(HealthDay News) — A considerable number of women testing negative for BRCA1/2 may have pathogenic mutations in other genes, according to a study published online April 14 in the Journal of Clinical Oncology.

Allison W. Kurian, MD, from the Stanford University School of Medicine in California, and colleagues investigated the performance of a customized germline-DNA sequencing panel for cancer-risk assessment. DNA was extracted from samples taken from patients referred for clinical BRCA1/2 testing from 2000 to 2012 and frozen at −80 degrees Celsius. 

The entire coding regions, exon-intron boundaries, and pathogenic variants in other regions were sequenced for 42 genes with known cancer risk associations in samples from 198 women, including 174 with breast cancer. Fifty-seven of the women harbored germline BRCA1/2 mutations.

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The researchers observed full concordance for BRCA1/2 analysis with prior testing. Among 141 women without BRCA1/2 mutations, 16 pathogenic variants (11.4%) were identified in nine genes (ATM, BLM, CDH1, CDKN2A, MUTYH, MLH1, NBN, PRSS1, and SLX4). 

Fifteen pathogenic variants identified in 14 participants warranted a potential change in care; these participants were invited for targeted screening recommendations, facilitating colonoscopy-based early detection and removal of a tubular adenoma. 

On average, among the 42 genes, participants carried 2.1 variants of unknown significance.

“Our study demonstrates an early signal for the clinical relevance of multiple-gene sequencing and provides a strong rationale for future research to define its most effective use,” the researchers wrote.

Several authors disclosed financial ties to the biotechnology industry.


  1. Kurian AW, Hare EE, Mills MA, et al. Clinical Evaluation of a Multiple-Gene Sequencing Panel for Hereditary Cancer Risk Assessment. J Clin Oncol. 2014;doi: 10.1200/JCO.2013.53.6607.