Hereditary Renal Cancer Panel

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).

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.

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

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