Comprehensive BRACAnalysis^®
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 BRCA1 or BRCA2. The cause of the pattern of cancer in the patient and the family is still undetermined.

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BRACAnalysis^® No Mutation Detected or Favor Polymorphism

There are three possible explanations for a no mutation detected result from Comprehensive BRACAnalysis^®. 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 BRCA1 or BRCA2.

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. A BRCA1 or BRCA2 mutation is present, but current technology is not able to detect such a change. Currently, Comprehensive BRACAnalysis^® includes full sequence analysis of BRCA1 and BRCA2 , and analysis of five specific large rearrangements in the BRCA1 gene. Large rearrangements other than the five that are currently analyzed will NOT be detected by Comprehensive BRACAnalysis^®. The proportion of clinically significant defects in BRCA1 and BRCA2 attributable to undetected genomic rearrangements is estimated to be 3-4% (Myriad Genetic Laboratories unpublished data). The patient's personal and/or family histories of cancer should be evaluated, to determine the level of suspicion of an undetected mutation.

3. The cancer history in the patient or relative(s) is due to a mutation in a different gene. Mutations in BRCA1 or BRCA2 are responsible for the majority of families with a strong history of early-onset breast cancer AND ovarian cancer. Among families with a clustering of only breast cancer, a smaller, but still significant, proportion is due to a BRCA1 or BRCA2 mutation. Other genes for breast and ovarian cancer susceptibility remain the subject of research, but are not available for testing at this time.
   
   If other specific cancers or clinical findings are present in the patient or family, consideration of a less common hereditary cancer syndrome may be warranted. Syndromes that include an increased risk of breast cancer and/or ovarian cancer are listed below. For more detailed information about these syndromes, please visit www.genetests.org.

• Cowden Syndrome - 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.

• 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.

• Peutz Jeghers Syndrome - 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.

• Hereditary Non-Polyposis Colorectal Cancer (HNPCC or Lynch Syndrome) - HNPCC 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.

It is likely that the clustering of breast cancer 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.

If a patient is affected with breast cancer or ovarian cancer and receives a no mutation detected result, it may be worthwhile for another family member to undergo Comprehensive BRACAnalysis^®. 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 breast 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 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 BRACAnalysis^®. It is most informative to first test a family member who has had breast cancer at a young age or ovarian cancer, in order to determine if the cancers in the family are due to a detectable mutation in BRCA1 or BRCA2. Without knowing if the cancers in the family are due to a detectable mutation in BRCA1 or BRCA2, 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 BRCA1 or BRCA2 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 BRCA1 or BRCA2, the unaffected patient's no mutation detected result can then be interpreted to mean that she has the same risk of breast and ovarian cancers as the general population.

Medical Management Recommendations

When the results of Comprehensive BRACAnalysis^® 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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