Unusual mutation in BRCA2 associated with high risk #malebreastcancer – a clue to its biology?

Identification of a new BRCA2 large genomic deletion associated with high risk male breast cancer

Timoteo AR, Albuquerque BM, Moura PC, Ramos CC, Agnez-Lima LF, Walsh T, King MC, Lajus TB

Hered Cancer Clin Pract. 2015 Jan 16;13(1):2. doi: 10.1186/s13053-014-0022-x. eCollection 2015


Mutation in certain genes is associated with predisposition to specific cancers. Germline mutations in BRCA1 and BRCA2 genes are associated with increased risk of breast and ovarian cancers, and there is a large literature describing families in which such mutations are inherited and where many members of the family have these cancers. Most famously, Angelina Jolie has shared that she has a familial BRCA1 mutation and has taken preventive measures to reduce her risk of getting breast and ovarian cancer.

Familial cancers are the minority of cancer cases, meaning that most cancers are due to mutations picked up during the person’s lifetime, rather inherited at birth from their parents. For the BRCA genes only about 6-7% of breast cancers and 10% of ovarian cancers are thought to be due to germline mutations. So this is a relatively rare scenario.

In the ~1% of breast cancers that are men, there are also some familial cases, of course, but these are a rare group within a rare group. Here BRCA2 mutations are more commonly found, for reasons that are not yet understood.

Then, when considering the types of mutations the BRCA genes suffer, the majority to date are so-called point mutations, which are changes in single letters of the genetic code. They lead to profound damage to the BRCA proteins that are made from these mutated genes – so called truncations. You can think of this as a letter in a very long sentence being mutated to a period, bringing it to a premature stop and truncating the meaning. However, very rarely other kinds of mutations are encountered. This paper is a case report about such a mutation.


This paper presents genomic analysis of the male breast cancer of a man who presented at age 64 in Brazil, and succumbed to his cancer about 5 years later. He was proband of a family with a lot of breast cancer – all of his 6 sisters had it, as well as his mother. Many male relatives had unknown cancers…

The family tree of the proband whose tumor was analyzed. (image from http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4308828/figure/Fig1/)

The family tree of the proband whose tumor was analyzed. (image from http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4308828/figure/Fig1/)

The interesting finding is that the BRCA2 gene in this individual – and perhaps in his family – had suffered a large genomic deletion, rather than a point mutation. This is a novel observation, and a rare one given that familial cancer are rare and male breast cancer is rare.


The observation itself is of value, given that it is new, but I think it goes beyond this and further exploration is warranted.

First, while the effect on the BRCA2 protein is probably quite similar to a truncating point mutation (the protein is incomplete and so non-functional and probably unstable also), the way the mutation occurred is probably biologically quite different. The mechanisms that prevent and corrected point mutations and large deletions are different, and so understanding this might be of interest in understanding why BRCA genes favor one kind of defect over the other. (Other genes associated with familial cancers – tumor suppressor genes – show different mutational patterns.)

More interesting still, potentially, is the observation that in addition to the proband’s 6 sisters having breast cancers 4 of his 5 brothers died of “unknown” cancers. If these were all breast cancer, then the penetrance of this mutation into the male side of the family appears unusually high to me. If true, then perhaps there is something unusual about this mutation that could provide clues on the male disease, which as the authors state in their introduction is incompletely understood. More research on male breast cancer is needed.

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