next gen sequencing finds BRCA1/BRCA2 mutations in “negative” #malebreastcancer patients

Retesting BRCA1/BRCA2 mutation negative male breast cancer patients using next generation sequencing technologies

Piera Rizzolo Valentina Silvestri and Laura Ottini

Breast Cancer Res Treat DOI 10.1007/s10549-017-4108-9


BRCA1 and BRCA2 are well known, high penetrance familial cancer genes for breast cancer. For men, BRCA2 is the more common mutation, and when you inherit a mutated form of this gene, your risk of developing breast cancer rises significantly. Current data suggests that about 12% of male breast cancers show BRCA2 mutations, and about 1% show BRCA1 mutations.
Mutations in the BRCA genes are detected by a variety of laboratory tests. All of the common tests focus on the commonly known mutations in the BRCA genes and use approaches that are relatively fast and inexpensive to focus in on these. They include the Protein Truncation Test (many mutations cause genes to make proteins that are incomplete and so non-functional), and the Single-Strand Conformation Polymorphism and the Denaturing High-Performance Liquid Chromatography tests ( which both use the structure of DNA as a way to detect abnormalities).
One way to think about these tests is that they cover the common reasons for an inherited breast cancer that is due to that gene. They interrogate the mutational hotspots of the gene and in most cases that is sufficient to give you the answer.
Now, with Next Generation Sequencing (NGS) technologies it is becoming easier and more affordable to look at every single piece of the gene. This current study then looks to see if the current set of BRCA genetic tests missed any mutations that could be found with NGS.


The answer is yes. The authors did germline sequencing using NGS on 200 cases of male breast cancer and found 5 cases where mutations were present but had been missed by the conventional tests. One was in BRCA1 and four were in BRCA2. This represents an increase in the frequency of mutations by about 2 percent – not insignificant.
If this change in frequency is found across the board it might be more accurate to say that around 15% of male breast cancers have BRCA mutations.


As NGS becomes more and more affordable and available it is likely to replace other kinds of genetic tests, as ultimately it gives you a complete view of the gene’s sequence and so reduces, and perhaps eliminates, the chance of missing a mutation.
The authors suggest that breast cancer patients who have previously tested negative for mutations with the conventional tests might be considered for retesting with NGS, and I would agree that in cases where there is a family history of breast cancer, or perhaps any cancer, this is justified.

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