Characterization of the Cancer Spectrum in Men With Germline BRCA1 and BRCA2 Pathogenic Variants: Results From the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA)

Key Points

Question  Are there cancer phenotype differences between male BRCA1 and BRCA2 pathogenic variant carriers?

Findings  In this cohort study of 6902 men with a BRCA1 or BRCA2 pathogenic variant, being affected by cancer, particularly breast, prostate, and pancreatic cancers and developing multiple primary tumors, was associated with a higher probability for a man of being a BRCA2, rather than a BRCA1, pathogenic variant carrier.

Meaning  Surveillance programs in men with BRCA1 and BRCA2 pathogenic variants should be tailored in light of these gene-specific cancer phenotype differences. These results may inform the design of prospective studies on cancer risks in male BRCA1 and BRCA2 pathogenic variant carriers.

Importance  The limited data on cancer phenotypes in men with germline BRCA1 and BRCA2 pathogenic variants (PVs) have hampered the development of evidence-based recommendations for early cancer detection and risk reduction in this population.

Objective  To compare the cancer spectrum and frequencies between male BRCA1 and BRCA2 PV carriers.

Design, Setting, and Participants  Retrospective cohort study of 6902 men, including 3651 BRCA1 and 3251 BRCA2 PV carriers, older than 18 years recruited from cancer genetics clinics from 1966 to 2017 by 53 study groups in 33 countries worldwide collaborating through the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Clinical data and pathologic characteristics were collected.

Main Outcomes and Measures  BRCA1/2 status was the outcome in a logistic regression, and cancer diagnoses were the independent predictors. All odds ratios (ORs) were adjusted for age, country of origin, and calendar year of the first interview.

Results  Among the 6902 men in the study (median [range] age, 51.6 [18-100] years), 1634 cancers were diagnosed in 1376 men (19.9%), the majority (922 of 1,376 [67%]) being BRCA2 PV carriers. Being affected by any cancer was associated with a higher probability of being a BRCA2, rather than a BRCA1, PV carrier (OR, 3.23; 95% CI, 2.81-3.70; P < .001), as well as developing 2 (OR, 7.97; 95% CI, 5.47-11.60; P < .001) and 3 (OR, 19.60; 95% CI, 4.64-82.89; P < .001) primary tumors. A higher frequency of breast (OR, 5.47; 95% CI, 4.06-7.37; P < .001) and prostate (OR, 1.39; 95% CI, 1.09-1.78; P = .008) cancers was associated with a higher probability of being a BRCA2 PV carrier. Among cancers other than breast and prostate, pancreatic cancer was associated with a higher probability (OR, 3.00; 95% CI, 1.55-5.81; P = .001) and colorectal cancer with a lower probability (OR, 0.47; 95% CI, 0.29-0.78; P = .003) of being a BRCA2 PV carrier.

Conclusions and Relevance  Significant differences in the cancer spectrum were observed in male BRCA2, compared with BRCA1, PV carriers. These data may inform future recommendations for surveillance of BRCA1/2-associated cancers and guide future prospective studies for estimating cancer risks in men with BRCA1/2 PVs.

While there are a substantial number of studies on cancer risks and the cancer spectrum in female carriers of germline pathogenic variants (PVs) in BRCA1 (OMIM 113705) and BRCA2 (OMIM 600185),^1-4 data on male BRCA1/2 PV carriers are limited and have primarily focused on breast and/or prostate cancers. Population-based studies have shown that BRCA1 and BRCA2 PVs account for up to 2% and 13% of male breast cancer cases, respectively.⁵ The lifetime risk of male breast cancer has been estimated at 1% to 5% for BRCA1 and 5% to 10% for BRCA2 PV carriers, vs 0.1% in the general male population.^2,3,6-8Quiz Ref ID Additionally, BRCA1 and BRCA2 PVs have been estimated to account for less than 1% and approximately 2% of incident prostate cancer diagnoses, respectively.^9,10 Estimates of lifetime prostate cancer risk associated with BRCA1 and BRCA2 PVs vary, with some studies reporting higher risk for male BRCA2 PV carriers,^10-15 while other studies did not find any increased risk.^16-18 Pathogenic variants in BRCA1 and, more frequently, in BRCA2 have been reported in male patients diagnosed with other cancer types.^13,14,19-24 However, current risk estimates for cancers other than breast and prostate are based on handfuls of cases in a limited number of families.

BRCA1/2-associated tumors in men exhibit specific pathologic features and poor clinical outcome. A specific BRCA2-associated breast cancer phenotype, hallmarked by high histopathologic grade, a feature suggestive of biological aggressiveness, has been reported in men.²⁵ Compared with age-matched controls, men with BRCA1/2-associated prostate cancer more frequently have early-onset (<65 years) and aggressive disease.^15,26 Specifically, BRCA2 PVs were identified as an independent negative prognostic factor in patients with prostate cancer.²⁷ There is also some evidence suggesting that patients with BRCA1/2-associated pancreatic cancer may exhibit worse prognosis compared with noncarriers.²⁸ In the aggregate, these observations highlight the need for large collaborations to improve and expand data on the cancer spectrum in male BRCA1/2 PV carriers to optimize guidelines for cancer risk management in this group.²⁹

The Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) is an international collaboration that has collected data on female and male BRCA1/2 PV carriers.³⁰ Using this series, to our knowledge the largest collected worldwide, we aimed to characterize the spectrum of cancers diagnosed in male BRCA1/2 PV carriers and identify differences between BRCA1 and BRCA2 PV carriers. Such information could form the foundation for future screening and surveillance recommendations regarding BRCA1/2-associated cancers in men and for future studies aimed to estimate lifetime risks of cancers other than breast and prostate in male BRCA1/2 PV carriers.

Investigators collaborating through CIMBA (http://cimba.ccge.medschl.cam.ac.uk/) have collected data on men older than 18 years who carry pathogenic and likely pathogenic BRCA1 or BRCA2 variants, with the majority of carriers identified and recruited via cancer genetics clinics.²⁵ Variant pathogenicity was defined as previously described.³¹ The present study includes data from 6902 male BRCA1/2 PV carriers collected by 53 study groups in 33 countries from 1966 to 2017 (eTables 1 and 2 in the Supplement).

Data collected for each individual included year of birth, a unique family identifier, ethnicity, age at cancer diagnosis, primary tumor site (International Statistical Classification of Diseases and Related Health Problems, Tenth Revision [ICD-10] coding), age at last observation, and clinical data from medical, pathology, or tumor registry records.²⁵ Most individuals (77%) reported herein are self-reported as white Caucasian, with other ethnicities not as equally represented (eTable 3 in the Supplement). Recruited BRCA1 or BRCA2 PV carriers include probands and tested family members (eTable 4 in the Supplement). Data on first-degree and second-degree family history of male breast, prostate, and female breast cancer were also collected and were available for a subset of individuals (eTable 5 in the Supplement). Written informed consent was obtained from all study participants, as part of the protocol approved by the individual ethics committees at the participating centers.

The primary objective was to compare cancer diagnoses between male BRCA1 and BRCA2 PV carriers. We used logistic regression to estimate the association between BRCA1/2 PV status (outcome) and cancer diagnosis (independent variable). Individuals with no cancer diagnosis at last follow-up were considered unaffected (reference group), whereas individuals with 1 or more diagnoses of cancer at any site were grouped as affected. This provides an estimate of the odds ratio (OR) comparing the odds of being a BRCA2 PV carrier in the affected group to the odds of being a BRCA2 PV carrier in the unaffected group. In practice, under a univariate analysis, this can be interpreted as the OR of a BRCA2 carrier being affected compared with the odds of a BRCA1 PV carrier being affected. Differences in age at first cancer diagnosis by cancer site (breast, prostate, other sites) between BRCA1 and BRCA2 PV carriers and in intercancer intervals were assessed by the nonparametric Mann-Whitney test.

A separate cancer-only logistic regression was performed (using the same approach described above) restricted to affected individuals in which all tumors arising in affected male carriers were taken into consideration. The independent variables were defined as the cancer site (breast cancer vs all cancers but breast; prostate cancer vs all cancers but prostate; cancers at other sites vs breast and prostate cancers). A further analysis was performed, including only tumors at sites other than breast and prostate to address possible ascertainment bias of breast and prostate cancers. In this analysis, the independent variables were specific cancer sites, namely colorectal cancer, melanoma, and pancreatic cancer (colorectal cancer vs all other cancers; melanoma vs all other cancers; pancreatic cancer vs all other cancers). To assess the potential influence of survival bias, these analyses were also repeated after omitting cancer diagnoses occurring more than 5 years prior to study recruitment.

Confounders included in the logistic regression models were prespecified and were chosen on the basis of previous studies on CIMBA male carrier series^25,31 and by considering factors related to the study design. All analyses were adjusted for age at cancer diagnosis (affected individuals) or age at last follow-up (unaffected individuals) and country of origin. In addition, adjustments for calendar year of the first interview were included in all analyses as a surrogate for year of genetic testing, based on the groupings of 2000 or earlier, 2001-2010, and after 2010, to account for ascertainment biases owing to differential genetic testing approaches and inclusion criteria over time. A logistic regression adjusted also for proband status, estimated considering as probands individuals with a cancer diagnosis date preceding interview prior genetic testing date, was performed. To assess the potential influence of family history, analyses were repeated adjusting for family history of male breast cancer, female breast cancer, and prostate cancer, all included as separate covariates, with each variable grouped as positive, negative, or unknown family history. A robust variance approach was used to allow for dependencies between related individuals. P values of .05 or less were considered statistically significant. All analyses were carried out using Stata, version 13 (StataCorp).

