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Renal / Urinary Cancer Comprehensive Panel

Diseases Targeted:

Renal Tumors
Renal Cell Carcinoma
Papillary Renal Cell Carcinoma
Clear Cell Renal Carcinoma
Urinary Tract Tumors
Urinary Tract Cancers
Wilms Tumor
Renal Sarcoma
Rhabdoid Kidney Tumors
Renal Medullary Carcinoma

Overview:

The Renal/ Urinary Cancer Comprehensive Panel examines 28 genes associated with an increased risk for hereditary renal tumors or cancer, as well as tumors or cancers of the urinary tract. This test includes both well-established cancer susceptibility genes, as well as candidate genes with limited evidence of an association where additional research is needed.

Who is this test for?

Patients with a personal or family history suggestive of a hereditary renal tumor/cancer syndrome, or an inherited susceptibility to urinary tract cancer or tumors. Red flags for hereditary cancer could include onset of cancer prior to the age of 50 years, more than one primary cancer in a single person, and multiple affected people within a family. After consideration of a patient’s clinical and family history, this testing may be appropriate for some pediatric patients. (If there are specific genes that you do NOT want included, please indicate this on the test requisition form.) This test is designed to detect individuals with a germline pathogenic variant, and is not validated to detect mosaicism below the level of 20%. It should not be ordered on tumor tissue.

What are the potential benefits for my patient?

Patients identified with an inherited susceptibility can benefit from increased surveillance and preventative steps to better manage their risk for cancer. Information obtained from candidate gene testing may potentially be helpful in guiding clinical management in the future. Also, if an inherited susceptibility is found, your patient’s family members can be tested to help define their risk. If a pathogenic variant is identified in your patient, close relatives (children, siblings, parents) could have as high as a 50% risk to also be at increased risk. In some cases, screening should begin in childhood.

Order Options

Sequencing (included)
Del/Dup (included)

 

Genes

BAP1, CDC73, CDKN1C, DICER1, DIS3L2, EPCAM, FH, FLCN, GPC3, MET, MITF, MLH1, MSH2, MSH6, MUTYH, PMS2, PTEN, SDHA, SDHB, SDHC, SDHD, SMARCA4, SMARCB1, TP53, TSC1, TSC2, VHL, WT1 ( 28 genes )

Coverage:

99% at 50x

Specimen Requirements:

Blood (two 4ml EDTA tubes, lavender top) or Extracted DNA (3ug in EB buffer) or Buccal Swab or Saliva (kits available upon request)

Test Limitations:

Test results and variant interpretation are based on the proper identification of the submitted specimen and use of correct human reference sequences at the queried loci. In very rare instances, errors may result due to mix-up or co-mingling of specimens. Positive results do not imply that there are no other contributions, genetic or otherwise, to the patient's phenotype, and negative results do not rule out a genetic cause for the indication for testing. Result interpretation is based on the collected information and Alamut annotation available at the time of reporting. This assay is not designed or validated for the detection of mosaicism. DNA alterations in regulatory regions or deep intronic regions (greater than 20bp from an exon) will not be detected by this test. There are technical limitations on the ability of DNA sequencing to detect small insertions and deletions. Our laboratory uses a sensitive detection algorithm, however these types of alterations are not detected as reliably as single nucleotide variants. Rarely, due to systematic chemical, computational, or human error, DNA variants may be missed. Although next generation sequencing technologies and our bioinformatics analysis significantly reduce the confounding contribution of pseudogene sequences or other highly-homologous sequences, sometimes these may still interfere with the technical ability of the assay to identify pathogenic variant alleles in both sequencing and deletion/duplication analyses. Deletion/duplication analysis can identify alterations of genomic regions which are a single exon in size. When novel DNA duplications are identified, it is not possible to discern the genomic location or orientation of the duplicated segment, hence the effect of the duplication cannot be predicted. Where deletions are detected, it is not always possible to determine whether the predicted product will remain in-frame or not. Unless otherwise indicated, in regions that have been sequenced by Sanger, deletion/duplication analysis has not been performed.

Patients with Bone Marrow Transplants:
DNA extracted from cultured fibroblasts should be submitted instead of blood/saliva/buccal samples from individuals who have undergone allogeneic bone marrow transplant and from patients with hematologic malignancy.

