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Purpose: To evaluate rates of familial disclosure of hereditary cancer syndrome information. Methods: A systematic review and meta-analysis was conducted in accordance with PRISMA guidelines (PROSPERO no.: CRD42020134276). Key electronic databases were searched to identify studies evaluating hereditary cancer syndrome cascade relative disclosure. Eligible studies were subjected to meta-analysis. Results: Thirty-four studies met inclusion criteria. Among 11,711 included relatives, 70% (95% CI 60 - 78%) were informed of their risk of carrying a cancer-associated pathogenic variant; of 2,875 relatives informed of their risk who were evaluated for uptake of cascade testing, 43% (95% CI 27 - 61%) completed testing. Rates of disclosure were higher among female vs male relatives (79% [95% CI 73% - 84%] vs 67% [95% CI 57% - 75%]) and first-degree vs second-degree relatives (83% [95% CI 77% - 88%] vs 58% [95% CI 45 – 69%]). Conclusion: Nearly one-third of at-risk relatives remain uninformed of their risk of carrying a cancer-associated pathogenic variant. Even among those informed, fewer than half subsequently complete genetic testing, representing a critical missed opportunity for precision cancer prevention. Innovation: Five studies evaluating interventions to improve disclosure rates were generally ineffective. Urgent work is needed to elucidate barriers to relative disclosure by probands to develop targeted interventions that can optimize proband-mediated cascade genetic testing rates.

Background: Minorities at increased risk for Hereditary Breast and Ovarian Cancer (HBOC) frequently have low awareness and use of genetic counseling and testing (GCT). Making sure that evidence-based interventions (EBIs) reach minorities is key to reduce disparities. BRCA-Gist is a theory-informed EBI that has been proven to be efficacious in mostly non-Hispanic White non-clinical populations. We conducted formative work to inform adaptations of BRCA-Gist for use in clinical settings with at-risk diverse women. Methods: Genetic counselors (n = 20) were recruited nationally; at-risk Latinas and Blacks (n = 21) were recruited in Washington DC and Virginia. They completed the BRCA-Gist EBI between April 2018 – September 2019. Participants completed an acceptability scale and an interview to provide suggestions about implementation adaptations. T-tests for independent samples compared acceptability between at-risk women and genetic counselors. The Consensual Qualitative Research Framework was used to code adaptation suggestions. Suggested adaptations were discussed by a multidisciplinary team to integrate fidelity and adaptation considerations. Results: At-risk women had a significantly higher acceptability (M = 4.17, SD = 0.47 vs. M = 3.24, SD = 0.64; p = 0.000; scale 1–5) and satisfaction scores (M = 8.3, SD = 1.3 vs. M = 4.2, SD = 2.0; p = 0.000; scale 1–10) than genetic counselors. Genetic counselors and at-risk women suggested contextual (e.g. format) and content (e.g. shortening) adaptations to enhance the fit of BRCA-Gist for diverse clinical populations. Conclusions: Findings illustrate the process of integrating fidelity and adaptation considerations to ensure that EBIs retain their core components while enhancing the fit to minoritized clinical populations. Future studies will test the efficacy of the adapted BRCA-Gist in a Randomized Controlled Trial.

Summary: Functional assessment of genomic variants provides a promising approach to systematically examine the potential pathogenicity of variants independent of associated clinical data. However, making such conclusions requires validation with appropriate clinical findings. To this end, here, we use variant calls from exome data and BRCA1-related cancer diagnoses from electronic health records to demonstrate an association between published laboratory-based functional designations of BRCA1 variants and BRCA1-related cancer diagnoses in an unselected cohort of patient-participants. These findings validate and support further exploration of functional assay data to better understand the pathogenicity of rare variants. This information may be valuable in the context of healthy population genomic screening, where many rare, potentially pathogenic variants may not have sufficient associated clinical data to inform their interpretation directly.

