{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T04:30:55Z","timestamp":1791865855192,"version":"4.3.4"},"reference-count":170,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2024,2,8]],"date-time":"2024-02-08T00:00:00Z","timestamp":1707350400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Fondazione Emma ed Ernesto Rulfo per la Genetica Medica","award":["MUR_DM737_2022"],"award-info":[{"award-number":["MUR_DM737_2022"]}]},{"name":"BANDO DI ATENEO PER LA RICERCA 2022","award":["MUR_DM737_2022"],"award-info":[{"award-number":["MUR_DM737_2022"]}]},{"name":"University of Parma","award":["MUR_DM737_2022"],"award-info":[{"award-number":["MUR_DM737_2022"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Germline variants occurring in BRCA1 and BRCA2 give rise to hereditary breast and ovarian cancer (HBOC) syndrome, predisposing to breast, ovarian, fallopian tube, and peritoneal cancers marked by elevated incidences of genomic aberrations that correspond to poor prognoses. These genes are in fact involved in genetic integrity, particularly in the process of homologous recombination (HR) DNA repair, a high-fidelity repair system for mending DNA double-strand breaks. In addition to its implication in HBOC pathogenesis, the impairment of HR has become a prime target for therapeutic intervention utilizing poly (ADP-ribose) polymerase (PARP) inhibitors. In the present review, we introduce the molecular roles of HR orchestrated by BRCA1 and BRCA2 within the framework of sensitivity to PARP inhibitors. We examine the genetic architecture underneath breast and ovarian cancer ranging from high- and mid- to low-penetrant predisposing genes and taking into account both germline and somatic variations. Finally, we consider higher levels of complexity of the genomic landscape such as polygenic risk scores and other approaches aiming to optimize therapeutic and preventive strategies for breast and ovarian cancer.<\/jats:p>","DOI":"10.3390\/genes15020219","type":"journal-article","created":{"date-parts":[[2024,2,8]],"date-time":"2024-02-08T09:00:02Z","timestamp":1707382802000},"page":"219","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":52,"title":["Genetic Basis of Breast and Ovarian Cancer: Approaches and Lessons Learnt from Three Decades of Inherited Predisposition Testing"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7711-2156","authenticated-orcid":false,"given":"Valeria","family":"Barili","sequence":"first","affiliation":[{"name":"Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7520-3721","authenticated-orcid":false,"given":"Enrico","family":"Ambrosini","sequence":"additional","affiliation":[{"name":"Medical Genetics, University Hospital of Parma, 43126 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beatrice","family":"Bortesi","sequence":"additional","affiliation":[{"name":"Medical Oncology Unit, University Hospital of Parma, 43126 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4808-0308","authenticated-orcid":false,"given":"Roberta","family":"Minari","sequence":"additional","affiliation":[{"name":"Medical Oncology Unit, University Hospital of Parma, 43126 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2104-4016","authenticated-orcid":false,"given":"Erika","family":"De Sensi","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilenia Rita","family":"Cannizzaro","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-4282-6801","authenticated-orcid":false,"given":"Antonietta","family":"Taiani","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Michiara","sequence":"additional","affiliation":[{"name":"Medical Oncology Unit, University Hospital of Parma, 43126 Parma, Italy"},{"name":"Breast Unit, University Hospital of Parma, 43126 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angelica","family":"Sikokis","sequence":"additional","affiliation":[{"name":"Medical Oncology Unit, University Hospital of Parma, 43126 Parma, Italy"},{"name":"Breast Unit, University Hospital of Parma, 43126 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela","family":"Boggiani","sequence":"additional","affiliation":[{"name":"Medical Oncology Unit, University Hospital of Parma, 43126 Parma, Italy"},{"name":"Breast Unit, University Hospital of Parma, 43126 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9230-9288","authenticated-orcid":false,"given":"Chiara","family":"Tommasi","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy"},{"name":"Medical Oncology Unit, University Hospital of Parma, 43126 Parma, Italy"},{"name":"Breast Unit, University Hospital of Parma, 43126 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olga","family":"Serra","sequence":"additional","affiliation":[{"name":"Medical Oncology Unit, University Hospital of Parma, 43126 Parma, Italy"},{"name":"Breast Unit, University Hospital of Parma, 43126 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Bonatti","sequence":"additional","affiliation":[{"name":"Medical Oncology Unit, University Hospital of Parma, 43126 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessia","family":"Adorni","sequence":"additional","affiliation":[{"name":"Medical Oncology Unit, University Hospital of Parma, 43126 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anita","family":"Luberto","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrizia","family":"Caggiati","sequence":"additional","affiliation":[{"name":"Medical Genetics, University Hospital of Parma, 43126 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7572-7031","authenticated-orcid":false,"given":"Davide","family":"Martorana","sequence":"additional","affiliation":[{"name":"Medical Genetics, University Hospital of Parma, 43126 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vera","family":"Uliana","sequence":"additional","affiliation":[{"name":"Medical Genetics, University Hospital of Parma, 43126 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3268-6786","authenticated-orcid":false,"given":"Antonio","family":"Percesepe","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy"},{"name":"Medical Genetics, University Hospital of Parma, 43126 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7979-6261","authenticated-orcid":false,"given":"Antonino","family":"Musolino","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy"},{"name":"Medical Oncology Unit, University Hospital of Parma, 43126 Parma, Italy"},{"name":"Breast Unit, University Hospital of Parma, 43126 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benedetta","family":"Pellegrino","sequence":"additional","affiliation":[{"name":"Medical Oncology Unit, University Hospital of Parma, 43126 Parma, Italy"},{"name":"Breast Unit, University Hospital of Parma, 43126 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,2,8]]},"reference":[{"key":"ref_1","unstructured":"Broca, P. (1866). Trait\u00e9 des Tumeurs, P. Asselin."