{"paper_id":"2bd86c93-9962-493e-abbe-e7616db6e969","body_text":"Genetic patterns and clinical associations of BRCA1 and BRCA2 mutations in familial and hereditary breast cancer: a cross-sectional study from Surakarta, Central Java. | 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 Genetic patterns and clinical associations of BRCA1 and BRCA2 mutations in familial and hereditary breast cancer: a cross-sectional study from Surakarta, Central Java. Widyanti Soewoto, Joko Purnomo, Senyum Indrakila, Amru Sungkar, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8504525/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 8 You are reading this latest preprint version Abstract Background Pathogenic variants in BRCA1 and BRCA2 are key determinants of hereditary breast cancer risk. However, data describing mutation patterns and their clinical associations in Southeast Asian populations remain scarce. Regional differences in genetic background and healthcare access may influence both mutation prevalence and phenotype. This study aimed to characterize BRCA1 and BRCA2 mutation patterns and evaluate their associations with demographic and clinicopathological features among patients with familial and hereditary breast cancer in Surakarta, Central Java, Indonesia. Methods A cross-sectional study was conducted at Dr. Moewardi Hospital, a tertiary referral center in Surakarta, between January 2024 and May 2025. Eighty consecutive patients with histologically confirmed breast cancer and available peripheral blood samples were included. Genomic DNA was analyzed using next-generation sequencing to identify BRCA1 and BRCA2 variants. Variant pathogenicity was determined according to established clinical classification guidelines. Associations between mutation status and age, breast cancer subtype (triple-negative versus non–triple-negative), and family history of cancer were assessed using chi-square or Fisher’s exact tests, followed by logistic regression analysis. Statistical significance was defined as P < 0.05. Results Pathogenic BRCA1/2 mutations were detected in 9 of 80 patients (11.25%), including 5 BRCA1 and 4 BRCA2 variants. Mutation prevalence did not differ significantly by age at diagnosis ( P = 0.587) or breast cancer subtype ( P = 0.847). In contrast, a significant association was observed between mutation status and family history of cancer ( P = 0.0002). Patients with a family history of non–breast malignancies had markedly increased odds of carrying a pathogenic BRCA mutation (odds ratio 21.4; 95% confidence interval 2.6–175.9). Conclusions In this Indonesian cohort, BRCA1/2 mutations were strongly associated with family cancer history but not with age or tumor subtype. These findings emphasize the importance of comprehensive family-history assessment and support the integration of early genetic counseling into hereditary breast cancer evaluation in resource-limited settings. Trial registration Not applicable (cross-sectional observational study). BRCA1 BRCA2 Familial breast cancer Hereditary breast cancer Surakarta BACKGROUND Breast cancer is the most frequently diagnosed malignancy among women worldwide and remains a major contributor to cancer-related mortality. While the majority of breast cancer cases arise sporadically, an estimated 5–10% are attributable to inherited germline mutations, most commonly involving the BRCA1 and BRCA2 genes. These tumor suppressor genes are essential components of the homologous recombination DNA repair pathway, and pathogenic variants substantially increase lifetime risks of breast and ovarian cancers, often leading to earlier disease onset and distinct clinicopathological features. The identification of BRCA1 and BRCA2 mutations has significantly reshaped the clinical management of hereditary breast cancer. Knowledge of mutation status informs individualized risk assessment, surveillance strategies, and preventive interventions, including intensified screening and prophylactic surgery. In addition, BRCA mutation status has emerged as a predictive biomarker for therapeutic response to platinum-based chemotherapy and poly(ADP-ribose) polymerase (PARP) inhibitors, further emphasizing its clinical relevance. Despite extensive investigation in Western populations, the prevalence and phenotypic expression of BRCA1/2 mutations vary considerably across ethnic groups and geographic regions. Differences in mutation spectra, penetrance, and associated tumor characteristics have been reported, reflecting population-specific genetic backgrounds and environmental modifiers. In Southeast Asia, and particularly in Indonesia, data on hereditary breast cancer genetics remain limited. This lack of regional evidence poses challenges for developing context-appropriate genetic screening policies and counseling strategies. Indonesia is characterized by substantial ethnic diversity and a growing burden of breast cancer, yet information regarding BRCA1/2 mutation patterns and their clinical correlates is scarce. Understanding these patterns is critical to improving identification of high-risk individuals and optimizing genetic services in resource-limited settings. This study therefore aimed to characterize the distribution of BRCA1 and BRCA2 mutations among patients with familial and hereditary breast cancer in Central Java, Indonesia, and to evaluate their associations with age, tumor subtype, and family history of cancer. METHODS Study design and setting A cross-sectional analytical study was conducted at Dr. Moewardi Hospital, a tertiary referral center in Surakarta, Central Java, Indonesia, between January 2024 and May 2025. Ethical approval was obtained from the Ethics Committee of Dr. Moewardi Hospital (Approval No. 709/III/HREC/2025). Written informed consent was obtained from all participants prior to enrollment. Participants Eighty patients with histologically confirmed breast cancer were included. Both female and male patients were eligible, and cases encompassed triple-negative breast cancer (TNBC) and non-TNBC subtypes. Inclusion criteria were: (1) confirmed diagnosis of invasive breast cancer, (2) completion of BRCA1/2 genetic testing, and (3) availability of family cancer history data. Patients were excluded if BRCA testing results were incomplete, family history information was unavailable, or histological or subtype classification was uncertain. Participants were categorized according to age at diagnosis (< 45 years vs ≥ 45 years), tumor subtype (TNBC vs non-TNBC), and family history of cancer (breast cancer, other cancers, or no family history). BRCA1 and BRCA2 mutation analysis Peripheral whole blood samples were collected from each participant, and genomic DNA was extracted using the QIAamp Blood Mini Kit (Qiagen Ltd.) following the manufacturer’s protocol. DNA concentration was measured using a Qubit 3.0 fluorometer (Thermo Fisher Scientific). Next-generation sequencing was performed using the Oncomine™ BRCA Research Assay and Ion AmpliSeq™ Library Kit Plus, with sequencing conducted on the GeneStudio™ S5 System (Thermo Fisher Scientific). Sequence reads were quality-trimmed and aligned to the human reference genome (GRCh37/hg19) for BRCA1 (NM_007300.3) and BRCA2 (NM_000059.3). Variant calling and annotation were performed using Torrent Suite and Ion Reporter software. Variant interpretation referenced the National Center for Biotechnology Information and Breast Cancer Information Core databases. Pathogenicity was classified according to established clinical guidelines. Statistical analysis Associations between BRCA mutation status and clinicopathological variables were assessed using chi-square or Fisher’s exact tests, as appropriate. Variables included age category, tumor subtype, and family history of cancer. Post hoc analyses were conducted to identify specific group differences when overall associations were statistically significant. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using logistic regression. Statistical significance was defined as p < 0.05. Analyses were performed using SPSS version 27.0. Ethics approval The study protocol was approved by the Health Research Ethics Committee of Dr. Moewardi General Hospital (approval no. 709/III/HREC/2025). All patient data were anonymized prior to analysis to maintain confidentiality. Trial registration was not applicable for this cross-sectional design. RESULTS Patient characteristics A total of 80 patients were included in the analysis. The cohort was predominantly female (98.8%), with a mean age concentrated in the ≥ 45-year group (63.7%). TNBC constituted 63.8% of cases, while non-TNBC accounted for 36.2%. Most participants reported no family history of cancer (68.8%), followed by a family history of breast cancer (26.2%) and other malignancies (5.0%). Overall, 9 patients (11.25%) carried pathogenic BRCA1/2 mutations (see Table 1 ). Table 1 Frequency Distribution of Patients’ Baseline Characteristics Category N (80) % Gender Female (P) 79 98.8 Male (L) 1 1.2 Age < 45 29 36.2 ≥ 45 51 63.7 Breast Cancer Subtype TNBC 51 63.8 Non-TNBC 29 36.2 Family History of Cancer No Family History 55 68.8 Family history of breast cancer 21 26.2 Family history of other cancers 4 5.0 BRCA Mutation Result Negative 71 88.8 Positive 9 11.2 Distribution of BRCA1 and BRCA2 mutations Pathogenic germline variants were identified in 5 patients with BRCA1 mutations and 4 patients with BRCA2 mutations (see Table 2 ). Mutations were distributed across several exons, with exon 11 representing the most frequently affected region in BRCA2 . Identified variants included frameshift, nonsense, and missense mutations, all classified as pathogenic. Table 2 Germline BRCA1 and BRCA2 Pathogenic Mutation Gene Exon DNA Change Protein change Number of Patients Age (yr) BRCA1 6 c.329_330insA p.Glu111fs 1 44 7 c.470_471delCT p.Ser157Ter 1 71 10 c.1723g > T p.E575* 1 40 11 c.4148C > G p.Ser1383* 1 53 20 c.5291t > C p.Leu1764Pro 1 53 BRCA2 11 c.2471_2476del p.L824_E826delins* 3 35,43,50 11 c.6634_6637del p.C2212lfs*16_E826delins* 1 57 Association between BRCA mutation status and clinical variables No significant association was observed between BRCA mutation status and age at diagnosis ( p = 0.587) or tumor subtype ( p = 0.847). In contrast, family history of cancer was strongly associated with BRCA positivity ( p = 0.0002) (see Table 3 ). Table 3 Results of Correlation Tests Between Variables Variable Value df Sig BRCA vs Age 0,2947 1 0,5872 BRCA vs Subtype 0,0373 1 0,8468 BRCA vs Family History of Cancer 17,4239 2 0,0002* Post hoc analysis demonstrated that patients with a family history of non-breast malignancies had a markedly higher likelihood of carrying a pathogenic BRCA mutation compared with those with a family history of breast cancer alone or no family history (see Table 4 ). Table 4 Results of Post Hoc Test Variable P Fisher P Bonferroni OR (CI95%) Family History of Other Cancers vs Family History of Breast Cancer 0,0067 0,0202* 31,89 (2,54–400,81) Family History of Other Cancers vs No Family History 0,0064 0,0193* 21,42 (2,61–175,92) Family History of Breast Cancer vs No Family History 1,0 1,0 0,67 (0,10 − 4,39) DISCUSSION This cross-sectional study provides novel insight into the distribution and clinical correlates of BRCA1 and BRCA2 mutations in familial and hereditary breast cancer within a Central Java population. In this cohort, pathogenic germline BRCA variants were identified in 11.25% of patients, a prevalence that is consistent with reports from other Asian familial breast cancer cohorts, which range from approximately 8% to 31% depending on selection criteria and ethnicity [ 1 , 9 – 11 ]. These findings contribute important population-specific data to a field that has historically been dominated by evidence from Western populations. The relative distribution of BRCA1 and BRCA2 mutations observed in this study, with a slight predominance of BRCA1, aligns with several regional studies but contrasts with others reporting BRCA2 as the more frequent mutation in Asian cohorts [ 9 – 11 ]. This heterogeneity underscores the importance of regional mutation profiling. Notably, recurrent involvement of exon 11 in BRCA2 is consistent with global mutation spectra, as exon 11 represents a known mutational hotspot due to its large coding region and critical functional domains [ 12 ]. The specific variants identified in this study, including truncating and frameshift mutations documented in ClinVar, further support their pathogenic classification and relevance to clinical risk assessment [ 2 – 8 ]. Contrary to findings from Western populations, BRCA mutation status in this cohort was not significantly associated with younger age at diagnosis or with triple-negative breast cancer phenotype. In European and North American studies, BRCA1 mutations are strongly linked to early-onset disease and triple-negative histology [ 12 ]. However, emerging evidence from Asian populations suggests that this association may be less consistent, potentially reflecting differences in genetic background, modifier genes, reproductive patterns, and environmental exposures [ 9 , 11 , 13 ]. Our findings reinforce the notion that extrapolation of Western-derived genotype–phenotype correlations to Southeast Asian populations should be approached with caution. In contrast, family history of cancer demonstrated a strong association with BRCA positivity, particularly when the family history included malignancies other than breast cancer. This observation is biologically plausible given the well-established pleiotropic cancer risks associated with BRCA1 and BRCA2 mutations, including ovarian, pancreatic, and prostate cancers [ 12 , 14 ]. Similar patterns have been reported in Asian studies emphasizing that broad family cancer history may be a more sensitive indicator of hereditary risk than breast cancer history alone [ 9 , 14 ]. In resource-limited settings such as Indonesia, where universal genetic testing is not feasible, this finding has practical implications for prioritizing patients for genetic counseling and testing. From a public health perspective, these results gain further relevance in light of the rising burden of breast cancer across low- and middle-income countries, including Indonesia [ 15 ]. Incorporating structured family history assessment into routine oncology practice may represent a cost-effective strategy to identify individuals at high hereditary risk, facilitate cascade testing, and enable risk-reducing interventions. Several limitations should be acknowledged. First, the relatively small sample size and single-center design may limit generalizability and statistical power, particularly for subgroup analyses. Second, family history data were self-reported and may be subject to recall bias or incomplete knowledge of relatives’ diagnoses. Third, only BRCA1 and BRCA2 were analyzed; other susceptibility genes such as PALB2, CHEK2, and ATM were not assessed and may account for additional hereditary risk. Finally, the cross-sectional design precludes assessment of long-term outcomes or penetrance. Future research should focus on multicenter studies across diverse Indonesian regions to capture ethnic heterogeneity and improve representativeness. Expansion to multigene panel testing would allow a more comprehensive evaluation of hereditary breast cancer susceptibility. Longitudinal follow-up of mutation carriers is also needed to clarify clinical outcomes and inform locally appropriate screening and prevention strategies. In conclusion, this study demonstrates that BRCA1 and BRCA2 mutations contribute meaningfully to hereditary breast cancer risk in Central Java and that family history of cancer, particularly beyond breast cancer alone, is a strong clinical indicator of mutation carriage. These findings support the integration of detailed family history assessment into routine care and highlight the need for population-specific genetic data to inform precision cancer prevention strategies. CONCLUSIONS Pathogenic BRCA1/2 mutations were identified in a substantial proportion of patients with familial and hereditary breast cancer in Central Java. Mutation status was strongly associated with family history of cancer but not with age at diagnosis or tumor subtype. These findings emphasize the importance of thorough family history evaluation and support the integration of genetic counseling into breast cancer care in Indonesia. Larger, multicenter studies are warranted to further define the genetic architecture of hereditary breast cancer and to inform region-specific screening and prevention strategies. Abbreviations BRCA1 Breast Cancer Susceptibility Gene 1 BRCA2 Breast Cancer Susceptibility Gene 2 CI Confidence Interval DNA Deoxyribonucleic Acid ER Estrogen Receptor HER2 Human Epidermal Growth Factor Receptor 2 IHC Immunohistochemistry NGS Next-Generation Sequencing OR Odds Ratio PARP Poly (Adenosine Diphosphate–Ribose) Polymerase PR Progesterone Receptor TNBC Triple-Negative Breast Cancer Declarations Conflicts of interest The authors declare that they have no competing interests Ethics approval and consent to participate The study protocol was approved by the Health Research Ethics Committee of Dr. Moewardi General Hospital, Surakarta, Indonesia (approval no. 709/III/HREC/2025). All patient data were fully anonymized prior to analysis; therefore, the requirement for informed consent was waived by the committee. Consent for publication Not applicable. This study does not contain any individual person’s data in any form (including images or videos). Competing interests The authors declare that they have no competing interests. Funding This study was supported by the Faculty of Medicine Research Group, Sebelas Maret University, through the Sebelas Maret University research grant (No. 371/UN27.22/PT.01.03/2025). Funding This study was supported by Sebelas Maret University Research Group, through Sebelas Maret University research grant (371/UN27.22/PT.01.03/2025). Author Contribution 1. WS (Widyanti Soewoto): Conceptualization and formal analysis.2. JP (Joko Purnomo): Histopathological evaluation and supervision.3. SI (Senyum Indrakila): Data curation and critical review.4. AS (Amru Sungkar): Data curation and critical review.5. DAS (Dea Alberta Setiawati): Methodology, statistical analysis, and writing original draft.All authors read and approved the final manuscript. Acknowledgements The austhors would like to express their sincere gratitude to the Faculty of Medicine, Sebelas Maret University, Surakarta, Central Java, Indonesia, for the continuous support and valuable contribution to this research. Data Availability The datasets generated and/or analysed during the current study are not publicly available due to privacy restrictions but are available from the corresponding author, Widyanti Soewoto ( [email protected] ), on reasonable request. References Armstrong N, Ryder S, Forbes C, Ross J, Quek RG. A systematic review of the international prevalence of BRCA mutation in breast cancer. Clin Epidemiol. 