The series included 6902 men with PVs in BRCA1 (n = 3651 [52.9%]) or BRCA2 (n = 3251 [47.1%]). Of the 6902 male BRCA1/2 PV carriers, 1376 (19.9%) had at least 1 cancer diagnosis, the majority of whom (67.0%) harbored a BRCA2 PV. Median (range) age in the whole series was 51.6 (18-100) years. Age distribution is reported in the eFigure in the Supplement.

Of the 1376 carriers with cancer, 1144 (83.1%) were diagnosed with 1 cancer, 206 (15.0%) had 2 cancers, and 26 (1.9%) had 3 independent cancer diagnoses (Table 1). The number and type of cancer diagnoses varied greatly depending on which gene was mutated (Table 1 and Figure 1). Notably, all individuals diagnosed with 2 independent breast cancers had a BRCA2 PV. Quiz Ref IDOverall, being affected by any cancer was associated with a higher probability of being a BRCA2, rather than a BRCA1, PV carrier (OR, 3.23; 95% CI, 2.81-3.70; P < .001). Similarly, developing multiple cancers, particularly 2 (OR, 7.97; 95% CI, 5.47-11.60; P < .001) and 3 (OR, 19.60; 95% CI, 4.64-82.89; P < .001) primary tumors, was associated with a higher probability of being a BRCA2 PV carrier in analyses adjusted for age, country of origin, and calendar year of interview (Table 1). Analyses adjusted also for family history of male breast cancer, female breast cancer, and prostate cancer gave similar results (eTable 6 in the Supplement).

Among male BRCA2 PV carriers with more than 1 cancer diagnosis, significantly shorter median intercancer intervals were observed for cases with a first diagnosis of breast (5.0 years) or prostate (3.4 years) cancers compared with cases with a first diagnosis of other cancers (7 years; Mann-Whitney test P = .03 and P = .005, respectively). Focusing on the first cancer diagnosed, breast (n = 485 [35.3%]) and prostate (n = 337 [24.5%]) cancers represented the majority of all first diagnoses (Table 2). Both breast and prostate cancers occurred more frequently in BRCA2 PV carriers (46.4% and 25.6%, respectively) compared with BRCA1 PV carriers (12.5% and 22.3%) (Table 2; eTable 7 in the Supplement). Median age at first cancer diagnosis was 61.5 years for breast cancer and 63.2 years for prostate cancer and were similar for BRCA1 and BRCA2 PV carriers (Table 2). Nonbreast and nonprostate cancers combined (n = 554) represented 40.2% of all first cancer diagnoses, with a median age at diagnosis of 59.2 years (Table 2). Quiz Ref IDThe proportion of cancers other than breast and prostate taken together is larger in BRCA1 PV carriers (65.2%) compared with BRCA2 PV carriers (28.0%), while mean age at first diagnosis was statistically significantly older in BRCA1 (61.8 years) compared with BRCA2 PV carriers (56.5 years; Mann-Whitney test P = .003).

A total of 1634 cancers were reported in the 1376 affected individuals, of which 494 (30.2%) were in BRCA1 PV carriers and 1140 (69.8%) were in BRCA2 PV carriers (Table 3). The analysis restricted to affected individuals and adjusted for age, country of origin, and calendar year of interview showed that a higher frequency of breast (OR, 5.47; 95% CI, 4.06-7.37; P < .001) and prostate (OR, 1.39; 95% CI, 1.09-1.78; P = .008) cancers, and a lower frequency of cancers other than breast and prostate combined (OR, 0.22; 95% CI, 0.18-0.28; P < .001) were associated with a higher probability of being a BRCA2, rather than a BRCA1, PV carrier. Specifically, 643 of 1634 tumors (39.4%) were in sites other than breast and prostate, of which 319 (64.6%) were diagnosed in BRCA1 PV carriers and 324 (28.4%) were diagnosed in BRCA2 PV carriers (Table 3).

Considering cancers other than breast and prostate, more than 60 different cancer sites were reported (eTable 8 in the Supplement). Quiz Ref IDThe most common nonbreast and nonprostate cancer types (>60 diagnoses each) were nonmelanoma skin cancer, colorectal cancer and melanoma; other frequently reported cancer types (>30 diagnoses each) were head and neck, pancreatic, lung, and bladder cancers (Figure 2; eTable 8 in the Supplement). Cancer phenotype varied between BRCA1 and BRCA2 PV carriers (Figure 2 and Table 3). In particular, among the nonbreast and nonprostate cancers, pancreatic cancer was associated with a higher probability of being a BRCA2 carrier (OR, 3.00; 95% CI, 1.55-5.81; P = .001), and colorectal cancer was associated with a lower probability of being a BRCA2 PV carrier (OR, 0.47; 95% CI, 0.29-0.78; P = .003), in analyses adjusted for age, country of origin, and calendar year of interview (Table 3). No statistically significant differences in the frequencies of other cancer diagnoses between BRCA1 and BRCA2 PV carriers were found. Analyses adjusted also for family history of male breast cancer, female breast cancer, and prostate cancer gave similar results (eTable 9 in the Supplement). Similar findings were also obtained in analyses omitting cancer diagnoses occurring more than 5 years prior to study recruitment (eTable 10 in the Supplement).

Men with BRCA1/2 PVs represent an underinvestigated group that poses clinical challenges. The paucity of data on cancers arising in male BRCA1/2 PV carriers has limited the development of evidence-based clinical guidelines for surveillance and prevention in men harboring BRCA1/2 PVs.²⁹

By taking advantage of data collected through CIMBA, we characterized the cancer spectrum in male BRCA1/2 PV carriers and compared BRCA1 with BRCA2 PV carriers in terms of number, site, and age of cancer diagnoses. We believe this study comprises the largest series of male BRCA1/2 PV carriers collected worldwide to date.

Quiz Ref IDOur results highlight specific, unique differences in the cancer spectrum of male BRCA2 vs BRCA1 PV carriers. Being affected with cancer and developing multiple cancer types at younger ages was associated with a higher probability of being a BRCA2 PV carrier.

Intercancer intervals were shorter in male BRCA2 PV carriers with a first diagnosis of breast or prostate cancers, compared with other cancers, thus suggesting that BRCA2-associated breast and prostate cancers may have a worse prognosis. However, age difference at first diagnosis, being older for breast or prostate cancer compared with the other cancers, may affect intercancer intervals.

While recommended guidelines for early detection and cancer risk reduction for female BRCA1/2 PV carriers are evidence based,³² only limited recommendations, based on low-level evidence or expert opinion, are available for male BRCA1/2 PV carriers.²⁹ Current National Comprehensive Cancer Network (NCCN),³² European Society for Medical Oncology (August 2016),³³ and American Society of Clinical Oncology (2017)³⁴ guidelines recommend annual clinical breast examination starting at age 30 to 35 years, and clinical prostate cancer screening, particularly for BRCA2 PV carriers, starting at age 40 to 45 years. American Society of Clinical Oncology recommendations also suggest consideration of baseline mammograms on an individual basis.³⁴

Recent studies have shown that mammography can detect clinically occult breast cancer when screening high-risk men, including BRCA1/2 PV carriers.^35-37 Moreover, interim results from the International Prospective Prostate Cancer Screening (IMPACT) study have shown that the use of systematic prostate-specific antigen screening can detect clinically significant prostate cancers in male BRCA2 PV carriers.³⁸ Based on those findings and on our data demonstrating that male BRCA2 PV carriers more frequently develop breast and prostate cancers as a first or second tumor, future guidelines should consider recommending mammography and systematic prostate-specific antigen testing for male BRCA2 PV carriers, although formal evaluation of these screening strategies is warranted in this set.

Our data also show that among the nonbreast and nonprostate cancers, pancreatic cancer was associated with a higher probability of being a BRCA2 PV carrier. This observation reinforces the evidence of a sex-independent association between BRCA2 PVs and pancreatic cancer.^14,19,20 Our findings are consistent with those from previous studies of families with BRCA2 PVs showing that the spectrum of cancers for male carriers is largely attributable to the excess of breast, prostate, and pancreatic cancers.¹⁹

A prospective study on screening protocols for male BRCA1/2 PV carriers suggested a role for screening for pancreatic cancer in addition to prostate and breast cancer.²⁴ Both National Comprehensive Cancer Network and European Society for Medical Oncology guidelines suggest individualizing screening for pancreatic cancer based on family specific-cancer history.^32-34 Our results provide further evidence to consider screening for pancreatic cancer in male BRCA2 PV carriers. However, given the lack of data regarding the effectiveness of any pancreatic cancer screening program, male BRCA2 PV carriers should be strongly encouraged to participate in clinical trials evaluating such screening strategies.³³

In our study, most of the commonly reported cancers in male BRCA1/2 PV carriers are also common in the general population and are possibly associated with environmental or lifestyle risk factors, such as smoking, although a role of gene-environment interactions in increasing cancer risks may be suggested.^39-42 However, country-specific environmental influences and lifestyle factors cannot be excluded. The absence of reliable risk estimates in BRCA1/2 PV carriers for these cancers, especially for colorectal cancer,⁴³ leads to uncertainty about appropriate screening protocols. Nevertheless, education and awareness regarding signs and symptoms of these cancer types and strict adherence to population screening guidelines are highly warranted for male BRCA1/2 PV carriers.

There are some limitations to the current study. First, this study was largely retrospective, and data may not have been systematically collected. Second, cases were mostly recruited from high-risk clinics and/or high-risk families, and hence a selection bias toward having more affected individuals seems likely. However, the proportions of BRCA1 and BRCA2 PV carriers, as well as affected to unaffected ratios, are consistent with previously reported series of male BRCA1/2 PV carriers.^2,7-9,14 Furthermore, the series included male carriers, both family probands and members, collected by different centers, and ascertainment bias may have occurred.

We assumed similar biases for BRCA1/2; thus, the study was designed to compare BRCA1 with BRCA2 PV carriers. However, BRCA1/2 genetic testing might have been performed based on cancer types or cancer family history, and genetic testing approaches and inclusion criteria might have changed over time. To account for such biases, different models, adjusted for cancer family history, proband status, and calendar year of the first interview, were performed. To assess the potential influence of survival bias, key analyses were repeated considering only cancer diagnoses within 5 years from study recruitment.

A high number of BRCA1/2 mutations is reported in our series. Recently, an association between specific regions of BRCA2 and prostate cancer risk was demonstrated.³¹ Genotype-phenotype associations deserve to be further investigated for other cancers, particularly breast and pancreatic, arising in male BRCA2 PV carriers.

The present study design does not allow for inference on the associations of specific cancer types in men with BRCA1 or BRCA2 PVs owing to the lack of a similar comparison group without PVs. Thus, associations between the observed cancer types and BRCA1 or BRCA2 PVs could not be analyzed, and age-specific cancer risks for male carriers could not be estimated. Further research, ideally large prospective studies, to obtain reliable cancer risk estimates in male BRCA1/2 PV carriers is urgently needed to refine clinical management strategies.

Our results, derived from analyses of the largest available (to our knowledge) male BRCA1/2 PV carrier data set, provide reliable data on the cancer spectrum in male BRCA1 and BRCA2 PV carriers. Being affected by any cancer and developing multiple cancers, particularly breast, prostate, and pancreatic cancers, was associated with a higher probability of being a BRCA2, rather than a BRCA1, PV carrier. These data may represent a step toward evidence-based guidelines and may help to refine existing recommendations in specifying distinct surveillance guidelines for men with either BRCA1 or BRCA2 PVs.

Accepted for Publication: April 6, 2020.

Published Online: July 2, 2020. doi:10.1001/jamaoncol.2020.2134

Correction: This article was corrected on September 10, 2020, to fix an incorrect author name.

Corresponding Author: Laura Ottini, MD, Department of Molecular Medicine, Sapienza University of Rome, Viale Regina Elena, 324, 00161 Rome, Italy (laura.ottini@uniroma1.it).

CIMBA Group Authors: Bjarni A. Agnarsson, MD; Kristiina Aittomäki, MD, PhD; Elisa Alducci, MSc; Irene L. Andrulis, PhD; Rosa B. Barkardottir, CandSci; Alicia Barroso, MLT; Daniel Barrowdale, BSc; Javier Benitez, PhD; Bernardo Bonanni, MD; Ake Borg, PhD; Saundra S. Buys, MD; Trinidad Caldés, MD; Maria A. Caligo, PhD; Carlo Capalbo, MD; Ian Campbell, PhD; Wendy K. Chung, MD, PhD; Kathleen B.M. Claes, PhD; Sarah V. Colonna, MD; Laura Cortesi, MD; Fergus J. Couch, PhD; Miguel de la Hoya, PhD; Orland Diez, PhD; Yuan Chun Ding, PhD; Susan Domchek, MD; Douglas F. Easton, PhD; Bent Ejlertsen, MD; Christoph Engel, MD; D. Gareth Evans, MD; Lidia Feliubadalò, PhD; Lenka Foretova, MD, PhD; Florentia Fostira, PhD; Lajos Géczi, MD; Anne-Marie Gerdes, MD; Gord Glendon, MSc; Andrew K. Godwin, PhD; David E. Goldgar, PhD; Eric Hahnen, PhD; Frans B.L. Hogervorst, PhD; John L. Hopper, PhD; Peter J. Hulick, MD; Claudine Isaacs, MD; Angel Izquierdo, MD; Paul A. James, PhD; Ramunas Janavicius, PhD; Uffe Birk Jensen, MD, PhD; Esther M. John, PhD; Vijai Joseph, PhD; Irene Konstantopoulou, PhD; Allison W. Kurian, MD; Ava Kwong, PhD; Elisabetta Landucci, MD; Fabienne Lesueur, PhD; Jennifer T. Loud, DNP; Eva Machackova, PhD; Phuong L. Mai, MD; Keivan Majidzadeh-A, MD, MPH, PhD; Siranoush Manoukian, MD; Marco Montagna, PhD; Lidia Moserle, PhD; Anna Marie Mulligan, MBBCh; Katherine L. Nathanson, PhD; Heli Nevanlinna, PhD; Joanne Ngeow, MBBS; Liene Nikitina-Zake, PhD; Kenneth Offit, MD; Edith Olah, PhD; Olufunmilayo I. Olopade, MD; Ana Osorio, PhD; Laura Papi, MD; Sue K. Park, PhD; Inge Sokilde Pedersen, PhD; Pedro Perez-Segura, MD; Annabeth H. Petersen, PhD; Pedro Pinto, PhD; Berardino Porfirio, PhD; Miquel Angel Pujana, PhD; Paolo Radice, PhD; Johanna Rantala, PhD; Muhammad U. Rashid, MBBS, PhD; Barak Rosenzweig, MD; Maria Rossing, PhD; Marta Santamariña, PhD; Rita K. Schmutzler, MD; Leigha Senter, MS; Jacques Simard, PhD; Christian F. Singer, MD; Angela R. Solano, PhD; Melissa C. Southey, PhD; Linda Steele, BS; Zoe Steinsnyder, BA; Dominique Stoppa-Lyonnet, MD, PhD; Yen Yen Tan, PhD; Manuel R. Teixeira, PhD; Soo H. Teo, PhD; Mary Beth Terry, PhD; Mads Thomassen, PhD; Amanda E. Toland, PhD; Sara Torres-Esquius, MSc; Nadine Tung, MD; Christi J. van Asperen, PhD; Ana Vega, PhD; Alessandra Viel, PhD; Jeroen Vierstraete, MSc; Barbara Wappenschmidt, MD; Jeffrey N. Weitzel, MD; Greet Wieme, MSc; Sook-Yee Yoon, MA; Kristin K. Zorn, MD; Lesley McGuffog; Michael T. Parsons, BSc; Ute Hamann, PhD; Mark H. Greene, MD; Judy A. Kirk, MD; Susan L. Neuhausen, PhD; Timothy R. Rebbeck, PhD; Marc Tischkowitz, MD, PhD; Georgia Chenevix-Trench, PhD; Antonis C. Antoniou, PhD; Eitan Friedman, MD; Laura Ottini, MD.

Affiliations of CIMBA Group Authors: Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy (Capalbo, Ottini); Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom (Barrowdale, Easton, McGuffog, Antoniou); Department of Pathology, Landspitali University Hospital, Reykjavik, Iceland (Agnarsson, Barkardottir); School of Medicine, University of Iceland, Reykjavik, Iceland (Agnarsson); Department of Clinical Genetics, Helsinki University Hospital, University of Helsinki, Helsinki, Finland (Aittomäki); Immunology and Molecular Oncology Unit, Veneto Institute of Oncology IOV–IRCCS, Padua, Italy (Alducci, Montagna, Moserle); Lunenfeld-Tanenbaum Research Institute, Fred A. Litwin Center for Cancer Genetics, Mount Sinai Hospital, Toronto, Ontario, Canada (Andrulis, Glendon); Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada (Andrulis); BMC (Biomedical Centre), Faculty of Medicine, University of Iceland, Reykjavik, Iceland (Barkardottir); Human Genetics Group, Human Cancer Genetics Programme, Spanish National Cancer Research Centre, Madrid, Spain (Barroso, Osorio); Human Genetics Group and Genotyping Unit, CEGEN, Human Cancer Genetics Programme, Spanish National Cancer Research Centre, Madrid, Spain (Benitez); Spanish Network on Rare Diseases (CIBERER), Madrid, Spain (Benitez, Osorio); Division of Cancer Prevention and Genetics–IEO, European Institute of Oncology IRCCS, Milan, Italy (Bonanni); Department of Oncology, Lund University, Skåne University Hospital, Lund, Sweden (Borg); Huntsman Cancer Institute, Department of Internal Medicine, University of Utah Health, Salt Lake City (Buys, Colonna); Instituto de Investigación Sanitaria San Carlos (IdISSC), Centro Investigación Biomédica en Red de Cáncer (CIBERONC), Medical Oncology Department, Hospital Clínico San Carlos, Madrid, Spain (Caldés, de la Hoya, Perez-Segura); Section of Molecular Genetics, Department of Laboratory Medicine, University Hospital of Pisa, Pisa, Italy (Caligo); Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Victoria, Australia (Campbell, James); Departments of Pediatrics and Medicine, Columbia University, New York, New York (Chung); Centre for Medical Genetics, Ghent University, Gent, Belgium (Claes, Vierstraete, Wieme); Department of Oncology and Haematology, University of Modena and Reggio Emilia, Modena, Italy (Cortesi); Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota (Couch); Hereditary Cancer Genetics Group, Vall d’Hebron Institute of Oncology, Barcelona, Spain (Diez, Torres-Esquius); Area of Clinical and Molecular Genetics, University Hospital of Vall d’Hebron, Barcelona, Spain (Diez); Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, California (Ding, Steele, Neuhausen); Abramson Cancer Center, Perelman School of Medicine, Department of Medicine, University of Pennsylvania, Philadelphia (Domchek, Nathanson); Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, United Kingdom (Easton); Department of Oncology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark (Ejlertsen); Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany (Engel); Genomic Medicine, Manchester Academic Health Sciences Centre, Division of Evolution and Genomic Science, Manchester University, Manchester University Hospitals NHS Foundation Trust, Manchester, United Kingdom (Evans); Molecular Diagnostic Unit, Hereditary Cancer Program, IDIBELL (Bellvitge Biomedical Research Institute), Catalan Institute of Oncology, CIBERONC, Barcelona, Spain (Feliubadalò); Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute, Brno, Czech Republic (Foretova, Machackova); Molecular Diagnostics Laboratory, INRASTES, National Centre for Scientific Research “Demokritos”, Athens, Greece (Fostira, Konstantopoulou); Medical Oncology Center, National Institute of Oncology, Budapest, Hungary (Géczi); Department of Clinical Genetics, Rigshospitalet, Copenhagen, Denmark (Gerdes); Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City (Godwin); Huntsman Cancer Institute, Department of Dermatology, University of Utah School of Medicine, Salt Lake City (Goldgar); Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany (Hahnen, Schmutzler, Wappenschmidt); Center for Hereditary Breast and Ovarian Cancer, University Hospital of Cologne, Cologne, Germany (Hahnen, Schmutzler, Wappenschmidt); Family Cancer Clinic, Netherlands Cancer Institute, Amsterdam, the Netherlands (Hogervorst); Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia (Hopper); Center for Medical Genetics, NorthShore University HealthSystem, Evanston, Illinois (Hulick); The University of Chicago Pritzker School of Medicine, Chicago, Illinois (Hulick); Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC (Isaacs); Genetic Counseling Unit, Hereditary Cancer Program, IDIBGI (Institut d’Investigació Biomèdica de Girona), Catalan Institute of Oncology, CIBERONC, Girona, Spain (Izquierdo); Parkville Familial Cancer Centre, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia (James); Hematology, Oncology and Transfusion Medicine Center, Department of Molecular and Regenerative Medicine, Vilnius University Hospital Santariskiu Clinics, Vilnius, Lithuania (Janavicius); Department of Clinical Genetics, Aarhus University Hospital, Aarhus, Denmark (Jensen); Department of Epidemiology and Population Health, Division of Oncology, Department of Medicine, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, California (John, Kurian); Clinical Genetics Research Lab, Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, New York (Joseph, Offit, Steinsnyder); Hong Kong Hereditary Breast Cancer Family Registry, Cancer Genetics Centre, Happy Valley, Hong Kong (Kwong); Department of Surgery, University of Hong Kong, Pok Fu Lam, Hong Kong (Kwong); Department of Surgery and Cancer Genetics Center, Hong Kong Sanatorium and Hospital, Happy Valley, Hong Kong (Kwong); UO Oncologia Medica, Azienda Ospedaliero Universitaria Pisana, Pisa, Italy (Landucci); Genetic Epidemiology of Cancer Team, Inserm, U900, Paris, France (Lesueur); Institut Curie, Paris, France (Lesueur); Mines ParisTech, Fontainebleau, France (Lesueur); Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland (Loud, Greene); Magee-Womens Hospital, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania (Mai, Zorn); Breast Cancer Research Center, Genetics Department, Motamed Cancer Institute, ACECR, Tehran, Iran (Majidzadeh-A); Unit of Medical Genetics, Department of Medical Oncology and Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori (INT), Milan, Italy (Manoukian); Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada (Mulligan); Laboratory Medicine Program, University Health Network, Toronto, Ontario, Canada (Mulligan); Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland (Nevanlinna); Cancer Genetics Service, National Cancer Centre Singapore, Singapore (Ngeow); Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore (Ngeow); Latvian Biomedical Research and Study Centre, Riga, Latvia (Nikitina-Zake); Clinical Genetics Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York (Offit); Department of Molecular Genetics, National Institute of Oncology, Budapest, Hungary (Olah); Center for Clinical Cancer Genetics, The University of Chicago, Chicago, Illinois (Olopade); Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy (Papi, Porfirio); Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Korea (Park); Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, Korea (Park); Cancer Research Institute, Seoul National University, Seoul, Korea (Park); Molecular Diagnostics, Department of Clinical Medicine, Aalborg University Hospital, Aalborg University, Aalborg, Denmark (Pedersen); Department of Clinical Genetics, Vejle Hospital, Vejle, Denmark (Petersen); Department of Genetics, Portuguese Oncology Institute, Porto, Portugal (Pinto, Teixeira); ProCURE, Catalan Institute of Oncology, IDIBELL (Bellvitge Biomedical Research Institute), Barcelona, Spain (Pujana); Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori (INT), Milan, Italy (Radice); Clinical Genetics, Karolinska Institutet, Stockholm, Sweden (Rantala); Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany (Rashid, Hamann); Department of Basic Sciences, Shaukat Khanum Memorial Cancer Hospital and Research Centre (SKMCH & RC), Lahore, Pakistan (Rashid); Male High Risk Clinic, Uro-Oncology Service, Urology Department, Chaim Sheba Medical Center, Tel-Hashomer, Israel (Rosenzweig); Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, Israel (Rosenzweig, Friedman); Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark (Rossing); Fundación Pública Galega Medicina Xenómica-SERGAS, Santiago de Compostela, Spain (Santamariña, Vega); Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Santiago de Compostela, Spain (Santamariña, Vega); Centro de Investigación en Red de Enfermedades Raras (CIBERER), Spain (Santamariña, Vega); Clinical Cancer Genetics Program, The Comprehensive Cancer Center, Division of Human Genetics, Department of Internal Medicine, The Ohio State University, Columbus (Senter); Genomics Center, Centre Hospitalier Universitaire de Québec–Université Laval, Research Centre, Québec City, Québec, Canada (Simard); Comprehensive Cancer Center, Department of OB/GYN, Medical University of Vienna, Vienna, Austria (Singer); INBIOMED, Faculty of Medicine/UBA-CONICET and Genotyping Laboratory, Department of Clinical Chemistry, Centro de Educacion Medica e Investigaciones Clinicas, CABA, Argentina (Solano); Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia (Southey); Department of Clinical Pathology, The University of Melbourne, Melbourne, Victoria, Australia (Southey); Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia (Southey); Service de Génétique, Institut Curie, Paris, France (Stoppa-Lyonnet); Department of Tumour Biology, INSERM U830, Paris, France (Stoppa-Lyonnet); Université de Paris, Paris, France (Stoppa-Lyonnet); Department of OB/GYN, Medical University of Vienna, Vienna, Austria (Tan); Biomedical Sciences Institute (ICBAS), University of Porto, Porto, Portugal (Teixeira); Cancer Research Malaysia, Subang Jaya, Selangor, Malaysia (Teo, Yoon); Breast Cancer Research Unit, Cancer Research Institute, University Malaya Medical Centre, Kuala Lumpur, Malaysia (Teo); Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, New York (Terry); Department of Clinical Genetics, Odense University Hospital, Odense, Denmark (Thomassen); Department of Cancer Biology and Genetics, The Ohio State University, Columbus (Toland); Department of Medical Oncology, Beth Israel Deaconess Medical Center, Boston, Massachusetts (Tung); Department of Clinical Genetics, Leiden University Medical Center, Leiden, the Netherlands (van Asperen); Division of Functional onco-genomics and genetics, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Aviano, Italy (Viel); Clinical Cancer Genetics, City of Hope, Duarte, California (Weitzel); Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia (Parsons, Chenevix-Trench); Centre for Cancer Research, University of Sydney at The Westmead Institute for Medical Research, and Familial Cancer Service, Westmead Hospital, New South Wales, Australia (Kirk); Harvard T.H. Chan School of Public Health, Boston, Massachusetts (Rebbeck); Dana-Farber Cancer Institute, Boston, Massachusetts (Rebbeck); Program in Cancer Genetics, Departments of Human Genetics and Oncology, McGill University, Montréal, Quebec, Canada (Tischkowitz); Department of Medical Genetics, National Institute for Health Research Cambridge Biomedical Research Centre, University of Cambridge, Cambridge, United Kingdom (Tischkowitz); The Suzanne Levy-Gertner Oncogenetics Unit, Chaim Sheba Medical Center, Ramat Gan, Israel (Friedman).

Author Contributions: Dr Ottini had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Drs Friedman and Ottini contributed equally to the work as co–last authors.

Study concept and design: Silvestri, Colonna, Domchek, Konstantopoulou, Schmutzler, Solano, Friedman, Ottini.

Acquisition, analysis, or interpretation of data: Silvestri, Leslie, Barnes, Agnarsson, Aittomäki, Alducci, Andrulis, Barkardottir, Barroso, Barrowdale, Benítez, Bonanni, Borg, Buys, Caldés, Caligo, Capalbo, Campbell, Chung, Claes, Cortesi, Couch, de la Hoya, Diez, Ding, Domchek, Easton, Ejlertsen, Engel, Evans, Feliubadaló Elorza, Foretova, Fostira, Géczi, Gerdes, Glendon, Godwin, Goldgar, Hahnen, Hogervorst, Hopper, Hulick, Isaacs, Izquierdo Font, James, Janavicius, Jensen, John, Joseph, Konstantopoulou, Kurian, Kwong, Landucci, Lesueur, Loud, Machackova, Mai, Majidzadeh-A, Manoukian, Montagna, Moserle, Mulligan, Nathanson, Nevanlinna, Ngeow, Nikitina-Zake, Offit, Oláh, Olopade, Osorio, Papi, Park, Pedersen, Perez-Segura, Petersen, Pinto, Porfirio, Pujana, Radice, Rantala, Rashid, Rosenzweig, Rossing, Santamariña, Schmutzler, Senter, Simard, Singer, Southey, Steele, Steinsnyder, Stoppa-Lyonnet, Tan, Teixeira, Teo, Terry, Thomassen, Toland, Torres-Esquius, Tung, van Asperen, Vega, Viel, Vierstraete, Wappenschmidt, Weitzel, Wieme, Yoon, Zorn, McGuffog, Parsons, Hamann, Greene, Kirk, Neuhausen, Rebbeck, Tischkowitz, Chenevix-Trench, Antoniou, Friedman, Ottini.

