Public Release: 

US commercial genetic testing does not detect all cancer-associated mutations in certain genes

The JAMA Network Journals

Despite a negative (normal) genetic test for mutations in the BRCA1 and BRCA2 genes, about 12 percent of breast cancer patients from high-risk families carried previously undetected cancer-associated mutations, according to a study in the March 22/29 issue of JAMA, a theme issue on women's health.

Co-author Mary-Claire King, Ph.D., of the University of Washington, Seattle, presented the findings of the study today at a JAMA media briefing on women's health in New York.

Inherited mutations in BRCA1 and BRCA2 predispose to high risks of breast and ovarian cancer. Lifetime risks of breast cancer are as high as 80 percent among U.S. women with mutations in these genes, according to background information in the article. Risks for young women with inherited BRCA1 or BRCA2 mutations are particularly increased. Among white women in the U.S., 5 percent to 10 percent of breast cancer cases are due to inherited mutations in BRCA1 and BRCA2. Inherited mutations in other genes, including CHEK2, TP53 and PTEN, can also influence risk of breast cancer.

Clinical options for women at high genetic risk of breast cancer include screening starting at a young age, the use of highly sensitive detection methods, and prophylactic surgeries of the ovaries or breast. Because prophylactic surgeries, while highly effective in reducing risk, are also highly invasive, it is particularly important to distinguish mutation carriers from noncarriers with similarly severe family histories. Women with BRCA1 or BRCA2 mutations are possible candidates for such surgeries. Genetic testing to identify harmful BRCA1 and BRCA2 mutations in as-yet unaffected women with severe family histories of breast or ovarian cancer has become an integral part of clinical practice in many communities. To provide accurate and complete information to high-risk patients, it is critical to understand the implications of a negative test result.

Dr. King and colleagues conducted a study to determine the frequency and types of undetected cancer-predisposing mutations in BRCA1, BRCA2, CHEK2, TP53, and PTEN among patients with breast cancer from high-risk families (4 or more cases of breast or ovarian cancer) with negative results from commercial genetic testing of BRCA1 and BRCA2. Between 2002-2005, the researchers evaluated DNA and RNA samples from 300 breast cancer probands (initial member of a family to come under study) and used multiple different screening approaches to identify mutations of all genomic classes in BRCA1, BRCA2, CHEK2, TP53, and PTEN.

The researchers found that of the 300 probands, 52 (17 percent) carried previously undetected mutations, including 35 (12 percent) with genomic rearrangements of BRCA1 or BRCA2, 14 (5 percent) with CHEK2 mutations, and 3 (1 percent) with TP53 mutations. No inherited mutations were detected in PTEN. At BRCA1 and BRCA2, 22 different genomic rearrangements were found. Of these, 14 were not previously described and all were individually rare. Inherited rearrangements of BRCA1 were more frequent among probands diagnosed when younger than 40 years (16 percent) than among probands diagnosed when 40 years or older (6.5 percent).

"Women at high risk and their clinicians want accurate assessment of genetic risk prior to embarking on ... invasive and expensive risk management options. Our results suggest that genetic testing, as currently carried out in the United States, does not provide all available information to women at risk. Our data indicate that 12 percent of those from high-risk families with breast cancer and with negative (wild-type) commercial genetic test results for BRCA1 and BRCA2 nonetheless carry cancer-predisposing genomic deletions or duplications in one of these genes," the authors write.

"The clinical dilemma is what to offer to women with a high probability of carrying a mutation in BRCA1 or BRCA2 but with negative commercial test results. Technically, the answer is at hand. The mutations identified in our study that were missed by commercial testing are detectable using other approaches that are currently available," the researchers write. They add that for families testing negative (wild type) for BRCA1 and BRCA2 by conventional sequencing, multiplex ligation-dependent probe amplification (MLPA - a molecular method to detect genetic variation) followed by sequence confirmation of breakpoints in patients' genomic DNA is the current best choice for evaluating the wide range of genomic rearrangements in BRCA1 and BRCA2. Clinical testing using MLPA is currently not available in the U.S.

"As more breast cancer susceptibility genes of different penetrances are identified, clinicians will be increasingly challenged to offer the most appropriate genetic tests, to assist patients in interpreting the results, and to optimize risk reduction strategies," the authors conclude. "Effective methods for identifying these mutations should be made available to women at high risk."


(JAMA. 2006;295:1379-1388. Available pre-embargo to the media at

Editor's Note: For funding/support information, please see the JAMA article.

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