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Bilateral oophorectomy is one method of hormone suppression for premenopausal patients with hormone receptor-positive breast cancer. Such specimens could, in theory, harbor occult early ovarian cancer and/or metastatic breast cancer but guidelines for tissue sampling for pathologic examination remain to be addressed. Therefore, we evaluated oophorectomy specimens from 166 patients who underwent ovarian ablation for hormone receptor-positive breast cancer. Results of germline genetic testing were documented by the surgeon in only 31.3% of the pathology specimen requisition forms, whereas that information was available for 81.3% of patients elsewhere in the electronic medical records. All but 5.2% tested negative for a hereditary ovarian cancer gene pathogenic variant before oophorectomy. Complete tissue sampling was performed in 77.1% of the cases and representative sampling in the remainder. No cases of ovarian cancer were observed. Ovarian metastasis of breast cancer was identified in 9.6% of patients, all of whom were already known to have advanced-stage disease. The number of tissue cassettes per ovary required for complete tissue submission was on average three times higher than that for representative tissue sampling (P < 0.01) and ranged up to 20 cassettes per ovary when multiple follicle cysts were present. We propose that guidelines for tissue sampling in this context be defined by a combination of hereditary risk and macroscopic examination; representative sampling is reasonable for macroscopically normal ovaries in hormone receptor-positive breast cancer patients whose germline genetic testing is negative. Positive genetic test results merit complete tissue submission even if macroscopically normal. This strategy balances the goals of early ovarian cancer detection and optimal resource utilization. However, it depends on clear documentation of genetic test results. Our study demonstrates that many opportunities remain to close gaps in the communication of genetic test results by clinicians submitting oophorectomy specimens for pathologic evaluation.
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The NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic focus primarily on assessment of pathogenic/likely pathogenic (P/LP) variants associated with increased risk of breast, ovarian, pancreatic, and prostate cancer, including BRCA1, BRCA2, CDH1, PALB2, PTEN, and TP53, and recommended approaches to genetic counseling/testing and care strategies in individuals with these P/LP variants. These NCCN Guidelines Insights summarize important updates regarding: (1) a new section for transgender, nonbinary and gender diverse people who have a hereditary predisposition to cancer focused on risk reduction strategies for ovarian cancer, uterine cancer, prostate cancer, and breast cancer; and (2) testing criteria and management associated with TP53 P/LP variants and Li-Fraumeni syndrome.
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Neoplasias da Mama , Neoplasias Ovarianas , Masculino , Feminino , Humanos , Mutação em Linhagem Germinativa , Testes Genéticos , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/genética , Predisposição Genética para Doença , Fatores de Risco , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/genéticaRESUMO
OBJECTIVE: Genetic testing for ovarian cancer (OC) patients is essential to consideration of PARP inhibitor therapy. To improve access, we piloted a Genetic Testing Station (GTS) allowing patients to have a same-day genetic testing visit facilitated by Genetic Counselor Assistants (GCAs) under the supervision of Genetic Counselors (GCs). METHODS: The GTS was implemented December 2018 and operated through February 2020. Gynecologic Oncologists offered ovarian cancer patients a same-day GTS visit with a GCA. The patient received education via videos designed by GCs and then provided consent, a brief family history, and a sample for a standardized 133-gene panel. Results were provided by a GC. Patients were retrospectively identified by querying the medical record for OC patients seen 12 months prior to and 18 months after GTS implementation. RESULTS: A total of 482 patients pre-GTS were compared to 625 patients post-GTS. Genetic testing increased from 68.5% to 75.4% (p = 0.012) after implementation, primarily in patients with epithelial histologies (80% vs 89% in pre-GTS vs post-GTS, p = 0.005). Time from referral for genetic testing to obtaining results was evaluated in the post-GTS cohort, comparing patients who had traditional counseling to those who utilized the GTS. Time to obtaining results was 21 days in the GTS group (95% CI [10, 34]) compared to 56 days (95% CI [41,76]) in the traditional genetic counseling group. CONCLUSIONS: The GTS reduces barriers to care and facilitates discussion of precision treatment within a timely fashion while optimizing GC clinic time. Access improvement remains integral to improving uptake of genetic testing.