Objective: To identify factors contributing to baseline knowledge in women with BRCA1/2 pathogenic variants (PVs) and knowledge gain after decision aid (DA) use., Methods: Women with PVs in BRCA1 or BRCA2 genes were randomly assigned to an intervention group (IG) receiving DAs or a control group (CG). Of the total sample, 417 completed the baseline survey and were included in this analysis. Two multiple regression analyses were conducted: baseline data on socio-demographic, medical, decision-related and psychological variables were used to identify predictors for (1) baseline knowledge within the total group and (2) knowledge gain within the IG after DA use three months post study inclusion., Results: At baseline, higher education status, no breast cancer history, and lower decisional conflict related to higher knowledge within the total group. After DA use within the IG, higher baseline scores for decisional conflict predicted higher knowledge gain, and higher baseline scores for depression and intrusion predicted lower knowledge gain., Conclusions: This study identified predictors of baseline knowledge and knowledge gain after DA use in women with BRCA1/2 PVs., Practice Implications: Awareness of facilitating and hindering factors on these women's knowledge can improve understanding of their health literacy and enable further targeted support interventions., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Background: Genetic counseling and testing (GCT) informs risk reduction and management strategies in women at risk for carrying a pathogenic variation in the BRCA1 or BRCA2 (BRCA1/2) genes. African American (hereinafter referred to as Black) women are less likely to receive GCT services for hereditary breast and ovarian cancer (HBOC). The objective of this work was to examine existing literature regarding successful culturally tailored GCT interventions for Black women and to describe the rationale and protocol for a randomized feasibility trial to test the efficacy of a culturally tailored GCT intervention., Methods/design: The For Our Health (FOH) study is a two-arm randomized control trial designed to test the efficacy of a video intervention to promote the uptake of GCT among Black women with a high risk of HBOC. The culturally tailored video intervention targets key beliefs, knowledge gaps, misconceptions, and key anticipated emotions relevant for GCT. After completing the baseline survey, 50 women at risk of HBOC will be randomized (1:1) to one of two trial arms: a YouTube video intervention or a publicly available fact sheet. Final assessments will immediately follow receipt of either video or fact sheet., Conclusion: Few studies have tested interventions to improve GCT uptake among Black women. The FOH trial will fill an important scientific gap in knowledge regarding strategies to reduce disparities in GCT among Black women at risk of HBOC., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflict of interest., (Copyright © 2023. Published by Elsevier Inc.)

Purpose: Several genes on hereditary breast and ovarian cancer susceptibility test panels have not been systematically examined for strength of association with disease. We employed the Clinical Genome Resource (ClinGen) clinical validity framework to assess the strength of evidence between selected genes and breast or ovarian cancer., Methods: Thirty-one genes offered on cancer panel testing were selected for evaluation. The strength of gene-disease relationship was systematically evaluated and a clinical validity classification of either Definitive, Strong, Moderate, Limited, Refuted, Disputed, or No Reported Evidence was assigned., Results: Definitive clinical validity classifications were made for 10/31 and 10/32 gene-disease pairs for breast and ovarian cancer respectively. Two genes had a Moderate classification whereas, 6/31 and 6/32 genes had Limited classifications for breast and ovarian cancer respectively. Contradictory evidence resulted in Disputed or Refuted assertions for 9/31 genes for breast and 4/32 genes for ovarian cancer. No Reported Evidence of disease association was asserted for 5/31 genes for breast and 11/32 for ovarian cancer., Conclusion: Evaluation of gene-disease association using the ClinGen clinical validity framework revealed a wide range of classifications. This information should aid laboratories in tailoring appropriate gene panels and assist health-care providers in interpreting results from panel testing.

Genetic counseling is under-utilized in women who meet family history criteria for BRCA1 and BRCA2 (BRCA1/2) testing, particularly among racial/ethnic minorities. We evaluated the uptake of BRCA1/2 genetic testing among women presenting for screening mammography in a predominantly Hispanic, low-income population of Washington Heights in New York City. We administered the Six-Point Scale (SPS) to women presenting for screening mammography at Columbia University Irving Medical Center (CUIMC) in the Washington Heights neighborhood of New York, NY. The SPS is a family history screener to determine eligibility for BRCA1/2 genetic testing based upon U.S. Preventive Services Task Force (USPSTF) guidelines that has been validated in low-income, multiethnic populations. Among women who underwent screening mammography at CUIMC between November 2014 and June 2016, 3,055 completed the SPS family history screener. Participants were predominantly Hispanic (76.7%), and 12% met family history criteria for BRCA1/2 testing, of whom <5% had previously undergone testing. In a multiethnic population, a significant proportion met family history criteria for BRCA1/2 testing, but uptake of genetic testing was low. Such underutilization of BRCA1/2 genetic testing among minorities further underscores the need to develop programs to engage high-risk women from underrepresented populations in genetic testing services., (Copyright © 2019. Published by Elsevier Inc.)

