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Melanoma Comprehensive Panel

Diseases Targeted:

Melanoma

Overview:

The Melanoma Comprehensive Panel examines 14 genes associated with an increased risk for melanoma. This test includes both well-established melanoma susceptibility genes, as well as candidate genes with limited evidence of an association.

Who is this test for?

Patients with a personal or family history suggestive of a hereditary melanoma syndrome. 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. The presence of more than one melanoma in first or second degree relatives, as well as the presence of astrocytoma or breast, colon, ovarian, pancreatic or prostate cancer in a patient’s clinical or family history indicate that genetic testing for a hereditary melanoma syndrome may be warranted (PubMed: 28283772). After consideration of a patient’s clinical and family history, this testing may be appropriate for some pediatric patients as preventative steps may be warranted in childhood. (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?

Highly penetrant genes are responsible for approximately 45% of familial melanoma cases, with the remainder likely influenced by lower penetrant genes and environmental or other risk factors (PubMed: 28283772). Patients identified with a hereditary melanoma syndrome 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, BRCA2, CDK4, CDKN2A, CHEK2, MC1R, MITF, MUTYH, POT1, PTEN, RB1, SLC45A2, TP53, TYR ( 14 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
BRCA2 Autosomal dominant mutations in the BRCA2 gene are implicated in the hereditary breast and ovarian cancer syndrome (HBOC). Additionally, biallelic mutations in BRCA2 gene are associated with autosomal recessive Fanconi anemia Type D1 . Some studies have shown that heterozygous pathogenic BRCA2 variants may be associated with an increased risk for both ocular and cutaneous melanoma. PubMed: 22187320, 12065746, 12677558, 9497246, 17416853, 18042939, 20301425, 22846731
CDK4 Heterozygous pathogenic CDK4 variants are associated with an increased risk for melanoma and possibly for pancreatic cancer, as well. PubMed: 28283772, 26337759, 17047042
CDKN2A Heterozygous pathogenic CDKN2A variants are associated with an increased risk for hereditary melanoma and familial atypical multiple mole melanoma-pancreatic carcinoma (FAMMPC) syndrome. PubMed: 28283772, 26337759, 21249757, 19260062; OMIM: 600160
MITF Heterozygous pathogenic variants in MITF are associated with an increased risk for melanoma, and possibly renal cell carcinoma and others. PubMed: 22012259, 26337759, 28283772
PTEN Autosomal dominant mutations in PTEN have been associated with Cowden syndrome, which is associated with a 5% lifetime risk of melanoma, as well as other clinical findings. PubMed: 20301661; OMIM: 601728
RB1 Heterozygous and biallelic pathogenic variants in RB1 are association with an increased risk for retinoblastoma, melanoma, and osteo- and soft tissue sarcomas. Individuals with biallelic variants are more severely affected than those who are heterozygous. PubMed: 20301625
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
BAP1 Heterozygous pathogenic variants in BAP1 are associated with BAP1 tumor predisposition syndrome (BAP1-TPDS). PubMed: 21874003, 23684012, 27748099, 28283772; OMIM: 614327
CHEK2 Heterozygous pathogenic variants in CHEK2 are associated with an increased risk for melanoma, as well as other CHEK-2 related cancers. PubMed: 21956126,16998506, 18172190, 21876083, 27595995, 15492928, 11719428, 20597917, 21807500, 21876083, 21956126, 23713947, 23296741, 24240112, 24599715, 24879340, 25431674, 28283864
POT1 Autosomal dominant pathogenic variants in POT1 has been associated with an increased risk for melanoma and gliomas PubMed: 26337759, 28283772, 25482530, 24686846, 27528712, 24686849; OMIM: 606478
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