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Comprehensive COLARIS AP®
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 APC or MYH. The cause of the pattern of cancer in the patient and the family is still undetermined.
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COLARIS AP® No Mutation Detected or Favor Polymorphism
There are three possible explanations for a no mutation detected result from Comprehensive COLARIS AP®. For an individual patient, you should consider which is most likely by reviewing the patient's personal and family histories of cancer, and considering the pre-test probability of detecting a mutation in APC or MYH.
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The cancer history in the patient or relative(s) is due to a mutation in a different gene. Mutations in APC or MYH are responsible for the majority of cases of adenomatous polyposis. As such, there are likely to be other genes identified that are less commonly associated with this condition. Although the chances that the patient has an adenomatous polyposis syndrome have been decreased significantly, the diagnosis has not been ruled out. Therefore, your patient's personal and/or family histories of cancer should be re-evaluated to determine the level of suspicion of an undetected mutation and for consideration of further genetic evaluation.
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 colorectal polyps and gastrointestinal cancer. Some are listed below. For more detailed information about these syndromes, please visit www.genetests.org or http://www3.ncbi.nlm.nih.gov/entrez/query.fcgi?db=OMIM.
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Hereditary nonpolyposis colorectal cancer (HNPCC or Lynch Syndrome) is an autosomal dominant disorder characterized by a significantly increased risk of colorectal, endometrial, ovarian, and gastric cancers. The majority of genetically characterized HNPCC is due to mutations in the MLH1, MSH2, or MSH6 genes. Other genes, such as PMS2, are less commonly involved.
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Turcot syndrome is an autosomal dominant disorder associated with colon cancer and CNS tumors, usually medulloblastoma. Two-thirds of persons with Turcot syndrome have a mutation in the APC gene, and one-third have mutations in one of the genes that cause hereditary non-polyposis colon cancer (HNPCC) The CNS tumors in individuals with HNPCC are usually glioblastoma multiforme.
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Peutz-Jeghers syndrome is an autosomal dominant disorder characterized by the development of hamartomatous polyps throughout the GI tract, mucocutaneous hyperpigmentation, and an increased risk of GI malignancy, as well as cancers of the breast and ovary. Approximately 70% of families meeting the clinical criteria for Peutz Jeghers syndrome have a detectable mutation in the STK11 gene.
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Cowden syndrome is an autosomal dominant disorder characterized by the development of multiple hamartomas, a high risk of benign and malignant tumors of the breast, thyroid, and endometrium, and particular physical manifestations. Most patients meeting the clinical criteria for Cowden syndrome have a detectable mutation in the PTEN gene.
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Juvenile polyposis syndrome (JPS) is an autosomal dominant disorder characterized by the development of hamartomatous polyps in the gastrointestinal (GI) tract, specifically in the stomach, small intestine, colon, and rectum. JPS is diagnosed if any one of the following is present: more than five juvenile polyps of the colorectum OR multiple juvenile polyps throughout the GI tract OR any number of juvenile polyps and a family history of juvenile polyps.
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Hereditary mixed polyposis syndrome is characterized by atypical juvenile polyps, polyps containing mixed histology, or multiple polyps of more than one histologic type in an individual. The mode of inheritance is unknown at this time.
It is possible that the clustering of polyposis and/or colorectal cancers in some families is due to the effect of genetic variants in numerous low-penetrant genes and/or environmental exposures, which moderately increase adenoma and cancer risk. At the present time, genetic testing for these low-penetrant alleles is not clinically available.
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The adenoma and/or 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.
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APC or MYH mutation(s) is present, but was not detected by the current laboratory methods. Currently, Comprehensive COLARIS AP® includes full sequence analysis and large rearrangement analysis of the APC gene. The MYH gene is analyzed for the two most common mutations in patients with European ancestry (Y165C and G382D). It has been suggested that in some cases, especially if the patient is not of European ancestry, there could be other MYH mutations outside of the two analyzed by Comprehensive COLARIS AP®. Additionally, in rare cases, there could be mutations in regions of the APC or MYH genes that were not sequenced. Therefore, although the chances that the patient has a hereditary adenomatous polyposis syndrome have been decreased significantly, the diagnosis has not been ruled out. In this case, the patient's personal and/or family history of cancer should be evaluated to determine the level of suspicion of an undetected mutation and for consideration of further genetic evaluation.
If a patient is affected with cancer and/or adenomas and receives a no mutation detected result, it may be worthwhile for another affected family member to undergo Comprehensive COLARIS AP®. It is possible that a mutation(s) responsible for an adenomatous polyposis syndrome 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 colorectal 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 adenomatous polyposis syndromes.
If a patient who has NOT had cancer or polyposis receives a no mutation detected result, the most closely related affected family member should undergo Comprehensive COLARIS AP®. It is most informative to first test a family member who has had a cancer and/or polyposis in order to determine if the cancers/adenomas in the family are due to a detectable mutation(s) in APC or MYH. Without knowing if the cancers in the family are due to a detectable mutation(s) in APC or MYH, a no mutation detected result in an unaffected patient is inconclusive and cannot rule out FAP/AFAP or MAP. The cancers in the unaffected patient's family may not be due to an APC or MYH mutation(s), in which case cancer risk must be estimated based on the strength of the personal and/or family history of polyposis and cancer. In contrast, if an affected relative tests positive for a deleterious mutation(s) in APC or MYH, the unaffected patient's no mutation detected result can then be interpreted to mean that the patient has the same risk of cancer as the general population.
Medical Management Recommendations
When the results of Comprehensive COLARIS AP® indicate no mutation detected, the patient's risk of cancer and recommendations for medical management must be based on the personal and family history of cancer. For more information on this topic, please click here for details on this concept and case examples to illustrate important points.
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