Comprehensive MELARIS^®
NO MUTATION DETECTED

When a mutation has not been previously identified in the family, a no mutation detected result means that the current technology did not find a mutation in the p16 gene. The cause of the pattern of cancer in the patient and the family is still undetermined.

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MELARIS^® No Mutation Detected or Favor Polymorphism

There are three possible explanations for a no mutation detected result from Comprehensive MELARIS^®. For an individual patient, you should consider which is most likely by reviewing the patient's personal and family history of cancer, and considering the pre-test probability of detecting a mutation in p16.

1. The cancer history in the patient or relative may be due to the combined effects of chance, environmental factors, and lifestyle factors, as opposed to a mutation in a single gene. The following is a website listing several risk factors for melanoma:
   http://www.skincarephysicians.com/skincancernet/risk.html

2. The cancer history in the patient or relative(s) is due to a mutation in a different gene. Mutations in p16 account for the greatest known genetic cause of hereditary melanoma. However, there are other genes that have been identified in a few hereditary melanoma families (p14ARF and CDK4), and other suspected hereditary melanoma genes that have not yet been identified.
   
   If other specific cancers or clinical findings are present in the patient or family, consideration of a different hereditary cancer syndrome may be warranted. Several genetic syndromes include an increased risk of melanoma and/or pancreatic cancer. Some are listed below. For more detailed information about these syndromes, please visit www.genetests.org.

   • Hereditary Breast/Ovarian Cancer Syndrome - Hereditary Breast/Ovarian Cancer syndrome is an autosomal dominant disorder characterized by a significantly increased risk for breast and ovarian cancer. The majority of hereditary breast/ovarian cancer syndrome is due to mutations in the BRCA1 and BRCA2 genes. Increased risks for pancreatic cancer and melanoma have been described in some patients.

   • Li-Fraumeni Syndrome - Li-Fraumeni syndrome is an autosomal dominant disorder characterized by a predisposition to several cancers, including childhood cancers, soft-tissue sarcoma, breast cancer, leukemia, osteosarcoma, melanoma, and cancer of the colon, pancreas, adrenal cortex, and brain. More than 50% of patients meeting the clinical criteria for Li Fraumeni syndrome have a detectable mutation in the p53 gene.

   • Von Hippel Lindau - Von Hippel-Lindau syndrome (VHL syndrome) is an autosomal dominant disorder characterized by hemangioblastomas of the brain, spinal cord, and retina; renal cysts and clear cell renal cell carcinoma; pheochromocytoma; and endolymphatic sac tumors. Pancreatic cysts are seen in VHL, and rarely neuroendocrine tumors develop in the pancreas that have malignant potential. VHL is caused by mutations in the VHL gene.

3. A p16 mutation is present, but was missed by the current laboratory technology. Currently, Comprehensive MELARIS^® includes full sequence analysis of the p16 gene. Not every mutation in p16 will be identified (i.e. large genomic rearrangements, promoter mutations, etc). It is not currently known what percentage of p16 mutations are undetectable by sequence analysis. The patient's personal and/or family histories of cancer should be evaluated to determine the level of suspicion of an undetected mutation.

If a patient is affected with melanoma or pancreatic cancer and receives a no mutation detected result, it may be worthwhile for another affected family member to undergo Comprehensive MELARIS^®. It is possible that a mutation responsible for hereditary cancer is present in the family, but that the patient tested did not inherit it. This possibility is more likely if the patient was diagnosed with cancer at a later age than is typical for hereditary cancer, or if the patient had a type of cancer that is not characteristic of the hereditary cancer syndrome for which he/she was tested.

If a patient who has NOT had cancer receives a no mutation detected result, the most closely related affected family member should undergo Comprehensive MELARIS^®. It is most informative to first test a family member who has had melanoma or pancreatic cancer in order to determine if the cancers in the family are due to a detectable mutation in p16. Without knowing if the cancers in the family are due to a detectable mutation in p16, a no mutation detected result in an unaffected patient cannot rule out an increased risk of cancer. The cancers in the unaffected patient's family may not be due to a p16 mutation, in which case cancer risk must be estimated based on the strength of the family history. In contrast, if an affected relative tests positive for a deleterious mutation in p16, the unaffected patient's no mutation detected result can then be interpreted to mean that the patient is not at hereditary risk for melanoma or pancreatic cancer.

Medical Management Recommendations

When the results of Comprehensive MELARIS^® indicate no mutation detected, the patient's risk of cancer and recommendations for medical management must be based on personal and family history of cancer. Please click here for more details on this concept and case examples to illustrate important points.

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