The Spectrum of FANCM Protein Truncating Variants in European Breast Cancer Cases

Abstract

Germline protein truncating variants (PTVs) in the FANCM gene have been associated with a 2-4-fold increased breast cancer risk in case-control studies conducted in different European populations. However, the distribution and the frequency of FANCM PTVs in Europe have never been investigated. In the present study, we collected the data of 114 European female breast cancer cases with FANCM PTVs ascertained in 20 centers from 13 European countries. We identified 27 different FANCM PTVs. The p.Gln1701* PTV is the most common PTV in Northern Europe with a maximum frequency in Finland and a lower relative frequency in Southern Europe. On the contrary, p.Arg1931* seems to be the most common PTV in Southern Europe. We also showed that p.Arg658*, the third most common PTV, is more frequent in Central Europe, and p.Gln498Thrfs*7 is probably a founder variant from Lithuania. Of the 23 rare or unique FANCM PTVs, 15 have not been previously reported. We provide here the initial spectrum of FANCM PTVs in European breast cancer cases.

Keywords: FANCM truncating variants; PTVs; breast cancer predisposition; breast cancer risk factors; mutation spectrum.

Figure 1

Distribution of the common and rare FANCM PTVs found in the 114 European female breast cancer probands. The common PTVs p.Gln498Thrfs*7, p.Arg658*, p.Gln1701*, and p.Arg1931* are indicated in black, green, orange, and red, respectively; the rare PTVs are indicated in light blue. Numbers of PTV carriers are reported according to their country of origin. The 26 PTV carriers from Germany are derived from previously published studies (Neidhardt et al., 21 probands [9]; Schubert et al., 5 probands [13]).