Mutations in several genes, including components of the Fanconi anemia DNA repair pathway, have been implicated in familial breast cancer risk, but much of the underlying genetic architecture remains unknown. A study by Heli Nevanlinna and colleagues (Proc. Natl. Acad. Sci. USA doi:10.1073/pnas.1407909111; 6 October 2014) now reports the discovery of an association between a variant in FANCM and breast cancer risk in the Finnish population. To identify new susceptibility genes, the authors performed exome sequencing on 24 patients with breast cancer from 11 Finnish families without mutations in BRCA1 or BRCA2. After applying several filters, they further prioritized variants in DNA repair genes and genotyped the most promising candidate risk variants in two large collections of breast cancer cases and controls from the Helsinki and Tampere regions of Finland. In a combined analysis of all data sets, they identified a nonsense variant in FANCM (encoding p.Gln1701*) that was associated with a two-fold increase in risk of breast cancer (P = 0.0018). This variant shows strongest association with triple-negative breast cancer and is present at a frequency of 1–2% in the Finnish population. Although the variant is rare in other populations, this finding suggests that distinct FANCM variants might contribute to breast cancer risk in different populations.
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Vogan, K. FANCM and breast cancer risk. Nat Genet 46, 1159 (2014). https://doi.org/10.1038/ng.3132