Hereditary Melanoma Panel, Sequencing and Deletion/Duplication

Last Literature Review: December 2022 Last Update:

To compare directly to other hereditary cancer panels offered by ARUP Laboratories, refer to the ARUP Hereditary Cancer Panel Comparison table.

  • Recommended test to confirm a hereditary cause of melanoma in individuals with a personal or family history of melanoma
  • Testing minors for adult-onset conditions is not recommended; testing will not be performed in minors without prior approval. For additional information, please contact an ARUP genetic counselor at 800-242-2787 ext. 2141.

If a familial sequence variant has been previously identified, targeted sequencing for that variant may be appropriate; refer to the Laboratory Test Directory for additional information.

Pathogenic germline variants in multiple genes have been implicated in hereditary melanoma. Hereditary melanoma is usually characterized by an early age of cancer onset (typically before age 50), multiple primary melanomas, internal organ malignancies, and/or similar cancers in one or more closely related family members.



Refer to the Genes Tested table for genes included in the panel.


Less than 10% of melanoma is associated with a hereditary cause.


  • Typically autosomal dominant (AD)
  • Some genes are associated with an autosomal recessive (AR) transmission

Test Interpretation

Contraindications for Ordering

  • This test should not be ordered to detect somatic variants associated with malignancy because sensitivity for mosaic variants is low with the 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 cultured fibroblasts is required for the accurate interpretation of test results.


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 the 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.
  • Bidirectional Sanger sequencing is performed on the following gene and exon:
    • PTEN (NM_000314) 9


Clinical Sensitivity

  • Pathogenic variants in the CDKN2A gene are identified in 20-40% of families affected by hereditary melanoma. 
  • The prevalence of other gene variants in hereditary melanoma is uncertain.

Analytic Sensitivity

Variant Class Analytic Sensitivity (PPA) Estimatea (%) and 95% Credibility Region (%) Analytic Specificity (NPA) Estimate (%)


>99 (96.9-99.4)


Deletions 1-10 bpb

93.8 (84.3-98.2)


Insertions 1-10 bpb

94.8 (86.8-98.5)


Exon-levelc deletions

97.8 (90.3-99.8) [2 exons or larger]

62.5 (38.3-82.6) [single exon]


Exon-levelc duplications

83.3 (56.4-96.4) [3 exons or larger]


aPPA values are derived from larger methods-based MPS and/or Sanger validations. These values do not apply to testing performed by MLPA unless otherwise indicated.

bVariants greater than 10 bp may be detected, but the analytic sensitivity may be reduced.

cIn most cases, a single exon deletion or duplication is less than 450 bp, and 3 exons span a genomic region larger than 700 bp.

bp, base pairs; MLPA, multiplex ligation-dependent probe amplification; NPA, negative percent agreement; PPA, positive percent agreement; SNVs, single nucleotide variants


  • A negative result does not exclude a heritable form of melanoma or another cancer.
  • Diagnostic errors can occur due to rare sequence variations.
  • The interpretation of this test result may be impacted if this patient has had an allogeneic stem cell transplantation.
  • The following will not be evaluated:
    • Variants outside the coding regions and intron-exon boundaries of targeted gene(s)
    • Regulatory region and deep intronic variants
    • Breakpoints of large deletions/duplications
    • The following exons are not sequenced due to technical limitations of the assay:
      • MITF (NM_001354607) exon 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
    • Low-level somatic variants
    • Certain other variants due to technical limitations in the presence of pseudogenes and/or repetitive/homologous regions
    • The following regions may have reduced sequencing sensitivity due to technical limitations of the assay:
      • RB1 (NM_000321) exon 22
    • Deletions/duplications in the following exons:
      • CDKN2A (NM_000077, NM_001195132, NM_001363763, NM_058195) 2
      • MITF (NM_001354607) 2
      • PTEN (NM_000314, NM_001304718) 9
      • PTEN (NM_001304717) 1,10
      • RB1 (NM_000321) 22

Genes Tested

To compare directly to other hereditary cancer panels offered by ARUP Laboratories, refer to the ARUP Hereditary Cancer Panel Comparison table.

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




BAP1-inactivated melanocytic tumors, basal cell carcinoma, cutaneous melanoma, malignant mesothelioma, renal cell carcinoma, uveal melanoma




HBOC syndrome

Breast, fallopian tube, melanoma, ovarian, pancreatic, peritoneal, prostate


Fanconi anemia, complementation group D1




Cutaneous melanoma, pancreatica




FAMMM syndrome (also known as melanoma-pancreatic cancer syndrome)

Cutaneous melanoma, pancreatic




Cutaneous melanomaa




Waardenburg syndrome type II

Cutaneous melanoma




POT1 tumor predisposition syndrome

Angiosarcoma, chronic lymphocytic leukemia, cutaneous melanoma, glioma




Cowden syndrome/PTEN hamartoma tumor syndrome

Breast, colorectal, endometrial, Lhermitte-Duclos disease (cerebellar dysplastic gangliocytoma), melanoma,a renal cell carcinoma, thyroid, and others




Hereditary retinoblastoma

Melanoma,a osteosarcoma, pineoblastoma, retinoblastoma, retinoma, soft tissue sarcoma




Dyskeratosis congenita

Acute myelogenous leukemia, melanoma,a pulmonary fibrosis

AD and AR




Adrenocortical carcinoma, breast, choroid plexus carcinoma, CNS, colorectal, melanoma, osteosarcoma, pancreas, prostate, renal, rhabdomyosarcoma, soft tissue sarcoma, stomach, thyroid, and others


aAssociation is suggested but not well-established at this time.

BAP1-TPDS, BAP1 tumor predisposition syndrome; CNS, central nervous system; FAMMM, familial atypical multiple mole melanoma; HBOC, hereditary breast and ovarian cancer; LFS, Li-Fraumeni syndrome