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1126\/science.7545954","article-title":"A Strong Candidate for the Breast and Ovarian Cancer Susceptibility Gene BRCA1","volume":"266","author":"Miki","year":"1994","journal-title":"Science"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2088","DOI":"10.1126\/science.8091231","article-title":"Localization of a Breast Cancer Susceptibility Gene, BRCA2, to Chromosome 13q12-13","volume":"265","author":"Wooster","year":"1994","journal-title":"Science"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1080\/14636778.2014.914849","article-title":"Social, Ethical and Legal Considerations Raised by the Discovery and Patenting of the BRCA1 and BRCA2 Genes","volume":"33","author":"Joly","year":"2014","journal-title":"New Genet. Soc."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2243","DOI":"10.1056\/NEJMsr1501341","article-title":"Gene-Panel Sequencing and the Prediction of Breast-Cancer Risk","volume":"372","author":"Easton","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"ref_6","unstructured":"Petrucelli, N., Daly, M.B., and Pal, T. (1998). BRCA1- and BRCA2-Associated Hereditary Breast and Ovarian Cancer, University of Washington."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2402","DOI":"10.1001\/jama.2017.7112","article-title":"Risks of Breast, Ovarian, and Contralateral Breast Cancer for BRCA1 and BRCA2 Mutation Carriers","volume":"317","author":"Kuchenbaecker","year":"2017","journal-title":"JAMA"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"812","DOI":"10.1093\/jnci\/djt095","article-title":"Cancer Risks for BRCA1 and BRCA2 Mutation Carriers: Results from Prospective Analysis of EMBRACE","volume":"105","author":"Mavaddat","year":"2013","journal-title":"JNCI J. Natl. Cancer Inst."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2078","DOI":"10.1158\/1055-9965.2078.13.12","article-title":"Prevalence of BRCA1 Mutation Carriers among U.S. Non-Hispanic Whites","volume":"13","author":"Whittemore","year":"2004","journal-title":"Cancer Epidemiol. Biomark. Prev."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1093\/jnci\/dju380","article-title":"Cost-Effectiveness of Population Screening for BRCA Mutations in Ashkenazi Jewish Women Compared with Family History\u2013Based Testing","volume":"107","author":"Manchanda","year":"2015","journal-title":"JNCI J. Natl. Cancer Inst."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1470","DOI":"10.1126\/science.1252230","article-title":"Cancer Suppression by the Chromosome Custodians, BRCA1 and BRCA2","volume":"343","author":"Venkitaraman","year":"2014","journal-title":"Science"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"E10642","DOI":"10.1073\/pnas.1803177115","article-title":"BRCA1 Ensures Genome Integrity by Eliminating Estrogen-Induced Pathological Topoisomerase II\u2013DNA Complexes","volume":"115","author":"Sasanuma","year":"2018","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"814","DOI":"10.1038\/nrc1457","article-title":"Hallmarks of \u201cBRCAness\u201d in Sporadic Cancers","volume":"4","author":"Turner","year":"2004","journal-title":"Nat. Rev. Cancer"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Toss, A., Molinaro, E., Venturelli, M., Domati, F., Marcheselli, L., Piana, S., Barbieri, E., Grandi, G., Piombino, C., and Marchi, I. (2020). BRCA Detection Rate in an Italian Cohort of Luminal Early-Onset and Triple-Negative Breast Cancer Patients without Family History: When Biology Overcomes Genealogy. Cancers, 12.","DOI":"10.21203\/rs.3.rs-16152\/v1"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"D1062","DOI":"10.1093\/nar\/gkx1153","article-title":"ClinVar: Improving Access to Variant Interpretations and Supporting Evidence","volume":"46","author":"Landrum","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"100240","DOI":"10.1016\/j.xhgg.2023.100240","article-title":"BRCA1 Frameshift Variants Leading to Extended Incorrect Protein C Termini","volume":"4","author":"Nepomuceno","year":"2023","journal-title":"Hum. Genet. Genom. Adv."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1097\/CEJ.0000000000000337","article-title":"BRCA1\/2 Germline Missense Mutations: A Systematic Review","volume":"27","author":"Corso","year":"2018","journal-title":"Eur. J. Cancer Prev."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"Standards and Guidelines for the Interpretation of Sequence Variants: A Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"102668","DOI":"10.1016\/j.dnarep.2019.102668","article-title":"How Do Mutations Affecting the Breast Cancer Genes BRCA1 and BRCA2 Cause Cancer Susceptibility?","volume":"81","author":"Venkitaraman","year":"2019","journal-title":"DNA Repair"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1016\/j.ajhg.2018.07.002","article-title":"A Dominantly Inherited 5\u2032 UTR Variant Causing Methylation-Associated Silencing of BRCA1 as a Cause of Breast and Ovarian Cancer","volume":"103","author":"Evans","year":"2018","journal-title":"Am. J. Hum. Genet."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1347","DOI":"10.1001\/jama.2014.5985","article-title":"Association of Type and Location of BRCA1 and BRCA2 Mutations with Risk of Breast and Ovarian Cancer","volume":"313","author":"Rebbeck","year":"2015","journal-title":"JAMA"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1038\/ng0197-103","article-title":"Variation of Risks of Breast and Ovarian Cancer Associated with Different Germline Mutations of the BRCA2 Gene","volume":"15","author":"Gayther","year":"1997","journal-title":"Nat. Genet."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"38","DOI":"10.3109\/0284186X.2015.1067714","article-title":"Increased Risk of Male Cancer and Identification of a Potential Prostate Cancer Cluster Region in BRCA2","volume":"55","author":"Petersen","year":"2016","journal-title":"Acta Oncol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"624","DOI":"10.1158\/0008-5472.CAN-19-1840","article-title":"Association of Genomic Domains in BRCA1 and BRCA2 with Prostate Cancer Risk and Aggressiveness","volume":"80","author":"Patel","year":"2020","journal-title":"Cancer Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1052","DOI":"10.1136\/jmg-2022-109111","article-title":"Pancreatic Cancer Cluster Region Identified in BRCA2","volume":"60","author":"Chian","year":"2023","journal-title":"J. Med. Genet."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1488","DOI":"10.1002\/humu.24276","article-title":"Altered Regulation of BRCA1 Exon 11 Splicing Is Associated with Breast Cancer Risk in Carriers of BRCA1 Pathogenic Variants","volume":"42","author":"Mazoyer","year":"2021","journal-title":"Hum. Mutat."