Graphical Abstract Highlights d Biallelic germline NTHL1 mutations predispose to a multitumor syndrome d Biallelic germline NTHL1 mutation carriers are at risk for breast cancer d Tumors from NTHL1-deficient patients reveal a cross-cancer NTHL1-associated signature d Mutational signature analyses can assist to identify germline DNA repair defects

smMIP-based genetic testing enables automated and reliable analysis of the coding sequences of BRCA1 and BRCA2. The use of single-molecule tags, double-tiled targeted enrichment, and capturing and sequencing in duplo, in combination with automated library preparation and data analysis, results in a robust process and reduces routine turnaround times. Furthermore, smMIP-based copy number variation analysis could make independent copy number variation tools like multiplex ligation-dependent probes amplification dispensable.

Norwegian Cancer Society.

Germline BRCA1/2 testing of breast and ovarian cancer patients is growing rapidly as the result affects both treatment and cancer prevention in patients and relatives. Through the DNA-BONus study we offered BRCA1/2 testing and familial risk assessment to all new patients with breast (N = 893) or ovarian (N = 122) cancer diagnosed between September 2012 and April 2015, irrespective of family history or age, and without prior face-to-face genetic counselling. BRCA1/2 testing was accepted by 405 (45.4%) and 83 (68.0%) of the patients with breast or ovarian cancer, respectively. A pathogenic BRCA1/2 variant was found in 7 (1.7%) of the breast cancer patients and 19 (22.3%) of the ovarian cancer patients. In retrospect, all BRCA1/2 mutation carriers appeared to fulfill current criteria for BRCA1/2 testing. Hospital Anxiety and Depression Scale (HADS) scores showed that the mean levels of anxiety and depression were comparable to those reported for breast and gynecological cancer patients in general, with a significant drop in anxiety symptoms during a 6-month follow-up period, during which the test result was forwarded to the patients. These results show that BRCA1/2 testing is well accepted in newly diagnosed breast and ovarian cancer patients. Current test criteria based on age and family history are sufficient to identify most BRCA1/2 mutation carriers among breast cancer patients. We recommend germline BRCA1/2 testing in all patients with epithelial ovarian cancer because of the high prevalence of pathogenic BRCA1/2 variants. INTRODUCTIONBreast cancer is by far the most common cancer in women worldwide, with more than 1.6 million new cases diagnosed each year. Ovarian cancer is substantially less common, with ∼ 240 000 new cases each year, but with higher mortality. 1 Most cases of breast and ovarian cancer are sporadic, but a minor fraction (2-8% and 8-15%, respectively) is caused by inheritance of pathogenic germline variants in BRCA1 or BRCA2, with variation in prevalence and relative contribution of BRCA1 and BRCA2 in different populations. [2][3][4][5][6][7][8] It is important to identify these patients because the presence of such germline variants affects treatment, follow-up and further cancer prevention in patients with breast or ovarian cancer. 9,10 In addition, it may strongly influence upon their close relatives, as BRCA1/2 testing can identify healthy BRCA1/2 mutation carriers at high risk and thereby prevent cancer and cancer-related deaths through increased surveillance and prophylactic surgery. [10][11][12][13][14][15][16] The most common current practice of BRCA1/2 testing is based on referral of suspected high-risk patients to clinical genetics services for specialized face-to-face genetic counselling. This procedure traditionally includes collection and confirmation of family history, risk

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