2019;11:543–61. 10.2147/CLEP.S206949 . National Center for Biotechnology Information. ClinVar; NM_007294.4(BRCA1):c.5291T > C (p.Leu1764Pro), VCV000055510.27. Reviewed August 10, 2015. Accessed October 26, 2025. National Center for Biotechnology Information. ClinVar; NM_007294.4(BRCA1):c.1723G > T (p.Glu575Ter), RCV000794574.9. Reviewed September 11, 2023. Accessed October 26, 2025. National Center for Biotechnology Information. ClinVar; NM_007294.4(BRCA1):c.4148C > G (p.Ser1383Ter), VCV000037572.19. Reviewed September 8, 2016. Accessed October 26, 2025. National Center for Biotechnology Information. ClinVar; NM_007294.4(BRCA1):c.470_471delCT (p.Ser157Ter), VCV000037608.13. Reviewed August 23, 2017. Accessed October 26, 2025. National Center for Biotechnology Information. ClinVar; NM_007294.4(BRCA1):c.329dup (p.Glu111fs), RCV000031101.7. Accessed October 26, 2025. National Center for Biotechnology Information. ClinVar; NM_000059.3(BRCA2):c.2471_2476del (p.L824_E826delins*), VCV000051295.12. Accessed October 26, 2025. National Center for Biotechnology Information. ClinVar; NM_000059.3(BRCA2):c.6634_6637del (p.Cys2212Leufs*16), VCV000052140.12. Accessed October 26, 2025. Kwong A, Shin VY, Ho JC, et al. Comprehensive spectrum of BRCA1 and BRCA2 deleterious mutations in breast cancer in Asian countries. J Med Genet. 2016;53(1):15–23. 10.1136/jmedgenet-2015-103132 . Kang E, Seong MW, Park SK, et al. The prevalence and spectrum of BRCA1 and BRCA2 mutations in the Korean population: results from the Korean Hereditary Breast Cancer (KOHBRA) study. Breast Cancer Res Treat. 2015;151(1):157–68. 10.1007/s10549-015-3377-4 . Kim H, Choi DH. Distribution of BRCA1 and BRCA2 mutations in Asian patients with breast cancer. J Breast Cancer. 2013;16(4):357–65. 10.4048/jbc.2013.16.4.357 . Rebbeck TR, Friebel TM, Friedman E, et al. Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations. Hum Mutat. 2018;39(5):593–620. 10.1002/humu.23406 . Qin Z, Li J, Tam B, et al. Ethnic specificity, evolutionary origin, and deleteriousness of Asian BRCA variation revealed from over 7,500 variants. Int J Cancer. 2023;152(6):1159–73. 10.1002/ijc.34359 . Sun J, Meng H, Yao L, et al. Germline mutations in cancer susceptibility genes in a large series of unselected breast cancer patients. Clin Cancer Res. 2017;23(20):6113–9. 10.1158/1078-0432.CCR-16-3227 . Kim J, Harper A, McCormack V, Sung H, Houssami N, Morgan E, et al. Global patterns and trends in breast cancer incidence and mortality across 185 countries. Nat Med. 2025;31(4):1154–62. 10.1038/s41591-025-03502-3 . Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Review Version 1 posted Reviews received at journal 08 Mar, 2026 Reviewers agreed at journal 03 Mar, 2026 Reviewers agreed at journal 03 Mar, 2026 Reviewers invited by journal 24 Feb, 2026 Editor invited by journal 30 Jan, 2026 Editor assigned by journal 05 Jan, 2026 Submission checks completed at journal 05 Jan, 2026 First submitted to journal 03 Jan, 2026 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-8504525\",\"acceptedTermsAndConditions\":true,\"allowDirectSubmit\":false,\"archivedVersions\":[],\"articleType\":\"Research Article\",\"associatedPublications\":[],\"authors\":[{\"id\":596235919,\"identity\":\"ed6e4ddb-ecf2-452a-9b48-4e8d2a092daa\",\"order_by\":0,\"name\":\"Widyanti Soewoto\",\"email\":\"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABEklEQVRIie2SMUsDMRTH/3KSLqlZ36Fev0Lg4Bah/SonhU5XF0EcSnGKk/WzuByOkUBdzg/gJnRVCBQKQi0mpwjC3bk65DfkJTx+/N+DAIHAfySC9IW7m3Y1ET8dhrxLkU5hOTTS+OpPBV+KD5K/FbQo8jEq6f1+ewRRrdd2Jgk0NRazIQ56LYphF/FN5QajaUl66ZWzCWE5BuMvjUpmeEZ95ZV+Cc22c1CRuUU0GDWneCX+8IqoVlbvfEqRWuy6lcM6BQXoQdWKpD3VrowMOz85VqkbbJLR00IS468ZnS7GvG2X+NbcPb+pZARhVvZyI0n03GB2M0wG180pjn2q4/T3k/kjr/9DK5HtaAYCgUAA+ARjtk+NYFHNhQAAAABJRU5ErkJggg==\",\"orcid\":\"\",\"institution\":\"Sebelas Maret University\",\"correspondingAuthor\":true,\"prefix\":\"\",\"firstName\":\"Widyanti\",\"middleName\":\"\",\"lastName\":\"Soewoto\",\"suffix\":\"\"},{\"id\":596235920,\"identity\":\"16da7413-1383-4422-82a2-4196d146fdde\",\"order_by\":1,\"name\":\"Joko Purnomo\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Sebelas Maret University\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Joko\",\"middleName\":\"\",\"lastName\":\"Purnomo\",\"suffix\":\"\"},{\"id\":596235921,\"identity\":\"21219662-4dd4-45e6-b282-7f6f510e9fac\",\"order_by\":2,\"name\":\"Senyum Indrakila\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Sebelas Maret University\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Senyum\",\"middleName\":\"\",\"lastName\":\"Indrakila\",\"suffix\":\"\"},{\"id\":596235922,\"identity\":\"d1e6480e-596b-44f1-87ca-a7a27c73e5f2\",\"order_by\":3,\"name\":\"Amru Sungkar\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Sebelas Maret University\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Amru\",\"middleName\":\"\",\"lastName\":\"Sungkar\",\"suffix\":\"\"},{\"id\":596235923,\"identity\":\"1bf69902-970d-43c9-b126-6b65742551f0\",\"order_by\":4,\"name\":\"Dea Alberta Setiawati\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Dr. Arif Zainudin Hospital\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Dea\",\"middleName\":\"Alberta\",\"lastName\":\"Setiawati\",\"suffix\":\"\"}],\"badges\":[],\"createdAt\":\"2026-01-03 05:23:27\",\"currentVersionCode\":1,\"declarations\":\"\",\"doi\":\"10.21203/rs.3.rs-8504525/v1\",\"doiUrl\":\"https://doi.org/10.21203/rs.3.rs-8504525/v1\",\"draftVersion\":[],\"editorialEvents\":[],\"editorialNote\":\"\",\"failedWorkflow\":false,\"files\":[{\"id\":103507490,\"identity\":\"f157fba3-265a-46d2-bc38-61cfb5dd5ef0\",\"added_by\":\"auto\",\"created_at\":\"2026-02-26 13:41:34\",\"extension\":\"pdf\",\"order_by\":0,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"manuscript-pdf\",\"size\":728517,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"manuscript.pdf\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-8504525/v1/7a9bb956-8767-43c3-ae0e-5839f2939e78.pdf\"}],\"financialInterests\":\"No competing interests reported.\",\"formattedTitle\":\"Genetic patterns and clinical associations of BRCA1 and BRCA2 mutations in familial and hereditary breast cancer: a cross-sectional study from Surakarta, Central Java.\",\"fulltext\":[{\"header\":\"BACKGROUND\",\"content\":\"\\u003cp\\u003eBreast cancer is the most frequently diagnosed malignancy among women worldwide and remains a major contributor to cancer-related mortality. While the majority of breast cancer cases arise sporadically, an estimated 5\\u0026ndash;10% are attributable to inherited germline mutations, most commonly involving the \\u003cem\\u003eBRCA1\\u003c/em\\u003e and \\u003cem\\u003eBRCA2\\u003c/em\\u003e genes. These tumor suppressor genes are essential components of the homologous recombination DNA repair pathway, and pathogenic variants substantially increase lifetime risks of breast and ovarian cancers, often leading to earlier disease onset and distinct clinicopathological features.\\u003c/p\\u003e \\u003cp\\u003eThe identification of \\u003cem\\u003eBRCA1\\u003c/em\\u003e and \\u003cem\\u003eBRCA2\\u003c/em\\u003e mutations has significantly reshaped the clinical management of hereditary breast cancer. Knowledge of mutation status informs individualized risk assessment, surveillance strategies, and preventive interventions, including intensified screening and prophylactic surgery. In addition, \\u003cem\\u003eBRCA\\u003c/em\\u003e mutation status has emerged as a predictive biomarker for therapeutic response to platinum-based chemotherapy and poly(ADP-ribose) polymerase (PARP) inhibitors, further emphasizing its clinical relevance.\\u003c/p\\u003e \\u003cp\\u003eDespite extensive investigation in Western populations, the prevalence and phenotypic expression of \\u003cem\\u003eBRCA1/2\\u003c/em\\u003e mutations vary considerably across ethnic groups and geographic regions. Differences in mutation spectra, penetrance, and associated tumor characteristics have been reported, reflecting population-specific genetic backgrounds and environmental modifiers. In Southeast Asia, and particularly in Indonesia, data on hereditary breast cancer genetics remain limited. This lack of regional evidence poses challenges for developing context-appropriate genetic screening policies and counseling strategies.\\u003c/p\\u003e \\u003cp\\u003eIndonesia is characterized by substantial ethnic diversity and a growing burden of breast cancer, yet information regarding \\u003cem\\u003eBRCA1/2\\u003c/em\\u003e mutation patterns and their clinical correlates is scarce. Understanding these patterns is critical to improving identification of high-risk individuals and optimizing genetic services in resource-limited settings. This study therefore aimed to characterize the distribution of \\u003cem\\u003eBRCA1\\u003c/em\\u003e and \\u003cem\\u003eBRCA2\\u003c/em\\u003e mutations among patients with familial and hereditary breast cancer in Central Java, Indonesia, and to evaluate their associations with age, tumor subtype, and family history of cancer.