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Despite previous suggestion of pathogenicity, variant classification in public databases is still conflicting, needing additional evidence.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Maximum likelihood penetrance of breast\/ovarian and other cancer types was estimated using full pedigree data from 53 informative Italian families. The effect of the variant on BRCA1\u2010ABRAXAS1 interaction was assessed using a GFP\u2010fragment reassembly\u2010based PPI assay. Results were combined with additional data from multiple sources to classify the variant according to ACMG\/AMP classification rules specified for\n                      <jats:italic>BRCA1\/2<\/jats:italic>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Variant\u2010carriers displayed increased risk for ovarian cancer (HR\u2009=\u200933.0, 95% CI\u2009=\u20097.0\u2013155.0; cumulative risk at age 70\u2009=\u200927.6%, 95% CI\u2009=\u200912.6\u201340.0%) but not for breast cancer (HR\u2009=\u20090.7, 95% CI\u2009=\u20090.2\u20132.2). An increased risk of uterine cancer (HR\u2009=\u20098.0, 95% CI\u2009=\u20091.03\u201361.6) emerged, warranting further evaluation. Likelihood\u2010ratio in favor of pathogenicity was 98898642.82 under assumption of standard\n                      <jats:italic>BRCA1<\/jats:italic>\n                      breast and ovarian penetrance, and 104240832.84 after excluding breast cancer diagnoses (based on penetrance results). Functional analysis demonstrated that the variant abrogates the BRCA1\u2010ABRAXAS1 binding, supporting the PS3 code assignment within the ACMG\/AMP rule\u2010based model. Collectively, these findings allowed to classify the variant as pathogenic.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      Pathogenicity of\n                      <jats:italic>BRCA1<\/jats:italic>\n                      :c.5017_5019del(p.His1673del) has been confirmed; however, breast cancer risk in Italian families is not increased, unlike in families from other countries and in carriers of most\n                      <jats:italic>BRCA1<\/jats:italic>\n                      pathogenic variants. The knowledge of atypical risk profiles for this and other variants will pave the way for personalized management based on specific genotype.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/cam4.70114","type":"journal-article","created":{"date-parts":[[2024,8,28]],"date-time":"2024-08-28T09:29:45Z","timestamp":1724837385000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Atypical cancer risk profile in carriers of Italian founder\n                    <scp>\n                      <i>BRCA1<\/i>\n                    <\/scp>\n                    variant p.His1673del: Implications for classification and clinical management"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6909-2412","authenticated-orcid":false,"given":"Giovanni","family":"Innella","sequence":"first","affiliation":[{"name":"Department of Medical and Surgical Sciences (DIMEC) University 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