Although 25% of ovarian cancer cases are due to inherited factors, most of the genetic risk remains unexplained. We previously identified candidate genes through germline whole exome sequencing of BRCA1/BRCA2 negative ovarian cancer patients with familial risk. Here, we performed functional assessment to determine whether they act as BRCA-like tumor suppressors. Seven candidate risk genes were targeted by siRNA for mRNA depletion followed by functional assays for clonogenic survival, cytotoxicity to DNA damaging agents, and involvement in homologous recombination repair. BRCA1 and BRCA1 were targeted as standards for loss of function outcome. Knockdown of various candidate genes led to tumor suppressor phenotypes also observed in BRCA1/BRCA2 deficient cells. Deficiency of CHEK1, FANCM and TP53I3 led to reduced homologous recombination repair efficiency. Knockdown of RAD1, CHEK1 or FANCM led to a decrease in cellular viability and cells deficient in CHEK1, RAD1 or TP53I3 displayed increased sensitivity to cisplatin. Functional studies of candidate genes identified by whole exome sequencing complements bioinformatics techniques and aid the implication of novel risk loci. The results of this study suggest that genes found mutated in hereditary ovarian cancer, FANCM, RAD1, CHEK1 and TP53I3, act as BRCA-like tumor suppressors., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: The identification of carriers of hereditary breast and ovarian cancer (HBOC) gene variants through family cancer history alone is suboptimal, and most population-based genetic testing studies have been limited to founder mutations in high-risk populations. Here, we determine the clinical utility of identifying actionable variants in a healthy cohort of women., Methods: Germline DNA from a subset of healthy Australian women participating in the lifepool project was screened using an 11-gene custom sequencing panel. Women with clinically actionable results were invited to attend a familial cancer clinic (FCC) for post-test genetic counseling and confirmatory testing. Outcomes measured included the prevalence of pathogenic variants, and the uptake rate of genetic counseling, risk reduction surgery, and cascade testing., Results: Thirty-eight of 5908 women (0.64%) carried a clinically actionable pathogenic variant. Forty-two percent of pathogenic variant carriers did not have a first-degree relative with breast or ovarian cancer and 89% pursued referral to an FCC. Forty-six percent (6/13) of eligible women pursued risk reduction surgery, and the uptake rate of cascade testing averaged 3.3 family members per index case., Conclusion: Within our cohort, HBOC genetic testing was well accepted, and the majority of high-risk gene carriers identified would not meet eligibility criteria for genetic testing based on their existing family history.

Explaining genetic predisposition in Hereditary Breast and Ovarian Cancer (HBOC) families without BRCA mutations is crucial. Germline PALB2 inactivating mutations were associated with an increased risk of HBOC due to its role in DNA repair through cooperation with BRCA proteins. The prevalence and penetrance of PALB2 mutations in Spanish HBOC patients remains unexplained. PALB2 mutation screening has been conducted in 160 high-risk BRCA-negative patients and 320 controls. We evaluated four predicted splicing disruption variants and large genomic rearrangements by multiplex ligation-dependent probe amplification. We have found a frameshift mutation which segregates in an early onset cancer family; and four rare missense variants. None of the variants tested for a predicted splicing disruption showed an aberrant transcript pattern. No large genomic rearrangements were detected. Although PALB2 truncating mutations are rarely identified, segregation analysis and early onset cancer suggest a significant contribution to HBOC susceptibility in the Spanish population. PALB2 screening may improve genetic counselling through prevention measures, pedigree management and PARP inhibitor therapy selection., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

By analyzing multiple gene panels, next-generation sequencing is more effective than conventional procedures in identifying disease-related mutations that are useful for clinical decision-making. Here, we aimed to test the efficacy of an 84 genes customized-panel in BRCA1 and BRCA2 mutation-negative patients. Twenty-four patients were enrolled in this study. DNA libraries were prepared using a picodroplet PCR-based approach and sequenced with the MiSeq System. Highly putative pathogenic mutations were identified in genes other than the commonly tested BRCA1/2: 2 pathogenic mutations one in TP53 and one in MUTYH; 2 missense variants in MSH6 and ATM, respectively; 2 frameshift variants in KLLN, and ATAD2, respectively; an intronic variant in ANPEP, and 3 not functionally known variants (a frameshift variant in ATM a nonsense variant in ATM and a missense variant in NFE2L2). Our results show that this molecular screening will increase diagnostic sensitivity leading to a better risk assessment in breast cancer patients and their families. This strategy could also reveal genes that have a higher penetrance for breast and ovarian cancers by matching gene mutation with familial and clinical data, thereby increasing information about hereditary breast and ovarian cancer genetics and improving cancer prevention measures or therapeutic approaches., (Copyright © 2018. Published by Elsevier B.V.)

