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Breast Cancer Patients Referred for Genetic Testing Likely to Have Mutations Other Than BRCA1/2

Sandra Hanner
Published Online: 4:51 PM, Wed January 21, 2015

Lavania Sharma

In an analysis of more than 17,000 patients with breast cancer, who are at risk for a genetic mutation, subjects were as likely to have a mutation in a gene other than BRCA1 and BRCA2 as they were to have these common mutations, researchers reported at the 2014 San Antonio Breast Cancer Symposium.

This means that a relevant genetic mutation could have been missed in about half the patients referred for genetic testing, had they undergone a single-syndrome test rather than the 25-gene panel test that was used on the samples in this study, said Lavania Sharma, who holds a Masters of Science degree in Genetic Counseling and who works for Myriad Genetic Laboratories in Salt Lake City, Utah.

“Obviously, when we think of breast cancer we have historically thought of BRCA1 and BRCA2 mutations. But this year at San Antonio, there is a lot of focus on other genes that also increase breast cancer risk,” Sharma said in an interview.

Testing patients with a personal history of breast cancer using a 25-gene panel identified 51.1% of mutations in genes other than BRCA1 and BRCA2, and this represents an increase of 104.5% in mutations identified by single-syndrome testing, she reported at the meeting.

“That’s a lot of patients, when you think about how to care for them and their families,” she said.

Interesting Findings From the 25-Gene Panel

The purpose of the analysis presented by Sharma was to determine the spectrum of mutations harbored by patients with a personal history of breast cancer. Sharma et al analyzed the Myriad commercial database of 17,142 patients who underwent 25-gene hereditary cancer panel testing between September 2013 and November 2014.

Results revealed that 1608 (9.5%) of females and 32 (16.2%) of males were positive for at least one deleterious or suspected deleterious mutation. Interestingly, among these mutations:
  • 48.9% were detected in the Hereditary Breast and Ovarian Cancer (HBOC) genes BRCA1 and BRCA2.
  • 42.1% were detected in other genes associated with breast cancer.
  • 6.6% were detected in Lynch syndrome genes (MLH1, MSH2, MSH6, PMS2, EPCAM).
  • 2.3% were detected in other genes not associated with breast cancer (APC, MUTYH, RAD51D, CDKN2A, SMAD4).
“We had an almost 50/50 distribution between genes that were positive for BRCA1/2 and for other breast cancer genes. If we had not tested these women in the 25-gene panel, about 50% of them would have been missed,” she noted.

“Also, around 9% had genes not associated with breast cancer at all but with significant other cancer risks,” she added. These were primarily genes related to colorectal cancer risk (Lynch syndrome genes and APC) that would have been missed in a breast cancer-specific panel. The most common mutations were in PMS2 and MSH6.

This has significance for preventing these other cancers, both in the patient and the extended family. “If you have a mutation in, say, a Lynch syndrome gene, an immediate colonoscopy might be warranted,” she said.

The assay also identified 45 patients with 2 mutations; BRCA1/2 accounted for at least one of these in 31 patients.

Age at Diagnosis

The majority of patients were diagnosed between the ages of 40 and 59 years. Most mutation-positive patients who were diagnosed with breast cancer before age 40 were identified as having a mutation in BRCA1 or BRCA2. But patients diagnosed between ages 40 and 59 years had similar likelihoods of having a mutation in these or in one of the 10 other breast cancer-predisposing genes on the panel.

Patients diagnosed past the age of 60 were more likely to have mutations in genes other than BRCA1 and BRCA2, ie, the moderate-penetrance genes, she said.

“Age itself is not a predictor for single-syndrome or panel testing,” Sharma indicated.

Need for Genetic Counseling

Sharma emphasized the value of genetic counseling for individuals found to carry a cancer-related mutation. Clinicians should be cognizant of any genetic counselors in their area to whom they can refer patients; lacking those, they can call Myriad and speak to a genetic counselor, she said.

“I speak with lots of physicians who have patients with strong family histories,” she said. “Genetic counselors are often now in academic centers, but they can’t be everywhere. We are there to help them.”


  1. Sharma L, Evans B, Abernethy J et al. Spectrum of mutations identified in a 25-gene hereditary cancer panel for patients with breast cancer. 2014 San Antonio Breast Cancer Symposium. Abstract P4-12-02. December 12, 2014.

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