\\u003c/p\\u003e\"},{\"header\":\"METHODS\",\"content\":\"\\u003cdiv id=\\\"Sec3\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eStudy design and setting\\u003c/h2\\u003e \\u003cp\\u003eA cross-sectional analytical study was conducted at Dr. Moewardi Hospital, a tertiary referral center in Surakarta, Central Java, Indonesia, between January 2024 and May 2025. Ethical approval was obtained from the Ethics Committee of Dr. Moewardi Hospital (Approval No. 709/III/HREC/2025). Written informed consent was obtained from all participants prior to enrollment.\\u003c/p\\u003e \\u003c/div\\u003e\\n\\u003ch3\\u003eParticipants\\u003c/h3\\u003e\\n\\u003cp\\u003eEighty patients with histologically confirmed breast cancer were included. Both female and male patients were eligible, and cases encompassed triple-negative breast cancer (TNBC) and non-TNBC subtypes. Inclusion criteria were: (1) confirmed diagnosis of invasive breast cancer, (2) completion of \\u003cem\\u003eBRCA1/2\\u003c/em\\u003e genetic testing, and (3) availability of family cancer history data. Patients were excluded if \\u003cem\\u003eBRCA\\u003c/em\\u003e testing results were incomplete, family history information was unavailable, or histological or subtype classification was uncertain.\\u003c/p\\u003e \\u003cp\\u003eParticipants were categorized according to age at diagnosis (\\u0026lt;\\u0026thinsp;45 years vs\\u0026thinsp;\\u0026ge;\\u0026thinsp;45 years), tumor subtype (TNBC vs non-TNBC), and family history of cancer (breast cancer, other cancers, or no family history).\\u003c/p\\u003e\\n\\u003ch3\\u003eBRCA1 and BRCA2 mutation analysis\\u003c/h3\\u003e\\n\\u003cp\\u003e Peripheral whole blood samples were collected from each participant, and genomic DNA was extracted using the QIAamp Blood Mini Kit (Qiagen Ltd.) following the manufacturer\\u0026rsquo;s protocol. DNA concentration was measured using a Qubit 3.0 fluorometer (Thermo Fisher Scientific). Next-generation sequencing was performed using the Oncomine\\u0026trade; BRCA Research Assay and Ion AmpliSeq\\u0026trade; Library Kit Plus, with sequencing conducted on the GeneStudio\\u0026trade; S5 System (Thermo Fisher Scientific).\\u003c/p\\u003e \\u003cp\\u003eSequence reads were quality-trimmed and aligned to the human reference genome (GRCh37/hg19) for \\u003cem\\u003eBRCA1\\u003c/em\\u003e (NM_007300.3) and \\u003cem\\u003eBRCA2\\u003c/em\\u003e (NM_000059.3). Variant calling and annotation were performed using Torrent Suite and Ion Reporter software. Variant interpretation referenced the National Center for Biotechnology Information and Breast Cancer Information Core databases. Pathogenicity was classified according to established clinical guidelines.\\u003c/p\\u003e \\u003cdiv id=\\\"Sec6\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eStatistical analysis\\u003c/h2\\u003e \\u003cp\\u003eAssociations between \\u003cem\\u003eBRCA\\u003c/em\\u003e mutation status and clinicopathological variables were assessed using chi-square or Fisher\\u0026rsquo;s exact tests, as appropriate. Variables included age category, tumor subtype, and family history of cancer. Post hoc analyses were conducted to identify specific group differences when overall associations were statistically significant. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using logistic regression. Statistical significance was defined as \\u003cem\\u003ep\\u003c/em\\u003e\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.05. Analyses were performed using SPSS version 27.0.\\u003c/p\\u003e \\u003c/div\\u003e\\n\\u003ch3\\u003eEthics approval\\u003c/h3\\u003e\\n\\u003cp\\u003eThe study protocol was approved by the Health Research Ethics Committee of Dr. Moewardi General Hospital (approval no. 709/III/HREC/2025). All patient data were anonymized prior to analysis to maintain confidentiality. Trial registration was not applicable for this cross-sectional design.\\u003c/p\\u003e\"},{\"header\":\"RESULTS\",\"content\":\"\\u003cdiv id=\\\"Sec9\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003ePatient characteristics\\u003c/h2\\u003e \\u003cp\\u003eA total of 80 patients were included in the analysis. The cohort was predominantly female (98.8%), with a mean age concentrated in the \\u0026ge;\\u0026thinsp;45-year group (63.7%). TNBC constituted 63.8% of cases, while non-TNBC accounted for 36.2%. Most participants reported no family history of cancer (68.8%), followed by a family history of breast cancer (26.2%) and other malignancies (5.0%). Overall, 9 patients (11.25%) carried pathogenic \\u003cem\\u003eBRCA1/2\\u003c/em\\u003e mutations (see Table\\u0026nbsp;\\u003cspan refid=\\\"Tab1\\\" class=\\\"InternalRef\\\"\\u003e1\\u003c/span\\u003e).\\u003c/p\\u003e \\u003cp\\u003e \\u003cdiv class=\\\"gridtable\\\"\\u003e\\u003ctable float=\\\"Yes\\\" id=\\\"Tab1\\\" border=\\\"1\\\"\\u003e \\u003ccaption language=\\\"En\\\"\\u003e \\u003cdiv class=\\\"CaptionNumber\\\"\\u003eTable 1\\u003c/div\\u003e \\u003cdiv class=\\\"CaptionContent\\\"\\u003e \\u003cp\\u003eFrequency Distribution of Patients\\u0026rsquo; Baseline Characteristics\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/caption\\u003e \\u003ccolgroup cols=\\\"3\\\"\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c1\\\" colnum=\\\"1\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"char\\\" char=\\\".\\\" class=\\\"colspec\\\" colname=\\\"c2\\\" colnum=\\\"2\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"char\\\" char=\\\".\\\" class=\\\"colspec\\\" colname=\\\"c3\\\" colnum=\\\"3\\\"\\u003e\\u003c/div\\u003e \\u003cthead\\u003e \\u003ctr\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eCategory\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eN (80)\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e%\\u003c/p\\u003e \\u003c/th\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eGender\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u0026nbsp;\\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u0026nbsp;\\u003c/th\\u003e \\u003c/tr\\u003e \\u003c/thead\\u003e \\u003ctbody\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eFemale (P)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e79\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e98.8\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eMale (L)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e1\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e1.2\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eAge\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e\\u0026lt;\\u0026thinsp;45\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e29\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e36.2\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e\\u0026ge;\\u0026thinsp;45\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e51\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e63.7\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eBreast Cancer Subtype\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eTNBC\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e51\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e63.8\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eNon-TNBC\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e29\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e36.2\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eFamily History of Cancer\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eNo Family History\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e55\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e68.8\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eFamily history of breast cancer\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e21\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e26.2\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eFamily history of other cancers\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e4\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e5.0\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eBRCA Mutation Result\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eNegative\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e71\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e88.8\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003ePositive\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e9\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e11.2\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003c/tbody\\u003e \\u003c/colgroup\\u003e \\u003c/table\\u003e\\u003c/div\\u003e \\u003c/p\\u003e \\u003c/div\\u003e\\n\\u003ch3\\u003eDistribution of BRCA1 and BRCA2 mutations\\u003c/h3\\u003e\\n\\u003cp\\u003ePathogenic germline variants were identified in 5 patients with \\u003cem\\u003eBRCA1\\u003c/em\\u003e mutations and 4 patients with \\u003cem\\u003eBRCA2\\u003c/em\\u003e mutations (see Table\\u0026nbsp;\\u003cspan refid=\\\"Tab2\\\" class=\\\"InternalRef\\\"\\u003e2\\u003c/span\\u003e). Mutations were distributed across several exons, with exon 11 representing the most frequently affected region in \\u003cem\\u003eBRCA2\\u003c/em\\u003e. Identified variants included frameshift, nonsense, and missense mutations, all classified as pathogenic.