Purpose: Germline variants in double-strand DNA damage repair (dsDDR) genes (e.g., BRCA1/2) predispose to pancreatic adenocarcinoma (PDAC) and may predict sensitivity to platinum-based chemotherapy and poly(ADP) ribose polymerase (PARP) inhibitors. We sought to determine the prevalence and significance of germline cancer susceptibility gene variants in PDAC with paired somatic and survival analyses., Methods: Using a customized next-generation sequencing panel, germline/somatic DNA was analyzed from 289 patients with resected PDAC ascertained without preselection for high-risk features (e.g., young age, personal/family history). All identified variants were assessed for pathogenicity. Outcomes were analyzed using multivariable-adjusted Cox proportional hazards regression., Results: We found that 28/289 (9.7%; 95% confidence interval [CI] 6.5-13.7%) patients carried pathogenic/likely pathogenic germline variants, including 21 (7.3%) dsDDR gene variants (3 BRCA1, 4 BRCA2, 14 other dsDDR genes [ATM, BRIP1, CHEK2, NBN, PALB2, RAD50, RAD51C]), 3 Lynch syndrome, and 4 other genes (APC p.I1307K, CDKN2A, TP53). Somatic sequencing and immunohistochemistry identified second hits in the tumor in 12/27 (44.4%) patients with germline variants (1 failed sequencing). Compared with noncarriers, patients with germline dsDDR gene variants had superior overall survival (hazard ratio [HR] 0.54; 95% CI 0.30-0.99; P = 0.05)., Conclusion: Nearly 10% of PDAC patients harbor germline variants, although the majority lack somatic second hits, the therapeutic significance of which warrants further study.

Purpose: To assess the implementation of evidence-based genomic medicine and its population-level impact on health outcomes and to promote public health genetics interventions, in 2015 the Roundtable on Genomics and Precision Health of the National Academies of Sciences, Engineering, and Medicine formed an action collaborative, the Genomics and Public Health Action Collaborative (GPHAC). This group engaged key stakeholders from public/population health agencies, along with experts in the fields of health disparities, health literacy, implementation science, medical genetics, and patient advocacy., Methods: In this paper, we present the efforts to identify performance objectives and outcome metrics. Specific attention is placed on measures related to hereditary breast ovarian cancer (HBOC) syndrome and Lynch syndrome (LS), two conditions with existing evidence-based genomic applications that can have immediate impact on morbidity and mortality., Results: Our assessment revealed few existing outcome measures. Therefore, using an implementation research framework, 38 outcome measures were crafted., Conclusion: Evidence-based public health requires outcome metrics, yet few exist for genomics. Therefore, we have proposed performance objectives that states might use and provided examples of a few state-level activities already under way, which are designed to collect outcome measures for HBOC and LS.