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"djv315","DOI":"10.1093\/jnci\/djv315","article-title":"BRCA2 Polymorphic Stop Codon K3326X and the Risk of Breast, Prostate, and Ovarian Cancers","volume":"108","author":"Meeks","year":"2016","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Cline, M.S., Liao, R.G., Parsons, M.T., Paten, B., Alquaddoomi, F., Antoniou, A., Baxter, S., Brody, L., Cook-Deegan, R., and Coffin, A. (2018). BRCA Challenge: BRCA Exchange as a Global Resource for Variants in BRCA1 and BRCA2. PLoS Genet., 14.","DOI":"10.1371\/journal.pgen.1007752"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"830","DOI":"10.1038\/gim.2014.40","article-title":"Utilization of Multigene Panels in Hereditary Cancer Predisposition Testing: Analysis of More than 2,000 Patients","volume":"16","author":"LaDuca","year":"2014","journal-title":"Genet. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1721","DOI":"10.1002\/cncr.30498","article-title":"A Study of over 35,000 Women with Breast Cancer Tested with a 25-gene Panel of Hereditary Cancer Genes","volume":"123","author":"Buys","year":"2017","journal-title":"Cancer"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"6113","DOI":"10.1158\/1078-0432.CCR-16-3227","article-title":"Germline Mutations in Cancer Susceptibility Genes in a Large Series of Unselected Breast Cancer Patients","volume":"23","author":"Sun","year":"2017","journal-title":"Clin. Cancer Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"440","DOI":"10.1056\/NEJMoa2005936","article-title":"A Population-Based Study of Genes Previously Implicated in Breast Cancer","volume":"384","author":"Hu","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"428","DOI":"10.1056\/NEJMoa1913948","article-title":"Breast Cancer Risk Genes\u2014Association Analysis in More than 113,000 Women","volume":"384","author":"Dorling","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1056\/NEJMe2035083","article-title":"Which Genes for Hereditary Breast Cancer?","volume":"384","author":"Narod","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1136\/jmedgenet-2018-105807","article-title":"Clinical Spectrum and Pleiotropic Nature of CDH1 Germline Mutations","volume":"56","author":"Figueiredo","year":"2019","journal-title":"J. Med. Genet."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2360","DOI":"10.1001\/jama.297.21.2360","article-title":"Founder and Recurrent CDH1 Mutations in Families with Hereditary Diffuse Gastric Cancer","volume":"297","author":"Kaurah","year":"2007","journal-title":"JAMA"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"486","DOI":"10.1136\/jmedgenet-2012-101472","article-title":"CDH1 Germline Mutations and the Hereditary Diffuse Gastric and Lobular Breast Cancer Syndrome: A Multicentre Study","volume":"50","author":"Benusiglio","year":"2013","journal-title":"J. Med. Genet."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"e386","DOI":"10.1016\/S1470-2045(20)30219-9","article-title":"Hereditary Diffuse Gastric Cancer: Updated Clinical Practice Guidelines","volume":"21","author":"Blair","year":"2020","journal-title":"Lancet Oncol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1016\/B978-0-12-394311-8.00015-7","article-title":"E-Cadherin Alterations in Hereditary Disorders with Emphasis on Hereditary Diffuse Gastric Cancer","volume":"116","author":"Oliveira","year":"2013","journal-title":"Prog. Mol. Biol. Transl. Sci."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1136\/jmedgenet-2018-105337","article-title":"Hereditary Lobular Breast Cancer with an Emphasis on E-Cadherin Genetic Defect","volume":"55","author":"Corso","year":"2018","journal-title":"J. Med. Genet."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Fairoosa, P., and Witharana, C. (2020). Gene Mutations in Hereditary Breast Cancer\u2014A Review. Eur. J. Med. Health Sci., 2.","DOI":"10.24018\/ejmed.2020.2.3.286"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1000","DOI":"10.6004\/jnccn.2023.0051","article-title":"NCCN Guidelines\u00ae Insights: Genetic\/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic, Version 2.2024","volume":"21","author":"Daly","year":"2023","journal-title":"J. Natl. Compr. Canc. Netw."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Angeli, D., Salvi, S., and Tedaldi, G. (2020). Genetic Predisposition to Breast and Ovarian Cancers: How Many and Which Genes to Test?. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21031128"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"674","DOI":"10.1200\/JCO.19.01907","article-title":"Cancer Risks Associated with Germline PALB2 Pathogenic Variants: An International Study of 524 Families","volume":"38","author":"Yang","year":"2020","journal-title":"J. Clin. Oncol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1038\/s10038-019-0680-7","article-title":"A Systematic Review of Predicted Pathogenic PALB2 Variants: An Analysis of Mutational Overlap between Epithelial Cancers","volume":"65","author":"Janssen","year":"2020","journal-title":"J. Hum. Genet."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"6384190","DOI":"10.1155\/2020\/6384190","article-title":"Secondary Prevention in Hereditary Breast and\/or Ovarian Cancer Syndromes Other Than BRCA","volume":"2020","author":"Piombino","year":"2020","journal-title":"J. Oncol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1038\/sj.ejhg.5200289","article-title":"Novel PTEN Mutations in Patients with Cowden Disease: Absence of Clear Genotype\u2013Phenotype Correlations","volume":"7","author":"Nelen","year":"1999","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Pilarski, R. (2019). PTEN Hamartoma Tumor Syndrome: A Clinical Overview. Cancers, 11.","DOI":"10.3390\/cancers11060844"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1111\/cge.13875","article-title":"A Review on Age-related Cancer Risks in PTEN Hamartoma Tumor Syndrome","volume":"99","author":"Hendricks","year":"2021","journal-title":"Clin. Genet."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1387","DOI":"10.1038\/s41431-020-0651-7","article-title":"Cancer Surveillance Guideline for Individuals with PTEN Hamartoma Tumour Syndrome","volume":"28","author":"Tischkowitz","year":"2020","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1093\/jnci\/djac188","article-title":"Cancer Risks by Sex and Variant Type in PTEN Hamartoma Tumor Syndrome","volume":"115","author":"Hendricks","year":"2023","journal-title":"JNCI J. Natl. Cancer Inst."