\\u003c/p\\u003e \\u003cp\\u003e \\u003cdiv class=\\\"gridtable\\\"\\u003e\\u003ctable float=\\\"Yes\\\" id=\\\"Tab2\\\" border=\\\"1\\\"\\u003e \\u003ccaption language=\\\"En\\\"\\u003e \\u003cdiv class=\\\"CaptionNumber\\\"\\u003eTable 2\\u003c/div\\u003e \\u003cdiv class=\\\"CaptionContent\\\"\\u003e \\u003cp\\u003eGermline BRCA1 and BRCA2 Pathogenic Mutation\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/caption\\u003e \\u003ccolgroup cols=\\\"6\\\"\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c1\\\" colnum=\\\"1\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"char\\\" char=\\\".\\\" class=\\\"colspec\\\" colname=\\\"c2\\\" colnum=\\\"2\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c3\\\" colnum=\\\"3\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c4\\\" colnum=\\\"4\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"char\\\" char=\\\".\\\" class=\\\"colspec\\\" colname=\\\"c5\\\" colnum=\\\"5\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"char\\\" char=\\\".\\\" class=\\\"colspec\\\" colname=\\\"c6\\\" colnum=\\\"6\\\"\\u003e\\u003c/div\\u003e \\u003cthead\\u003e \\u003ctr\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eGene\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eExon\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eDNA Change\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eProtein change\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003eNumber of Patients\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003eAge (yr)\\u003c/p\\u003e \\u003c/th\\u003e \\u003c/tr\\u003e \\u003c/thead\\u003e \\u003ctbody\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\" morerows=\\\"4\\\" rowspan=\\\"5\\\"\\u003e \\u003cp\\u003eBRCA1\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e6\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003ec.329_330insA\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003ep.Glu111fs\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e1\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e44\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e7\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003ec.470_471delCT\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003ep.Ser157Ter\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e1\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e71\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e10\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003ec.1723g\\u0026thinsp;\\u0026gt;\\u0026thinsp;T\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003ep.E575*\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e1\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e40\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e11\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003ec.4148C\\u0026thinsp;\\u0026gt;\\u0026thinsp;G\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003ep.Ser1383*\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e1\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e53\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e20\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003ec.5291t\\u0026thinsp;\\u0026gt;\\u0026thinsp;C\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003ep.Leu1764Pro\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e1\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e53\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eBRCA2\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e11\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003ec.2471_2476del\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003ep.L824_E826delins*\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e3\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e35,43,50\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e11\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003ec.6634_6637del\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003ep.C2212lfs*16_E826delins*\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e1\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e57\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003c/tbody\\u003e \\u003c/colgroup\\u003e \\u003c/table\\u003e\\u003c/div\\u003e \\u003c/p\\u003e \\u003cdiv id=\\\"Sec11\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eAssociation between BRCA mutation status and clinical variables\\u003c/h2\\u003e \\u003cp\\u003eNo significant association was observed between \\u003cem\\u003eBRCA\\u003c/em\\u003e mutation status and age at diagnosis (\\u003cem\\u003ep\\u003c/em\\u003e\\u0026thinsp;=\\u0026thinsp;0.587) or tumor subtype (\\u003cem\\u003ep\\u003c/em\\u003e\\u0026thinsp;=\\u0026thinsp;0.847). In contrast, family history of cancer was strongly associated with \\u003cem\\u003eBRCA\\u003c/em\\u003e positivity (\\u003cem\\u003ep\\u003c/em\\u003e\\u0026thinsp;=\\u0026thinsp;0.0002) (see Table\\u0026nbsp;\\u003cspan refid=\\\"Tab3\\\" class=\\\"InternalRef\\\"\\u003e3\\u003c/span\\u003e).\\u003c/p\\u003e \\u003cp\\u003e \\u003cdiv class=\\\"gridtable\\\"\\u003e\\u003ctable float=\\\"Yes\\\" id=\\\"Tab3\\\" border=\\\"1\\\"\\u003e \\u003ccaption language=\\\"En\\\"\\u003e \\u003cdiv class=\\\"CaptionNumber\\\"\\u003eTable 3\\u003c/div\\u003e \\u003cdiv class=\\\"CaptionContent\\\"\\u003e \\u003cp\\u003eResults of Correlation Tests Between Variables\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/caption\\u003e \\u003ccolgroup cols=\\\"4\\\"\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c1\\\" colnum=\\\"1\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"char\\\" char=\\\".\\\" class=\\\"colspec\\\" colname=\\\"c2\\\" colnum=\\\"2\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"char\\\" char=\\\".\\\" class=\\\"colspec\\\" colname=\\\"c3\\\" colnum=\\\"3\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c4\\\" colnum=\\\"4\\\"\\u003e\\u003c/div\\u003e \\u003cthead\\u003e \\u003ctr\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eVariable\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eValue\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003edf\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eSig\\u003c/p\\u003e \\u003c/th\\u003e \\u003c/tr\\u003e \\u003c/thead\\u003e \\u003ctbody\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eBRCA vs Age\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e0,2947\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e1\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e0,5872\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eBRCA vs Subtype\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e0,0373\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e1\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e0,8468\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eBRCA vs Family History of Cancer\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e17,4239\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e2\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e0,0002*\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003c/tbody\\u003e \\u003c/colgroup\\u003e \\u003c/table\\u003e\\u003c/div\\u003e \\u003c/p\\u003e \\u003cp\\u003ePost hoc analysis demonstrated that patients with a family history of non-breast malignancies had a markedly higher likelihood of carrying a pathogenic \\u003cem\\u003eBRCA\\u003c/em\\u003e mutation compared with those with a family history of breast cancer alone or no family history (see Table\\u0026nbsp;\\u003cspan refid=\\\"Tab4\\\" class=\\\"InternalRef\\\"\\u003e4\\u003c/span\\u003e).\\u003c/p\\u003e \\u003cp\\u003e \\u003cdiv class=\\\"gridtable\\\"\\u003e\\u003ctable float=\\\"Yes\\\" id=\\\"Tab4\\\" border=\\\"1\\\"\\u003e \\u003ccaption language=\\\"En\\\"\\u003e \\u003cdiv class=\\\"CaptionNumber\\\"\\u003eTable 4\\u003c/div\\u003e \\u003cdiv class=\\\"CaptionContent\\\"\\u003e \\u003cp\\u003eResults of Post Hoc Test\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/caption\\u003e \\u003ccolgroup cols=\\\"4\\\"\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c1\\\" colnum=\\\"1\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"char\\\" char=\\\".\\\" class=\\\"colspec\\\" colname=\\\"c2\\\" colnum=\\\"2\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c3\\\" colnum=\\\"3\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"char\\\" char=\\\".