Objective: To examine men's approaches to managing BRCA-related cancer risks., Methods: 25 Qualitative interviews were conducted with men who are at risk for BRCA-related cancers. Thematic analysis was conducted using the constant comparison., Results: Qualitative analysis revealed two different approaches for how men managed their BRCA-related cancer risks. Men were engaged when: (1) initially seeking information, (2) uptake of genetic testing, and (3) population screening procedures. Men were passively avoidant for: (1) follow-up information seeking, (2) uptake of genetic testing, and (3) BRCA-specific screening. Men's justifications for engaged risk management were to: (1) protect their family, (2) respond to encouragement from others, and (3) get knowledge for themselves. Their justifications for passively avoidant management were due to: (1) limited access to clear risk information, (2) little fear of cancer development, (3) barriers to testing/screening, and (4) reliance on incomplete illness representations., Conclusions: Men at risk for developing BRCA-related cancers approached risk management by primarily using a passive avoidance approach. That approach should be interpreted in context with the inconsistent information available to them, and the minimal NCCN guidelines for their risk surveillance., Practice Implications: Findings may assist healthcare providers and family members in helping men manage their BRCA-related cancer risks., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Objective: To investigate BRCA-positive, unaffected patients' - referred to as previvors - information needs after testing positive for a deleterious BRCA genetic mutation., Methods: 25 qualitative interviews were conducted with previvors. Data were analyzed using the constant comparison method of grounded theory., Results: Analysis revealed a theoretical model of previvors' information needs related to the stage of their health journey. Specifically, a four-stage model was developed based on the data: (1) pre-testing information needs, (2) post-testing information needs, (3) pre-management information needs, and (4) post-management information needs. Two recurring dimensions of desired knowledge also emerged within the stages-personal/social knowledge and medical knowledge., Conclusions: While previvors may be genetically predisposed to develop cancer, they have not been diagnosed with cancer, and therefore have different information needs than cancer patients and cancer survivors., Practice Implications: This model can serve as a framework for assisting healthcare providers in meeting the specific information needs of cancer previvors., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Mutations in BRCA1 and BRCA2 confer a highly increased risk of cancers, mainly of the breast and ovary. Most variants are point mutations or small insertions/deletions detectable by Sanger sequencing. Large genomic rearrangements, including deletions/duplications of multiple exons, are not routinely detectable by Sanger sequencing, but can be reliably identified by Multiplex Ligation-dependent Probe Amplification (MLPA), and account for 5-17% mutations in different populations. Comprehensive mutation testing using these two methods has been facilitated via our centre since 2005. The aim of this study was to investigate the incidence of and phenotype associated with large genomic rearrangements in BRCA1 and BRCA2 in an Irish cohort. An observational cohort study was undertaken. Patients with large genomic rearrangements in BRCA1/BRCA2 were identified from a prospectively maintained database of MLPA test results. Phenotypic and genotypic data were retrieved by chart review. Large genomic rearrangements in BRCA1 were identified in 49 families; and in BRCA2 in 7 families, representing ~11% of mutations in BRCA1/BRCA2 in Ireland. The most common large genomic rearrangement in BRCA1 was deletion of exons 1-23 (11 families, 7 from Co. Galway). Other common mutations included deletions of exon 3 (8 families) and exons 1-2 (6 families). Deletion of exons 19-20 in BRCA2 represented the familial mutation in five families, all from East Ireland (Wexford/Wicklow/Dublin). It is evident that a significant proportion of highly penetrant pathogenic variants in BRCA1 and BRCA2 will be missed if testing is limited to PCR-based Sanger sequencing alone. Screening for large genomic rearrangements in BRCA1 and BRCA2 in the routine diagnostic workflow is critical to avoid false negative results., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objective: Black women have a higher rate of BRCA1 and BRCA2 (BRCA) mutations, compared with other populations, that increases their risk for hereditary breast and ovarian cancer (HBOC). However, Black women are less likely to know about HBOC and genetic testing. Based on a request from a community advisory panel of breast cancer survivors, community leaders and healthcare providers in the Black community, our team developed a culturally targeted educational brochure to promote awareness of HBOC among Black women., Methods: To reach the target population we utilized a passive dissemination strategy. Using Diffusion of Innovations (DOI) as a framework, we traced dissemination of the brochure over a five year period using self-addressed postcards contained inside the brochure that included several open-ended questions about the utility of the brochure, and a field for written comments. Closed-ended responses were analyzed using descriptive statistics and thematic analysis was conducted on the open-ended responses., Results: DOI captured the proliferation of the brochure among Black women across the US., Practice Implications: The use of passive dissemination strategies among pre-existing social networks proved to be a useful and sustainable method for increasing knowledge of HBOC among Black women., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Germline mutations in BRCA1 or BRCA2 (BRCA) are responsible for 5-15% of breast (BC) and ovarian cancers (OC), predisposing to the development of early onset and often multiple primary tumors. Since mutation carriers can benefit from risk-reducing interventions, the identification of individuals with hereditary breast and ovarian cancer (HBOC) syndrome has a significant clinical impact. We assessed whether a panel assay for recurrent Hispanic BRCA mutations (HISPANEL) has an adequate breadth of coverage to be suitable as a cost effective screening tool for HBOC in a cohort of patients from Southern Brazil. A multiplex, PCR-based panel was used to genotype 232 unrelated patients for 114 germline BRCA mutations, finding deleterious mutations in 3.5% of them. This mutation prevalence is within the range detected by the HISPANEL among BC patients unselected for family history in other Latin American settings. The HISPANEL would have accounted for 27% of the BRCA mutations detected by complete sequencing in a comparison cohort (n = 193). This prevalence may be region-specific since significant differences in population structure exist in Brazil. Comprehensive analysis of BRCA in a larger set of HBOC patients from different Brazilian regions is warranted, and the results could inform customization of the HISPANEL as an affordable mutation screening tool., (Copyright © 2016. Published by Elsevier Inc.)