Drafting of the manuscript: Silvestri, Barnes, Barroso, Colonna, Couch, Evans, Glendon, Konstantopoulou, Ngeow, Olopade, Park, Rosenzweig, Torres-Esquius, Weitzel, Tischkowitz, Friedman, Ottini.

Critical revision of the manuscript for important intellectual content: Silvestri, Leslie, Barnes, Agnarsson, Aittomäki, Alducci, Andrulis, Barkardottir, Barrowdale, Benítez, Bonanni, Borg, Buys, Caldés, Caligo, Capalbo, Campbell, Chung, Claes, Cortesi, Couch, de la Hoya, Diez, Ding, Domchek, Easton, Ejlertsen, Engel, Evans, Feliubadaló Elorza, Foretova, Fostira, Géczi, Gerdes, Godwin, Goldgar, Hahnen, Hogervorst, Hopper, Hulick, Isaacs, Izquierdo Font, James, Janavicius, Jensen, John, Joseph, Konstantopoulou, Kurian, Kwong, Landucci, Lesueur, Loud, Machackova, Mai, Majidzadeh-A, Manoukian, Montagna, Moserle, Mulligan, Nathanson, Nevanlinna, Ngeow, Nikitina-Zake, Offit, Oláh, Osorio, Papi, Park, Pedersen, Perez-Segura, Petersen, Pinto, Porfirio, Pujana, Radice, Rantala, Rashid, Rossing, Santamariña, Schmutzler, Senter, Simard, Singer, Solano, Southey, Steele, Steinsnyder, Stoppa-Lyonnet, Tan, Teixeira, Teo, Terry, Thomassen, Toland, Tung, van Asperen, Vega, Viel, Vierstraete, Wappenschmidt, Weitzel, Wieme, Yoon, Zorn, McGuffog, Parsons, Hamann, Greene, Kirk, Neuhausen, Rebbeck, Tischkowitz, Chenevix-Trench, Antoniou, Ottini.

Statistical analysis: Silvestri, Barnes, Capalbo, Easton, Park.

Obtained funding: Buys, Couch, John, Kwong, Nathanson, Radice, Southey, Vega, Antoniou, Ottini.

Administrative, technical, or material support: Agnarsson, Aittomäki, Barkardottir, Barrowdale, Benítez, Borg, Caligo, Campbell, Claes, Colonna, Cortesi, Couch, Ding, Domchek, Evans, Foretova, Géczi, Gerdes, Glendon, Godwin, Hahnen, Hogervorst, Hopper, James, Janavicius, Joseph, Konstantopoulou, Lesueur, Loud, Machackova, Majidzadeh-A, Manoukian, Montagna, Moserle, Nathanson, Nevanlinna, Ngeow, Offit, Olopade, Papi, Pedersen, Perez-Segura, Petersen, Pinto, Pujana, Rosenzweig, Rossing, Schmutzler, Simard, Singer, Solano, Southey, Steinsnyder, Tan, Teo, Terry, Toland, Torres-Esquius, van Asperen, Vega, Vierstraete, Wappenschmidt, Wieme, McGuffog, Hamann, Greene, Neuhausen, Chenevix-Trench, Antoniou.

Study supervision: Bonanni, Caldés, de la Hoya, Foretova, Konstantopoulou, Majidzadeh-A, Oláh, Perez-Segura, Rashid, Singer, Solano, Southey, Antoniou, Friedman, Ottini.

Conflict of Interest Disclosures: Dr Andrulis reported grants from National Institutes of Health (NIH) during the conduct of the study. Dr Barrowdale reported grants from Cancer Research UK during the conduct of the study. Dr Borg reported personal fees from AstraZeneca outside the submitted work. Dr Cortesi reported personal fees from Merck Sharp & Dohme, AstraZeneca, Pfizer, Novartis, Tesaro, Clovis Oncology, and Teva Pharmaceuticals outside the submitted work. Dr Couch reported grants from NIH and Breast Cancer Research Foundation during the conduct of the study, and personal fees from Ambry Genetics, AstraZeneca, and Qiagen outside the submitted work. Dr Domchek reported personal fees from AstraZeneca, Clovis Oncology, and Bristol-Myers Squibb outside the submitted work. Dr Ejlertsen reported institutional grants from NanoString, Roche, Novartis, and Oncology Venture outside the submitted work. Dr Engel reported institutional grants from German Cancer Aid during the conduct of the study. Dr Evans reported personal fees from AstraZeneca outside the submitted work. Dr Glendon reported grants from NIH, Epidemiology and Genomics Research Program/National Cancer Institute (NCI) during the conduct of the study. Dr Godwin reported grants from NIH/NCI, National Institute of General Medical Sciences, Department of Defense, Ovarian Cancer Research Alliance, Tina’s Wish, Mary Kay Foundation, and Noah’s Bandage Project, and government contracts from Leidos Biomedical Research during the conduct of the study, and personal fees from Sinochips Diagnostics, Personal Genome Diagnostics, and NanoString outside the submitted work. Dr Hahnen reported personal fees from AstraZeneca outside the submitted work. Dr Isaacs reported grants from NCI during the conduct of the study, and grants from Tesaro and personal fees from Pfizer, AstraZeneca, and Genentech outside the submitted work. Dr Kurian reported grants from Myriad Genetics to her institution outside the submitted work. Dr Kwong reported grants from the Dr. Ellen Li Charitable Foundation and Kerry Kuok Foundation during the conduct of the study, and grants from AstraZeneca Hong Kong outside the submitted work. Dr Nevanlinna reported grants from the Finnish Cancer Society, Sigrid Juselius Foundation, and Helsinki University Hospital Research Fund during the conduct of the study, and personal fees from AstraZeneca outside the submitted work. Dr Ngeow reported grants from AstraZeneca during the conduct of the study and outside the submitted work. Dr Olopade reported serving as a cofounder of CancerIQ and on a scientific advisory board for Tempus outside the submitted work. Dr Pujana reported grants from Roche Pharma during the conduct of the study. Dr Radice reported grants from the Italian Association for Cancer Research during the conduct of the study. Dr Schmutzler reported grants from the German Cancer Society during the conduct of the study. Dr Senter reported personal fees from AstraZeneca and Clovis Oncology outside the submitted work. Dr Singer reported grants from Amgen and grants and personal fees from AstraZeneca during the conduct of the study, and grants and personal fees from Amgen, AstraZeneca, and Novartis outside the submitted work. Dr Steele reported grants from NIH NCI during the conduct of the study. Dr Terry reported grants from Columbia University (U01CA16492007) during the conduct of the study. Dr Toland reported grants and nonfinancial support from The Ohio State University during the conduct of the study and funding from the NIH and the Department of Defense. Dr Weitzel reported personal fees from AstraZeneca outside the submitted work. Dr Yoon reported grants from AstraZeneca outside the submitted work. Dr McGuffog reported grants from Cancer Research UK during the conduct of the study. Dr Antoniou reported being a creator of the Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA), which has been licensed to Cambridge Enterprise, with potential for royalties if commercialization is realized, outside the submitted work. Dr Ottini reported grants from Fondazione AIRC (Associazione Italiana Ricerca sul Cancro). No other disclosures were reported.

Funding/Support: The CIMBA data management and data analysis were supported by Cancer Research UK grants (C12292/A20861, C12292/A11174). The research leading to these results has received funding from Fondazione AIRC (Associazione Italiana Ricerca sul Cancro) under IG 2018–ID. 21389 project—P.I. Ottini Laura and Italian Ministry of Education, Universities and Research–Dipartimenti di Eccellenza-L. 232/2016. Dr Antoniou is a Cancer Research UK Senior Cancer Research Fellow. Dr Chenevix-Trench is a National Health and Medical Research Council Research Fellow. Dr Olopade is an ACS Clinical Research Professor. The work is also supported by the Breast Cancer Family Registry: UM1 CA164920 from the NCI; Lithuania (BFBOCC-LT): Research Council of Lithuania grant SEN-18/2015; BIDMC: Breast Cancer Research Foundation; CNIO: Spanish Ministry of Health PI16/00440 supported by FEDER funds, the Spanish Ministry of Economy and Competitiveness (MINECO) SAF2014-57680-R and the Spanish Research Network on Rare Diseases (CIBERER); COH-CCGCRN: Research reported in this publication was supported by the NCI of the NIH (R25CA112486, RC4CA153828) (PI: J. Weitzel); CONSIT: Fondazione AIRC (Associazione Italiana Ricerca sul Cancro, IG2014 No. 15547) to P. Radice, Italian Ministry of Health; CZ-BRCA: Supported by MH CZ-DRO (MMCI, 00209805) and to LM2018125; DEMOKRITOS: European Union (European Social Fund) and Greek national funds through the Operational Program “Education and Lifelong Learning” of the National Strategic Reference Framework—Research Funding Program of the General Secretariat for Research and Technology: SYN11_10_19 NBCA—Investing in knowledge society through the European Social Fund; DFKZ: German Cancer Research Center; EMBRACE: Cancer Research UK grants C1287/A10118 and C1287/A11990, and Dr Evans is supported by the Manchester NIHR Biomedical Research Centre (IS-BRC-1215-20007); FCCC: The University of Kansas Cancer Center (P30 CA168524) and the Kansas Bioscience Authority Eminent Scholar Program, and Dr Godwin was funded by R0 1CA140323, R01 CA214545, and by the Chancellors Distinguished Chair in Biomedical Sciences Professorship; FPGMX: the Spanish Health Research Foundation, Instituto de Salud Carlos III (ISCIII) partially supported by FEDER funds, through the Research Activity Intensification Program (contract grants INT15/00070, INT16/00154, INT17/00133), and through Centro de Investigación Biomédica en Red de Enferemdades Raras CIBERER (ACCI 2016: ER17P1AC7112/2018); Autonomous Government of Galicia (Consolidation and Structuring Program: IN607B), and by the Fundación Mutua Madrileña (call 2018); GC-HBOC: German Cancer Aid (grant 110837, Dr Schmutzler); GEMO: The GEMO resource was initially funded by the French National Institute of Cancer (INCa, PHRC Ile de France, grant AOR 01 082, 2001-2003, grant 2013-1-BCB-01-ICH-1), the Association “Le cancer du sein, parlons-en!” Award (2004), the Association for International Cancer Research (2008-2010), and the Fondation ARC pour la recherche sur le cancer (grant PJA 20151203365) and also received support from the Canadian Institute of Health Research for the “CIHR Team in Familial Risks of Breast Cancer” program (2008-2013), and the European Commission FP7, Project Collaborative Ovarian, breast and prostate Gene-environment Study (COGS), large-scale integrating project (2009-2013); GEMO is currently supported by the INCa grant SHS-E-SP 18-015. The work is also supported by Georgetown: the Non-Therapeutic Subject Registry Shared Resource at Georgetown University (NIH/NCI grant P30-CA051008), the Fisher Center for Hereditary Cancer and Clinical Genomics Research, and Swing For the Cure; HCSC: Spanish Ministry of Health PI15/00059, PI16/01292, and CB-161200301 CIBERONC from ISCIII (Spain), partially supported by European Regional Development FEDER funds; HEBCS: Helsinki University Hospital Research Fund, the Finnish Cancer Society and the Sigrid Juselius Foundation; the HEBON study is supported by the Dutch Cancer Society grants NKI1998-1854, NKI2004-3088, and NKI2007-3756, the Netherlands Organisation of Scientific Research grant NWO 91109024, the Pink Ribbon grants 110005 and 2014-187.WO76, BBMRI grant NWO 184.021.007/CP46, and the Transcan grant JTC 2012 Cancer 12-054; HRBCP: Dr Ellen Li Charitable Foundation, Kerry Kuok Foundation, and Hong Kong Hereditary Breast Cancer Family Registry; Hungarian Breast and Ovarian Cancer Study: Hungarian Research Grants KTIA-OTKA CK-80745, OTKA K-112228, and Thematic Excellence Program TUDFO/51757/2019-ITM; ICO: The authors would like to particularly acknowledge the support of the Asociación Española Contra el Cáncer (AECC), the Instituto de Salud Carlos III (organismo adscrito al Ministerio de Economía y Competitividad) and “Fondo Europeo de Desarrollo Regional (FEDER), una manera de hacer Europa” (PI10/01422, PI13/00285, PIE13/00022, PI15/00854, PI16/00563, PI18/01029 and CIBERONC) and the Institut Català de la Salut and Autonomous Government of Catalonia (2009SGR290, 2014SGR338, 2017SGR449, PERIS Project MedPerCan, and CERCA program); ILUH: Icelandic Association “Walking for Breast Cancer Research” and the Landspitali University Hospital Research Fund; IOVHBOCS: Ministero della Salute and “5x1000” Istituto Oncologico Veneto grant; IPOBCS: Liga Portuguesa Contra o Cancro; kConFab: The National Breast Cancer Foundation, and previously by the National Health and Medical Research Council, the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania and South Australia, and the Cancer Foundation of Western Australia; MAYO: NIH grants CA116167, CA192393 and CA176785, an NCI Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201), and a grant from the Breast Cancer Research Foundation; MSKCC: the Breast Cancer Research Foundation, the Robert and Kate Niehaus Clinical Cancer Genetics Initiative, the Andrew Sabin Research Fund and a Cancer Center Support Grant/Core Grant (P30 CA008748); NCI: the Intramural Research Program of the US National Cancer Institute, NIH, and by support services contracts NO2-CP-11019-50, N02-CP-21013-63 and N02-CP-65504 with Westat, Inc, Rockville, MD; OSUCCG: Ohio State University Comprehensive Cancer Center; PBCS: Italian Association of Cancer Research (AIRC) (IG 2013 N.14477), Tuscany Institute for Tumors grant 2014-2015-2016 and Fondazione Pisana per la Scienza; SEABASS: Ministry of Science, Technology and Innovation, Ministry of Higher Education (UM.C/HlR/MOHE/06) and Cancer Research Initiatives Foundation; SWE-BRCA: the Swedish Cancer Society; UCHICAGO: NCI Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA125183), R01 CA142996, 1U01CA161032 and by the Ralph and Marion Falk Medical Research Trust, the Entertainment Industry Fund National Women’s Cancer Research Alliance and the Breast Cancer Research Foundation; UPENN: Breast Cancer Research Foundation; Susan G. Komen Foundation for the Cure, Basser Center for BRCA; UPITT/MWH: Hackers for Hope Pittsburgh; VFCTG: Victorian Cancer Agency, Cancer Australia, National Breast Cancer Foundation.

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Disclaimer: The content of this manuscript does not necessarily reflect the views or policies of the NIH, NCI, or any of the collaborating centers in the Breast Cancer Family Registry, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government or the Breast Cancer Family Registry.

Additional Contributions: Nonauthor contributions to data collection, analysis, or writing/editing assistance: The following collaborators helped in data collection within their local study groups. The persons named in this section did not receive compensation for this study.

EMBRACE (Epidemiological Study of Familial Breast Cancer): The Coordinating Centre—University of Cambridge, Cambridge, UK: Douglas Easton, PhD, Antonis Antoniou, PhD, Daniel Barrowdale, BSc, Debra Frost, ONC, Joanne Perkins, Sabrina Cano-Morales, MSc. UK and Ireland Collaborating Centres—Guy’s and St Thomas’ NHS Foundation Trust, London: Louise Izatt, MD, and Vishakha Tripathi, MBBS, MSc; Central Manchester University Hospitals NHS Foundation Trust, Manchester: Gareth Evans, MD, PhD; Chapel Allerton Hospital, Leeds: Julian Adlard, MD; The Institute of Cancer Research and Royal Marsden NHS Foundation Trust, Sutton: Ros Eeles, MD, PhD; Birmingham Women’s Hospital Healthcare NHS Trust, Birmingham: Kai-Ren Ong, MD; South Glasgow University Hospitals, Glasgow: Rosemarie Davidson, MD; Addenbrooke’s Hospital, Cambridge: Marc Tischkowitz, MD, PhD; St Georges, London: Katie Snape, MD, PhD, and Helen Hanson, MD; Royal Devon and Exeter Hospital, Exeter: Carole Brewer, MD; Southampton University Hospitals NHS Trust, Southampton: Lucy E. Side, MD; Sheffield Children’s Hospital, Sheffield: Jackie Cook, MD; Newcastle Upon Tyne Hospitals NHS Trust, Newcastle: Paul Brennan, MD; Great Ormond Street Hospital for Children NHS Trust, London: Munaza Ahmed, MD(Res); Churchill Hospital, Oxford: Lisa Walker, PhD; Western General Hospital, Edinburgh: Mary Porteous, MD; St Michael’s Hospital, Bristol: Alan Donaldson, MD; Belfast City Hospital, Belfast: Patrick Morrison, MD; Nottingham University Hospitals NHS Trust, Nottingham: Jacqueline Eason, MD; University Hospital of Wales, Cardiff: Mark T. Rogers, MD; Alder Hey Hospital, Liverpool: Claire Miller, MD; Kennedy Galton Centre, Harrow: Angela Brady, MD; Trinity College Dublin and St James’s Hospital, Dublin, Ireland: David Gallagher, MD; University Hospitals of Leicester NHS Trust, Leicester: Julian Barwell, MD; NHS Grampian and University of Aberdeen, Aberdeen: Helen Gregory, MD; Glan Clwyd Hospital, Rhyl: Caroline Pottinger, MD; Singleton Hospital, Swansea: Alex Murray, MD.

FPGMX (Galician Foundation of Genomic Medicine): Ana Blanco, PhD, and Miguel Aguado, MD, Fundación Pública Galega de Medicina Xenómica, Grupo de Medicina Xenómica (USC), Santiago de Compostela, Spain; Instituto de Investigación Sanitaria de Santiago de Compostela, Spain.

