Comprehensive COLARIS^® and MSH6 Analysis
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 MLH1, MSH2 or MSH6. The cause of the pattern of cancer in the patient and the family is still undetermined.

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COLARIS^® No Mutation Detected or Favor Polymorphism

There are three possible explanations for a no mutation detected result after both Comprehensive COLARIS^® and Reflex MSH6 Analysis have been completed. 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 MLH1, MSH2 or MSH6.

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.
   
   
2. The cancer history in the patient or relative(s) is due to a mutation in a different gene. Mutations in MLH1, MSH2 or MSH6 are responsible for the majority of families with HNPCC. Currently, approximately 90-95% of genetically characterized cases of HNPCC are caused by mutations in MLH1, MSH2 or MSH6. As such, there are other genes that less commonly cause HNPCC. For example, rarely, mutations in the PMS2 gene are found in patients at-risk for HNPCC. Therefore, your patient's personal and/or family history of cancer should be re-evaluated to determine the level of suspicion of an undetected mutation and for consideration of further evaluation of these genes or other genes.
   
   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, endometrial, gastric, or other HNPCC-associated cancers. 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.
   
   •  Attenuated familial adenomatous polyposis (AFAP) is an autosomal dominant disorder characterized by fewer polyps and later age of onset than classic FAP

   •  The I1307K mutation of the APC gene.  This APC missense mutation is not associated with the classic FAP phenotype; however, individuals with this mutation have approximately a twofold increased risk for colon cancer. This mutation is associated with Ashkenazi Jewish ancestry. Approximately 6% of the Ashkenazi have this mutation.

   •  MYH -associated polyposis is an autosomal recessive disorder characterized by multiple adenomatous polyps. The highest prevalence of mutations has been found in individuals with 15-100 polyps, with approximately 30% of these individuals having biallelic MYH mutations.

   •  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. 

   •  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.

   •  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.

   •  Hereditary diffuse gastric cancer (HDGC) is an autosomal dominant disorder characterized by gastric cancers, typically adenocarcinoma, caused by alterations in the CDH1 gene.
   
   It is likely that the clustering of HNPCC-associated cancers in many families is due to the effect of genetic variants in numerous low-penetrance genes, which moderately increase cancer risk. At the present time, genetic testing for low-penetrance alleles is not clinically available.
   

3. An MLH1, MSH2 or MSH6 mutation is present, but was missed by the current laboratory technology. Currently, Comprehensive COLARIS^® includes full sequence and large rearrangement analysis of the MLH1 and MSH2 genes. MSH6 Analysis includes full sequence analysis of the MSH6 gene. Not every mutation in these genes will be identified. In rare cases, there could be mutations in regions of the genes that were not sequenced or epigenetic changes (e.g., promoter methylation) that could play a role. Therefore, although the chances that the patient has an MLH1, MSH2 or MSH6 mutation have been decreased significantly, the diagnosis of HNPCC 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. For example, tumor tissue analysis (i.e. microsatellite instability testing with immunohistochemistry of the HNPCC-related genes) might be helpful to determine whether or not there is expression of MLH1, MSH2 or MSH6. If there is a lack of expression of one of these genes, it is more likely that a mutation is present that current technology was unable to detect.

If a patient is affected with an HNPCC-associated cancer and receives a no mutation detected result, it may be worthwhile for another affected family member to undergo Comprehensive COLARIS^® and, if negative, Reflex MSH6 Analysis. It is possible that an MLH1, MSH2 or MSH6 mutation 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 HNPCC.

If a patient who has NOT had cancer receives a no mutation detected result, the most closely related affected family member should undergo Comprehensive COLARIS^® and, if negative, Reflex MSH6 Analysis. It is most informative to first test a family member who has had an HNPCC-associated cancer, in order to determine if the cancers in the family are due to a detectable mutation in MLH1, MSH2 or MSH6. Without knowing if the cancers in the family are due to a detectable mutation in MLH1, MSH2 or MSH6; a no mutation detected result in an unaffected patient is inconclusive and cannot rule out an increased risk of cancer. The cancers in the unaffected patient's family may not be due to an MLH1, MSH2 or MSH6 mutation, in which case cancer risk must be estimated based on the strength of the personal and/or family history. In contrast, if an affected relative tests positive for a deleterious mutation in MLH1, MSH2 or MSH6, the unaffected patient's no mutation detected result can then be interpreted to mean that she has the same risk of cancer as the general population.

Medical Management Recommendations

When the results of both Comprehensive COLARIS^® and Reflex MSH6 Analysis 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.