BRCA1 interacts with several proteins implicated in homologous and non homologous recombination and in mismatch repair. The aim of this study is to determine if MSH2, a well known partner of BRCA1 involved in DNA repair, may contribute to breast and ovarian cancer development and progression. To better understand the functional interaction between BRCA1 and MSH2, we studied the effect of the deletion of MSH2 gene on BRCA1-induced genome instability in yeast. Preliminary results in yeast indicated that MSH2 and BRCA1 may interact to modulate homologous recombination (HR). We also carried out a genetic and epigenetic profiling of MSH2 gene by mutational analysis and promoter methylation evaluation in 9 breast and 2 ovarian tumors from carriers of BRCA1 unknown significance variants (VUS). 2/2 ovarian and 2/9 breast tumors carried MSH2 somatic mutations possible pathogenics (4/11, 36%): a missense mutation in exon 3 (p.G162R), a duplication of exon 1 and a deletion of exon 2. In addition, two germline synonymous variants in exon 11 were identified. None of the tumors showed promoter methylation. In conclusion, a surprisingly high frequency of MSH2 gene mutations has been found in tumor tissues from BRCA1 VUS carrier patients. This result supports the indication deriving from the yeast model that BRCA1 driven tumorigenesis may be modulated by MSH2., (Copyright © 2015. Published by Elsevier Masson SAS.)

Background: In the Tunisian population, as yet a limited number of BRCA1/2 germline mutations have been reported in hereditary breast and/or ovarian cancer. These mutations are located in a few exons of BRCA1/2. The aim of the present study was to search for these mutations in 66 unrelated patients with hereditary breast and/or ovarian cancer in order to assess the interest in such a targeted approach for genetic testing in Tunisia., Materials and Methods: Blood specimens from the 66 Tunisian patients, with family history of breast and/or ovarian cancer, were collected at the Salah Azaiz Cancer Institute of Tunis. The exons 5, 20 and part of exon 11 of BRCA1 as well as part of exons 10 and 11 of BRCA2 were analyzed by Sanger sequencing., Results: 12 patients had deleterious mutations in the BRCA1 or BRCA2 genes (18%), including a novel frame-shift mutation of BRCA1 (c.3751dup; 3780insT). Four distinct BRCA1 mutations were detected eight patients: c.5266dup (5382insC) and c.211dup (330insA) each in three patients, c.3751dup (3870insT) and c.4041&#95;4042del (4160delAG) each in one patient. The four remaining cases all carried the same BRCA2 mutation, c.1310&#95;1313del (1538delAAGA). Besides these deleterious mutations, eight polymorphisms and unclassified variants were detected, one of them being never reported (BRCA1c.3030T>G, p.Pro1010Pro)., Conclusion: In this study, we show that targeting relevant exons in BRCA1 and BRCA2 genes allows detection of a substantial percentage of mutations in the Tunisian population. Therefore such an approach may be of interest in genetic testing of high-risk breast and ovarian cancer families in Tunisia.

There is limited knowledge about the BRCA1/2 mutational profile in Lithuania. We aimed to define the full BRCA1 and BRCA2 mutational spectrum and the clinically relevant prevalence of these gene mutations in Lithuania. A data set of 753 unrelated probands, recruited through a clinical setting, was used and consisted of 380 female breast cancer cases, 213 epithelial ovarian cancer cases, 20 breast and ovarian cancer cases, and 140 probands with positive family history of breast or ovarian cancer. A comprehensive mutation analysis of the BRCA1/2 genes by high resolution melting analysis coupled with Sanger sequencing and multiplex ligation-dependent probe amplification analysis was performed. Genetic analysis revealed 32 different pathogenic germline BRCA1/2 mutations: 20 in the BRCA1 gene and 12 in the BRCA2 gene, including four different large genomic rearrangements in the BRCA1 gene. In all, 10 novel BRCA1/2 mutations were found. Nine different recurrent BRCA1 mutations and two recurrent BRCA2 mutations were identified, which comprised 90.4% of all BRCA1/2 mutations. BRCA1 exon 1-3 deletion and BRCA2 c.658&#95;659del are reported for the first time as recurrent mutations, pointing to a possible Baltic founder effect. Approximately 7% of breast cancer and 22% of ovarian cancer patients without family history and an estimated 0.5-0.6% of all Lithuanian women were found to be carriers of mutations in the BRCA1 or BRCA2 gene., (Copyright © 2014 Elsevier Inc. All rights reserved.)