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1132","DOI":"10.1038\/mp.2014.125","article-title":"Molecular and Phenotypic Abnormalities in Individuals with Germline Heterozygous PTEN Mutations and Autism","volume":"20","author":"Frazier","year":"2015","journal-title":"Mol. Psychiatry"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1250","DOI":"10.1200\/JCO.2008.16.6959","article-title":"Beyond Li Fraumeni Syndrome: Clinical Characteristics of Families with P53 Germline Mutations","volume":"27","author":"Gonzalez","year":"2009","journal-title":"J. Clin. Oncol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"3673","DOI":"10.1002\/cncr.30248","article-title":"Risks of First and Subsequent Cancers among TP53 Mutation Carriers in the National Cancer Institute Li-Fraumeni Syndrome Cohort","volume":"122","author":"Mai","year":"2016","journal-title":"Cancer"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"908","DOI":"10.1002\/cncr.26377","article-title":"Early Onset HER2-Positive Breast Cancer Is Associated with Germline TP53 Mutations","volume":"118","author":"Bojadzieva","year":"2012","journal-title":"Cancer"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1379","DOI":"10.1038\/s41431-020-0638-4","article-title":"Guidelines for the Li\u2013Fraumeni and Heritable TP53-Related Cancer Syndromes","volume":"28","author":"Frebourg","year":"2020","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1136\/jmedgenet-2017-104976","article-title":"Contribution of de Novo and Mosaic TP53 Mutations to Li-Fraumeni Syndrome","volume":"55","author":"Charbonnier","year":"2018","journal-title":"J. Med. Genet."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"809","DOI":"10.1038\/gim.2017.196","article-title":"Somatic TP53 Variants Frequently Confound Germ-Line Testing Results","volume":"20","author":"Weitzel","year":"2018","journal-title":"Genet. Med."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1097\/MOH.0000000000000509","article-title":"P53 Involvement in Clonal Hematopoiesis of Indeterminate Potential","volume":"26","author":"Chen","year":"2019","journal-title":"Curr. Opin. Hematol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1016\/j.canlet.2005.12.039","article-title":"The TP53 Mutation, R337H, Is Associated with Li-Fraumeni and Li-Fraumeni-like Syndromes in Brazilian Families","volume":"245","author":"Achatz","year":"2007","journal-title":"Cancer Lett."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1781","DOI":"10.1158\/1535-7163.MCT-15-0945","article-title":"ATM Mutations in Cancer: Therapeutic Implications","volume":"15","author":"Choi","year":"2016","journal-title":"Mol. Cancer Ther."},{"key":"ref_62","first-page":"573","article-title":"The Incidence and Gene Frequency of Ataxia-Telangiectasia in the United States","volume":"39","author":"Swift","year":"1986","journal-title":"Am. J. Hum. Genet."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1001\/jamaoncol.2018.2956","article-title":"Association of Breast and Ovarian Cancers with Predisposition Genes Identified by Large-Scale Sequencing","volume":"5","author":"Lu","year":"2019","journal-title":"JAMA Oncol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1056\/NEJMoa1603144","article-title":"Inherited DNA-Repair Gene Mutations in Men with Metastatic Prostate Cancer","volume":"375","author":"Pritchard","year":"2016","journal-title":"N. Engl. J. Med."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1158\/2159-8290.CD-11-0194","article-title":"ATM Mutations in Patients with Hereditary Pancreatic Cancer","volume":"2","author":"Roberts","year":"2012","journal-title":"Cancer Discov."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"906","DOI":"10.1038\/ng.3342","article-title":"Loss-of-Function Variants in ATM Confer Risk of Gastric Cancer","volume":"47","author":"Helgason","year":"2015","journal-title":"Nat. Genet."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1121","DOI":"10.1080\/09553002.2017.1344363","article-title":"ATM, Radiation, and the Risk of Second Primary Breast Cancer","volume":"93","author":"Bernstein","year":"2017","journal-title":"Int. J. Radiat. Biol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"R73","DOI":"10.1186\/bcr2919","article-title":"Rare Variants in the ATMgene and Risk of Breast Cancer","volume":"13","author":"Goldgar","year":"2011","journal-title":"Breast Cancer Res."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1158\/1940-6207.CAPR-20-0448","article-title":"Germline Pathogenic Variants in the Ataxia Telangiectasia Mutated (ATM) Gene Are Associated with High and Moderate Risks for Multiple Cancers","volume":"14","author":"Hall","year":"2021","journal-title":"Cancer Prev. Res."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"2080","DOI":"10.1200\/JCO.20.00299","article-title":"Management of Hereditary Breast Cancer: American Society of Clinical Oncology, American Society for Radiation Oncology, and Society of Surgical Oncology Guideline","volume":"38","author":"Tung","year":"2020","journal-title":"J. Clin. Oncol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"4274","DOI":"10.1200\/JCO.20.02151","article-title":"TBCRC 048: Phase II Study of Olaparib for Metastatic Breast Cancer and Mutations in Homologous Recombination-Related Genes","volume":"38","author":"Tung","year":"2020","journal-title":"J. Clin. Oncol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"2091","DOI":"10.1056\/NEJMoa1911440","article-title":"Olaparib for Metastatic Castration-Resistant Prostate Cancer","volume":"382","author":"Mateo","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"430","DOI":"10.1038\/ng1296-430","article-title":"Identification of a RING Protein That Can Interact in Vivo with the BRCA1 Gene Product","volume":"14","author":"Wu","year":"1996","journal-title":"Nat. Genet."},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"\u015aniadecki, M., Brzezi\u0144ski, M., Darecka, K., Klasa-Mazurkiewicz, D., Poniewierza, P., Krzeszowiec, M., Kmie\u0107, N., and Wydra, D. (2020). BARD1 and Breast Cancer: The Possibility of Creating Screening Tests and New Preventive and Therapeutic Pathways for Predisposed Women. Genes, 11.","DOI":"10.20944\/preprints202008.0371.v1"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"1190","DOI":"10.1001\/jamaoncol.2017.0424","article-title":"Associations Between Cancer Predisposition Testing Panel Genes and Breast Cancer","volume":"3","author":"Couch","year":"2017","journal-title":"JAMA Oncol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"855","DOI":"10.1093\/jnci\/djy106","article-title":"Triple-Negative Breast Cancer Risk Genes Identified by Multigene Hereditary Cancer Panel Testing","volume":"110","author":"Shimelis","year":"2018","journal-title":"JNCI J. Natl. Cancer Inst."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"718","DOI":"10.1038\/ng.374","article-title":"Common Variations in BARD1 Influence Susceptibility to High-Risk Neuroblastoma","volume":"41","author":"Capasso","year":"2009","journal-title":"Nat. Genet."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1186\/s13058-019-1137-9","article-title":"Germline Loss-of-Function Variants in the BARD1 Gene Are Associated with Early-Onset Familial Breast Cancer but Not Ovarian Cancer","volume":"21","author":"Borde","year":"2019","journal-title":"Breast Cancer Res."