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ATM is generally described as a moderate‐risk breast cancer susceptibility gene. However, some of ATM variants might encounter higher risk. ATM c.7570G>C, p.Ala2524Pro, (rs769142993) is a pathogenic Finnish founder variant causative for recessively inherited ataxia‐telangiectasia. At cellular level, it has been reported to have a dominant‐negative effect. ATM c.7570G>C has recurrently been described in Finnish breast cancer families and unselected case cohorts collected from different parts of the country, but the rarity of the allele (MAF 0.0002772 in Finns) and lack of confirming segregation analyses have prevented any conclusive risk estimates. Here, we describe seven families from genetic counseling units with ATM c.7570G>C variant showing co‐segregation with breast cancer. Further analysis of the unselected breast cancer cohort from Northern Finland (n = 1822), a geographical region previously indicated to have enrichment of the variant, demonstrated that c.7570G>C significantly associates with breast cancer, and the risk is estimated as high (odds ratio [OR] = 8.5, 95% confidence interval [CI] = 1.04‐62.46, P =.018). Altogether, these results place ATM c.7570G>C variant among the high‐risk alleles for breast cancer, which should be taken into consideration in genetic counseling. [ABSTRACT FROM AUTHOR]

Several known breast cancer susceptibility genes with moderate‐to‐high risk alleles encode proteins involved in DNA damage response (DDR). As these explain less than half of the hereditary breast cancer cases, additional predisposing alleles are likely to be discovered. Many of the previous studies utilizing massive parallel sequencing have focused on the protein‐truncating variants, and the role of rare missense mutations has remained poorly addressed. To identify novel susceptibility factors, we have systematically analyzed the data from our parallel sequencing of 796 DDR genes in 189 Northern Finnish hereditary breast cancer patients for rare missense variants, predicted as deleterious. Thirty‐five variants were studied here for the disease association using Finnish breast cancer case (n = 492–2,035) and control (n = 277–1,539) cohorts. As a result, two missense variants in genes involved in DNA replication, RECQL p.I156M and POLG p.L392V, the former involving genomic and the latter mitochondrial DNA replication, showed significant association with risk of breast cancer. Rare RECQL p.I156M allele was observed in breast cancer cases only (6/1,946, 0.3%, p = 0.043), whereas POLG p.L392V was two times more frequent in breast cancer cases (53/2,238, 2.4%) compared to controls (18/1,539, 1.2%, OR = 2.1, 95% CI 1.2–3.5, p = 0.010). Based on the current genetic data, both RECQL p.I156M and POLG p.L392V represent novel breast cancer predisposing alleles. [ABSTRACT FROM AUTHOR]

Breast cancer (BC) is a heterogeneous disease, and different tumor characteristics and genetic variation may affect the clinical outcome. The FANCM c.5101C > T nonsense mutation in the Finnish population associates with increased risk of breast cancer, especially for triple-negative breast cancer patients. To investigate the association of the mutation with disease prognosis, we studied tumor phenotype, treatment outcome, and patient survival in 3,933 invasive breast cancer patients, including 101 FANCM c.5101C > T mutation carriers and 3,832 non-carriers. We also examined association of the mutation with nuclear immunohistochemical staining of DNA repair markers in 1,240 breast tumors. The FANCM c.5101C > T mutation associated with poor 10-year breast cancer-specific survival (hazard ratio (HR)=1.66, 95% confidence interval (CI) 1.09-2.52, p = 0.018), with a more pronounced survival effect among familial cases (HR = 2.93, 95% CI 1.5-5.76, p = 1.80 × 10−3). Poor disease outcome of the carriers was also found among the estrogen receptor (ER) positive subgroup of patients (HR = 1.8, 95% CI 1.09-2.98, p = 0.021). Reduced survival was seen especially among patients who had not received radiotherapy (HR = 3.43, 95% CI 1.6-7.34, p = 1.50 × 10−3) but not among radiotherapy treated patients (HR = 1.35, 95% CI 0.82-2.23, p = 0.237). Significant interaction was found between the mutation and radiotherapy ( p = 0.040). Immunohistochemical analyses show that c.5101C > T carriers have reduced PAR-activity. Our results suggest that FANCM c.5101C > T nonsense mutation carriers have a reduced breast cancer survival but postoperative radiotherapy may diminish this survival disadvantage. [ABSTRACT FROM AUTHOR]