Strong evidence that the common variant S384F in BRCA2 has no pathogenic relevance in hereditary breast cancer

INTRODUCTION: Unclassified variants (UVs) of unknown clinical significance are frequently detected in the BRCA2 gene. In this study, we have investigated the potential pathogenic relevance of the recurrent UV S384F (BRCA2, exon 10). METHODS: For co-segregation, four women from a large kindred (BN326) suffering from breast cancer were analysed. Moreover, paraffin-embedded tumours from two patients were analysed for loss of heterozygosity. Co-occurrence of the variant with a deleterious mutation was further determined in a large data set of 43,029 index cases. Nature and position of the UV and conservation among species were evaluated. RESULTS: We identified the unclassified variant S384F in three of the four breast cancer patients (the three were diagnosed at 41, 43 and 57 years of age). One woman with bilateral breast cancer (diagnosed at ages 32 and 50) did not carry the variant. Both tumours were heterozygous for the S384F variant, so loss of the wild-type allele could be excluded. Ser384 is not located in a region of functional importance and cross-species sequence comparison revealed incomplete conservation in the human, dog, rodent and chicken BRCA2 homologues. Overall, the variant was detected in 116 patients, five of which co-occurred with different deleterious mutations. The combined likelihood ratio of co-occurrence, co-segregation and loss of heterozygosity revealed a value of 1.4 × 10(-8 )in favour of neutrality of the variant. CONCLUSION: Our data provide conclusive evidence that the S384F variant is not a disease causing mutation

Prevalence of pathogenic BRCA1/2 germline mutations among 802 women with unilateral triple-negative breast cancer without family cancer history

Background: There is no international consensus up to which age women with a diagnosis of triple-negative breast cancer (TNBC) and no family history of breast or ovarian cancer should be offered genetic testing for germline BRCA1 and BRCA2 (gBRCA) mutations. Here, we explored the association of age at TNBC diagnosis with the prevalence of pathogenic gBRCA mutations in this patient group. Methods: The study comprised 802 women (median age 40 years, range 19–76) with oestrogen receptor, progesterone receptor, and human epidermal growth factor receptor type 2 negative breast cancers, who had no relatives with breast or ovarian cancer. All women were tested for pathogenic gBRCA mutations. Logistic regression analysis was used to explore the association between age at TNBC diagnosis and the presence of a pathogenic gBRCA mutation. Results: A total of 127 women with TNBC (15.8%) were gBRCA mutation carriers (BRCA1: n = 118, 14.7%; BRCA2: n = 9, 1.1%). The mutation prevalence was 32.9% in the age group 20–29 years compared to 6.9% in the age group 60–69 years. Logistic regression analysis revealed a significant increase of mutation frequency with decreasing age at diagnosis (odds ratio 1.87 per 10 year decrease, 95%CI 1.50–2.32, p < 0.001). gBRCA mutation risk was predicted to be > 10% for women diagnosed below approximately 50 years. Conclusions: Based on the general understanding that a heterozygous mutation probability of 10% or greater justifies gBRCA mutation screening, women with TNBC diagnosed before the age of 50 years and no familial history of breast and ovarian cancer should be tested for gBRCA mutations. In Germany, this would concern approximately 880 women with newly diagnosed TNBC per year, of whom approximately 150 are expected to be identified as carriers of a pathogenic gBRCA mutation

Comprehensive analysis of 989 patients with breast or ovarian cancer provides BRCA1 and BRCA2 mutation profiles and frequencies for the German population

The main focus of this German-wide multi-center study was to establish a BRCA1/2 mutation profile and to determine family types with high frequencies of mutations in these genes. In a comprehensive study, the entire coding sequences of the breast cancer genes BRCA1 and BRCA2 were analyzed in 989 unrelated patients from German breast/ovarian cancer families. A total of 77 BRCA1 and 63 BRCA2 distinct deleterious mutations were found in 302 patients. More than ⅓ of these mutations are novel and might be specific for the German population. Eighteen common mutations were found in 68% of cases in BRCA1 and 13 recurrent mutations in 44% of cases in BRCA2, facilitating prescreening approaches. Haplotype analysis indicate that 14 out of 20 recurrent mutations are likely originating from a common founder. An additional 50 different rare sequence variants with unknown relevance for tumorigenesis were found in 72 families. Correlation of BRCA1/BRCA2 detection rates with family history identified families with both breast and ovarian cancer to be at highest risk for BRCA1/BRCA2 mutations (43% and 10%, respectively), followed by families with at least 2 premenopausal cases of breast cancer (24% BRCA1 and 13% BRCA2 mutations). These data provide strong evidence for further predisposing genes in the German population. In breast cancer families with 2 or 3 affected females but only a single or no premenopausal case, mutations were detected with low frequencies (about 10% or less for both genes). The decision for or against molecular diagnosis is now aided by considering the expected mutation detection rates that greatly depend on family history and structure

Prevalence of BRCA1/2 germline mutations in 21 401 families with breast and ovarian cancer

Purpose To characterise the prevalence of pathogenic germline mutations in BRCA1 and BRCA2 in families with breast cancer (BC) and ovarian cancer (OC) history. Patients and methods Data from 21 401 families were gathered between 1996 and 2014 in a clinical setting in the German Consortium for Hereditary Breast and Ovarian Cancer, comprising full pedigrees with cancer status of all individual members at the time of first counselling, and BRCA1/2 mutation status of the index patient. Results The overall BRCA1/2 mutation prevalence was 24.0% (95% CI 23.4% to 24.6%). Highest mutation frequencies were observed in families with at least two OCs (41.9%, 95% CI 36.1% to 48.0%) and families with at least one breast and one OC (41.6%, 95% CI 40.3% to 43.0%), followed by male BC with at least one female BC or OC (35.8%; 95% CI 32.2% to 39.6%). In families with a single case of early BC (<36 years), mutations were found in 13.7% (95% CI 11.9% to 15.7%). Postmenopausal unilateral or bilateral BC did not increase the probability of mutation detection. Occurrence of premenopausal BC and OC in the same woman led to higher mutation frequencies compared with the occurrence of these two cancers in different individuals (49.0%; 95% CI 41.0% to 57.0% vs 31.5%; 95% CI 28.0% to 35.2%). Conclusions Our data provide guidance for healthcare professionals and decision-makers to identify individuals who should undergo genetic testing for hereditary breast and ovarian cancer. Moreover, it supports informed decision-making of counselees on the uptake of genetic testing