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1038\/nrc.2017.116","article-title":"Fanconi Anaemia and Cancer: An Intricate Relationship","volume":"18","author":"Nalepa","year":"2018","journal-title":"Nat. Rev. Cancer"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"1239","DOI":"10.1038\/ng1902","article-title":"Truncating Mutations in the Fanconi Anemia J Gene BRIP1 Are Low-Penetrance Breast Cancer Susceptibility Alleles","volume":"38","author":"Seal","year":"2006","journal-title":"Nat. Genet."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1136\/jmedgenet-2015-103529","article-title":"No Evidence That Protein Truncating Variants in BRIP1 Are Associated with Breast Cancer Risk: Implications for Gene Panel Testing","volume":"53","author":"Easton","year":"2016","journal-title":"J. Med. Genet."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1186\/s13048-020-00654-3","article-title":"BRIP1, RAD51C, and RAD51D Mutations Are Associated with High Susceptibility to Ovarian Cancer: Mutation Prevalence and Precise Risk Estimates Based on a Pooled Analysis of ~30,000 Cases","volume":"13","author":"Suszynska","year":"2020","journal-title":"J. Ovarian Res."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"857","DOI":"10.1158\/0008-5472.CAN-19-1991","article-title":"Rare BRIP1 Missense Alleles Confer Risk for Ovarian and Breast Cancer","volume":"80","author":"Moyer","year":"2020","journal-title":"Cancer Res."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"3747","DOI":"10.1200\/JCO.2010.34.0778","article-title":"Risk of Breast Cancer in Women with a CHEK2 Mutation with and without a Family History of Breast Cancer","volume":"29","author":"Cybulski","year":"2011","journal-title":"J. Clin. Oncol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"860","DOI":"10.1136\/jmedgenet-2011-100380","article-title":"CHEK2*1100delC Homozygosity Is Associated with a High Breast Cancer Risk in Women","volume":"48","author":"Adank","year":"2011","journal-title":"J. Med. Genet."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1002\/ijc.20299","article-title":"CHEK2 Variant I157T May Be Associated with Increased Breast Cancer Risk","volume":"111","author":"Kilpivaara","year":"2004","journal-title":"Int. J. Cancer"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"732","DOI":"10.1136\/jmedgenet-2017-104588","article-title":"Rare, Protein-Truncating Variants in ATM, CHEK2 and PALB2, but Not XRCC2, Are Associated with Increased Breast Cancer Risks","volume":"54","author":"Decker","year":"2017","journal-title":"J. Med. Genet."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"1162","DOI":"10.1158\/1055-9965.EPI-18-1102","article-title":"Frequency of Pathogenic Germline Variants in CDH1, BRCA2, CHEK2, PALB2, BRCA1, and TP53 in Sporadic Lobular Breast Cancer","volume":"28","author":"Petridis","year":"2019","journal-title":"Cancer Epidemiol. Biomark. Prev."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1038\/gim.2016.147","article-title":"Genetic Modifiers of CHEK2*1100delC-Associated Breast Cancer Risk","volume":"19","author":"Muranen","year":"2017","journal-title":"Genet. Med."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"1324","DOI":"10.1038\/gim.2018.12","article-title":"A Counseling Framework for Moderate-Penetrance Colorectal Cancer Susceptibility Genes","volume":"20","author":"Katona","year":"2018","journal-title":"Genet. Med."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"1228","DOI":"10.1001\/jamaoncol.2018.1986","article-title":"Prevalence of Germline Mutations in Cancer Susceptibility Genes in Patients with Advanced Renal Cell Carcinoma","volume":"4","author":"Carlo","year":"2018","journal-title":"JAMA Oncol."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"548","DOI":"10.1002\/ijc.29426","article-title":"CHEK2 Mutations and the Risk of Papillary Thyroid Cancer","volume":"137","author":"Cybulski","year":"2015","journal-title":"Int. J. Cancer"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"514","DOI":"10.1001\/jamaoncol.2018.6477","article-title":"Association of Inherited Pathogenic Variants in Checkpoint Kinase 2 (CHEK2) with Susceptibility to Testicular Germ Cell Tumors","volume":"5","author":"AlDubayan","year":"2019","journal-title":"JAMA Oncol."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1007\/s10549-016-4085-4","article-title":"Male Breast Cancer in a Multi-Gene Panel Testing Cohort: Insights and Unexpected Results","volume":"161","author":"Pritzlaff","year":"2017","journal-title":"Breast Cancer Res. Treat."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1038\/s41436-019-0633-8","article-title":"A Clinical Guide to Hereditary Cancer Panel Testing: Evaluation of Gene-Specific Cancer Associations and Sensitivity of Genetic Testing Criteria in a Cohort of 165,000 High-Risk Patients","volume":"22","author":"LaDuca","year":"2020","journal-title":"Genet. Med."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1016\/j.ygyno.2006.05.040","article-title":"CHEK2 Variants Predispose to Benign, Borderline and Low-Grade Invasive Ovarian Tumors","volume":"102","author":"Szymanska","year":"2006","journal-title":"Gynecol. Oncol."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1136\/jmedgenet-2012-100852","article-title":"A Finnish Founder Mutation in RAD51D: Analysis in Breast, Ovarian, Prostate, and Colorectal Cancer: Table 1","volume":"49","author":"Pelttari","year":"2012","journal-title":"J. Med. Genet."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"2046","DOI":"10.1093\/annonc\/mdy338","article-title":"Associations between RAD51D Germline Mutations and Breast Cancer Risk and Survival in BRCA1\/2-Negative Breast Cancers","volume":"29","author":"Chen","year":"2018","journal-title":"Ann. Oncol."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1016\/j.cancergen.2015.12.013","article-title":"Increased Yield of Actionable Mutations Using Multi-Gene Panels to Assess Hereditary Cancer Susceptibility in an Ethnically Diverse Clinical Cohort","volume":"209","author":"Ricker","year":"2016","journal-title":"Cancer Genet."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"2001","DOI":"10.1200\/JCO.2013.53.6607","article-title":"Clinical Evaluation of a Multiple-Gene Sequencing Panel for Hereditary Cancer Risk Assessment","volume":"32","author":"Kurian","year":"2014","journal-title":"J. Clin. Oncol."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1186\/s13073-019-0690-2","article-title":"Recommendations for Application of the Functional Evidence PS3\/BS3 Criterion Using the ACMG\/AMP Sequence Variant Interpretation Framework","volume":"12","author":"Brnich","year":"2020","journal-title":"Genome Med."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"3812","DOI":"10.1093\/nar\/gkg509","article-title":"SIFT: Predicting Amino Acid Changes That Affect Protein Function","volume":"31","author":"Ng","year":"2003","journal-title":"Nucleic Acids Res."