Massively Parallel Sequencing/Exonic Oligonucleotide-based CGH Microarray
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-TPDS |
AD |
DICER1 |
606241 |
DICER1-related disorders |
AD |
FH |
136850 |
HLRCC |
AD |
Fumarase deficiency |
AR |
||
FLCN |
607273 |
BHDS |
AD |
MET |
164860 |
HPRCC |
AD |
MLH1 |
120436 |
Lynch syndrome/HNPCC |
AD |
CMMRD |
AR |
||
MSH2 |
609309 |
Lynch syndrome/HNPCC |
AD |
CMMRD |
AR |
||
MSH6 |
600678 |
Lynch syndrome/HNPCC |
AD |
CMMRD |
AR |
||
PMS2 |
600259 |
Lynch syndrome/HNPCC |
AD |
CMMRD |
AR |
||
PTEN |
601728 |
Cowden syndrome/PTEN hamartoma tumor syndrome |
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 |
AD |
SMARCB1 |
601607 |
Rhabdoid tumor predisposition syndrome |
AD |
TP53 |
191170 |
LFS |
AD |
TSC1 |
605284 |
TSC |
AD |
TSC2 |
191092 |
TSC |
AD |
VHL |
608537 |
VHL syndrome |
AD |
WT1 |
607102 |
WT1-telated Wilms tumor, WAGR syndrome, DDS, Frasier syndrome |
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; DDS, Denyis-Drash syndrome; GIST, gastrointestinal stromal tumor; HLRCC, hereditary leiomyomatosis and renal cell cancer; HNPCC, hereditary nonpolyposis colorectal cancer; HPRCC, hereditary papillary renal cell carcinoma; LFS, Li-Fraumeni syndrome; SEGA, subependymal giant cell astrocytoma; TSC, tuberous sclerosis complex; VHL, von Hippel-Lindau |
29978187
Carlo MI, Mukherjee S, Mandelker D, et al. Prevalence of germline mutations in cancer susceptibility genes in patients with advanced renal cell carcinoma. JAMA Oncol. 2018;4(9):1228-1235.
GeneReviews - Wilms Tumor Predisposition
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GeneReviews - FH tumor predisposition syndrome
Kamihara J, Schultz KA, Rana HQ. FH tumor predisposition syndrome. In: Adam MP, Ardinger HH, Pagon RA, et al, editors. GeneReviews, University of Washington; 1993-2020. [Last update: Apr 2020; Accessed: Jul 2020]
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NCCN - genetic/familial high-risk assessment: breast, ovarian, and pancreatic v 2.2021
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NCCN - Genetic/familial high-risk assessment: colorectal v1.2020
National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: genetic/familial high-risk assessment—colorectal. Version 1.2020. [Updated: Jul 2020; Accessed: Feb 2021]
GeneReviews - Rhabdoid Tumor Predisposition Syndrome
Nemes K, Bens S, Bourdeaut F, et al. Rhabdoid tumor predisposition syndrome. In: Adam MP, Ardinger HH, Pagon RA, et al, editors. GeneReviews, University of Washington; 1993-2020. [Initial Posting: Dec 2017; Accessed: Feb 2020]
GeneReviews - Tuberous Sclerosis Complex
Northrup H, Koenig MK, Pearson DA, et al. Tuberous sclerosis complex. In: Adam MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews, University of Washington; 1993-2022. [Revised: Dec 2021; Accessed: Jun 2022]
GeneReviews - BAP1 Tumor Predisposition Syndrome
Pilarski R, Rai K, Cebulla C, et al. BAP1 tumor predisposition syndrome. In: Adam MP, Ardinger HH, Pagon RA, et al, editors. GeneReviews, University of Washington; 1993-2020. [Initial Posting: Oct 2016; Accessed: Feb 2020]
GeneReviews - Birt-Hogg-Dubé Syndrome
Sattler EC, Steinlein OK. Birt-Hogg-Dubé syndrome. In: Adam MP, Ardinger HH, Pagon RA, et al, editors. GeneReviews, University of Washington; 1993-2020. [Last Update: Jan 2020; Accessed: Feb 2020]
GeneReviews - Von Hippel-Lindau Syndrome
van Leeuwaarde RS, Ahmad S, Links TP, et al. Von Hippel-Lindau syndrome. In: Adam MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews, University of Washington; 1993-2021. [Last update: Sep 2018; Accessed: Apr 2020]
Indication for testing: