# Spectrum and Frequency of Germline FANCM Protein-Truncating Variants in 44,803 European Female Breast Cancer Cases

Gisella Figlioli, Amandine Billaud, Qin Wang, Manjeet K Bolla, Joe Dennis, Michael Lush, Anders Kvist, Muriel A Adank, Thomas U Ahearn, Natalia N Antonenkova, et al.

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## To cite this version:

Gisella Figlioli, Amandine Billaud, Qin Wang, Manjeet K Bolla, Joe Dennis, et al.. Spectrum and Frequency of Germline FANCM Protein-Truncating Variants in 44,803 European Female Breast Cancer Cases. Cancers, 2023, 15 (13), 10.3390/cancers15133313. [hal-04191503](https://hal.science/hal-04191503v1)

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Submitted on 11 Sep 2023

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Communication

# Spectrum and Frequency of Germline FANCM Protein-Truncating Variants in 44,803 European Female Breast Cancer Cases

Gisella Figlioli <fnref n="1" />, Amandine Billaud <fnref n="1" />, Qin Wang <fnref n="2" />, Manjeet K. Bolla <fnref n="2" />, Joe Dennis <fnref n="2" />, Michael Lush <fnref n="2" />, Anders Kvist <fnref n="3" />, Muriel A. Adank <fnref n="4" />, Thomas U. Ahearn <fnref n="5" />, Natalia N. Antonenkova <fnref n="6" />, Päivi Auvinen <fnref n="7" />,<fnref n="8" />,<fnref n="9" />, Sabine Behrens <fnref n="10" />, Marina Bermisheva <fnref n="11" />, Natalia V. Bogdanova <fnref n="6" />,<fnref n="12" />,<fnref n="13" />, Stig E. Bojesen <fnref n="14" />,<fnref n="15" />,<fnref n="16" />, Bernardo Bonanni <fnref n="17" />, Thomas Brüning <fnref n="18" />, Nicola J. Camp <fnref n="19" />, Archie Campbell <fnref n="20" />,<fnref n="21" />, Jose E. Castelao ²², Melissa H. Cessna ²³, NBCS Collaborators ²⁴,²⁵,²⁶,²⁷,²⁸,²⁹,³⁰,³¹,³²,³³,³⁴,³⁵, Kamila Czene ³⁶, Peter Devilee ³⁷,³⁸, Thilo Dörk <fnref n="13" />, Mikael Eriksson ³⁶, Peter A. Fasching ³⁹, Henrik Flyger ⁴⁰, Marike Gabrielson ³⁶, Manuela Gago-Dominguez ⁴¹, Montserrat García-Closas <fnref n="5" />, Gord Glendon ⁴²,⁴³, Encarna B. Gómez Garcia ⁴⁴, Anna González-Neira ⁴⁵, Felix Grassmann ³⁶,⁴⁶, Pascal Guénel ⁴⁷, Eric Hahnen ⁴⁸,⁴⁹, Ute Hamann ⁵⁰, Peter Hillemanns <fnref n="13" />, Maartje J. Hooning ⁵¹, Reiner Hoppe ⁵²,⁵³, Anthony Howell ⁵⁴, Keith Humphreys ³⁶, kConFab Investigators ⁵⁵,⁵⁶, Anna Jakubowska ⁵⁷,⁵⁸, Elza K. Khusnutdinova <fnref n="11" />,⁵⁹, Vessela N. Kristensen ²⁵,⁶⁰, Annika Lindblom ⁶¹,⁶², Maria A. Loizidou ⁶³, Jan Lubiński ⁵⁷, Arto Mannermaa <fnref n="7" />,⁶⁴,⁶⁵, Tabea Maurer ⁶⁶, Dimitrios Mavroudis ⁶⁷, William G. Newman ⁶⁸,⁶⁹, Muhammad U. Rashid ⁵⁰,⁷², Valerie Rhenius ⁷³, Matthias Ruebner ³⁹, Emmanouil Saloustros ⁷⁴, Elinor J. Sawyer ⁷⁵, Marjanka K. Schmidt ⁷⁶,⁷⁷,⁷⁸, Rita K. Schmutzler ⁴⁸,⁴⁹,⁷⁹, Mitul Shah ⁷³, Melissa C. Southey ⁸⁰,⁸¹,⁸², Ian Tomlinson ⁸³, Thérèse Truong ⁴⁷, Elke M. van Veen ⁶⁸,⁶⁹, Camilla Wendt ⁸⁴, Xiaohong R. Yang <fnref n="5" />, Kyriaki Michailidou <fnref n="2" />,²⁷, Alison M. Dunning ⁷³, Paul D. P. Pharoah <fnref n="2" />,⁷³,⁸⁵, Douglas F. Easton <fnref n="2" />,⁷³, Irene L. Andrulis ⁴²,⁸⁶, D. Gareth Evans ⁶⁸,⁶⁹, Antoinette Hollestelle ⁵¹, Jenny Chang-Claude <fnref n="10" />,⁶⁶, Roger L. Milne ⁸⁰,⁸²,⁸⁷ and Paolo Peterlongo <fnref n="1" />,*

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**Citation:** Figlioli, G.; Billaud, A.; Wang, Q.; Bolla, M.K.; Dennis, J.; Lush, M.; Kvist, A.; Adank, M.A.; Ahearn, T.U.; Antonenkova, N.N.; et al. Spectrum and Frequency of Germline FANCM Protein-Truncating Variants in 44,803 European Female Breast Cancer Cases. *Cancers* **2023**, *15*, 3313. https://doi.org/10.3390/cancers15133313

Academic Editor: David Wong

Received: 17 April 2023

Revised: 30 May 2023

Accepted: 2 June 2023

Published: 23 June 2023

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**Copyright:** © 2023 by the authors.
Licensee MDPI, Basel, Switzerland.
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4.0/).

<footnote n="1">¹ Genome Diagnostics Program, IFOM ETS—The AIRC Institute of Molecular Oncology, 20139 Milan, Italy; gisella.figlioli@ifom.eu (G.F.)</footnote>

<footnote n="2">² Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK</footnote>

<footnote n="3">³ Division of Oncology, Department of Clinical Sciences Lund, Lund University, 22185 Lund, Sweden</footnote>

<footnote n="4">⁴ The Netherlands Cancer Institute—Antoni van Leeuwenhoek Hospital, Family Cancer Clinic, 1066 CX Amsterdam, The Netherlands</footnote>

<footnote n="5">5 Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health (NIH), Department of Health and Human Services, Bethesda, MD 20892, USA</footnote>

<footnote n="6">6 N.N. Alexandrov Research Institute of Oncology and Medical Radiology, 223040 Minsk, Belarus</footnote>

<footnote n="7">7 Translational Cancer Research Area, University of Eastern Finland, 70210 Kuopio, Finland</footnote>

<footnote n="8">8 Institute of Clinical Medicine, Oncology, University of Eastern Finland, 70210 Kuopio, Finland</footnote>

<footnote n="9">9 Department of Oncology, Cancer Center, Kuopio University Hospital, 70210 Kuopio, Finland</footnote>

<footnote n="10">10 Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany</footnote>

<footnote n="11">11 Institute of Biochemistry and Genetics of the Ufa Federal Research Centre of the Russian Academy of Sciences, 450054 Ufa, Russia</footnote>

<footnote n="12">12 Department of Radiation Oncology, Hannover Medical School, 30625 Hannover, Germany</footnote>

<footnote n="13">13 Gynaecology Research Unit, Hannover Medical School, 30625 Hannover, Germany</footnote>

<footnote n="14">14 Copenhagen General Population Study, Copenhagen University Hospital, Herlev and Gentofte Hospital, 2730 Herlev, Denmark</footnote>

<footnote n="15">15 Department of Clinical Biochemistry, Copenhagen University Hospital, Herlev and Gentofte Hospital, 2730 Herlev, Denmark</footnote>

<footnote n="16">16 Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark</footnote>

<footnote n="17">17 Division of Cancer Prevention and Genetics, IEO, European Institute of Oncology IRCCS, 20141 Milan, Italy</footnote>

<footnote n="18">18 Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum (IPA), 44789 Bochum, Germany</footnote>

<footnote n="19">19 Department of Internal Medicine and Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA</footnote>

<footnote n="20">20 Centre for Genomic and Experimental Medicine, Institute of Genetics & Cancer, University of Edinburgh, Edinburgh EH4 2XU, UK</footnote>

<footnote n="21">21 Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh EH16 4UX, UK</footnote>
22 Oncology and Genetics Unit, Instituto de Investigación Sanitaria Galicia Sur (IISGS), Xerencia de Xestión Integrada de Vigo-SERGAS, 36312 Vigo, Spain

23 Intermountain Health, Salt Lake City, UT 84111, USA

24 Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital-Radiumhospitalet, 0379 Oslo, Norway

25 Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, 0450 Oslo, Norway

26 Department of Research, Vestre Viken Hospital, 3019 Drammen, Norway

27 Biostatistics Unit, The Cyprus Institute of Neurology & Genetics, 2371 Nicosia, Cyprus

28 Section for Breast- and Endocrine Surgery, Department of Cancer, Division of Surgery, Cancer and Transplantation Medicine, Oslo University Hospital-Ullevål, 0450 Oslo, Norway

29 Department of Radiology and Nuclear Medicine, Oslo University Hospital, 0379 Oslo, Norway

30 Department of Pathology, Akershus University Hospital, 1478 Lørenskog, Norway

31 Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, 0379 Oslo, Norway

32 Department of Oncology, Division of Surgery, Cancer and Transplantation Medicine, Oslo University Hospital-Radiumhospitalet, 0379 Oslo, Norway

33 National Advisory Unit on Late Effects after Cancer Treatment, Oslo University Hospital, 0379 Oslo, Norway

34 Department of Oncology, Akershus University Hospital, 1478 Lørenskog, Norway

35 Oslo Breast Cancer Research Consortium, Oslo University Hospital, 0379 Oslo, Norway

36 Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, 171 76 Stockholm, Sweden

37 Department of Pathology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands

38 Department of Human Genetics, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands

39 Department of Gynecology and Obstetrics, University Hospital Erlangen, Comprehensive Cancer Center Erlangen-EMN, Friedrich-Alexander University Erlangen-Nuremberg, 91054 Erlangen, Germany

40 Department of Breast Surgery, Copenhagen University Hospital, Herlev and Gentofte Hospital, 2730 Herlev, Denmark

41 Instituto de Investigación Sanitaria de Santiago de Compostela (FIDIS) Foundation, IDIS Cancer Genetics and Epidemiology Group, Genomic Medicine Group, Complejo Hospitalario Universitario de Santiago, SERGAS, 15706 Santiago de Compostela, Spain

42 Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Fred A. Litwin Center for Cancer Genetics, Toronto, ON M5G 1X5, Canada

43 Laboratory Medicine Program, University Health Network, Toronto, ON M5G 2C4, Canada

44 Department of Clinical Genetics, Maastricht University Medical Center, 6229 HX Maastricht, The Netherlands

45 Human Genotyping Unit-CeGen, Spanish National Cancer Research Centre (CNIO), 28029 Madrid, Spain

46 Department of Medicine, Institute for Clinical Research and Systems Medicine, Health and Medical University, 14467 Potsdam, Germany

47 CESP U1018, Inserm "Exposome, Heredity, Cancer and Health" Team, UVSQ, University Paris-Saclay, Gustave Roussy, 94805 Villejuif, France

48 Center for Familial Breast and Ovarian Cancer, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50937 Cologne, Germany

49 Center for Integrated Oncology (CIO), Faculty of Medicine and University Hospital Cologne, University of Cologne, 50937 Cologne, Germany

50 German Cancer Research Center (DKFZ), Molecular Genetics of Breast Cancer, 69120 Heidelberg, Germany

51 Department of Medical Oncology, Erasmus MC Cancer Institute, 3015 GD Rotterdam, The Netherlands

52 Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, 70376 Stuttgart, Germany

53 University of Tübingen, 72074 Tübingen, Germany

54 Division of Cancer Sciences, University of Manchester, Manchester M13 9PL, UK

55 Research Department, Peter MacCallum Cancer Center, Melbourne, VIC 3000, Australia

56 Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3000, Australia

57 Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University in Szczecin, 71-252 Szczecin, Poland

58 Independent Laboratory of Molecular Biology and Genetic Diagnostics, Pomeranian Medical University in Szczecin, 71-252 Szczecin, Poland

59 Department of Genetics and Fundamental Medicine, Ufa University of Science and Technology, 450076 Ufa, Russia

60 Department of Medical Genetics, Oslo University Hospital and University of Oslo, 0379 Oslo, Norway

61 Department of Molecular Medicine and Surgery, Karolinska Institutet, 171 76 Stockholm, Sweden

62 Department of Clinical Genetics, Karolinska University Hospital, 171 76 Stockholm, Sweden

63 Department of Cancer Genetics, Therapeutics and Ultrastructural Pathology, The Cyprus Institute of Neurology & Genetics, 2371 Nicosia, Cyprus

64 Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, 70210 Kuopio, Finland

65 Kuopio University Hospital, Biobank of Eastern Finland, 70210 Kuopio, Finland
66 Cancer Epidemiology Group, University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany

67 Department of Medical Oncology, University Hospital of Heraklion, 711 10 Heraklion, Greece

68 Division of Evolution, Infection and Genomics, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PL, UK

69 Manchester Centre for Genomic Medicine, St. Mary's Hospital, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester M13 9WL, UK

70 University Medical Center Hamburg-Eppendorf, Institute for Medical Biometry and Epidemiology, 20246 Hamburg, Germany

71 Unit of 'Predictive Medicine: Molecular Bases of Genetic Risk', Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori (INT), 20133 Milan, Italy

72 Department of Basic Sciences, Shaukat Khanum Memorial Cancer Hospital and Research Centre (SKMCH & RC), Lahore 54000, Pakistan

73 Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge CB1 8RN, UK

74 Department of Oncology, University Hospital of Larissa, 411 10 Larissa, Greece

75 King's College London, School of Cancer & Pharmaceutical Sciences, Comprehensive Cancer Centre, Guy's Campus, London SE1 9RT, UK

76 Division of Molecular Pathology, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands

77 Division of Psychosocial Research and Epidemiology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, 1066 CX Amsterdam, The Netherlands

78 Department of Clinical Genetics, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands

79 Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany

80 Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC 3168, Australia

81 Department of Clinical Pathology, The University of Melbourne, Melbourne, VIC 3000, Australia

82 Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, VIC 3004, Australia

83 Cancer Research Centre, The University of Edinburgh, Edinburgh EH4 2XU, UK

84 Department of Clinical Science and Education, Karolinska Institutet, Södersjukhuset, 118 83 Stockholm, Sweden

85 Department of Computational Biomedicine, Cedars-Sinai Medical Center, West Hollywood, CA 90069, USA

86 Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada

87 Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, VIC 3010, Australia

* Correspondence: paolo.peterlongo@ifom.eu; Tel.: +39-02-57430-3867

**Simple Summary:** Mutations in the *FANCM* gene may cause a particular type of breast cancer known as ER-negative. In this study, we describe the geographic distribution of 66 different *FANCM* mutations identified in 44,803 female breast cancer cases from Europe, USA, Canada and Australia. We found that the *FANCM*:p.Gln1701* mutation is most common in Northern Europe and has lower frequencies in Southern European countries. In contrast, the *FANCM*:p.Gly1906Alafs*12 mutation is most common in Southern Europe and rarer in Central and Northern Europe. We found that the *FANCM*:p.Arg658* mutation is most prevalent in Central Europe and that the *FANCM*:p.Gln498Thrfs*7 mutation originates from Lithuania. Finally, we showed that many and varied *FANCM* mutations are present in Southwestern and Central Europeans while a much more limited range of mutations is present in Northeastern Europeans. The knowledge of this geographic distribution of *FANCM* mutations is important to establish more efficient genetic testing strategies in specific populations.

**Abstract:** FANCM germline protein truncating variants (PTVs) are moderate-risk factors for ER-negative breast cancer. We previously described the spectrum of FANCM PTVs in 114 European breast cancer cases. In the present, larger cohort, we report the spectrum and frequency of four common and 62 rare FANCM PTVs found in 274 carriers detected among 44,803 breast cancer cases. We confirmed that p.Gln1701* was the most common PTV in Northern Europe with lower frequencies in Southern Europe. In contrast, p.Gly1906Alafs*12 was the most common PTV in Southern Europe with decreasing frequencies in Central and Northern Europe. We verified that p.Arg658* was prevalent in Central Europe and had highest frequencies in Eastern Europe. We also confirmed that the fourth most common PTV, p.Gln498Thrfs*7, might be a founder variant from
Lithuania. Based on the frequency distribution of the carriers of rare PTVs, we showed that the FANCM PTVs spectra in Southwestern and Central Europe were much more heterogeneous than those from Northeastern Europe. These findings will inform the development of more efficient FANCM genetic testing strategies for breast cancer cases from specific European populations.

**Keywords:** breast cancer predisposition; breast cancer risk factors; FANCM PTVs spectrum; protein truncating variants; PTVs

# 1. Introduction

Breast cancer is a common disease in which up to 25% of the cases are expected to be caused by genetic risk factors [1]. Germline pathogenic variants in the *BRCA1* and *BRCA2* genes are associated with high risks of developing breast cancer. Specifically, the cumulative risks for the disease by age 80 were estimated to be 72% and 69% in women with a *BRCA1* or *BRCA2* pathogenic variant, respectively [2]. Since the identification of *BRCA1* and *BRCA2* thirty years ago, many other genes have been proposed to be associated with moderate to high risk for breast cancer; however, limited and sometimes contradictory findings from studies have impeded a conclusive annotation. In 2020, modified segregation analyses performed in 524 breast cancer families with pathogenic variants in *PALB2* confirmed that this gene confers a risk for breast cancer that is comparable to that of *BRCA2* [3]. One year later, two very large association studies were conducted, and several known and putative predisposition genes were sequenced in a total of more than 178,000 female breast cancer cases and controls [4,5]. The unprecedented statistical power of such large datasets enabled confirmation that protein-truncating variants (PTVs) in *BRCA1*, *BRCA2*, *PALB2* and the Li-Fraumeni syndrome gene *TP53* confer high risk for breast cancer. In addition, these data clarified that PTVs in *BARD1*, *RAD51C* and *RAD51D* are associated with moderate risk of estrogen receptor ER-negative breast cancer and that PTVs in *ATM* and *CHEK2* are associated with moderate risk of ER-positive breast cancer [4,5].

The above-mentioned breast cancer predisposition genes have been tested worldwide and many founder variants, and variants prevalent in specific ethnic or geographic groups, have been described. This knowledge could be used to inform first pass genetic screening and more efficient strategies for genetic testing in specific populations. The prevalence and spectrum of *BRCA1* and *BRCA2* pathogenic variants have been reported in many different populations. Probably the two largest studies conducted so far in these genes are based one on pathogenic variants found in more than 29,000 families from 49 countries, and the other in families from the Middle East, North Africa and Southern Europe [6,7]. Comprehensive analyses of the mutational spectra of *PALB2*, *BARD1*, *RAD51C* and *RAD51D* were described in three systematic reviews including 151 [8], 123 [9] and 101 [10] studies. Finally, a study of the mutational spectrum of *CHEK2* pathogenic variants was recently conducted, but was limited to the Baltic states [11].

While there is a consensus that the genes to be screened to predict the individual risk for breast cancer in diagnostic setting should be *BRCA1*, *BRCA2*, *PALB2*, *TP53*, *BARD1*, *RAD51C*, *RAD51D*, *ATM* and *CHEK2*, other predisposing genes, such as *FANCM*, are yet to be validated [12]. Burden analyses derived from *FANCM* sequencing, but also genotyping of the single most common variants, have shown that *FANCM* PTVs are generally associated with ER-negative or triple-negative breast cancer (TNBC, reviewed in [13]). In particular, the strongest association for these disease subtypes in Europeans is with the common p.Arg658* (c.1972C>T) variant, which truncates the 2048 amino acid FANCM protein at the N-terminus [14]. The risks associated with the other common FANCM PTVs p.Gln1701* (c.5101C>T) and p.Gly1906Alafs*12 (c.5791C>T, also known as p.Arg1931* [15]), which truncate the FANCM protein at the C-terminus, appear, in Europeans, to be of lower magnitude or have not been conclusively assessed. However, p.Gln1701* and p.Gly1906Alafs*12 PTVs have been associated with risk for ER-negative and TNBC subtypes in Finnish
women [16,17], which we speculate might be due to population-specific variants acting as risk modifiers [13].

We previously described the spectrum of 27 different *FANCM* germline PTVs found in 114 female breast cancer cases ascertained from 13 European countries [18]. In the present study, we analyzed *FANCM* sequencing data from 44,803 female breast cancer cases from 16 European countries and from USA, Canada and Australia, reported the frequency of PTV carriers, and described the spectrum of the 66 different *FANCM* germline PTVs that were found in the 274 carriers.

**2. Materials and Methods**

The 44,803 breast cancer cases included in the present analysis were originally ascertained by 39 studies from 16 European countries and from USA, Canada and Australia that participated in the BRIDGES study (https://bridges-research.eu/, Supplementary Table S1). All these breast cancer cases were women of European ancestry and were older than 18 years at breast cancer diagnosis. Women carrying a pathogenic variant in the *BRCA1* and/or *BRCA2* genes were excluded from the study. All the 44,803 breast cancer cases underwent complete sequencing of the *FANCM* coding region and intron/exon boundaries in the context of the BRIDGES study [4]. Details of the library preparation, sequencing, variant calling and quality control methods have been described elsewhere [4]. Germline *FANCM* PTVs were defined as frameshift or nonsense variants. As a proxy for the carrier's or PTV's geographical origin, we used the country where the study ascertaining the carrier was conducted. PTV carrier frequencies were compared using Pearson's chi-squared test, all tests were two-sided. *p*-values < 0.05 were considered statistically significant.

**3. Results and Discussion**

**3.1. Frequency of Germline FANCM PTVs**

Sixty-six different *FANCM* PTVs were found in 274 PTV carriers that were identified by gene sequencing of 44,803 female breast cancer cases (Figure 1, and Supplementary Table S2 and Table 1). A large percentage (65.3%) of the carriers carried either p.Gln1701* or p.Gly1906Alafs*12. Importantly, for these two PTVs the evidence of association with breast cancer risk was previously inconclusive [13]. Thus, we studied the frequencies of the carriers of all PTVs and of the carriers of all PTVs excluding p.Gln1701* and p.Gly1906Alafs*12. The frequencies of carriers of all PTVs in the 19 tested countries were heterogeneous, varying between 2.50% in Finland and 0.20% in Canada. However, the exclusion of p.Gln1701* or p.Gly1906Alafs*12 carriers resulted in PTV carrier frequencies which were more homogeneous, ranging between 0.11% in France and 0.63% in Belarus (Table 1). We also compared the frequencies of the two groups of PTV carriers with respect to their breast cancer family history and the ER status of their tumors. In these analyses, we observed a significantly higher PTV carrier frequency in familial versus sporadic cases (*p*-value = 0.032), and in ER-negative versus ER-positive cases (*p*-value = 0.048). When we excluded carriers of p.Gln1701* and p.Gly1906Alafs*12, these differences became greater in both familial versus sporadic cases (*p*-value = 0.021), and in ER-negative versus ER-positive cases (*p*-value = 0.0005, Table 2). The excess of PTV carriers in familial cases with respect to sporadic cases has been shown for other genes established as moderate-risk factors for breast cancer, for example *CHEK2*. Specifically, the *CHEK2:c.1100delC* PTV, which accounts for the majority of *CHEK2* PTVs, has been shown to have a 2.79-fold higher frequency or to confer a 1.77-fold higher risk in familial versus sporadic breast cancer cases [19,20]. *FANCM* has been reported as specifically associated with ER-negative breast cancer risk [13]. Hence, the excess of *FANCM* PTVs that we observed in familial cases and in ER-negative cases is reinforcing the knowledge that *FANCM* is a moderate-risk gene for breast cancer. Importantly, the fact that frequency differences increased after the exclusion of p.Gln1701* and p.Gly1906Alafs*12 carriers corroborates the hypothesis that these two PTVs have a lower impact on breast cancer risk.
<figure><img src="image_5.png" /><figcaption>**Figure 1.** Schematic representation of the 66 *FANCM* protein truncating variants (PTVs) with respect to functional and binding domains (in black). The exact positions of these domains (MPH1, ATP-dependent DNA helicase; MHF, domain of interaction with the Histone Fold 1 and 2 (MHF1/2); MM1, motif of interaction with FANCF within the Fanconi Anemia core complex; MM2, motif of interaction with RecQ-Mediated genome Instability protein 1 (RMI1); MM3, highly conserved motif of still unknown function; FAAP24, domain of interaction with the Fanconi Anemia core complex-Associated Protein 24) were derived from UniProt database and the published literature [21–23]. The 62 rare PTVs and the 4 common PTVs are shown in black and red, respectively. The protein N-terminus (N) and C-terminus (C) are also indicated.</figcaption></figure>

<table><caption>**Table 1.** Frequencies of all protein truncating variants (PTVs) carriers and those excluding p.Gln1701* and p.Gly1906Alafs*12 found in 44,803 breast cancer cases from 19 countries.</caption><thead><tr><th>Country</th><th>Breast Cancer Cases</th><th>Carriers of All PTV (Freq%)</th><th>Carriers of all PTV Excluding p.Gln1701* and p.Gly1906Alafs*12 (Freq%)</th></tr></thead><tbody><tr><td>UK</td><td>10,683</td><td>52 (0.9)</td><td>18 (0.17)</td></tr><tr><td>Germany</td><td>8659</td><td>51 (0.59)</td><td>21 (0.24)</td></tr><tr><td>Sweden</td><td>4607</td><td>55 (1.19)</td><td>6 (0.13)</td></tr><tr><td>Netherlands</td><td>3705</td><td>30 (0.81)</td><td>10 (0.27)</td></tr><tr><td>USA</td><td>2800</td><td>19 (0.68)</td><td>10 (0.36)</td></tr><tr><td>Denmark</td><td>2800</td><td>12 (0.43)</td><td>4 (0.14)</td></tr><tr><td>Australia</td><td>2460</td><td>13 (0.53)</td><td>8 (0.32)</td></tr><tr><td>Poland</td><td>2103</td><td>8 (0.38)</td><td>6 (0.28)</td></tr><tr><td>Spain</td><td>1126</td><td>3 (0.27)</td><td>3 (0.27)</td></tr><tr><td>Cyprus</td><td>974</td><td>0 (0)</td><td>0 (0)</td></tr><tr><td>France</td><td>938</td><td>2 (0.21)</td><td>1 (0.11)</td></tr><tr><td>Italy</td><td>933</td><td>6 (0.64)</td><td>2 (0.21)</td></tr><tr><td>Norway</td><td>565</td><td>3 (0.53)</td><td>1 (0.18)</td></tr><tr><td>Finland</td><td>560</td><td>14 (2.50)</td><td>1 (0.178)</td></tr><tr><td>Canada</td><td>491</td><td>1 (0.20)</td><td>1 (0.20)</td></tr><tr><td>Greece</td><td>472</td><td>0 (0)</td><td>0 (0)</td></tr><tr><td>Ireland</td><td>369</td><td>2 (0.54)</td><td>1 (0.27)</td></tr><tr><td>Belarus</td><td>319</td><td>2 (0.63)</td><td>2 (0.63)</td></tr><tr><td>Russia</td><td>239</td><td>1 (0.42)</td><td>0 (0)</td></tr></tbody><tfoot><tr><td>Total</td><td>44,803</td><td>274 (0.61)</td><td>95 (0.21)</td></tr></tfoot></table>

Freq, frequency.

<table><caption>**Table 2.** Frequencies of all protein truncating variants (PTVs) carriers and those excluding p.Gln1701* and p.Gly1906Alafs*12 found in 44,803 breast cancer cases grouped by their breast cancer family history and the ER status.</caption><thead><tr><th colspan="2">Breast Cancer Cases</th><th rowspan="2">Carriers of All PTV (Freq%)</th><th rowspan="2">p-Value</th><th rowspan="2">Carriers of All PTV Excluding p.Gln1701* and p.Gly1906Alafs*12 (Freq%)</th><th rowspan="2">p-Value</th></tr><tr><th>Group</th><th>Number</th></tr></thead><tbody><tr><td>All</td><td>44,803</td><td>274 (0.61)</td><td>-</td><td>95 (0.21)</td><td>-</td></tr><tr><td>Sporadic</td><td>26,539</td><td>150 (0.56)</td><td rowspan="2">0.032</td><td>49 (0.18)</td><td rowspan="2">0.021</td></tr><tr><td>Familial</td><td>10,680</td><td>81 (0.76)</td><td>33 (0.31)</td></tr><tr><td>ER-positive</td><td>25,679</td><td>137 (0.53)</td><td rowspan="2">0.048</td><td>44 (0.17)</td><td rowspan="2">0.0005</td></tr><tr><td>ER-negative</td><td>6572</td><td>49 (0.74)</td><td>26 (0.39)</td></tr></tbody></table>
## 3.2. Spectrum of Common and Rare FANCM PTVs

Among the 66 different variants, four, namely p.Gln498Thrfs*7 (FANCM:c.1491dupA), p.Arg658*, p.Gln1701* and p.Gly1906Alafs*12, were relatively common, each being identified in at least six carriers. The remaining 62 variants were unique or were found in a maximum of three carriers and were classified as “rare FANCM PTVs” (Figure 1, Supplementary Table S2). Of the 274 carriers, 202 (73.7%) carried one of the four common FANCM PTVs. Of these 202 carriers, 6 (3.0%), carried p.Gln498Thrfs*7, 17 (8.4%) carried p.Arg658*, 109 (54.0%) carried p.Gln1701* and 70 (34.6%) carried p.Gly1906Alafs*12. The remaining 72 carriers (26.3% of the total) carried one of the 62 rare PTVs (Figure 2a). Of the 62 rare PTVs, 54 were unique, six were found in two breast cancer cases, and two in three breast cancer cases (Supplementary Table S2). These results were consistent with those of a previous study in which we described the spectrum of 27 different FANCM PTVs identified in 114 European female breast cancer cases [18]. In fact, we observed that p.Gln1701* was the most common PTV in Northern Europe, with highest frequencies in Finland and Sweden and decreasing frequencies along the North-South axis (Figure 2a). Similarly, p.Gly1906Alafs*12 was validated to be the most common PTV in Southern Europe with decreasing frequencies in Central and Northern Europe. We also confirmed that p.Arg658* was the third most common PTV which was common in Central Europe with higher frequencies in Eastern Europe. Moreover, the geographical origin of the six p.Gln498Thrfs*7 carriers was compatible with our previous findings indicating that this PTV is probably a founder variant from Lithuania [18] (Figure 2a). Furthermore, with respect to the distribution of rare PTVs, it appears that carrier frequencies in Germany and Sweden are higher than those we previously reported [18] (Figure 2a). Finally, we observed heterogeneous spectra in Australia and USA consistent with the fact that those carriers are of European ancestry.

<figure><img src="image_6.png" /><figcaption>**Figure 2.** *Cont.*</figcaption></figure>
<figure><img src="image_7.png" /><figcaption>**Figure 2.** Geographic spectrum of common and rare FANCM PTVs presented by absolute number of PTV carriers identified per country. The pie charts sizes represent the total number of carriers per country. (a) Spectrum of 66 different FANCM PTVs found in 274 carriers by sequencing of 44,803 breast cancer cases in the present study. (b) Spectrum of 91 different FANCM PTVs found in a total of 487 carriers obtained by combining data from the present study with those we published previously (Figlioli et al., 114 carriers from several countries [18]) and with all the other available studies based on the FANCM sequencing in breast cancer cases (Cavaillé et al., 4 carriers from France [24]; Del Valle et al., 2 carriers from Spain [25]; Helgadottir et al., 4 carriers from Sweden [26]; Jarhelle et al., 2 carriers from Norway [27]; Neidhardt et al., 21 carriers from Germany [28]; Nurmi et al., 58 carriers from Finland [29]; Schubert et al., 5 carriers from Germany [30]; Southey et al., 3 carriers from Australia [31]). * One individual is a bi-allelic carrier of FANCM PTVs.</figcaption></figure>

3.3. *Comprehensive Spectrum of FANCM PTVs*

We combined the here presented data with those we published previously [18], and
with all the other available studies based on FANCM sequencing of European breast
cancer cases [24–31]. Figure 2b shows the distribution spectrum of a total of 91 different
FANCM PTVs found in 487 breast cancer cases from 23 countries. This map shows the
different frequency distributions and the specific prevalence of p.Gln498Thrfs*7, p.Arg658*,
p.Gln1701* and p.Gly1906Alafs*12 PTVs. It could be also observed that the spectra of
FANCM PTVs seem to be much more heterogeneous in Southwestern Europe (i.e., Portugal,
Spain and France) with respect to Northeastern Europe (i.e., Sweden, Finland and Norway
(Figure 2b)). To investigate this observation better, we grouped the tested countries in those
from Southwestern or Central Europe (Portugal, Spain, Italy, Greece, Macedonia, Hungary,
Czech Republic, Germany, France, the Netherlands, UK and Ireland) and those from
Northeastern Europe (Finland, Sweden, Norway, Denmark, Poland, Lithuania, Belarus
and Russia). If we consider the carriers of rare PTVs, there were 80 (33.1% of 242 total
carriers) in Southwestern and Central Europe versus only 13 (6.2% of 209 total carriers)
in Northeastern Europe (p-value < 0.0001). Considering specifically the single different
PTVs, we observed that there were 62 (25.6% of 242 carriers) in Southwestern and Central
Europe compared with 16 (7.6% of 209 carriers) in Northeastern Europe (p-value < 0.0001).
Only for some of the 87 rare different PTVs, it was possible to speculate on the geographic origin. In particular, we considered the eight PTVs that were found in at least three carriers (Table 3). Among these, p.Arg185Glufs*13 and p.Gln498* might be prevalent in Germany and the Netherlands, while p.Glu774* and p.Lys863Ilefs*12 might be specific to the Iberian Peninsula, and to Spain and France, respectively. Finally, p.Tyr1398* could be from the UK. However, since we could not exclude that some of these carriers were originally members of the same family that were ascertained as different probands, additional data are required to confirm these hypotheses.

<table><caption>**Table 3.** List of FANCM rare protein truncating variants (PTVs) that, through combining data from the present study with those from previously published studies, were identified in at least three individuals. For each PTV, the total number of detected carriers is reported along with the study/database and the country of origin.</caption><thead><tr><td>PTV</td><td>Number of Carriers</td><td>Study, Geographic Origin</td></tr></thead><tbody><tr><td>c.551dup; p.Arg185Glufs*13</td><td>3</td><td>This study, Germany (1) Netherlands (1); Neidhardt et al. [28], Germany (1)</td></tr><tr><td>c.1196C>G; p.Ser399*</td><td>3</td><td>This study, UK (2), Figlioli et al. [18], Spain (1)</td></tr><tr><td>c.1492C>T; p.Gln498*</td><td>3</td><td>This study, Germany (1) Netherlands (2)</td></tr><tr><td>c.2260C>T; p.Arg754*</td><td>3</td><td>Figlioli et al. [18], Czech Republic (2) France (1)</td></tr><tr><td>c.2320G>T; p.Glu774*</td><td>4</td><td>This study, Spain (1); Figlioli et al. [18], Spain (2) Portugal (1)</td></tr><tr><td>c.2586_2589del; p.Lys863Ilefs*12</td><td>3</td><td>This study, Spain (1); Figlioli et al. [18], Spain (1); Cavaillé et al. [24], France (1)</td></tr><tr><td>c.3088C>T; p.Arg1030*</td><td>3</td><td>This study, Spain (1); Figlioli et al. [18], Czech Republic (1); Neidhardt et al. [28], Germany (1)</td></tr><tr><td>c.4194T>G; p.Tyr1398*</td><td>3</td><td>This study, UK (3)</td></tr></tbody></table>

## 4. Conclusions

In this study, we report FANCM PTV carrier frequencies among 44,803 breast cancer cases from 19 countries. In addition, our data in combination with data from previous studies allowed us to describe the spectra of 91 FANCM PTVs in breast cancer cases from Europe, USA, Canada and Australia. These data could be used to inform first pass genotyping screening, and for more efficient genetic testing strategies in breast cancer cases from specific populations.

**Supplementary Materials:** The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/cancers15133313/s1, Supplementary Table S1: Description of the 39 studies included in the present analysis. Supplementary Table S2: List of the 274 breast cancer cases carrying one of the 66 FANCM protein truncating variants (PTVs).

**Author Contributions:** Conceptualization, G.F., A.B. and P.P.; Formal Analysis, G.F. and P.P.; Coordination of the BRIDGES study and funding acquisition, J.D., M.L., A.K., A.M.D., P.D.P.P., D.F.E. and P.P.; Data Curation (providing samples and clinical data), Q.W., M.K.B., J.D., M.L., A.K., M.A.A., T.U.A., N.N.A., P.A., S.B., M.B., N.V.B., S.E.B., B.B., T.B., N.J.C., A.C., J.E.C., M.H.C., NBCS Collaborators, K.C., P.D., T.D., M.E., P.A.F., H.F., M.G., M.G.-D., M.G.-C., G.G., E.B.G.G., A.G.-N., F.G., P.G., E.H., U.H., P.H., M.J.H., R.H., A.H. (Anthony Howelland), K.H., kConFab Investigators, A.J., E.K.K., V.N.K., A.L., M.A.L., J.L., A.M., T.M., D.M., W.G.N., N.O., M.I.P., P.R., M.U.R., V.R., M.R., E.S., E.J.S., M.K.S., R.K.S., M.S., M.C.S., I.T., T.T., E.M.v.V., C.W., X.R.Y., K.M., A.M.D., P.D.P.P., D.F.E., I.L.A., D.G.E. and A.H. (Antoinette Hollestelle), J.C.-C., R.L.M. and P.P.; Writing—Original Draft Preparation, G.F., P.P.; Writing—Review and Editing, G.F., A.B., I.L.A., D.G.E., A.H. (Antoinette Hollestelle), J.C.-C., R.L.M. and P.P.; Supervision, P.P. All authors have read and agreed to the published version of the manuscript.

**Funding:** This study was supported by Associazione Italiana Ricerca sul Cancro (AIRC; IG22860) to Paolo Peterlongo and by a fellowship from Fondazione Umberto Veronesi to Gisella Figlioli. BCAC is funded by the European Union's Horizon 2020 Research and Innovation Programme (grant numbers
634935 and 633784 for BRIDGES and B-CAST, respectively), and the PERSPECTIVE I&I project, funded by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research, the Ministère de l'Économie et de l'Innovation du Québec through Genome Québec, the Quebec Breast Cancer Foundation. The EU Horizon 2020 Research and Innovation Programme funding source had no role in study design, data collection, data analysis, data interpretation or writing of the report. Additional funding for BCAC is provided via the Confluence project which is funded with intramural funds from the National Cancer Institute Intramural Research Program, National Institutes of Health. The BRIDGES panel sequencing was supported by the European Union Horizon 2020 research and innovation program BRIDGES (grant number, 634935) and the Wellcome Trust (v203477/Z/16/Z). The ABCS study was supported by the Dutch Cancer Society [grants NKI 2007-3839; 2009 4363] and an institutional grant of the Dutch Cancer Society and of the Dutch Ministry of Health, Welfare and Sport. The work of the BBCC was partly funded by ELAN-Fond of the University Hospital of Erlangen. For BIGGS, ES is supported by NIHR Comprehensive Biomedical Research Centre, Guy's & St. Thomas' NHS Foundation Trust in partnership with King's College London, United Kingdom. IT is supported by the Oxford Biomedical Research Centre. The BREast Oncology GAIician Network (BREOGAN) is funded by Acción Estratégica de Salud del Instituto de Salud Carlos III FIS PI12/02125/Cofinanciado and FEDER PI17/00918/Cofinanciado FEDER; Acción Estratégica de Salud del Instituto de Salud Carlos III FIS Intrasalud (PI13/01136); Programa Grupos Emergentes, Cancer Genetics Unit, Instituto de Investigacion Biomedica Galicia Sur. Xerencia de Xestion Integrada de Vigo-SERGAS, Instituto de Salud Carlos III, Spain; Grant 10CSA012E, Consellería de Industria Programa Sectorial de Investigación Aplicada, PEME I + D e I + D Suma del Plan Gallego de Investigación, Desarrollo e Innovación Tecnológica de la Consellería de Industria de la Xunta de Galicia, Spain; Grant EC11-192. Fomento de la Investigación Clínica Independiente, Ministerio de Sanidad, Servicios Sociales e Igualdad, Spain; and Grant FEDER-Innterconecta. Ministerio de Economía y Competitividad, Xunta de Galicia, Spain. The BSUCH study was supported by the Dietmar-Hopp Foundation, the Helmholtz Society and the German Cancer Research Center (DKFZ). The CAMA study was funded by Consejo Nacional de Ciencia y Tecnología (CONACYT) (SALUD-2002-C01-7462). Sample collection and processing was funded in part by grants from the National Cancer Institute (NCI R01CA120120 and K24CA169004). CCGP is supported by funding from the University of Crete. The CECILE study was supported by Fondation de France, Institut National du Cancer (INCa), Ligue Nationale contre le Cancer, Agence Nationale de Sécurité Sanitaire, de l'Alimentation, de l'Environnement et du Travail (ANSES), Agence Nationale de la Recherche (ANR). The CGPS was supported by the Chief Physician Johan Boserup and Lise Boserup Fund, the Danish Medical Research Council and Herlev and Gentofte Hospital. The CNIO-BCS was supported by the Instituto de Salud Carlos III, the Red Temática de Investigación Cooperativa en Cáncer and grants from the Asociación Española Contra el Cáncer and the Fondo de Investigación Sanitario (PI11/00923 and PI12/00070). FHRISK and PROCAS are funded from NIHR grant PGfAR 0707-10031. DGE, AH and WGN are supported by the NIHR Manchester Biomedical Research Centre (IS-BRC-1215-20007). The GC-HBOC (German Consortium of Hereditary Breast and Ovarian Cancer) is supported by the German Cancer Aid (grant no 110837 and 70114178, coordinator: Rita K. Schmutzler, Cologne) and the Federal Ministry of Education and Research, Germany (grant no 01GY1901). This work was also funded by the European Regional Development Fund and Free State of Saxony, Germany (LIFE-Leipzig Research Centre for Civilization Diseases, project numbers 713-241202, 713-241202, 14505/2470, 14575/2470). The GENICA was funded by the Federal Ministry of Education and Research (BMBF) Germany grants 01KW9975/5, 01KW9976/8, 01KW9977/0 and 01KW0114, the Robert Bosch Foundation, Stuttgart, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, the Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum (IPA), Bochum, as well as the Department of Internal Medicine, Johanniter GmbH Bonn, Johanniter Krankenhaus, Bonn, Germany. Generation Scotland (GENSCOT) received core support from the Chief Scientist Office of the Scottish Government Health Directorates [CZD/16/6] and the Scottish Funding Council [HR03006]. Genotyping of the GS:SFHS samples was carried out by the Genetics Core Laboratory at the Edinburgh Clinical Research Facility, University of Edinburgh, Scotland and was funded by the Medical Research Council UK and the Wellcome Trust (Wellcome Trust Strategic Award "Stratifying Resilience and Depression Longitudinally" (STRADL) Reference 104036/Z/14/Z). Funding for identification of cases and contribution to BCAC funded in part by the Wellcome Trust Seed Award "Temporal trends in incidence and mortality of molecular subtypes of breast cancer to inform public health, policy and prevention" Reference 207800/Z/17/Z. The GESBC was supported by the Deutsche Krebshilfe e.
V. [70492] and the German Cancer Research Center (DKFZ). The HABCS study was supported by German Research Foundation (DFG Do761/15-1), the Claudia von Schilling Foundation for Breast Cancer Research, by the Lower Saxonian Cancer Society, and by the Rudolf Bartling Foundation. The HEBCS was financially supported by the Helsinki University Hospital Research Fund, the Sigrid Juselius Foundation and the Cancer Foundation Finland. The HEBON study is supported by the Dutch Cancer Society grants NKI1998-1854, NKI2004-3088, NKI2007-3756, NKI 12535, the Netherlands Organisation of Scientific Research grant NWO 91109024, the Pink Ribbon grants 110005 and 2014-187.WO76, the BBMRI grant NWO 184.021.007/CP46, and the Transcan grant JTC 2012 Cancer 12-054. The HMBCS was supported by the German Research Foundation (DFG Do761/15-1), a grant from the Friends of Hannover Medical School, and by the Rudolf Bartling Foundation. The HUBCS was supported by German Research Foundation (DFG Do761/15-1), a grant from the German Federal Ministry of Research and Education (RUS08/017), B.M. was supported by grant 17-44-020498, 17-29-06014 of the Russian Foundation for Basic Research, D.P. was supported by grant 18-29-09129 of the Russian Foundation for Basic Research, E.K was supported by the mega grant from the Government of Russian Federation (2020-220-08-2197), and the study was performed as part of the assignment of the Ministry of Science and Higher Education of the Russian Federation (№AAAAA-A16-116020350032-1). Financial support for KARBAC was provided through the regional agreement on medical training and clinical research (ALF) between Stockholm County Council and Karolinska Institutet, the Swedish Cancer Society, The Gustav V Jubilee foundation and Bert von Kantzows foundation. The KARMA study was supported by Märit and Hans Rausings Initiative Against Breast Cancer. The KBCP was financially supported by the special Government Funding (VTR) of Kuopio University Hospital grants, Cancer Fund of North Savo, the Finnish Cancer Organizations and by the strategic funding of the University of Eastern Finland. kConFab was supported by a grant from the National Breast Cancer Foundation, and previously by the National Health and Medical Research Council (NHMRC), the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania and South Australia and the Cancer Foundation of Western Australia. Financial support for the AOCS was provided by the United States Army Medical Research and Materiel Command [DAMD17-01-1-0729], Cancer Council Victoria, Queensland Cancer Fund, Cancer Council New South Wales, Cancer Council South Australia, The Cancer Foundation of Western Australia, Cancer Council Tasmania and the National Health and Medical Research Council of Australia (NHMRC; 400413, 400281, 199600). G.C.T. and P.W. were supported by the NHMRC. RB was a Cancer Institute NSW Clinical Research Fellow. The MARIE study was supported by the Deutsche Krebshilfe e.V. [70-2892-BR I, 106332, 108253, 108419, 110826, 110828], the Hamburg Cancer Society, the German Cancer Research Center (DKFZ) and the Federal Ministry of Education and Research (BMBF) Germany [01KH0402]. The MASTOS study was supported by "Cyprus Research Promotion Foundation" grants 0104/13 and 0104/17, and the Cyprus Institute of Neurology and Genetics. MBCSG is supported by grants from the Italian Association for Cancer Research (AIRC). The Melbourne Collaborative Cohort Study (MCCS) cohort recruitment was funded by VicHealth and Cancer Council Victoria. The MCCS was further augmented by Australian National Health and Medical Research Council grants 209057, 396414 and 1074383 and by infrastructure provided by Cancer Council Victoria. Cases and their vital status were ascertained through the Victorian Cancer Registry and the Australian Institute of Health and Welfare, including the National Death Index and the Australian Cancer Database. The NBCS has received funding from the K.G. Jebsen Centre for Breast Cancer Research; the Research Council of Norway grant 193387/V50 (to A-L Børresen-Dale and V.N. Kristensen) and grant 193387/H10 (to A-L Børresen-Dale and V.N. Kristensen), South Eastern Norway Health Authority (grant 39346 to A-L Børresen-Dale) and the Norwegian Cancer Society (to A-L Børresen-Dale and V.N. Kristensen). The NBHS was supported by NIH grant R01CA100374. Biological sample preparation was conducted the Survey and Biospecimen Shared Resource, which is supported by P30 CA68485. The Ontario Familial Breast Cancer Registry (OFBCR) was supported by grant U01CA164920 from the USA National Cancer Institute of the National Institutes of Health. The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the Breast Cancer Family Registry (BCFR), nor does mention of trade names, commercial products, or organizations imply endorsement by the USA Government or the BCFR. The PBCS was funded by Intramural Research Funds of the National Cancer Institute, Department of Health and Human Services, USA. Genotyping for PLCO was supported by the Intramural Research Program of the National Institutes of Health, NCI, Division of Cancer Epidemiology and Genetics. The PLCO is supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics and supported by contracts
from the Division of Cancer Prevention, National Cancer Institute, National Institutes of Health. The RBCS was funded by the Dutch Cancer Society (DDHK 2004-3124, DDHK 2009-4318). The SASBAC study was supported by funding from the Agency for Science, Technology and Research of Singapore (A\*STAR), the US National Institute of Health (NIH) and the Susan G. Komen Breast Cancer Foundation. SEARCH was funded by Cancer Research UK [C490/A10124, C490/A16561] and supported by the UK National Institute for Health Research Biomedical Research Centre at the University of Cambridge. The University of Cambridge has received salary support for PDPP from the NHS in the East of England through the Clinical Academic Reserve. SKKDKFZS was supported by the DKFZ. The SZBCS was supported by Grant PBZ_KBN_122/P05/2004 and the program of the Minister of Science and Higher Education under the name "Regional Initiative of Excellence" in 2019–2022 project number 002/RID/2018/19 amount of financing 12,000,000 PLN. UBCS was supported by funding from National Cancer Institute (NCI) grant R01 CA163353 (to N.J. Camp) and the Women’s Cancer Center at the Huntsman Cancer Institute (HCI). Data collection for UBCS was supported by the Utah Population Database (UPDB) and Utah Cancer Registry (UCR). Partial support for all datasets within the UPDB was provided by the University of Utah HCI and the HCI Cancer Center Support grant, P30 CA2014 from the NCI. The UCR is funded by the NCI’s SEER Program, Contract No. HHSN261201800016I, the US Centers for Disease Control and Prevention’s National Program of Cancer Registries, Cooperative Agreement No. NU58DP006320, with additional support from the University of Utah and Huntsman Cancer Foundation.

**Institutional Review Board Statement:** The study was conducted in accordance with the Declaration of Helsinki, and the participation of all the BCAC studies (Supplementary Table S2) was approved by their Institutional Review Board or Ethics Committee. The studies and their approving institutes (protocol code; date of approval) are: ABCS and ABCS-F-Leiden University Medical Center (LUMC) Commissie Medische Ethiek; Protocol Toetsingscommissie van Het Nederlands Kanker Instituut-Antoni van Leeuwenhoek Ziekenhuis (P02.164-gklWKlib, PTC09.1687/N07BOS, PTC09.2966/P09ABC; 27/09/2002, 27/08/2009, 29/12/2009); BBCC-Friedrich-Alexander-Universitat Erlangen-Nurnberg Medizinische Fakultat Ethik-Commission (2700; 10/06/2002); BIGGS-Galway University College Hospital Clinical Research Ethical Committee (protocol code not applicable; 09/04/1998); BREOGAN-Comité Autonómico de Ética de la Investigación de Galicia (2800/001; 31/03/2020); BSUCH-Ethikkommission Medizinische Fakultat Heidelberg, University of Heidelberg; CCGP-Epistimoniko Symvoulio, Scientific Council of the University General hospital of Heraklion (343; 13/03/2014); CECILE-Comité Consultatif de Protection des Personnes dans la Recherche Biomédicale de Bicêtre, Le Kremlin-Bicêtre FR-94270 (04-53; 18/01/2005); CGPS-Kobenhavns Amt den Videnskabsetiske Komite (Scientific ethical committee, Copenhagen County) (KA02152; 04/10/2003); CNIO-BCS-Comité de ética de la Investigación y de Bienestrar Animal del Insituto de Salud Carlos III; FHRISK-NRES Committee North West-Greater Manchester Central (V1.0-6.0; 11/02/2010, 13/06/2011, 03/08/2011, 17/10/2012, 18/12/2012, 21/05/2013); GC-HBOC-Ethik-Kommission der Medizinischen Fakultat der Universitat zu Koln (19-1360_4, 07-048; 28/09/2020, 25/10/2017); GENICA-Ethikkommission Rheinische Friedrich-Wilhels-Universität Bonn (Lfd Nr 68/00; 8/28/2000, 11/27/2003, 4/17/2006); GENSCOT-East of Scotland Research Ethics Service (EoSRES) (05/S1401/89; 18/08/2005); GESBC-Medizinische Fakultat Heidelberg Ethikkommission (S-584/2015; 08/03/2016); HABCS-Medizinische Hochschule Hannover Ethik-Kommission (6079; 08/12/2011); HEBON-Protocol Toetsingscommissie van het Nederlands Kanker Instituut/Antoni van Leeuwenhoek Ziekenhuis, Leiden University Medical Center (LUMC) Commissie Medische Ethiek, Medische Ethische Toetsings Commissie Erasmus Medisch Centrum, Medische Ethische Toetsingscommissie VU Medisch Centrum (GEO1: EV98168 (NKI 98-1854), GEO2: PTC05.0843 (NKI 2004-3088), GEO3: PTC07-1611 (NKI 2007-3756), PTC11.1799, IRBd19043, IRBd21-201; 1998, 2004, 2007, 2011, 2019, 2021); HMBCS-Medizinische Hochschule Hannover Ethik-Kommission; HUBCS-Ethical Committee of Institute of Biochemistry and Genetics, Ufa Scientific Center of Russian Academy of Sciences (N.3 and N.8; 13/09/2011, 13/09/2011); KARBAC-Regionala Etikprovningsnamnden i Stockholm (Regional Ethical Review Board in Stockholm) (2010/1156-31/2, 2013/928-32; 25/08/2010, 20/05/2013, 29/05/2013, 2013/749-32); KARMA-Regionala Etikprovningsnamnden i Stockholm (Regional Ethical Review Board in Stockholm) (2010/958-31/1 and 2013/2090-32; 2010, 2013); KBCP-Pohjois-Savon Sairraanhoitopiirin Kuntayhtyma Tutkimuseettinen Toimikunta (89, 225; 05/12/1989, 21/10/2008); kConFab/AOCS-Peter MacCallum Cancer Centre Ethics Committee (97/27; 08/2022); MARIE-Medizinische Fakultat Heidelberg Ethikkommission; Ethik-Kommission der Arztekammer Hamburg (HÄK 1791, S-042/2014; 07/03/2001, 21/02/2014, 05/05/2014, 10/03/2014, 01/10/2014); MASTOS-Cyprus National Bioethics committee (EEBK/ΕΠ/2016/38; 19/12/2016); MBCSG-Comitato
Etico Indipendente della Fondazione IRCCS "Istituto Nazionale dei Tumori" (INT 165/20; 22/07/2020); MCCS-Cancer Council Victoria Human Research Ethics Committee (#9001; 1990); NBCS-Regionale Komitere for Medisinsk og Helsefaglig Forskningsetikk (2016/2331; 08/05/2017); OFBCR-Mount Sinai Hospital Research Ethics Board (02-0076-U; 11/03/2022); PBCS-National Cancer Institute Special Studies Institutional Review Board (NCI-SSIRB) (OH99CN040; 13/04/2020); pKARMA-Regionala Etikprovningsnamnden i Stockholm (Regional Ethical Review Board in Stockholm) (2010/958-31/1, 2013/2090-32, 2009/254-31/4, 2011/2010-32; 2009, 2010, 2013); PLCO-National Cancer Institute Special Studies Institutional Review Board (NCI-SSIRB) (OH97CN041; 21/02/2023); PROCAS-NRES Committee North West-Greater Manchester Central (09/H1008/81; 08/07/2009); RBCS-Medische Ethische Toetsings Commissie Erasmus Medisch Centrum (MEC-2011-226; 27/06/2011); SASBAC-Regionala Etikprovningsnamnden i Stockholm (Regional Ethical Review Board in Stockholm) (155/93, 2006/1350-32; 2006); SEARCH-Multi Centre Research Ethics Committee (MREC) (v10.0; 03/01/2023); SKKDKFZS-Multi Centre Research Ethics Committee, MREC (S-079/2008; 15/04/2008); SZBCS-Komisji Bioetycznej Pomorskiej Akademii Medycznej (BN-001/33/04; 23/02/2004); UBCS-University of Utah Institutional Review Board (96990; 22/11/2022).

**Informed Consent Statement:** Informed consent was obtained from all subjects involved in the study.

**Data Availability Statement:** The data presented in this study are available on request to the BCAC Data Access Co-ordinating Committee (bcac@medschl.cam.ac.uk). The data are not publicly available due to privacy or ethical restrictions. Summary individual-level data are available in Supplementary Table S2.

**Acknowledgments:** We thank all the individuals who took part in these studies and all the researchers, clinicians, technicians and administrative staff who have enabled this work to be carried out. **ABCS** thanks the Blood bank Sanquin, The Netherlands. **BIGGS** thanks Niall McInerney, Gabrielle Colleran, Andrew Rowan, Angela Jones. The **BREOGAN** study would not have been possible without the contributions of the following: Manuela Gago-Dominguez, Jose Esteban Castelao, Angel Carracedo, Victor Muñoz Garzón, Alejandro Novo Domínguez, Maria Elena Martinez, Sara Miranda Ponte, Carmen Redondo Marey, Maite Peña Fernández, Manuel Enguix Castelo, Maria Torres, Manuel Calaza (BREOGAN), José Antúnez, Máximo Fraga and the staff of the Department of Pathology and Biobank of the University Hospital Complex of Santiago-CHUS, Instituto de Investigación Sanitaria de Santiago, IDIS, Xerencia de Xestión Integrada de Santiago-SERGAS; Joaquín González-Carreró and the staff of the Department of Pathology and Biobank of University Hospital Complex of Vigo, Instituto de Investigación Biomedica Galicia Sur, SERGAS, Vigo, Spain. The **BSUCH** study acknowledges the Principal Investigator, Barbara Burwinkel, and, thanks Peter Bugert, Medical Faculty Mannheim. **CCGP** thanks Styliani Apostolaki, Anna Margiolaki, Georgios Nintos, Maria Perraki, Georgia Saloustrou, Georgia Sevastaki, Konstantinos Pompodakis. **CGPS** thanks staff and participants of the Copenhagen General Population Study. For the excellent technical assistance: Dorthe Uldall Andersen, Maria Birna Arnadottir, Anne Bank, Dorthe Kjeldgård Hansen. The Danish Cancer Biobank is acknowledged for providing infrastructure for the collection of blood samples for the cases. The Danish Breast Cancer Cooperative Group (DBCG) are acknowledged for their provision of clinical case data. **CNIO-BCS** thanks Guillermo Pita, Charo Alonso, Nuria Álvarez, Pilar Zamora, Primitiva Menendez, the Human Genotyping-CEGEN Unit (CNIO). **FHRISK** and **PROCAS** thank NIHR for funding. The **GENICA** Network: Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart and University of Tübingen, Germany [RH, Hiltrud Brauch, Wing-Yee Lo], Department of Internal Medicine, Johanniter GmbH Bonn, Johanniter Krankenhaus, Bonn, Germany [Yon-Dschun Ko, Christian Baisch], Institute of Pathology, University of Bonn, Germany [Hans-Peter Fischer], Molecular Genetics of Breast Cancer, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany [UH], Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum (IPA), Bochum, Germany [TB, Beate Pesch, Sylvia Rabstein, Anne Lotz]; and Institute of Occupational Medicine and Maritime Medicine, University Medical Center Hamburg-Eppendorf, Germany [Volker Harth]. The Hereditary Breast and Ovarian Cancer Research Group Netherlands (**HEBON**) consists of the following Collaborating Centers: Netherlands Cancer Institute (coordinating center), Amsterdam, NL: M.K. Schmidt, F.B.L. Hogervorst, F.E. van Leeuwen, M.A. Adank, D.J. Stommel-Jenner, R. de Groot; Erasmus Medical Center, Rotterdam, NL: J.M. Collée, I. Geurts-Giele, M.J. Hooning, I.A. Boere; Leiden University Medical Center, NL: C.J. van Asperen, P. Devilee, R.B. van der Luijt, T.C.T.E.F. van Cronenburg; Radboud University Nijmegen Medical Center, NL: M.R. Wevers, A.R. Mensenkamp; University Medical Center Utrecht, NL: M.G.E.M. Ausems, M.J. Koudijs; Amsterdam UMC, NL: K.
van Engelen, J.J.P. Gille; Maastricht University Medical Center, NL: E.B. Gómez García, M.J. Blok, M. de Boer; University of Groningen, NL: L.P.V. Berger, A.H. van der Hout, M.J.E. Mourits, G.H. de Bock; The Netherlands Comprehensive Cancer Organisation (IKNL): S. Siesling, J. Verloop; The nationwide network and registry of histo- and cytopathology in The Netherlands (PALGA): Q.J.M. Voorham. HEBON thanks the study participants and the registration teams of IKNL and PALGA for part of the data collection. **HMBCS** thanks Peter Hillemanns, Hans Christiansen and Johann H. Karstens. **HUBCS** thanks Darya Prokofyeva and Shamil Gantsev. **KARMA** and **SASBAC** thank the Swedish Medical Research Counsel. **KBCP** thanks Eija Myöhänen. **kConFab/AOCS** wish to thank Heather Thorne, Eveline Niedermayr, all the kConFab research nurses and staff, the heads and staff of the Family Cancer Clinics and the Clinical Follow Up Study (which has received funding from the NHMRC, the National Breast Cancer Foundation, Cancer Australia and the National Institute of Health (USA)) for their contributions to this resource, and the many families who contribute to kConFab. The following are the KConFab investigators: David Amor, Lesley Andrews, Yoland Antill, Rosemary Balleine, Jonathan Beesley, Ian Bennett, Michael Bogwitz, Leon Botes, Meagan Brennan, Melissa Brown, Michael Buckley, Jo Burke, Phyllis Butow, Liz Caldon, Ian Campbell, Michelle Cao, Anannya Chakrabarti, Deepa Chauhan, Manisha Chauhan, Georgia Chenevix-Trench, Alice Christian, Paul Cohen, Alison Colley, Ashley Crook, James Cui, Eliza Courtney, Margaret Cummings, Sarah-Jane Dawson, Anna deFazio, Martin Delatycki, Rebecca Dickson, Joanne Dixon, Ted Edkins, Stacey Edwards, Gelareh Farshid, Andrew Fellows, Georgina Fenton, Michael Field, James Flanagan, Peter Fong, Laura Forrest, Stephen Fox, Juliet French, Michael Friedlander, Clara Gaff, Mike Gattas, Peter George, Sian Greening, Marion Harris, Stewart Hart, Nick Hayward, John Hopper, Cass Hoskins, Clare Hunt, Paul James, Mark Jenkins, Alexa Kidd, Judy Kirk, Jessica Koehler, James Kollias, Sunil Lakhani, Mitchell Lawrence, Jason Lee, Shuai Li, Geoff Lindeman, Lara Lipton, Liz Lobb, Sherene Loi, Graham Mann, Deborah Marsh, Sue Anne McLachlan, Bettina Meiser, Sophie Nightingale, Shona O'Connell, Sarah O'Sullivan, David Gallego Ortega, Nick Pachter, Jia-Min Pang, Gargi Pathak, Briony Patterson, Amy Pearn, Kelly Phillips, Ellen Pieper, Susan Ramus, Edwina Rickard, Bridget Robinson, Mona Saleh, Anita Skandarajah, Elizabeth Salisbury, Christobel Saunders, Jodi Saunus, Rodney Scott, Clare Scott, Adrienne Sexton, Andrew Shelling, Peter Simpson, Amanda Spurdle, Jessica Taylor, Renea Taylor, Heather Thorne, Alison Trainer, Kathy Tucker, Jane Visvader, Logan Walker, Rachael Williams, Ingrid Winship, Mary Ann Young, Milita Zaheed. **MARIE** thanks Petra Seibold, Nadia Obi, Sabine Behrens, Ursula Eilber and Muhabbet Celik. **MASTOS** thanks all the study participants and express appreciation to the doctors: Viola Marcou, Eleni Kakouri, Panayiotis Papadopoulos, Simon Malas and Maria Daniel, as well as to all the nurses and volunteers who provided valuable help towards the recruitment of the study participants. **MBCSG** (Milan Breast Cancer Study Group): Siranoush Manoukian, Bernard Peissel, Jacopo Azzollini, Erica Rosina, Daniela Zaffaroni, Irene Feroce, Mariarosaria Calvello, Aliana Guerrieri Gonzaga, Monica Marabelli, Davide Bondavalli and the personnel of the Cogentech Cancer Genetic Test Laboratory. The **MCCS** was made possible by the contribution of many people, including the original investigators, the teams that recruited the participants and continue working on follow-up, and the many thousands of Melbourne residents who continue to participate in the study. The following are **NBCS** Collaborators: Kristine K. Sahlberg), Anne-Lise Børresen-Dale, Lars Ottestad, Rolf Kåresen, Ellen Schlichting, Marit Muri Holmen, Toril Sauer, Vilde Haakensen, Olav Engebråten, Bjørn Naume, Alexander Fosså, Cecile E. Kiserud, Kristin V. Reinertsen, Åslaug Helland, Margit Riis, Jürgen Geisler, OSBREAC and Grethe I. Grenaker Alnæs. NBHS and SBCGS thank study participants and research staff for their contributions and commitment to the studies. The **OFBCR** thanks Teresa Selander, Nayana Weerasooriya and Steve Gallinger. **PBCS** thanks Louise Brinton, Mark Sherman, Neonila Szeszenia-Dabrowska, Beata Peplonska, Witold Zatonski, Pei Chao, Michael Stagner. The **RBCS** thanks Jannet Blom, Saskia Pelders, Wendy J.C. Prager-van der Smissen and the Erasmus MC Family Cancer Clinic. SBCS thanks Sue Higham, Helen Cramp, Dan Connley, Ian Brock, Sabapathy Balasubramanian and Malcolm W.R. Reed. We thank the **SEARCH** and EPIC teams. **SKKDKFZS** thanks all study participants, clinicians, family doctors, researchers and technicians for their contributions and commitment to this study. **UBCS** thanks all study participants as well as the ascertainment, laboratory, analytics and informatics teams at Huntsman Cancer Institute and Intermountain Healthcare for their important contributions to this study.

**Conflicts of Interest:** Peter A. Fasching conducts research funded by Amgen, Novartis and Pfizer. He received Honoraria from Roche, Novartis and Pfizer. Gareth Evans has a consultancy role with AstraZeneca and EverythingGenetic. All the other authors declare no competing interests.
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