Familial Disclosure and Cascade Testing in High-Risk Families is Influenced by Gene Variant Penetrance: Implications for Family based Breast Cancer Prevention

Familial Disclosure and Cascade Testing in High-Risk Families is Influenced by Gene Variant Penetrance: Implications for Family based Breast Cancer Prevention | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Familial Disclosure and Cascade Testing in High-Risk Families is Influenced by Gene Variant Penetrance: Implications for Family based Breast Cancer Prevention Achille VC Manirakiza, Jincong J Freeman, Fangyuan Zhao, Emma Keel, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9610726/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background and Methods: Point of care genetic testing has grown but cascade testing of At-Risk Relatives (ARR) remains underutilized. Between July and September 2023, we surveyed 912 individuals enrolled in the Cancer Prone Study, a registry of diverse high-risk families who received genetic counseling from cancer genetic experts. We analyzed correlates of familial disclosure and cascade testing among carriers of pathogenic/likely pathogenic variants (PV). Data on carrier status of PV in cancer-predisposing genes, penetrance level of variants, receipt of a family letter, familial disclosure, and follow up cascade testing of ARRs were collected. Results: Of 912 respondents, 39.4% were carriers of PV. Among these carriers, 78% had highly penetrant PVs (most common genes were BRCA1 : 39% and BRCA2 : 18%) and 17.5% had moderate penetrance PVs; Rate of disclosure of PV to at least one family member; receipt of family letter explaining genetic test results; and sharing of information with ARRs were 98%, 69% and 82% respectively. Cascade testing was more likely among carriers with highly penetrance PV (91.1%) compared to those with moderate penetrance PV (58.3%) (adjusted odds ratio [AOR], 5.70; 95% CI, 2.03-16.02), and among carriers who received a family letter than among those who did not receive (87.2% vs. 73.0%; AOR, 3.70; 95% CI, 1.42-9.61). These data suggest that access to family-based counseling facilitated by cancer genetic experts improves understanding of familial risks and improves cascade testing following results disclosure. Our data support family based clinical interventions to optimize precision prevention and cancer control in high-risk individuals. Medical Genetics Oncology Full Text Additional Declarations The authors declare potential competing interests as follows: Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-9610726","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":634305633,"identity":"f90af492-3285-4686-a817-544a027ad670","order_by":0,"name":"Achille VC Manirakiza","email":"","orcid":"https://orcid.org/0000-0002-3829-2016","institution":"King Faisal Hospital Rwanda","correspondingAuthor":false,"prefix":"","firstName":"Achille","middleName":"VC","lastName":"Manirakiza","suffix":""},{"id":634305634,"identity":"b78d9712-aacb-49a3-b7ee-4d4a719a5979","order_by":1,"name":"Jincong J Freeman","email":"","orcid":"https://orcid.org/0000-0002-1119-2146","institution":"The University of Chicago","correspondingAuthor":false,"prefix":"","firstName":"Jincong","middleName":"J","lastName":"Freeman","suffix":""},{"id":634306781,"identity":"24f179db-f70a-452c-bc86-efe4cd5a61dc","order_by":2,"name":"Fangyuan Zhao","email":"","orcid":"https://orcid.org/0000-0001-9776-3677","institution":"The University of Chicago","correspondingAuthor":false,"prefix":"","firstName":"Fangyuan","middleName":"","lastName":"Zhao","suffix":""},{"id":634306782,"identity":"509eeb6e-1d37-4f80-9814-652e86084ceb","order_by":3,"name":"Emma Keel","email":"","orcid":"https://orcid.org/0000-0002-6163-4168","institution":"The University of