GEMO (Genetic Modifiers of Cancer Risk in BRCA1/2 Mutation Carriers): GEMO is a study from the National Cancer Genetics Network UNICANCER Genetic Group, France. We wish to pay a tribute to Olga M. Sinilnikova, PhD, who with Dominique Stoppa-Lyonnet, MD, PhD, initiated and coordinated GEMO until her death on June 30, 2014. The team in Lyon (Olga Sinilnikova, PhD, Mélanie Léoné, BSc, Laure Barjhoux, BSc, Carole Verny-Pierre, BSc, Sylvie Mazoyer, PhD, Francesca Damiola, PhD, Valérie Sornin, BSc) managed the GEMO samples until the biological resource centre was transferred to Paris in December 2015 (Noura Mebirouk, BSc, Fabienne Lesueur, PhD, Dominique Stoppa-Lyonnet, MD, PhD). We want to thank all the GEMO collaborating groups for their contribution to data collection for this study: Coordinating Centre, Service de Génétique, Institut Curie, Paris, France: Muriel Belotti, BSc, Ophélie Bertrand, BSc, Anne-Marie Birot, BSc, Bruno Buecher, MD, Sandrine Caputo, PhD, Chrystelle Colas, MD, PhD, Anaïs Dupré, BSc, Emmanuelle Fourme, MD, Marion Gauthier-Villars, MD, Lisa Golmard, PhD, Marine Le Mentec, BSc, Virginie Moncoutier, BSc, Antoine de Pauw, PhD, Claire Saule, MD, Dominique Stoppa-Lyonnet, MD, PhD; and Inserm U900, Institut Curie, Paris, France: Fabienne Lesueur, PhD, Noura Mebirouk, BSc, Yue Jiao, PhD. Contributing Centres: Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Hospices Civils de Lyon—Centre Léon Bérard, Lyon, France: Nadia Boutry-Kryza, MD, Alain Calender, MD, Sophie Giraud, MD, Mélanie Léone, BSc. Institut Gustave Roussy, Villejuif, France: Brigitte Bressac-de-Paillerets, PhD, Odile Cabaret, PhD, Olivier Caron, MD, Marine Guillaud-Bataille, PhD, Etienne Rouleau, PhD. Centre Jean Perrin, Clermont-Ferrand, France: Yves-Jean Bignon, MD, Nancy Uhrhammer, MD. Centre Léon Bérard, Lyon, France: Valérie Bonadona, MD, Christine Lasset, MD. Centre François Baclesse, Caen, France: Pascaline Berthet, MD, Laurent Castera, PhD, Dominique Vaur, MD. Institut Paoli Calmettes, Marseille, France: Violaine Bourdon, BSc, Catherine Noguès, MD, Tetsuro Noguchi, MD, Cornel Popovici, PhD, Audrey Remenieras, BSc, Hagay Sobol, MD, PhD. CHU Arnaud-de-Villeneuve, Montpellier, France: Isabelle Coupier, MD, Pascal Pujol, MD. Centre Oscar Lambret, Lille, France: Claude Adenis, MD, Aurélie Dumont, MD, Françoise Révillion, MD. Centre Paul Strauss, Strasbourg, France: Danièle Muller, MD. Institut Bergonié, Bordeaux, France: Emmanuelle Barouk-Simonet, MD, Françoise Bonnet, MD, Virginie Bubien, PhD, Anne Floquet, BSc, Michel Longy, MD, Marie Louty, BSc, Cécile Maninna, BSc, Nicolas Sevenet, PhD. Institut Claudius Regaud, Toulouse, France: Laurence Gladieff, MD, Rosine Guimbaud, BSc, Viviane Feillel, BSc, Christine Toulas, MD. CHU Grenoble, France: Hélène Dreyfus, MD, Dominique Leroux, MD, Magalie Peysselon, BSc, Christine Rebischung, MD. CHU Dijon, France: Amandine Baurand, BSc, Geoffrey Bertolone, BSc, Fanny Coron, BSc, Laurence Faivre, MD, PhD, Caroline Jacquot, BSc, Sarab Lizard, MD. CHU St-Etienne, France: Caroline Kientz, MD, Marine Lebrun, BSc, Fabienne Prieur, MD. Hôtel Dieu Centre Hospitalier, Chambéry, France: Sandra Fert-Ferrer, MD. Centre Antoine Lacassagne, Nice, France: Véronique Mari, MD. CHU Limoges, France: Laurence Vénat-Bouvet, MD. CHU Nantes, France: Stéphane Bézieau, MD, Capucine Delnatte, MD. CHU Bretonneau, Tours and Centre Hospitalier de Bourges France: Isabelle Mortemousque, MD. Groupe Hospitalier Pitié-Salpêtrière, Paris, France: Florence Coulet, PhD, Mathilde Warcoin, BSc. CHU Vandoeuvre-les-Nancy, France: Myriam Bronner, BSc, Johanna Sokolowska, MD. CHU Besançon, France: Marie-Agnès Collonge-Rame, MD. CHU Poitiers, Centre Hospitalier d’Angoulême and Centre Hospitalier de Niort, France: Paul Gesta, MD. Centre Hospitalier de La Rochelle: Hakima Lallaoui, MD. CHU Nîmes Carémeau, France: Jean Chiesa, MD. CHI Poissy, France: Denise Molina-Gomes, MD. CHU Angers, France: Olivier Ingster, MD. CHU de Martinique, France: Odile Bera, MD; Mickaelle Rose, MD.

HEBCS (Helsinki Breast Cancer Family Study): Taru A Muranen, PhD, Helsinki University Hospital and University of Helsinki, Department of Obstetrics and Gynecology; Carl Blomqvist, MD, PhD, Helsinki University Hospital and University of Helsinki, Department of Oncology.

HEBON (Hereditary Breast and Ovarian Cancer Research Group Netherlands): HEBON consists of the following Collaborating Centers: Netherlands Cancer Institute (coordinating center), Amsterdam, NL: Matti A. Rookus, PhD, Flora E. van Leeuwen, PhD, Muriel A. Adank, PhD, Marjanka K. Schmidt, PhD, Denise J. Jenner, MSc; Erasmus Medical Center, Rotterdam, NL: J. Margriet Collée, PhD, Ans M.W. van den Ouweland, PhD, Maartje J. Hooning, PhD, Ingrid A. Boere, PhD; Leiden University Medical Center, NL: Peter Devilee, PhD, Rob B. van der Luijt, PhD, Twiggy C.T.E.F. van Cronenburg; Radboud University Nijmegen Medical Center, NL: Marijke R. Wevers, PhD, Arjen R. Mensenkamp, PhD; University Medical Center Utrecht, NL: Margreet G.E.M. Ausems, PhD, Marco J. Koudijs, PhD; Amsterdam Medical Center, NL: Theo A.M. van Os, PhD; VU University Medical Center, Amsterdam, NL: Klaartje van Engelen, PhD, Hans J.P. Gille, PhD; Maastricht University Medical Center, NL: Encarna B. Gómez-Garcia, PhD, Rien J. Blok, PhD, Maaike de Boer, PhD; University of Groningen, NL: Lieke P.V. Berger, MD, Annemieke H. van der Hout, PhD, Marian J.E. Mourits, PhD, Truuske H. de Bock, PhD; the Netherlands Comprehensive Cancer Organisation (IKNL): Sabine Siesling, PhD, Janneke Verloop, PhD; The nationwide network and registry of histo- and cytopathology in the Netherlands (PALGA): Esther C. van den Broek, PhD. HEBON thanks the study participants and the registration teams of IKNL and PALGA for part of the data collection.

HUNBOCS (Hungarian Breast and Ovarian Cancer Study): János Papp, PhD, Department of Molecular Genetics, National Institute of Oncology, Budapest, Hungary, Role: BRCA1/2 mutation analysis (coordination and data analysis for NGS studies), Anikó Bozsik, PhD, Department of Molecular Genetics, National Institute of Oncology, Budapest, Hungary, Role: BRCA1/2 mutation analysis (MLPA; NGS), Timea Pócza, PhD, Department of Molecular Genetics, National Institute of Oncology, Budapest, Hungary, Role: BRCA1/2 mutation analysis (NGS).

