequence variant, see Familial Mutation, Targeted Sequencing (2001961).
Familial Mutation, Targeted Sequencing 2001961
Method: Polymerase Chain Reaction/Sequencing

Indication for testing:

  • Recommended test if there is a known familial sequence variant previously identified in a family member.
  • A copy of the family member’s test result documenting the familial variant is required.

See Related Tests

Pathogenic variants in multiple genes have been implicated in hereditary renal cancer. Hereditary cancer predisposition is often characterized by early age of onset (typically before 50 years) and multiple, multifocal, and/or similar 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.

Disease Overview

Etiology

Approximately 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 table below for additional details.

Test Description

See Genes Tested table for genes included in the panel.

Clinical Sensitivity

Variable, dependent on phenotype/condition

Testing Strategy

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 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.
  • When a relative has a previously identified pathogenic variant, see Familial Mutation, Targeted Sequencing (2001961).

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
    • Deletions/duplications in SMARCA4 and WT1
    • Noncoding transcripts
    • The following exons are not sequenced due to technical limitations of the assay:
      • SDHC (NM_001035511) 5
      • SDHD (NM_001276506) 4
  • The following may not be detected:
    • Deletions/duplications/insertions of any size by massively parallel sequencing
    • Deletions/duplications less than 1kb in the targeted genes by array
    • Some variants due to technical limitations in the presence of pseudogenes, repetitive, or homologous regions
    • Low-level somatic variants
    • Single exon deletions/duplications in the following exons:
      • BAP1 (NM_004656) 1
      • FH (NM_000143) 1
      • FLCN (NM_144997) 8
      • MSH2 (NM_000251) 1; (NM_001258281) 2
      • MSH6 (NM_000179) 10
      • PTEN (NM_000314) 8, 9; (NM_001304717) 1
      • SDHD (NM_001276506) 4
      • SMARCB1 (NM_003073) 5
      • TP53 (NM_001126113) 10; (NM_001126114) 10
      • TSC2 (NM_000548) 17, 29, 41
      • VHL (NM_000551) 1

Analytical Sensitivity

For massively parallel sequencing:

Variant Class Analytical Sensitivity (PPA) Estimatea (%) Analytical Sensitivity (PPA) 95% Credibility Regiona (%)

SNVs

99.2

96.9-99.4

Deletions 1-10 bp

93.8

84.3-98.2

Deletions 11-44 bp

100

87.8-100

Insertions 1-10 bp

94.8

86.8-98.5

Insertions 11-23 bp

100

62.1-100

aGenes included on this test are a subset of a larger methods-based validation from which the PPA values are derived.

bp, base pairs; PPA, positive percent agreement; SNVs, single nucleotide variants

Genes Tested

Gene MIM Number Disorder/Associated Cancer(s)/Tumor(s) Inheritance

BAP1

603089

BAP1 tumor predisposition syndrome (BAP1-TPDS)
Associated cancer(s)/tumor(s): uveal melanoma, malignant mesothelioma, cutaneous melanoma, renal cell carcinoma, basal cell carcinoma

AD

DICER1

606241

DICER1-related disorders
Associated cancer(s)/tumor(s): pleuropulmonary blastoma, ovarian sex cord-stromal tumors, cystic nephroma, thyroid

AD

FH

136850

Hereditary leiomyomatosis and renal cell cancer (HLRCC)
Associated cancer(s)/tumor(s): papillary type 2 renal cancer, cutaneous and uterine leiomyomata

AD

Fumarase Deficiency

AR

FLCN

607273

Birt-Hogg-Dube syndrome (BHDS)
Associated cancer(s)/tumor(s): renal

AD

MET

164860

Hereditary papillary renal cell carcinoma (HPRCC)
Associated cancer(s)/tumor(s): papillary type 1 renal cancer

AD

MLH1

120436

Lynch syndrome/hereditary nonpolyposis colorectal cancer (HNPCC)
Associated cancer(s)/tumor(s): colorectal, endometrial, stomach, ovarian, and others

AD

Constitutional mismatch repair deficiency (CMMRD)

AR

MSH2

609309

Lynch syndrome/hereditary nonpolyposis colorectal cancer (HNPCC)
Associated cancer(s)/tumor(s): colorectal, endometrial, stomach, ovarian, and others

AD

Constitutional mismatch repair deficiency (CMMRD)

AR

MSH6

600678

Lynch syndrome/hereditary nonpolyposis colorectal cancer (HNPCC)
Associated cancer(s)/tumor(s): colorectal, endometrial, stomach, ovarian, and others

AD

Constitutional mismatch repair deficiency (CMMRD)

AR

PMS2

600259

Lynch syndrome/hereditary nonpolyposis colorectal cancer (HNPCC)
Associated cancer(s)/tumor(s): colorectal, endometrial, stomach, ovarian, and others

AD

Constitutional mismatch repair deficiency (CMMRD)

AR

PTEN

601728

Cowden syndrome/PTEN hamartoma tumor syndrome
Associated cancer(s)/tumor(s): breast, endometrial, thyroid, colon, renal cell carcinoma