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1038\/ng.2892","article-title":"A General Framework for Estimating the Relative Pathogenicity of Human Genetic Variants","volume":"46","author":"Kircher","year":"2014","journal-title":"Nat. Genet."},{"key":"ref_104","first-page":"7.20.1","article-title":"Predicting Functional Effect of Human Missense Mutations Using PolyPhen-2","volume":"76","author":"Adzhubei","year":"2013","journal-title":"Curr. Protoc. Hum. Genet."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1016\/j.cell.2018.12.015","article-title":"Predicting Splicing from Primary Sequence with Deep Learning","volume":"176","author":"Jaganathan","year":"2019","journal-title":"Cell"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1038\/s41586-021-03819-2","article-title":"Highly Accurate Protein Structure Prediction with AlphaFold","volume":"596","author":"Jumper","year":"2021","journal-title":"Nature"},{"key":"ref_107","doi-asserted-by":"crossref","unstructured":"Schmidt, A., R\u00f6ner, S., Mai, K., Klinkhammer, H., Kircher, M., and Ludwig, K.U. (2023). Predicting the Pathogenicity of Missense Variants Using Features Derived from AlphaFold2. Bioinformatics, 39.","DOI":"10.1093\/bioinformatics\/btad280"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"eadg7492","DOI":"10.1126\/science.adg7492","article-title":"Accurate Proteome-Wide Missense Variant Effect Prediction with AlphaMissense","volume":"381","author":"Cheng","year":"2023","journal-title":"Science"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"877","DOI":"10.1016\/j.ajhg.2016.08.016","article-title":"REVEL: An Ensemble Method for Predicting the Pathogenicity of Rare Missense Variants","volume":"99","author":"Ioannidis","year":"2016","journal-title":"Am. J. Hum. Genet."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1016\/j.ajhg.2017.07.014","article-title":"Variant Interpretation: Functional Assays to the Rescue","volume":"101","author":"Starita","year":"2017","journal-title":"Am. J. Hum. Genet."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1038\/nature13695","article-title":"Saturation Editing of Genomic Regions by Multiplex Homology-Directed Repair","volume":"513","author":"Findlay","year":"2014","journal-title":"Nature"},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1038\/s41586-018-0461-z","article-title":"Accurate Classification of BRCA1 Variants with Saturation Genome Editing","volume":"562","author":"Findlay","year":"2018","journal-title":"Nature"},{"key":"ref_113","doi-asserted-by":"crossref","unstructured":"Sahu, S., Sullivan, T.L., Mitrophanov, A.Y., Galloux, M., Nousome, D., Southon, E., Caylor, D., Mishra, A.P., Evans, C.N., and Clapp, M.E. (2023). Saturation Genome Editing of 11 Codons and Exon 13 of BRCA2 Coupled with Chemotherapeutic Drug Response Accurately Determines Pathogenicity of Variants. PLoS Genet., 19.","DOI":"10.1371\/journal.pgen.1010940"},{"key":"ref_114","doi-asserted-by":"crossref","unstructured":"Huang, H., Hu, C., Na, J., Hart, S.N., David Gnanaolivu, R., Abozaid, M., Rao, T., Tecleab, Y.A., Pesaran, T., and Cilas Morais Lyra, P. (2023). Saturation Genome Editing-Based Functional Evaluation and Clinical 2 Classification of BRCA2 Single Nucleotide Variants. bioRxiv.","DOI":"10.1101\/2023.12.14.571597"},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"2248","DOI":"10.1016\/j.ajhg.2021.11.001","article-title":"Closing the Gap: Systematic Integration of Multiplexed Functional Data Resolves Variants of Uncertain Significance in BRCA1, TP53, and PTEN","volume":"108","author":"Fayer","year":"2021","journal-title":"Am. J. Hum. Genet."},{"key":"ref_116","doi-asserted-by":"crossref","unstructured":"Esposito, D., Weile, J., Shendure, J., Starita, L.M., Papenfuss, A.T., Roth, F.P., Fowler, D.M., and Rubin, A.F. (2019). MaveDB: An Open-Source Platform to Distribute and Interpret Data from Multiplexed Assays of Variant Effect. Genome Biol., 20.","DOI":"10.1186\/s13059-019-1845-6"},{"key":"ref_117","doi-asserted-by":"crossref","unstructured":"Boonen, R.A.C.M., Vreeswijk, M.P.G., and van Attikum, H. (2020). Functional Characterization of PALB2 Variants of Uncertain Significance: Toward Cancer Risk and Therapy Response Prediction. Front. Mol. Biosci., 7.","DOI":"10.3389\/fmolb.2020.00169"},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1158\/0008-5472.CAN-21-1845","article-title":"Functional Analysis Identifies Damaging CHEK2 Missense Variants Associated with Increased Cancer Risk","volume":"82","author":"Boonen","year":"2022","journal-title":"Cancer Res."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"994","DOI":"10.1038\/nature06611","article-title":"Proportionally More Deleterious Genetic Variation in European than in African Populations","volume":"451","author":"Lohmueller","year":"2008","journal-title":"Nature"},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"2235","DOI":"10.1056\/NEJMsr1406261","article-title":"ClinGen\u2014The Clinical Genome Resource","volume":"372","author":"Rehm","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"ref_121","doi-asserted-by":"crossref","unstructured":"Fowler, D.M., Adams, D.J., Gloyn, A.L., Hahn, W.C., Marks, D.S., Muffley, L.A., Neal, J.T., Roth, F.P., Rubin, A.F., and Starita, L.M. (2023). An Atlas of Variant Effects to Understand the Genome at Nucleotide Resolution. Genome Biol., 24.","DOI":"10.1186\/s13059-023-02986-x"},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"1557","DOI":"10.1002\/humu.23818","article-title":"Large Scale Multifactorial Likelihood Quantitative Analysis of BRCA1and BRCA2 Variants: An ENIGMA Resource to Support Clinical Variant Classification","volume":"40","author":"Parsons","year":"2019","journal-title":"Hum. Mutat."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1002\/humu.21628","article-title":"ENIGMA-Evidence-Based Network for the Interpretation of Germline Mutant Alleles: An International Initiative to Evaluate Risk and Clinical Significance Associated with Sequence Variation in BRCA1 and BRCA2 Genes","volume":"33","author":"Spurdle","year":"2012","journal-title":"Hum. Mutat."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1038\/gim.2014.129","article-title":"Genomic Screening of the General Adult Population: Key Concepts for Assessing Net Benefit with Systematic Evidence Reviews","volume":"17","author":"Prince","year":"2015","journal-title":"Genet. Med."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"1526","DOI":"10.1002\/humu.22150","article-title":"A Guide for Functional Analysis of BRCA1 Variants of Uncertain Significance","volume":"33","author":"Millot","year":"2012","journal-title":"Hum. Mutat."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1002\/humu.22478","article-title":"Functional Assays for Analysis of Variants of Uncertain Significance in BRCA2","volume":"35","author":"Guidugli","year":"2014","journal-title":"Hum. Mutat."