Gene Specifics:

Gene Notes
MSH2 Inversion of MSH2 exons 1-7 ("Boland" inversion) is assessed for Lynch Syndrome, Colorectal, Endometrial, and Prostate Cancer Panel testing (for both Focus and Comprehensive Panels) as well as Comprehensive Gastric Cancer Panel testing. Unless otherwise specified, this testing is not performed for other cancer panels, but is available upon request.

CPT Codes:

CPT Code 81445, 81479

NOTE: The CPT codes listed on the website are in accordance with Current Procedural Terminology, a publication of the American Medical Association. CPT codes are provided here for the convenience of our clients. Clients who bill for services should make the final decision on which codes to use.

Gene Descriptions:

Gene Reason Reference
CDKN1C Autosomal dominant, maternally inherited, pathogenic variants in the CDKN1C gene are one cause of Beckwith-Wiedemann syndrome, which is associated with an increased risk for embryonal tumors, including Wilms tumor, hepatoblastoma, neuroblastoma, and rhabdomyosarcoma, as well as other clinical conditions. PubMed: 20301568; OMIM: 600856
FH Heterozygous germline pathogenic variants in FH are associated with Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC). Individuals with HLRCC have a 10-16% risk to develop renal tumors. Biallelic pathogenic variants in the FH gene cause fumarate hydratase deficiency. PubMed: 20301430; OMIM: 136850
GPC3 X-linked loss of function pathogenic variants in the GPC3 gene have been associated with type 1 Simpson-Golabi-Behmel syndrome which is an overgrowth syndrome that may include multiple congenital anomalies including intellectual disability, distinctive craniofacial features, organomegaly, and an increased risk of embryonal tumors, including Wilms tumor, hepaoblastoma and hepatocellular carcinoma, among others. PubMed: 25238977, 24459012; OMIM: 300037
MSH6 While heterozygous pathogenic variants in MSH6 are associated with Hereditary Non-Polyposis Colorectal Cancer (HNPCC), also known as Lynch Syndrome, biallelic pathogenic variants have been associated with constitutional mismatch repair deficiency syndrome (CMMRD). PubMed: 20301390, 22692065; OMIM: 120436
EPCAM Heterozygous pathogenic variants in the EPCAM gene cause Hereditary Non-Polyposis Colorectal Cancer (HNPCC), also known as Lynch Syndrome, which increases the risk for urinary tract cancers, including bladder cancer. Transitional carcinomas of the ureter and renal pelvis are most associated with Lynch syndrome. PubMed: 20301390, 23462293
MET Heterozygous pathogenic variants in the MET gene have been reported in rare cases of familial papillary renal cell carcinoma, although additional studies are needed given the small number of reported families. PubMed: 24359990, 11551094, 10417759; OMIM: 605074
MITF Heterozygous pathogenic variants in MITF may be associated with an increased risk for renal cell carcinoma. However, additional studies are needed. PubMed: 22012259, 26999813
MLH1 While heterozygous pathogenic variants in MLH1 are associated with Hereditary Non-Polyposis Colorectal Cancer (HNPCC), also known as Lynch Syndrome, biallelic pathogenic variants have been associated with constitutional mismatch repair deficiency syndrome (CMMRD). PubMed: 20301390, 22692065; OMIM: 120436
MSH2 While heterozygous pathogenic variants in MSH2 are associated with Hereditary Non-Polyposis Colorectal Cancer (HNPCC), also known as Lynch Syndrome, biallelic pathogenic variants have been associated with constitutional mismatch repair deficiency syndrome (CMMRD). PubMed: 20301390, 22692065; OMIM: 120436
PMS2 While heterozygous pathogenic variants in PMS2 are associated with Hereditary Non-Polyposis Colorectal Cancer (HNPCC), also known as Lynch Syndrome, biallelic pathogenic variants have been associated with constitutional mismatch repair deficiency syndrome (CMMRD). PubMed: 20301390, 22692065; OMIM: 120436
PTEN Individuals with heterozygous pathogenic PTEN variants are at a significantly increased risk for multiple types of cancers, including breast, thyroid, colorectal, endometrial, renal, and others. Autosomal dominant mutations in PTEN have been associated with Cowden syndrome, which is associated with a 35% lifetime risk for renal cell carcinoma. PubMed: 20301661; OMIM: 601728