\\\" class=\\\"colspec\\\" colname=\\\"c4\\\" colnum=\\\"4\\\"\\u003e\\u003c/div\\u003e \\u003cthead\\u003e \\u003ctr\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eVariable\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eP Fisher\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eP Bonferroni\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eOR\\u003c/p\\u003e \\u003cp\\u003e(CI95%)\\u003c/p\\u003e \\u003c/th\\u003e \\u003c/tr\\u003e \\u003c/thead\\u003e \\u003ctbody\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eFamily History of Other Cancers vs Family History of Breast Cancer\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e0,0067\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e0,0202*\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e31,89\\u003c/p\\u003e \\u003cp\\u003e(2,54\\u0026ndash;400,81)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eFamily History of Other Cancers vs No Family History\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e0,0064\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e0,0193*\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e21,42\\u003c/p\\u003e \\u003cp\\u003e(2,61\\u0026ndash;175,92)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eFamily History of Breast Cancer vs No Family History\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e1,0\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e1,0\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e0,67\\u003c/p\\u003e \\u003cp\\u003e(0,10\\u0026thinsp;\\u0026minus;\\u0026thinsp;4,39)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003c/tbody\\u003e \\u003c/colgroup\\u003e \\u003c/table\\u003e\\u003c/div\\u003e \\u003c/p\\u003e \\u003c/div\\u003e\"},{\"header\":\"DISCUSSION\",\"content\":\"\\u003cp\\u003eThis cross-sectional study provides novel insight into the distribution and clinical correlates of BRCA1 and BRCA2 mutations in familial and hereditary breast cancer within a Central Java population. In this cohort, pathogenic germline BRCA variants were identified in 11.25% of patients, a prevalence that is consistent with reports from other Asian familial breast cancer cohorts, which range from approximately 8% to 31% depending on selection criteria and ethnicity [\\u003cspan citationid=\\\"CR1\\\" class=\\\"CitationRef\\\"\\u003e1\\u003c/span\\u003e, \\u003cspan additionalcitationids=\\\"CR10\\\" citationid=\\\"CR9\\\" class=\\\"CitationRef\\\"\\u003e9\\u003c/span\\u003e\\u0026ndash;\\u003cspan citationid=\\\"CR11\\\" class=\\\"CitationRef\\\"\\u003e11\\u003c/span\\u003e]. These findings contribute important population-specific data to a field that has historically been dominated by evidence from Western populations.\\u003c/p\\u003e \\u003cp\\u003eThe relative distribution of BRCA1 and BRCA2 mutations observed in this study, with a slight predominance of BRCA1, aligns with several regional studies but contrasts with others reporting BRCA2 as the more frequent mutation in Asian cohorts [\\u003cspan additionalcitationids=\\\"CR10\\\" citationid=\\\"CR9\\\" class=\\\"CitationRef\\\"\\u003e9\\u003c/span\\u003e\\u0026ndash;\\u003cspan citationid=\\\"CR11\\\" class=\\\"CitationRef\\\"\\u003e11\\u003c/span\\u003e]. This heterogeneity underscores the importance of regional mutation profiling. Notably, recurrent involvement of exon 11 in BRCA2 is consistent with global mutation spectra, as exon 11 represents a known mutational hotspot due to its large coding region and critical functional domains [\\u003cspan citationid=\\\"CR12\\\" class=\\\"CitationRef\\\"\\u003e12\\u003c/span\\u003e]. The specific variants identified in this study, including truncating and frameshift mutations documented in ClinVar, further support their pathogenic classification and relevance to clinical risk assessment [\\u003cspan additionalcitationids=\\\"CR3 CR4 CR5 CR6 CR7\\\" citationid=\\\"CR2\\\" class=\\\"CitationRef\\\"\\u003e2\\u003c/span\\u003e\\u0026ndash;\\u003cspan citationid=\\\"CR8\\\" class=\\\"CitationRef\\\"\\u003e8\\u003c/span\\u003e].\\u003c/p\\u003e \\u003cp\\u003eContrary to findings from Western populations, BRCA mutation status in this cohort was not significantly associated with younger age at diagnosis or with triple-negative breast cancer phenotype. In European and North American studies, BRCA1 mutations are strongly linked to early-onset disease and triple-negative histology [\\u003cspan citationid=\\\"CR12\\\" class=\\\"CitationRef\\\"\\u003e12\\u003c/span\\u003e]. However, emerging evidence from Asian populations suggests that this association may be less consistent, potentially reflecting differences in genetic background, modifier genes, reproductive patterns, and environmental exposures [\\u003cspan citationid=\\\"CR9\\\" class=\\\"CitationRef\\\"\\u003e9\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR11\\\" class=\\\"CitationRef\\\"\\u003e11\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR13\\\" class=\\\"CitationRef\\\"\\u003e13\\u003c/span\\u003e]. Our findings reinforce the notion that extrapolation of Western-derived genotype\\u0026ndash;phenotype correlations to Southeast Asian populations should be approached with caution.\\u003c/p\\u003e \\u003cp\\u003eIn contrast, family history of cancer demonstrated a strong association with BRCA positivity, particularly when the family history included malignancies other than breast cancer. This observation is biologically plausible given the well-established pleiotropic cancer risks associated with BRCA1 and BRCA2 mutations, including ovarian, pancreatic, and prostate cancers [\\u003cspan citationid=\\\"CR12\\\" class=\\\"CitationRef\\\"\\u003e12\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR14\\\" class=\\\"CitationRef\\\"\\u003e14\\u003c/span\\u003e]. Similar patterns have been reported in Asian studies emphasizing that broad family cancer history may be a more sensitive indicator of hereditary risk than breast cancer history alone [\\u003cspan citationid=\\\"CR9\\\" class=\\\"CitationRef\\\"\\u003e9\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR14\\\" class=\\\"CitationRef\\\"\\u003e14\\u003c/span\\u003e]. In resource-limited settings such as Indonesia, where universal genetic testing is not feasible, this finding has practical implications for prioritizing patients for genetic counseling and testing.\\u003c/p\\u003e \\u003cp\\u003eFrom a public health perspective, these results gain further relevance in light of the rising burden of breast cancer across low- and middle-income countries, including Indonesia [\\u003cspan citationid=\\\"CR15\\\" class=\\\"CitationRef\\\"\\u003e15\\u003c/span\\u003e]. Incorporating structured family history assessment into routine oncology practice may represent a cost-effective strategy to identify individuals at high hereditary risk, facilitate cascade testing, and enable risk-reducing interventions.\\u003c/p\\u003e \\u003cp\\u003eSeveral limitations should be acknowledged. First, the relatively small sample size and single-center design may limit generalizability and statistical power, particularly for subgroup analyses. Second, family history data were self-reported and may be subject to recall bias or incomplete knowledge of relatives\\u0026rsquo; diagnoses. Third, only BRCA1 and BRCA2 were analyzed; other susceptibility genes such as PALB2, CHEK2, and ATM were not assessed and may account for additional hereditary risk. Finally, the cross-sectional design precludes assessment of long-term outcomes or penetrance.\\u003c/p\\u003e \\u003cp\\u003eFuture research should focus on multicenter studies across diverse Indonesian regions to capture ethnic heterogeneity and improve representativeness. Expansion to multigene panel testing would allow a more comprehensive evaluation of hereditary breast cancer susceptibility. Longitudinal follow-up of mutation carriers is also needed to clarify clinical outcomes and inform locally appropriate screening and prevention strategies.\\u003c/p\\u003e \\u003cp\\u003eIn conclusion, this study demonstrates that BRCA1 and BRCA2 mutations contribute meaningfully to hereditary breast cancer risk in Central Java and that family history of cancer, particularly beyond breast cancer alone, is a strong clinical indicator of mutation carriage. These findings support the integration of detailed family history assessment into routine care and highlight the need for population-specific genetic data to inform precision cancer prevention strategies.\\u003c/p\\u003e\"},{\"header\":\"CONCLUSIONS\",\"content\":\"\\u003cp\\u003ePathogenic \\u003cem\\u003eBRCA1/2\\u003c/em\\u003e mutations were identified in a substantial proportion of patients with familial and hereditary breast cancer in Central Java. Mutation status was strongly associated with family history of cancer but not with age at diagnosis or tumor subtype. These findings emphasize the importance of thorough family history evaluation and support the integration of genetic counseling into breast cancer care in Indonesia. Larger, multicenter studies are warranted to further define the genetic architecture of hereditary breast cancer and to inform region-specific screening and prevention strategies.\\u003c/p\\u003e\"},{\"header\":\"Abbreviations\",\"content\":\"\\u003cdiv class=\\\"DefinitionList\\\"\\u003e \\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e \\u003cdiv class=\\\"Term\\\"\\u003eBRCA1\\u003c/div\\u003e \\u003cdiv class=\\\"Description\\\"\\u003e \\u003cp\\u003eBreast Cancer Susceptibility Gene 1\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/div\\u003e \\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e \\u003cdiv class=\\\"Term\\\"\\u003eBRCA2\\u003c/div\\u003e \\u003cdiv class=\\\"Description\\\"\\u003e \\u003cp\\u003eBreast Cancer Susceptibility Gene 2\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/div\\u003e \\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e \\u003cdiv class=\\\"Term\\\"\\u003eCI\\u003c/div\\u003e \\u003cdiv class=\\\"Description\\\"\\u003e \\u003cp\\u003eConfidence Interval\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/div\\u003e \\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e \\u003cdiv class=\\\"Term\\\"\\u003eDNA\\u003c/div\\u003e \\u003cdiv class=\\\"Description\\\"\\u003e \\u003cp\\u003eDeoxyribonucleic Acid\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/div\\u003e \\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e \\u003cdiv class=\\\"Term\\\"\\u003eER\\u003c/div\\u003e \\u003cdiv class=\\\"Description\\\"\\u003e \\u003cp\\u003eEstrogen Receptor\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/div\\u003e \\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e \\u003cdiv class=\\\"Term\\\"\\u003eHER2\\u003c/div\\u003e \\u003cdiv class=\\\"Description\\\"\\u003e \\u003cp\\u003eHuman Epidermal Growth Factor Receptor 2\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/div\\u003e \\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e \\u003cdiv class=\\\"Term\\\"\\u003eIHC\\u003c/div\\u003e \\u003cdiv class=\\\"Description\\\"\\u003e \\u003cp\\u003eImmunohistochemistry\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/div\\u003e \\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e \\u003cdiv class=\\\"Term\\\"\\u003eNGS\\u003c/div\\u003e \\u003cdiv class=\\\"Description\\\"\\u003e \\u003cp\\u003eNext-Generation Sequencing\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/div\\u003e \\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e \\u003cdiv class=\\\"Term\\\"\\u003eOR\\u003c/div\\u003e \\u003cdiv class=\\\"Description\\\"\\u003e \\u003cp\\u003eOdds Ratio\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/div\\u003e \\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e \\u003cdiv class=\\\"Term\\\"\\u003ePARP\\u003c/div\\u003e \\u003cdiv class=\\\"Description\\\"\\u003e \\u003cp\\u003ePoly (Adenosine Diphosphate\\u0026ndash;Ribose) Polymerase\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/div\\u003e \\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e \\u003cdiv class=\\\"Term\\\"\\u003ePR\\u003c/div\\u003e \\u003cdiv class=\\\"Description\\\"\\u003e \\u003cp\\u003eProgesterone Receptor\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/div\\u003e \\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e \\u003cdiv class=\\\"Term\\\"\\u003eTNBC\\u003c/div\\u003e \\u003cdiv class=\\\"Description\\\"\\u003e \\u003cp\\u003eTriple-Negative Breast Cancer\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/div\\u003e \\u003c/div\\u003e\"},{\"header\":\"Declarations\",\"content\":\"\\u003cp\\u003e \\u003ch2\\u003eConflicts of interest\\u003c/h2\\u003e \\u003cp\\u003eThe authors declare that they have no competing interests\\u003c/p\\u003e \\u003c/p\\u003e\\u003cp\\u003e \\u003cstrong\\u003eEthics approval and consent to participate\\u003c/strong\\u003e \\u003cp\\u003e The study protocol was approved by the Health Research Ethics Committee of Dr. Moewardi General Hospital, Surakarta, Indonesia (approval no. 709/III/HREC/2025). All patient data were fully anonymized prior to analysis; therefore, the requirement for informed consent was waived by the committee.\\u003c/p\\u003e \\u003c/p\\u003e \\u003cp\\u003e \\u003cstrong\\u003eConsent for publication\\u003c/strong\\u003e \\u003cp\\u003eNot applicable. This study does not contain any individual person\\u0026rsquo;s data in any form (including images or videos).\\u003c/p\\u003e \\u003c/p\\u003e\\u003cp\\u003e \\u003ch2\\u003eCompeting interests\\u003c/h2\\u003e \\u003cp\\u003eThe authors declare that they have no competing interests.\\u003c/p\\u003e \\u003c/p\\u003e\\u003cp\\u003e \\u003ch2\\u003eFunding\\u003c/h2\\u003e \\u003cp\\u003eThis study was supported by the Faculty of Medicine Research Group, Sebelas Maret University, through the Sebelas Maret University research grant (No. 371/UN27.22/PT.01.03/2025).\\u003c/p\\u003e \\u003c/p\\u003e\\u003ch2\\u003eFunding\\u003c/h2\\u003e \\u003cp\\u003eThis study was supported by Sebelas Maret University Research Group, through Sebelas Maret University research grant (371/UN27.22/PT.01.03/2025).\\u003c/p\\u003e\\u003ch2\\u003eAuthor Contribution\\u003c/h2\\u003e\\u003cp\\u003e1. WS (Widyanti Soewoto): Conceptualization and formal analysis.2. JP (Joko Purnomo): Histopathological evaluation and supervision.3. SI (Senyum Indrakila): Data curation and critical review.4. AS (Amru Sungkar): Data curation and critical review.5. DAS (Dea Alberta Setiawati): Methodology, statistical analysis, and writing original draft.All authors read and approved the final manuscript.\\u003c/p\\u003e\\u003ch2\\u003eAcknowledgements\\u003c/h2\\u003e \\u003cp\\u003eThe austhors would like to express their sincere gratitude to the Faculty of Medicine, Sebelas Maret University, Surakarta, Central Java, Indonesia, for the continuous support and valuable contribution to this research.\\u003c/p\\u003e\\u003ch2\\u003eData Availability\\u003c/h2\\u003e\\u003cp\\u003eThe datasets generated and/or analysed during the current study are not publicly available due to privacy restrictions but are available from the corresponding author, Widyanti Soewoto (widyanti_s@staff.uns.ac.id), on reasonable request.\\u003c/p\\u003e\"},{\"header\":\"References\",\"content\":\"\\u003col\\u003e\\u003cli\\u003e\\u003cspan\\u003eArmstrong N, Ryder S, Forbes C, Ross J, Quek RG. A systematic review of the international prevalence of BRCA mutation in breast cancer. Clin Epidemiol. 2019;11:543\\u0026ndash;61. \\u003cspan class=\\\"ExternalRef\\\"\\u003e\\u003cspan class=\\\"RefSource\\\"\\u003e10.2147/CLEP.S206949\\u003c/span\\u003e\\u003cspan address=\\\"10.2147/CLEP.S206949\\\" targettype=\\\"DOI\\\" class=\\\"RefTarget\\\"\\u003e\\u003c/span\\u003e\\u003c/span\\u003e.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eNational Center for Biotechnology Information. ClinVar; NM_007294.4(BRCA1):c.5291T\\u0026thinsp;\\u0026gt;\\u0026thinsp;C (p.Leu1764Pro), VCV000055510.27. Reviewed August 10, 2015. Accessed October 26, 2025.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eNational Center for Biotechnology Information. ClinVar; NM_007294.4(BRCA1):c.1723G\\u0026thinsp;\\u0026gt;\\u0026thinsp;T (p.Glu575Ter), RCV000794574.9. Reviewed September 11, 2023. Accessed October 26, 2025.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eNational Center for Biotechnology Information. ClinVar; NM_007294.4(BRCA1):c.4148C\\u0026thinsp;\\u0026gt;\\u0026thinsp;G (p.Ser1383Ter), VCV000037572.19. Reviewed September 8, 2016. Accessed October 26, 2025.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eNational Center for Biotechnology Information. ClinVar; NM_007294.4(BRCA1):c.470_471delCT (p.Ser157Ter), VCV000037608.13. Reviewed August 23, 2017. Accessed October 26, 2025.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eNational Center for Biotechnology Information. ClinVar; NM_007294.4(BRCA1):c.329dup (p.Glu111fs), RCV000031101.7. Accessed October 26, 2025.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eNational Center for Biotechnology Information. ClinVar; NM_000059.3(BRCA2):c.2471_2476del (p.L824_E826delins*), VCV000051295.12. Accessed October 26, 2025.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eNational Center for Biotechnology Information. ClinVar; NM_000059.3(BRCA2):c.6634_6637del (p.Cys2212Leufs*16), VCV000052140.12. Accessed October 26, 2025.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eKwong A, Shin VY, Ho JC, et al. Comprehensive spectrum of BRCA1 and BRCA2 deleterious mutations in breast cancer in Asian countries. J Med Genet. 2016;53(1):15\\u0026ndash;23. \\u003cspan class=\\\"ExternalRef\\\"\\u003e\\u003cspan class=\\\"RefSource\\\"\\u003e10.1136/jmedgenet-2015-103132\\u003c/span\\u003e\\u003cspan address=\\\"10.1136/jmedgenet-2015-103132\\\" targettype=\\\"DOI\\\" class=\\\"RefTarget\\\"\\u003e\\u003c/span\\u003e\\u003c/span\\u003e.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eKang E, Seong MW, Park SK, et al. The prevalence and spectrum of BRCA1 and BRCA2 mutations in the Korean population: results from the Korean Hereditary Breast Cancer (KOHBRA) study. Breast Cancer Res Treat. 2015;151(1):157\\u0026ndash;68. \\u003cspan class=\\\"ExternalRef\\\"\\u003e\\u003cspan class=\\\"RefSource\\\"\\u003e10.1007/s10549-015-3377-4\\u003c/span\\u003e\\u003cspan address=\\\"10.1007/s10549-015-3377-4\\\" targettype=\\\"DOI\\\" class=\\\"RefTarget\\\"\\u003e\\u003c/span\\u003e\\u003c/span\\u003e.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eKim H, Choi DH. Distribution of BRCA1 and BRCA2 mutations in Asian patients with breast cancer. J Breast Cancer. 2013;16(4):357\\u0026ndash;65. \\u003cspan class=\\\"ExternalRef\\\"\\u003e\\u003cspan class=\\\"RefSource\\\"\\u003e10.4048/jbc.2013.16.4.357\\u003c/span\\u003e\\u003cspan address=\\\"10.4048/jbc.2013.16.4.357\\\" targettype=\\\"DOI\\\" class=\\\"RefTarget\\\"\\u003e\\u003c/span\\u003e\\u003c/span\\u003e.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eRebbeck TR, Friebel TM, Friedman E, et al. Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations. Hum Mutat. 2018;39(5):593\\u0026ndash;620. \\u003cspan class=\\\"ExternalRef\\\"\\u003e\\u003cspan class=\\\"RefSource\\\"\\u003e10.1002/humu.23406\\u003c/span\\u003e\\u003cspan address=\\\"10.1002/humu.23406\\\" targettype=\\\"DOI\\\" class=\\\"RefTarget\\\"\\u003e\\u003c/span\\u003e\\u003c/span\\u003e.