Chicago","correspondingAuthor":false,"prefix":"","firstName":"Emma","middleName":"","lastName":"Keel","suffix":""},{"id":634306783,"identity":"eb93a96a-8b61-4e81-bac4-d271660a4d6f","order_by":4,"name":"Christine Drogan","email":"","orcid":"https://orcid.org/0000-0002-9927-9739","institution":"The University of Chicago","correspondingAuthor":false,"prefix":"","firstName":"Christine","middleName":"","lastName":"Drogan","suffix":""},{"id":634306784,"identity":"1540e93f-4b59-4261-9c66-ff7587dcee6d","order_by":5,"name":"Iris Romero","email":"","orcid":"https://orcid.org/0000-0001-5849-5024","institution":"The University of Chicago","correspondingAuthor":false,"prefix":"","firstName":"Iris","middleName":"","lastName":"Romero","suffix":""},{"id":634306785,"identity":"3b2c5205-a716-49be-b500-9409e11e6eca","order_by":6,"name":"Dezheng Huo","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA4ElEQVRIiWNgGAWjYDCCG0D8sYGBsYGBgY0hASooQUgL40yStTDzwrTAAF4tfLd7DB/b7qiTbZBIfvbgQY2dXT8D88HbPHi0SN45Y2yce+awcYNEmrlBwrHk5JkNbMnW+LQY3Mgxk85tO5DYIJHDJpHYwJxscIDHTJqgFsu2OpiWeqAW/m+EtTC2McO0HLYD2sKGV4vkjbRiw16gX9p4nplJJBw7niDZzGZsOQePFr4byRsf/ASGWD978jPJHzXV9vzszQ9vvMGjBQ5gkQIMAWKUIwN7UjWMglEwCkbB8AcAVMhLM07ePyQAAAAASUVORK5CYII=","orcid":"https://orcid.org/0000-0002-4041-1678","institution":"The University of Chicago","correspondingAuthor":true,"prefix":"","firstName":"Dezheng","middleName":"","lastName":"Huo","suffix":""},{"id":634306786,"identity":"a446c43d-b8c3-444c-980e-8573e87f1af3","order_by":7,"name":"Olufunmilayo I. 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We analyzed correlates of familial disclosure and cascade testing among carriers of pathogenic/likely pathogenic variants (PV). Data on carrier status of PV in cancer-predisposing genes, penetrance level of variants, receipt of a family letter, familial disclosure, and follow up cascade testing of ARRs were collected.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOf 912 respondents, 39.4% were carriers of PV. Among these carriers, 78% had highly penetrant PVs (most common genes were \u003cem\u003eBRCA1\u003c/em\u003e: 39% and \u003cem\u003eBRCA2\u003c/em\u003e: 18%) and 17.5% had moderate penetrance PVs; Rate of disclosure of PV to at least one family member; receipt of family letter explaining genetic test results; and sharing of information with ARRs were 98%, 69% and 82% respectively. Cascade testing was more likely among carriers with highly penetrance PV (91.1%) compared to those with moderate penetrance PV (58.3%) (adjusted odds ratio [AOR], 5.70; 95% CI, 2.03-16.02), and among carriers who received a family letter than among those who did not receive (87.2% vs. 73.0%; AOR, 3.70; 95% CI, 1.42-9.61). These data suggest that access to family-based counseling facilitated by cancer genetic experts improves understanding of familial risks and improves cascade testing following results disclosure. Our data support family based clinical interventions to optimize precision prevention and cancer control in high-risk individuals.\u003c/p\u003e","manuscriptTitle":"Familial Disclosure and Cascade Testing in High-Risk Families is Influenced by Gene Variant Penetrance: Implications for Family based Breast Cancer Prevention","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-05-05 12:28:33","doi":"10.21203/rs.3.rs-9610726/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"11c761b3-3919-4cd9-8d15-08fa9e47c982","owner":[],"postedDate":"May 5th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":67505725,"name":"Medical Genetics"},{"id":67505726,"name":"Oncology"}],"tags":[],"updatedAt":"2026-05-05T12:28:33+00:00","versionOfRecord":[],"versionCreatedAt":"2026-05-05 12:28:33","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9610726","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9610726","identity":"rs-9610726","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}