kConFab (Kathleen Cuningham Foundation Consortium for Research into Familial Aspects of Breast Cancer): David Amor, PhD, Medical Geneticist Genetic Health Services Victoria Royal Children’s Hospital Melbourne, VIC; Lesley Andrews, MBBS, Hereditary Cancer Clinic Prince of Wales Hospital Randwick, NSW; Yoland Antill, PhD, Department of Haematology and Medical Oncology, Peter MacCallum Cancer Centre East Melbourne, VIC; Rosemary Balleine, PhD, FRCPA, Department of Translational Oncology, C/o Department of Medical Oncology Westmead Hospital, Westmead, NSW; Jonathan Beesley, PhD, Research Officer, Queensland Institute of Medical Research, Herston, QLD; Ian Bennett, FACS, Brisbane, QLD; Michael Bogwitz, PhD, Familial Cancer Centre, The Royal Melbourne Hospital, Parkville, VIC; Leon Botes, PhD, Clinical Nurse Specialist, Hereditary Cancer Centre, Prince of Wales Hospital, Randwick NSW; Meagan Brennan, PhD, NSW Breast Cancer Institute, Westmead NSW; Melissa Brown, PhD, Department of Biochemistry, University of Queensland, St Lucia, QLD; Michael Buckley, PhD, FRCPA, Molecular and Cytogenetics Unit, Prince of Wales Hospital, Randwick, NSW; Jo Burke, PhD, Royal Hobart Hospital, Hobart, TAS; Phyllis Butow, PhD, Medical Psychology Unit, Royal Prince Alfred Hospital, Camperdown, NSW; Liz Caldon, PhD, Replication and Genome Stability, Cancer Division, Garvan Institute of Medical Research, Darlinghurst, NSW; Ian Campbell, PhD, Peter MacCallum Cancer Centre, East Melbourne, VIC; Deepa Chauhan, PhD, School of Psychology, Brennan McCallum University of Sydney, NSW; Manisha Chauhan, GDip Gen Couns, St Vincent’s Hospital, Cancer Genetics Clinic, The Kinghorn Cancer Centre, Sydney, NSW; Georgia Chenevix-Trench, PhD, Queensland Institute of Medical Research, Royal Brisbane Hospital, Herston, QLD; Alice Christian, PhD, Genetics Department, Central Region Genetics Service, Wellington Hospital, New Zealand; Paul Cohen, MD, Director of Gynaecological Cancer Research, St John of God Subiaco Hospital, Subiaco, WA; Alison Colley, PhD, Department of Clinical Genetics, Liverpool Health Service, Liverpool, NSW; Ashley Crook, GDip Gen Couns, Department of Clinical Genetics, Royal North Shore Hospital, St Leonards, NSW; James Cui, PhD, Epidemiology and Preventive Medicine, Monash University, Prahan, VIC; Margaret Cummings, PhD, FRCPA, Department of Pathology, University of Queensland Medical School, Herston, NSW; Sarah-Jane Dawson, PhD, Molecular Genetics Department, Cambridge University, England; Anna deFazio, PhD, Department of Gynaecological Oncology, Westmead Institute for Cancer Research, Westmead Hospital, Westmead, NSW; Martin Delatycki, PhD, Director, Clinical Genetics, Austin Health Heidelberg Repatriation Hospital, Heidelberg West, VIC; Rebecca Dickson, GDip Gen Couns, Associate Genetic Counsellor, Royal North Shore Hospital, North Shore, NSW; Joanne Dixon, FRACP, Central Regional Genetic Services, Wellington Hospital, Wellington, New Zealand; Ted Edkins, PhD, Clinical Chemistry, Princess Margret Hospital for Children, Perth, WA; Stacey Edwards, PhD, Department of Biochemistry and Molecular Biology, University of Queensland, St Lucia, QLD; Gelareh Farshid, PhD, FRCPA, Tissue Pathology, IMVS, Adelaide, SA; Andrew Fellows, PhD, Molecular Diagnostic Development, Pathology Department, Peter MacCallum Cancer Centre, East Melbourne, VIC; Georgina Fenton, GDip Gen Couns, South West Family Cancer Clinic, Liverpool Hospital, Liverpool, BC, NSW; Michael Field, PhD, Clinical Geneticist, Royal North Shore Hospital, St Leonards, NSW; James Flanagan, PhD, Epigenetics Unit Department of Surgery and Oncology, Imperial College, London, England; Peter Fong, FRACP, Medical Oncology Department, Regional Cancer and Blood Services, Auckland City Hospital, Auckland, New Zealand; Laura Forrest, PhD, Psychosocial Cancer Genetics Research Group, Parkville Familial Cancer Centre, Melbourne, VIC; Stephen Fox, FRCPA, Pathology Department, Peter MacCallum Cancer Centre, East Melbourne, VIC; Juliet French, PhD, School of Molecular and Microbial Sciences, University of Queensland, St Lucia, QLD; Michael Friedlander, PhD, Professor of Medicine, Department of Medical Oncology, Prince of Wales Hospital, Randwick, NSW; Clara Gaff, PhD, Victorian Clinical Genetics Service, Royal Melbourne Hospital, Parkville, VIC; Mike Gattas, FRACP, Queensland Clinical Genetic Service, Royal Children’s Hospital, Bramston Terrace, Herston, QLD; Peter George, PhD, Clinical Biochemistry Unit, Canterbury Health Labs, Christchurch, New Zealand; Sian Greening, GDip Gen Couns, Illawarra Cancer Centre, Wollongong Hospital, South Coast Mail Centre, NSW; Marion Harris, FRACP, Familial Cancer Clinic, Peter MacCallum Cancer Centre, East Melbourne, VIC; Stewart Hart, FRACS, Breast and Ovarian Cancer Genetics, Monash Medical Centre, Bentleigh, East VIC; Nick Hayward, PhD, Queensland Institute for Medical Research, Royal Brisbane Hospital Post Office, Herston, QLD; John Hopper, PhD, Centre for M.E.G.A. Epidemiology University of Melbourne, Carlton, VIC; Cass Hoskins, BSci, Parkville Familial Cancer Centre, Peter MacCallum Cancer Centre & The Royal Melbourne Hospital, Melbourne; Clare Hunt, GDip Gen Couns, Southern Health Familial Cancer Centre, Monash Medical Centre, Clayton, Victoria; Paul James, PhD, Clinical Geneticist, Genetic Health Services, Monash Medical Centre, Clayton, VIC; Mark Jenkins, PhD, Centre for M.E.G.A. Epidemiology, The University of Melbourne, Carlton, VIC; Alexa Kidd, MRCGP, Clinical Genetics Departments, Central Regional Genetics Service, Wellington Hospital, New Zealand; Judy Kirk, PhD, Familial Cancer Service, Department of Medicine, Westmead Hospital, Westmead, NSW; Jessica Koehler, GDip Gen Couns, Hereditary Cancer Clinic, Prince of Wales Hospital, Randwick, NSW; James Kollias, FRACS, Breast Endocrine and Surgical Unit, Royal Adelaide Hospital, North Terrace, SA; Sunil Lakhani, MD, UQ Centre for Clinical Research, University of Queensland, The Royal Brisbane & Women’s Hospital, Herston, QLD; Mitchell Lawrence, PhD, Prostate Cancer Research Program, Monash University, Clayton; Geoff Lindeman, PhD, Breast Cancer Laboratory, Walter and Eliza Hall Institute PO Royal Melbourne Hospital, Parkville, VIC; Lara Lipton, PhD, Medical Oncology and Clinical Haematology Unit, Western Hospital, Footscray, VIC; Liz Lobb, PhD, Medical Psychology Research Unit, The University of Sydney, Camperdown, NSW; Graham Mann, PhD, Westmead Institute for Cancer Research, Westmead Millennium Institute, Westmead, NSW; Deborah Marsh, PhD, Kolling Institute of Medical Research, Royal North Shore Hospital, St Leonards, NSW; Sue Anne McLachlan, PhD, Department of Oncology, St Vincent’s Hospital, Fitzroy, VIC; Bettina Meiser, PhD, Hereditary Cancer Clinic, Prince of Wales Hospital, Randwick, NSW; Roger Milne, PhD, Centro Nacional de Investigaciones Oncologicas, Madrid, Spain; Sophie Nightingale, FRACS, Western Health and Peter MacCallum Cancer Centre, Consultant, General, Breast and Melanoma Surgeon, St Andrew’s Place, East Melbourne, Victoria; Shona O’Connell, GDip Gen Couns, Southern Health Familial Cancer Centre, Special Medicine Building, Clayton, VIC; Sarah O’Sullivan, GDip Gen Couns, Genetic Services of Western Subiaco, WA; David Gallego Ortega, PhD, Tumour Development Group, Garvan Institute of Medical Research, The Kinghorn Cancer Centre, Darlinghurst, NSW; Nick Pachter, MBChB, Familial Cancer and Clinical Genetics, Royal Melbourne Hospital, Parkville, VIC; Briony Patterson, GDip Gen Couns, Tas Clinical Genetics Service, Royal Hobart Hospital, Hobart, Tasmania; Amy Pearn, GDip Gen Couns, The Gene Council, Perth, North Perth, WA; Kelly Phillips, FRACP, Department of Medical Oncology, Peter MacCallum Cancer Centre, East Melbourne, VIC; Ellen Pieper, GDip Gen Couns, Associate Genetic Counsellor, Parkville Familial Cancer Centre and Genomic Medicine, Melbourne, VIC; Edwina Rickard, GDip Gen Couns, Familial Cancer Centre, Westmead Hospital, Westmead, NSW; Bridget Robinson, MD, FRACP, Oncology Service Christchurch Hospital, Christchurch, New Zealand; Mona Saleh, PhD, Centre for Genetic Education, Prince of Wales Hospital, Randwick, NSW; Elizabeth Salisbury, FRCPA, Anatomical Pathology, Conjoint Associate Professor, UNSW Prince of Wales Hospital, Randwick, NSW; Christobel Saunders, FAAHMS, School of Surgery and Pathology Medical Centre, Nedlands, WA; Jodi Saunus, PhD, Breast Pathology, University of Queensland Centre for Clinical Research, Royal Brisbane and Women’s Hospital, Herston, QLD; Rodney Scott, PhD, Hunter Area Pathology Service, John Hunter Hospital, NSW; Clare Scott, PhD, Research Department, WEHI C/o Royal Melbourne Hospital, Parkville, VIC; Adrienne Sexton, GDip Gen Couns, Familial Cancer Centre, Royal Melbourne Hospital, Parkville, VIC; Andrew Shelling, PhD, Obstetrics and Gynaecology, University of Auckland, New Zealand; Peter Simpson, The University of Queensland, RBWH Campus, Herston, QLD; Melissa Southey, PhD, Genetic Epidemiology Laboratory Department of Pathology, University of Melbourne, VIC; Amanda Spurdle, PhD, Cancer Unit, Queensland Institute of Medical Research, Herston, QLD; Jessica Taylor, GDip Gen Couns, Familial Cancer and Genetics Medicine, Royal Melbourne Hospital, Parkville, VIC; Renea Taylor, PhD, Deputy Head, Cancer Program, Monash University, Clayton VIC; Heather Thorne, Grad Dip Clin Res, Research Department, Peter MacCallum Cancer Centre, East Melbourne, VIC; Alison Trainer, PhD, University of NSW, Prince of Wales Hospital, Randwick, NSW; Kathy Tucker, FRACP, Heredity Cancer Clinic, Prince of Wales Hospital, Randwick, NSW; Jane Visvader, PhD, The Walter and Eliza Hall Institute of Medical Research, Post Office Royal Melbourne Hospital, Parkville, VIC; Logan Walker, PhD, Molecular Cancer Epidemiology Laboratory, Queensland Institute of Medical Research, PO Royal Brisbane Hospital, Herston, QLD; Rachael Williams, GDip Gen Couns, Family Cancer Clinic, St Vincent’s Hospital, Darlinghurst, NSW; Ingrid Winship, FAICD, Department of Genetics, Royal Melbourne Hospital, Parkville, VIC; Mary Ann Young, MHSc, Genome.One, NSW.