Several known breast cancer susceptibility genes encode proteins
involved in DNA damage response (DDR) and are characterized by rare
loss-of-function mutations. However, these explain less than half of the
familial cases. To identify novel susceptibility factors, 39 rare
truncating mutations, identified in 189 Northern Finnish hereditary
breast cancer patients in parallel sequencing of 796 DDR genes, were
studied for disease association. Mutation screening was performed for
Northern Finnish breast cancer cases (n = 578–1565) and controls
(n = 337–1228). Mutations showing potential cancer association were
analyzed in additional Finnish cohorts. c.7253dupT in TEX15, encoding a DDR factor important in meiosis, associated with hereditary breast cancer (p = 0.018)
and likely represents a Northern Finnish founder mutation. A
deleterious c.2715 + 1G > A mutation in the Fanconi anemia gene, FANCD2, was over two times more common in the combined Finnish hereditary cohort compared to controls. A deletion (c.640_644del5) in RNF168,
causative for recessive RIDDLE syndrome, had high prevalence in
majority of the analyzed cohorts, but did not associate with breast
cancer. In conclusion, truncating variants in TEX15 and FANCD2
are potential breast cancer risk factors, warranting further
investigations in other populations. Furthermore, high frequency of RNF168 c.640_644del5 indicates the need for its testing in Finnish patients with RIDDLE syndrome symptoms.