},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"759","DOI":"10.1016\/j.trecan.2022.04.009","article-title":"CHEK2 Variants: Linking Functional Impact to Cancer Risk","volume":"8","author":"Boonen","year":"2022","journal-title":"Trends Cancer"},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1046\/j.1365-2184.2001.00193.x","article-title":"P53 Functional Assays: Detecting P53 Mutations in Both the Germline and in Sporadic Tumours","volume":"34","author":"Camplejohn","year":"2001","journal-title":"Cell Prolif."},{"key":"ref_129","doi-asserted-by":"crossref","unstructured":"McCuaig, J., Armel, S., Care, M., Volenik, A., Kim, R., and Metcalfe, K. (2018). Next-Generation Service Delivery: A Scoping Review of Patient Outcomes Associated with Alternative Models of Genetic Counseling and Genetic Testing for Hereditary Cancer. Cancers, 10.","DOI":"10.3390\/cancers10110435"},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"29506","DOI":"10.1038\/srep29506","article-title":"Implementing Rapid, Robust, Cost-Effective, Patient-Centred, Routine Genetic Testing in Ovarian Cancer Patients","volume":"6","author":"George","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1136\/jmedgenet-2017-105140","article-title":"Mainstreamed Genetic Testing for Women with Ovarian Cancer: First-Year Experience","volume":"56","author":"Rahman","year":"2019","journal-title":"J. Med. Genet."},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1007\/s10689-019-00122-y","article-title":"Moving into the Mainstream: Healthcare Professionals\u2019 Views of Implementing Treatment Focussed Genetic Testing in Breast Cancer Care","volume":"18","author":"Hallowell","year":"2019","journal-title":"Fam. Cancer"},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1038\/gim.2014.101","article-title":"Primary-Care Providers\u2019 Perceived Barriers to Integration of Genetics Services: A Systematic Review of the Literature","volume":"17","author":"Larson","year":"2015","journal-title":"Genet. Med."},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1007\/s11606-016-3943-4","article-title":"Primary Care Providers\u2019 Cancer Genetic Testing-Related Knowledge, Attitudes, and Communication Behaviors: A Systematic Review and Research Agenda","volume":"32","author":"Hamilton","year":"2017","journal-title":"J. Gen. Intern. Med."},{"key":"ref_135","doi-asserted-by":"crossref","unstructured":"Wilkes, M.S., Day, F.C., Fancher, T.L., McDermott, H., Lehman, E., Bell, R.A., and Green, M.J. (2017). Increasing Confidence and Changing Behaviors in Primary Care Providers Engaged in Genetic Counselling. BMC Med. Educ., 17.","DOI":"10.1186\/s12909-017-0982-4"},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1038\/gim.2013.75","article-title":"A Cancer Genetics Toolkit Improves Access to Genetic Services through Documentation and Use of the Family History by Primary-Care Clinicians","volume":"16","author":"Scheuner","year":"2014","journal-title":"Genet. Med."},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"392","DOI":"10.1038\/nrg.2016.27","article-title":"Developing and Evaluating Polygenic Risk Prediction Models for Stratified Disease Prevention","volume":"17","author":"Chatterjee","year":"2016","journal-title":"Nat. Rev. Genet."},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1038\/s41576-018-0018-x","article-title":"The Personal and Clinical Utility of Polygenic Risk Scores","volume":"19","author":"Torkamani","year":"2018","journal-title":"Nat. Rev. Genet."},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"djv036","DOI":"10.1093\/jnci\/djv036","article-title":"Prediction of Breast Cancer Risk Based on Profiling with Common Genetic Variants","volume":"107","author":"Mavaddat","year":"2015","journal-title":"JNCI J. Natl. Cancer Inst."},{"key":"ref_140","doi-asserted-by":"crossref","first-page":"546","DOI":"10.1136\/jmedgenet-2018-105313","article-title":"Evaluation of Polygenic Risk Scores for Ovarian Cancer Risk Prediction in a Prospective Cohort Study","volume":"55","author":"Yang","year":"2018","journal-title":"J. Med. Genet."},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1136\/jmedgenet-2016-104125","article-title":"The Impact of a Panel of 18 SNPs on Breast Cancer Risk in Women Attending a UK Familial Screening Clinic: A Case\u2013Control Study","volume":"54","author":"Evans","year":"2017","journal-title":"J. Med. Genet."},{"key":"ref_142","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/j.ajhg.2018.11.002","article-title":"Polygenic Risk Scores for Prediction of Breast Cancer and Breast Cancer Subtypes","volume":"104","author":"Mavaddat","year":"2019","journal-title":"Am. J. Hum. Genet."},{"key":"ref_143","first-page":"djw302","article-title":"Evaluation of Polygenic Risk Scores for Breast and Ovarian Cancer Risk Prediction in BRCA1 and BRCA2 Mutation Carriers","volume":"10","author":"Kuchenbaecker","year":"2017","journal-title":"JNCI J. Natl. Cancer Inst."},{"key":"ref_144","doi-asserted-by":"crossref","first-page":"1653","DOI":"10.1038\/s41436-020-0862-x","article-title":"Polygenic Risk Scores and Breast and Epithelial Ovarian Cancer Risks for Carriers of BRCA1 and BRCA2 Pathogenic Variants","volume":"22","author":"Barnes","year":"2020","journal-title":"Genet. Med."},{"key":"ref_145","doi-asserted-by":"crossref","first-page":"680","DOI":"10.1093\/jnci\/djq088","article-title":"Assessing Women at High Risk of Breast Cancer: A Review of Risk Assessment Models","volume":"102","author":"Amir","year":"2010","journal-title":"JNCI J. Natl. Cancer Inst."},{"key":"ref_146","doi-asserted-by":"crossref","first-page":"1708","DOI":"10.1038\/s41436-018-0406-9","article-title":"BOADICEA: A Comprehensive Breast Cancer Risk Prediction Model Incorporating Genetic and Nongenetic Risk Factors","volume":"21","author":"Lee","year":"2019","journal-title":"Genet. Med."},{"key":"ref_147","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1038\/s10038-020-00832-7","article-title":"Deep Neural Network Improves the Estimation of Polygenic Risk Scores for Breast Cancer","volume":"66","author":"Zhang","year":"2021","journal-title":"J. Hum. Genet."},{"key":"ref_148","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1158\/1055-9965.EPI-16-0106","article-title":"The OncoArray Consortium: A Network for Understanding the Genetic Architecture of Common Cancers","volume":"26","author":"Amos","year":"2017","journal-title":"Cancer Epidemiol. Biomark. Prev."},{"key":"ref_149","doi-asserted-by":"crossref","unstructured":"Mital, S., and Nguyen, H.V. (2022). Cost-Effectiveness of Using Artificial Intelligence versus Polygenic Risk Score to Guide Breast Cancer Screening. BMC Cancer, 22.","DOI":"10.1186\/s12885-022-09613-1"},{"key":"ref_150","doi-asserted-by":"crossref","first-page":"e436","DOI":"10.1016\/S2589-7500(22)00042-5","article-title":"Cost-Effectiveness of Artificial Intelligence for Screening Colonoscopy: A Modelling Study","volume":"4","author":"Areia","year":"2022","journal-title":"Lancet Digit. Health"},{"key":"ref_151","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1001\/jamaophthalmol.2022.0223","article-title":"Cost-Effectiveness of Artificial Intelligence\u2013Based Retinopathy of Prematurity Screening","volume":"140","author":"Morrison","year":"2022","journal-title":"JAMA Ophthalmol."