AD

SDHB

185470

Associated cancer(s)/tumor(s): paraganglioma, pheochromocytoma, GIST, pulmonary chondroma, renal clear cell carcinoma

AD

SDHC

602413

Associated cancer(s)/tumor(s): paraganglioma, pheochromocytoma, GIST, pulmonary chondroma, renal clear cell carcinoma

AD

SDHD

602690

Associated cancer(s)/tumor(s): paraganglioma, pheochromocytoma, GIST, 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

Li-Fraumeni syndrome (LFS)
Associated cancer(s)/tumor(s): soft tissue sarcoma, osteosarcoma, central nervous system (CNS) tumor, breast, adrenocortical carcinoma, choroid plexus carcinoma, rhabdomyosarcoma

AD

TSC1

605284

Tuberous sclerosis complex (TSC)
Associated cancer(s)/tumor(s): cardiac rhabdomyoma, retinal and other hamartomas, renal angiomyolipoma, subependymal giant cell astrocytoma (SEGA), fibromas

AD

TSC2

191092

Tuberous sclerosis complex (TSC)
Associated cancer(s)/tumor(s): cardiac rhabdomyoma, retinal and other hamartomas, renal angiomyolipoma, subependymal giant cell astrocytoma (SEGA), fibromas

AD

VHL

608537

Von Hippel-Lindau (VHL) syndrome
Associated cancer(s)/tumor(s): hemangioblasoma, retinal angioma, renal cell carcinoma, pheochromocytoma, neuroendocrine tumors, endolymphatic sac tumors, epididymal and broad ligament cystadenomas

AD

WT1

607102

WT1-telated Wilms tumor; WAGR syndrome; Denys-Drash syndrome (DDS); Frasier syndrome
Associated cancer(s)/tumor(s): Wilms tumor

AD

aPaternal parent-of-origin effect

AD, autosomal dominant; AR, autosomal recessive
References 

Carlo MI, Mukherjee S, Mandelker D, Vijai J, Kemel Y, Zhang L, Knezevic A, Patil S, Ceyhan-Birsoy O, Huang K, Redzematovic A, Coskey DT, Stewart C, Pradhan N, Arnold AG, Hakimi A, Chen Y, Coleman JA, Hyman DM, Ladanyi M, Cadoo KA, Walsh MF, Stadler ZK, Lee C, Feldman DR, Voss MH, Robson M, Motzer RJ, Offit K. Prevalence of Germline Mutations in Cancer Susceptibility Genes in Patients With Advanced Renal Cell Carcinoma. JAMA Oncol. 2018; 4(9): 1228-1235. PubMed

Dome J, Huff V. Wilms Tumor Predisposition. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews, University of Washington, 1993-2018. Seattle, WA [Last Update: Oct 2016; Accessed: Nov 2018]

Haidle J, Howe JR. Juvenile Polyposis Syndrome. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews, University of Washington, 1993-2018. Seattle, WA [Last Update: Mar 2017; Accessed: Nov 2018]

NCCN Clinical Practice Guidelines in Oncology, Genetic/Familial High-Risk Assessment: Breast and Ovarian, Version 2.2019. National Comprehensive Cancer Network. Fort Washington, PA [Last Updated: Jul 2018; Accessed: Nov 2018]

NCCN Clinical Practice Guidelines in Oncology, Genetic/Familial High-Risk Assessment: Colorectal. Version 1.2018. National Comprehensive Cancer Network. Fort Washington, PA [Updated: Jul 2018; Accessed: Jan 2019]

Nemes K, Bens S, Bourdeaut F, Hasselblatt M, Kool M, Johann P, Kordes U, Schneppenheim R, Siebert R, Fruhwald M. Rhabdoid Tumor Predisposition Syndrome. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews, University of Washington, 1993-2018. Seattle, WA [Accessed: Nov 2018]

Northrup H, Koenig M, Pearson D, Au K. Tuberous Sclerosis Complex. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews, University of Washington, 1993-2018. Seattle, WA [Last Update: Jul 2018; Accessed: Nov 2018]

Pilarski R, Rai K, Cebulla C, Abdel-Rahman M. BAP1 Tumor Predisposition Syndrome. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews, University of Washington, 1993-2018. Seattle, WA [Accessed: Nov 2018]

Pithukpakorn M, Toro JR. Hereditary Leiomyomatosis and Renal Cell Cancer. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews, University of Washington, 1993-2018. Seattle, WA [Last Update: Aug 2015; Accessed: Nov 2018]

Toro JR. Birt-Hogg-Dubé Syndrome. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews, University of Washington, 1993-2018. Seattle, WA [Last Update: Aug 2014; Accessed: Nov 2018]

van Leeuwaarde R, Ahman S, Links T, Giles R. Von Hippel-Lindau Syndrome. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews, University of Washington, 1993-2018. Seattle, WA [Last Update: Sep 2018; Accessed: Nov 2018]

Related Information 
Tumor Markers

Last Update: March 2019