SDHA Autosomal dominant pathogenic variants in SDHA are one genetic cause of Hereditary Paragangliomas-Pheochromocytoma Syndromes (HPPS), and are responsible for approximately .6-3% of cases PubMed: 20301715, 26273102
SDHB Autosomal dominant pathogenic variants in SDHB are one genetic cause of Hereditary Paraganglioma-Pheochromocytoma syndrome (HPPS) and are responsible for approximately 22-38% of cases. They are also associated with Carney-Stratakis syndrome, which is characterized by the presence of paragangliomas and gastrointestinal stromal tumors. SDHB-related HPPS has the highest risk for malignancy in comparison to the different genetic causes of the condition. PubMed: 20301715, 26273102; OMIM: 606864
SDHC Heterozygous pathogenic variants in the SDHC gene are responsible for between 4 and 8% of cases of Hereditary Parganglioma-Pheochromocytoma syndrome (HPPS), which increased the risk for renal cell carcinoma. PubMed: 20301715; OMIM: 602413
SDHD Autosomal dominant pathogenic variants in the SDHC gene are the most common cause of Hereditary Parganglioma-Pheochromocytoma syndrome (HPPS), which is associated with an increased risk for renal cell carcinoma. Of note, tumor development occurs much more frequently when the pathogenic variant is inherited from the father (paternal origin). PubMed: 20301715; OMIM: 602690
SMARCA4 Autosomal dominant pathogenic variants in SMARCA4 are associated with Rhabdoid Tumor Predisposition Syndrome, which includes an increased risk for rhabdoid tumors of the kidney. This condition is generally associated with an increased risk for rhabdoid tumors, such as small cell carcinoma of the ovary, hypercalcemic type, as well as schwannomas. PubMed: 25494491, 24752781, 24658002
SMARCB1 Heterozygous pathogenic variants in SMARCB1 are associated with familial rhabdoid tumor predisposition syndrome, which increases the risk for renal medullary carcinoma. PubMed: 26941181; OMIM: 609322
TP53 Heterozygous pathogenic variants in the TP53 gene are associated with Li-Fraumeni syndrome, a condition that increases risk for many types of cancer. PubMed: 20301488, 26014290, 2614290; OMIM: 151623, 191170
TSC1 Autosomal dominant pathogenic variants in TSC1 cause Tuberous Sclerosis complex, which is associated with several types of tumors, including renal cell carcinoma. PubMed: 20301399; OMIM: 605284
TSC2 Autosomal dominant pathogenic variants in TSC2 cause Tuberous Sclerosis complex, which is associated with several types of tumors and other clinical conditions, including renal cell carcinoma. PubMed: 20301399; OMIM: 191092
VHL Heterozygous pathogenic variants in VHL cause von Hippel-Lindau (VHL) syndrome, which increases the risk for many types of cancer, including clear cell renal cell carcinoma, hemangioblastoma, pheochromocytoma, and neuroendocrine tumors. Individuals affected with VHL syndrome have a 70% risk to develop clear cell renal cell carcinoma by the age of 60 years. PubMed: 20301636, 27114602, 25834951, 24355456
WT1 Autosomal dominant pathogenic variants in the WT1 gene are associated with an increased risk for Wilms tumor. PubMed: 20301471; OMIM: 607102
BAP1 Heterozygous pathogenic variants in BAP1 are associated with BAP1 tumor predisposition syndrome (BAP1-TPDS). PubMed: 21874003, 23684012, 27748099, 28283772; OMIM: 614327
DICER1 Autosomal dominant mutations in DICER1 have been associated with DICER1 syndrome, a familial tumor susceptibility syndrome which includes susceptibility to many different kinds of tumors. PubMed: 24761742; OMIM: 606241
CDC73 Autosomal dominant pathogenic variants in CDC73 are associated with hyperparathyroidism-jaw tumor syndrome, which increases the risk for renal tumors (hamartomas, Wilms tumor), parathyroid tumors, and ossifying fibromas of the maxilla or mandible. PubMed: 27857527; OMIM: 607393
DIS3L2 Biallelic pathogenic variants in DIS3L2 are associated with Perlman syndrome, a congenital overgrowth syndrome associated with approximately a 30% risk to develop Wilms tumor. PubMed: 22306653, 20301471; OMIM: 614184
FLCN Autosomal dominant pathogenic variants in the FLCN gene have been associated with Birt-Hogg-Dube syndrome which is characterized by cutaneous manifestations, spontaneous pneumothorax and renal tumors, including renal cell carcinoma. PubMed: 20301695; OMIM: 607273
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