},{"key":"ref_152","doi-asserted-by":"crossref","first-page":"3764","DOI":"10.1158\/1078-0432.CCR-15-2477","article-title":"Homologous Recombination Deficiency (HRD) Score Predicts Response to Platinum-Containing Neoadjuvant Chemotherapy in Patients with Triple-Negative Breast Cancer","volume":"22","author":"Telli","year":"2016","journal-title":"Clin. Cancer Res."},{"key":"ref_153","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1186\/bcr3670","article-title":"Genomic Scars as Biomarkers of Homologous Recombination Deficiency and Drug Response in Breast and Ovarian Cancers","volume":"16","author":"Watkins","year":"2014","journal-title":"Breast Cancer Res."},{"key":"ref_154","doi-asserted-by":"crossref","first-page":"1949","DOI":"10.1016\/S0140-6736(17)32440-6","article-title":"Rucaparib Maintenance Treatment for Recurrent Ovarian Carcinoma after Response to Platinum Therapy (ARIEL3): A Randomised, Double-Blind, Placebo-Controlled, Phase 3 Trial","volume":"390","author":"Coleman","year":"2017","journal-title":"Lancet"},{"key":"ref_155","doi-asserted-by":"crossref","first-page":"2662","DOI":"10.1038\/s41467-020-16142-7","article-title":"Homologous Recombination DNA Repair Deficiency and PARP Inhibition Activity in Primary Triple Negative Breast Cancer","volume":"11","author":"Chopra","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_156","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1038\/nature12477","article-title":"Signatures of Mutational Processes in Human Cancer","volume":"500","author":"Alexandrov","year":"2013","journal-title":"Nature"},{"key":"ref_157","doi-asserted-by":"crossref","first-page":"888","DOI":"10.1111\/IGC.0b013e3181dc8292","article-title":"Ovarian and Uterine Carcinosarcomas: A Comparative Analysis of Prognostic Variables and Survival Outcomes","volume":"20","author":"Garg","year":"2010","journal-title":"Int. J. Gynecol. Cancer"},{"key":"ref_158","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/j.molcel.2010.09.019","article-title":"The DNA Damage Response: Making It Safe to Play with Knives","volume":"40","author":"Ciccia","year":"2010","journal-title":"Mol. Cell"},{"key":"ref_159","doi-asserted-by":"crossref","first-page":"6159","DOI":"10.1158\/1078-0432.CCR-10-1027","article-title":"A Marker of Homologous Recombination Predicts Pathologic Complete Response to Neoadjuvant Chemotherapy in Primary Breast Cancer","volume":"16","author":"Graeser","year":"2010","journal-title":"Clin. Cancer Res."},{"key":"ref_160","doi-asserted-by":"crossref","first-page":"4816","DOI":"10.1158\/1078-0432.CCR-14-0571","article-title":"Functional Ex Vivo Assay to Select Homologous Recombination\u2013Deficient Breast Tumors for PARP Inhibitor Treatment","volume":"20","author":"Naipal","year":"2014","journal-title":"Clin. Cancer Res."},{"key":"ref_161","doi-asserted-by":"crossref","first-page":"1203","DOI":"10.1093\/annonc\/mdy099","article-title":"RAD51 Foci as a Functional Biomarker of Homologous Recombination Repair and PARP Inhibitor Resistance in Germline BRCA-Mutated Breast Cancer","volume":"29","author":"Cruz","year":"2018","journal-title":"Ann. Oncol."},{"key":"ref_162","doi-asserted-by":"crossref","first-page":"e9172","DOI":"10.15252\/emmm.201809172","article-title":"A RAD51 Assay Feasible in Routine Tumor Samples Calls PARP Inhibitor Response beyond BRCA Mutation","volume":"10","author":"Cruz","year":"2018","journal-title":"EMBO Mol. Med."},{"key":"ref_163","doi-asserted-by":"crossref","first-page":"1697","DOI":"10.1056\/NEJMoa1506859","article-title":"DNA-Repair Defects and Olaparib in Metastatic Prostate Cancer","volume":"373","author":"Mateo","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"ref_164","doi-asserted-by":"crossref","first-page":"1006","DOI":"10.1158\/2159-8290.CD-17-0261","article-title":"Circulating Cell-Free DNA to Guide Prostate Cancer Treatment with PARP Inhibition","volume":"7","author":"Goodall","year":"2017","journal-title":"Cancer Discov."},{"key":"ref_165","doi-asserted-by":"crossref","first-page":"3154","DOI":"10.1093\/nar\/gkv160","article-title":"Involvement of ATM in Homologous Recombination after End Resection and RAD51 Nucleofilament Formation","volume":"43","author":"Bakr","year":"2015","journal-title":"Nucleic Acids Res."},{"key":"ref_166","doi-asserted-by":"crossref","first-page":"8109","DOI":"10.1158\/0008-5472.CAN-06-0140","article-title":"Deficiency in the Repair of DNA Damage by Homologous Recombination and Sensitivity to Poly(ADP-Ribose) Polymerase Inhibition","volume":"66","author":"McCabe","year":"2006","journal-title":"Cancer Res."},{"key":"ref_167","doi-asserted-by":"crossref","first-page":"1590","DOI":"10.1016\/j.annonc.2021.09.003","article-title":"Association of RAD51 with Homologous Recombination Deficiency (HRD) and Clinical Outcomes in Untreated Triple-Negative Breast Cancer (TNBC): Analysis of the GeparSixto Randomized Clinical Trial","volume":"32","author":"Loibl","year":"2021","journal-title":"Ann. Oncol."},{"key":"ref_168","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1016\/j.annonc.2020.11.009","article-title":"Olaparib Monotherapy as Primary Treatment in Unselected Triple Negative Breast Cancer","volume":"32","author":"Eikesdal","year":"2021","journal-title":"Ann. Oncol."},{"key":"ref_169","doi-asserted-by":"crossref","first-page":"510","DOI":"10.1007\/s12282-019-00951-w","article-title":"Reinterpretation of BRCA1 and BRCA2 Variants of Uncertain Significance in Patients with Hereditary Breast\/Ovarian Cancer Using the ACMG\/AMP 2015 Guidelines","volume":"26","author":"So","year":"2019","journal-title":"Breast Cancer"},{"key":"ref_170","doi-asserted-by":"crossref","first-page":"104847","DOI":"10.1016\/j.ejmg.2023.104847","article-title":"Reassessment of the NF1 Variants of Unknown Significance Found during the 20-Year Activity of a Genetics Diagnostic Laboratory","volume":"66","author":"Martorana","year":"2023","journal-title":"Eur. J. Med. Genet."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/15\/2\/219\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T13:57:13Z","timestamp":1760104633000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/15\/2\/219"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,2,8]]},"references-count":170,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2024,2]]}},"alternative-id":["genes15020219"],"URL":"https:\/\/doi.org\/10.3390\/genes15020219","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,2,8]]}}}