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eQin Z, Li J, Tam B, et al. Ethnic specificity, evolutionary origin, and deleteriousness of Asian BRCA variation revealed from over 7,500 variants. Int J Cancer. 2023;152(6):1159\\u0026ndash;73. \\u003cspan class=\\\"ExternalRef\\\"\\u003e\\u003cspan class=\\\"RefSource\\\"\\u003e10.1002/ijc.34359\\u003c/span\\u003e\\u003cspan address=\\\"10.1002/ijc.34359\\\" targettype=\\\"DOI\\\" class=\\\"RefTarget\\\"\\u003e\\u003c/span\\u003e\\u003c/span\\u003e.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eSun J, Meng H, Yao L, et al. Germline mutations in cancer susceptibility genes in a large series of unselected breast cancer patients. Clin Cancer Res. 2017;23(20):6113\\u0026ndash;9. \\u003cspan class=\\\"ExternalRef\\\"\\u003e\\u003cspan class=\\\"RefSource\\\"\\u003e10.1158/1078-0432.CCR-16-3227\\u003c/span\\u003e\\u003cspan address=\\\"10.1158/1078-0432.CCR-16-3227\\\" targettype=\\\"DOI\\\" class=\\\"RefTarget\\\"\\u003e\\u003c/span\\u003e\\u003c/span\\u003e.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eKim J, Harper A, McCormack V, Sung H, Houssami N, Morgan E, et al. Global patterns and trends in breast cancer incidence and mortality across 185 countries. Nat Med. 2025;31(4):1154\\u0026ndash;62. \\u003cspan class=\\\"ExternalRef\\\"\\u003e\\u003cspan class=\\\"RefSource\\\"\\u003e10.1038/s41591-025-03502-3\\u003c/span\\u003e\\u003cspan address=\\\"10.1038/s41591-025-03502-3\\\" targettype=\\\"DOI\\\" class=\\\"RefTarget\\\"\\u003e\\u003c/span\\u003e\\u003c/span\\u003e.\\u003c/span\\u003e\\u003c/li\\u003e\\u003c/ol\\u003e\"}],\"fulltextSource\":\"\",\"fullText\":\"\",\"funders\":[],\"hasAdminPriorityOnWorkflow\":false,\"hasManuscriptDocX\":true,\"hasOptedInToPreprint\":true,\"hasPassedJournalQc\":\"\",\"hasAnyPriority\":false,\"hideJournal\":false,\"highlight\":\"\",\"institution\":\"\",\"isAcceptedByJournal\":false,\"isAuthorSuppliedPdf\":false,\"isDeskRejected\":\"\",\"isHiddenFromSearch\":false,\"isInQc\":false,\"isInWorkflow\":false,\"isPdf\":false,\"isPdfUpToDate\":true,\"isWithdrawnOrRetracted\":false,\"journal\":{\"display\":true,\"email\":\"info@researchsquare.com\",\"identity\":\"bmc-cancer\",\"isNatureJournal\":false,\"hasQc\":true,\"allowDirectSubmit\":false,\"externalIdentity\":\"bcan\",\"sideBox\":\"Learn more about [BMC Cancer](http://bmccancer.biomedcentral.com/)\",\"snPcode\":\"\",\"submissionUrl\":\"https://www.editorialmanager.com/bcan/default.aspx\",\"title\":\"BMC Cancer\",\"twitterHandle\":\"BMC_series\",\"acdcEnabled\":true,\"dfaEnabled\":false,\"editorialSystem\":\"em\",\"reportingPortfolio\":\"BMC Series\",\"inReviewEnabled\":true,\"inReviewRevisionsEnabled\":true},\"keywords\":\"BRCA1, BRCA2, Familial breast cancer, Hereditary breast cancer, Surakarta\",\"lastPublishedDoi\":\"10.21203/rs.3.rs-8504525/v1\",\"lastPublishedDoiUrl\":\"https://doi.org/10.21203/rs.3.rs-8504525/v1\",\"license\":{\"name\":\"CC BY 4.0\",\"url\":\"https://creativecommons.org/licenses/by/4.0/\"},\"manuscriptAbstract\":\"\\u003ch2\\u003eBackground\\u003c/h2\\u003e \\u003cp\\u003ePathogenic variants in \\u003cem\\u003eBRCA1\\u003c/em\\u003e and \\u003cem\\u003eBRCA2\\u003c/em\\u003e are key determinants of hereditary breast cancer risk. However, data describing mutation patterns and their clinical associations in Southeast Asian populations remain scarce. Regional differences in genetic background and healthcare access may influence both mutation prevalence and phenotype. This study aimed to characterize \\u003cem\\u003eBRCA1\\u003c/em\\u003e and \\u003cem\\u003eBRCA2\\u003c/em\\u003e mutation patterns and evaluate their associations with demographic and clinicopathological features among patients with familial and hereditary breast cancer in Surakarta, Central Java, Indonesia.\\u003c/p\\u003e\\u003ch2\\u003eMethods\\u003c/h2\\u003e \\u003cp\\u003eA cross-sectional study was conducted at Dr. Moewardi Hospital, a tertiary referral center in Surakarta, between January 2024 and May 2025. Eighty consecutive patients with histologically confirmed breast cancer and available peripheral blood samples were included. Genomic DNA was analyzed using next-generation sequencing to identify \\u003cem\\u003eBRCA1\\u003c/em\\u003e and \\u003cem\\u003eBRCA2\\u003c/em\\u003e variants. Variant pathogenicity was determined according to established clinical classification guidelines. Associations between mutation status and age, breast cancer subtype (triple-negative versus non\\u0026ndash;triple-negative), and family history of cancer were assessed using chi-square or Fisher\\u0026rsquo;s exact tests, followed by logistic regression analysis. Statistical significance was defined as \\u003cem\\u003eP\\u003c/em\\u003e\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.05.\\u003c/p\\u003e\\u003ch2\\u003eResults\\u003c/h2\\u003e \\u003cp\\u003ePathogenic \\u003cem\\u003eBRCA1/2\\u003c/em\\u003e mutations were detected in 9 of 80 patients (11.25%), including 5 \\u003cem\\u003eBRCA1\\u003c/em\\u003e and 4 \\u003cem\\u003eBRCA2\\u003c/em\\u003e variants. Mutation prevalence did not differ significantly by age at diagnosis (\\u003cem\\u003eP\\u003c/em\\u003e\\u0026thinsp;=\\u0026thinsp;0.587) or breast cancer subtype (\\u003cem\\u003eP\\u003c/em\\u003e\\u0026thinsp;=\\u0026thinsp;0.847). In contrast, a significant association was observed between mutation status and family history of cancer (\\u003cem\\u003eP\\u003c/em\\u003e\\u0026thinsp;=\\u0026thinsp;0.0002). Patients with a family history of non\\u0026ndash;breast malignancies had markedly increased odds of carrying a pathogenic \\u003cem\\u003eBRCA\\u003c/em\\u003e mutation (odds ratio 21.4; 95% confidence interval 2.6\\u0026ndash;175.9).\\u003c/p\\u003e\\u003ch2\\u003eConclusions\\u003c/h2\\u003e \\u003cp\\u003eIn this Indonesian cohort, \\u003cem\\u003eBRCA1/2\\u003c/em\\u003e mutations were strongly associated with family cancer history but not with age or tumor subtype. These findings emphasize the importance of comprehensive family-history assessment and support the integration of early genetic counseling into hereditary breast cancer evaluation in resource-limited settings.\\u003c/p\\u003e\\u003ch2\\u003eTrial registration\\u003c/h2\\u003e \\u003cp\\u003eNot applicable (cross-sectional observational study).\\u003c/p\\u003e\",\"manuscriptTitle\":\"Genetic patterns and clinical associations of BRCA1 and BRCA2 mutations in familial and hereditary breast cancer: a cross-sectional study from Surakarta, Central Java.\",\"msid\":\"\",\"msnumber\":\"\",\"nonDraftVersions\":[{\"code\":1,\"date\":\"2026-02-26 11:33:40\",\"doi\":\"10.21203/rs.3.rs-8504525/v1\",\"editorialEvents\":[{\"type\":\"communityComments\",\"content\":0},{\"type\":\"editorInvitedReview\",\"content\":\"\",\"date\":\"2026-03-08T08:39:25+00:00\",\"index\":\"hide\",\"fulltext\":\"\"},{\"type\":\"reviewerAgreed\",\"content\":\"332948925820872725418905665204309973031\",\"date\":\"2026-03-03T15:43:00+00:00\",\"index\":\"hide\",\"fulltext\":\"\"},{\"type\":\"reviewerAgreed\",\"content\":\"71341002206106606665541300862731459601\",\"date\":\"2026-03-03T12:29:54+00:00\",\"index\":\"hide\",\"fulltext\":\"\"},{\"type\":\"reviewersInvited\",\"content\":\"\",\"date\":\"2026-02-24T10:48:37+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"editorInvited\",\"content\":\"\",\"date\":\"2026-01-30T20:43:24+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"editorAssigned\",\"content\":\"\",\"date\":\"2026-01-05T12:43:23+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"checksComplete\",\"content\":\"\",\"date\":\"2026-01-05T12:42:42+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"submitted\",\"content\":\"BMC Cancer\",\"date\":\"2026-01-03T05:11:51+00:00\",\"index\":\"\",\"fulltext\":\"\"}],\"status\":\"published\",\"journal\":{\"display\":true,\"email\":\"info@researchsquare.com\",\"identity\":\"bmc-cancer\",\"isNatureJournal\":false,\"hasQc\":true,\"allowDirectSubmit\":false,\"externalIdentity\":\"bcan\",\"sideBox\":\"Learn more about [BMC Cancer](http://bmccancer.biomedcentral.com/)\",\"snPcode\":\"\",\"submissionUrl\":\"https://www.editorialmanager.com/bcan/default.aspx\",\"title\":\"BMC Cancer\",\"twitterHandle\":\"BMC_series\",\"acdcEnabled\":true,\"dfaEnabled\":false,\"editorialSystem\":\"em\",\"reportingPortfolio\":\"BMC Series\",\"inReviewEnabled\":true,\"inReviewRevisionsEnabled\":true}}],\"origin\":\"\",\"ownerIdentity\":\"b1f8d0bb-8a9b-4a99-aa6d-b95fbca2e47f\",\"owner\":[],\"postedDate\":\"February 26th, 2026\",\"published\":true,\"recentEditorialEvents\":[],\"rejectedJournal\":[],\"revision\":\"\",\"amendment\":\"\",\"status\":\"under-review\",\"subjectAreas\":[],\"tags\":[],\"updatedAt\":\"2026-02-26T11:33:40+00:00\",\"versionOfRecord\":[],\"versionCreatedAt\":\"2026-02-26 11:33:40\",\"video\":\"\",\"vorDoi\":\"\",\"vorDoiUrl\":\"\",\"workflowStages\":[]},\"version\":\"v1\",\"identity\":\"rs-8504525\",\"journalConfig\":\"researchsquare\"},\"__N_SSP\":true},\"page\":\"/article/[identity]/[[...version]]\",\"query\":{\"redirect\":\"/article/rs-8504525\",\"identity\":\"rs-8504525\",\"version\":[\"v1\"]},\"buildId\":\"XKTyCvWXoU3ODBz1xrDgd\",\"isFallback\":false,\"isExperimentalCompile\":false,\"dynamicIds\":[84888],\"gssp\":true,\"scriptLoader\":[]}","source_license":"CC-BY-4.0","license_restricted":false}