'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.'

"We know abnormalities exist, we know that there are tests that can pick them up ... we need a better way of getting this knowledge from the bench to the bedside," said Len Lichtenfeld, deputy chief medical officer for the American Cancer Society, which was not involved in the study.

About 5 percent to 10 percent of breast cancers are caused by inherited mutations in a single gene. Women with mutations in BRCA1 or BRCA2 have about an 80 percent chance of getting breast cancer in their lifetimes.

The study, which is published Wednesday in the Journal of the American Medical Association, analyzed genetic material from 300 women with at least four cases of female breast cancer, ovarian cancer and/or male breast cancer in their family. All of the women tested negative for mutations in their BRCA genes.

Using a highly specific technique known as MLPA, the researchers found that the genes of 52 women were mutated, including 35 who had changes on their BRCA gene.

Other Approaches Available

"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," write the authors, a team of international researchers. "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."

However, the MLPA test is not clinically available in the United States.

"I suspect that there will be a significant interest in getting better tests into the mainstream," Lichtenfeld said.

Traditionally, genetic testing has proved most reliable for Jewish women of Eastern European heritage. And the best candidate for a test is a family member who already has cancer. That way clinicians are more likely to pinpoint any mutations in a culprit gene.

Prophylactic Mastectomy

The decision on how to best treat women with strong family histories, but negative genetic tests for mutations has always been difficult.

Typically patients are offered several options, including careful monitoring, a preventive mastectomy to remove a healthy breast, or medication such as tamoxifen, which blocks the effects of estrogen, a hormone that can fuel rapid cell growth and certain cancers.

Studies have found that prophylactic mastectomy reduces the risk of cancer, though studies involving tamoxifen for prevention are less clear.

"Even though the breast cancer is not genetic, they clearly are at risk," said Julia White, an associate professor of radiation oncology at the Medical College of Wisconsin who practices at Froedtert Memorial Lutheran Hospital.

"We all would like to have blood tests before recommending treatment, but this study tells us that there will always be genetic mutations that we don't know about," said White, who wasn't involved in the study.

Amy Stettner, a clinical genetic counselor at the University of Wisconsin Medical School in Madison, said negative test results in the face of a strong family history has always been "frustrating."

"You scratch your head and wonder, 'Did I test the wrong person in the family? Does this person have breast cancer?'" she said. "Usually we're sort of left with a negative result and not knowing where to go from there."