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OBJECTIVE: To evaluate the effect of risk-reducing salpingo-oophorectomy (RRSO) on change in bone mineral density (BMD) in women aged 34-50 years with pathogenic variants in BRCA1 or BRCA2 ( BRCA1 /2). METHODS: The PROSper (Prospective Research of Outcomes after Salpingo-oophorectomy) study is a prospective cohort of women aged 34-50 years with BRCA1 or two germline pathogenic variants that compares health outcomes after RRSO to a non-RRSO control group with ovarian conservation. Women aged 34-50 years, who were planning either RRSO or ovarian conservation, were enrolled for 3 years of follow-up. Spine and total hip BMD were measured by dual-energy X-ray absorptiometry (DXA) scans obtained at baseline before RRSO or at the time of enrollment for the non-RRSO group, and then at 1 and 3 years of study follow-up. Differences in BMD between the RRSO and non-RRSO groups, as well as the association between hormone use and BMD, were determined by using mixed effects multivariable linear regression models. RESULTS: Of 100 PROSper participants, 91 obtained DXA scans (RRSO group: 40; non-RRSO group: 51). Overall, total spine, and hip BMD decreased significantly from baseline to 12 months after RRSO (estimated percent change -3.78%, 95% CI -6.13% to -1.43% for total spine; -2.96%, 95% CI -4.79% to -1.14% for total hip) and at 36 months (estimated percent change -5.71%, 95% CI -8.64% to -2.77% for total spine; -5.19%, 95% CI -7.50% to -2.87% for total hip. In contrast, total spine and hip BMD were not significantly different from baseline for the non-RRSO group. The differences in mean percent change in BMD from baseline between the RRSO and non-RRSO groups were statistically significant at both 12 and 36 months for spine BMD (12-month difference -4.49%, 95% CI -7.67% to -1.31%; 36-month difference -7.06%, 95% CI -11.01% to -3.11%) and at 36 months for total hip BMD (12-month difference -1.83%, 95% CI -4.23% to 0.56%; 36-month difference -5.14%, 95% CI -8.11% to -2.16%). Across the study periods, hormone use was associated with significantly less bone loss at both the spine and hip within the RRSO group compared with no hormone use ( P <.001 at both 12 months and 36 months) but did not completely prevent bone loss (estimated percent change from baseline at 36 months -2.79%, 95% CI -5.08% to -0.51% for total spine BMD; -3.93%, 95% CI -7.27% to -0.59% for total hip BMD). CONCLUSION: Women with pathogenic variants in BRCA1 /2 who undergo RRSO before the age of 50 years have greater bone loss after surgery that is clinically significant when compared with those who retain their ovaries. Hormone use mitigates, but does not eliminate, bone loss after RRSO. These results suggest that women who undergo RRSO may benefit from routine screening for BMD changes to identify opportunities for prevention and treatment of bone loss. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov , NCT01948609.
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Neoplasias da Mama , Neoplasias Ovarianas , Feminino , Humanos , Densidade Óssea , Proteína BRCA1 , Proteína BRCA2 , Genes BRCA1 , Genes BRCA2 , Mutação , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/prevenção & controle , Ovariectomia/métodos , Estudos Prospectivos , Salpingo-Ooforectomia/métodos , Adulto , Pessoa de Meia-IdadeRESUMO
AIMS: Mutations and epimutations in genes encoding the succinate dehydrogenase complex (SDHx) are associated with multiple tumour types in which identification of SDH-deficiency has significant management implications. Immunohistochemistry (IHC) for the succinate dehydrogenase B (SDHB) subunit can help to detect SDH-deficiency, which manifests as complete loss of staining in tumour cells. However, a subset of SDH-deficient tumours can show aberrant cytoplasmic SDHB-IHC staining patterns and be misinterpreted as 'retained', a diagnostic pitfall complicating interpretation. Herein, we characterise in detail aberrant SDHB-IHC staining patterns in SDH-deficient tumours. METHODS AND RESULTS: We identified 23 tumours from patients with known germline SDHx and/or molecularly confirmed SDHx pathogenic/likely-pathogenic variants in their tumour. Of these, eight (35%) showed significant SDHB-IHC staining: one SDHA-, one SDHB-, three SDHC- and three SDHD-mutated cases. In all eight cases, closer inspection revealed differences in intensity and intracellular distribution of SDHB-IHC staining in tumour cells compared to adjacent non-neoplastic cells: non-neoplastic cells showed intense cytoplasmic coarse granular staining; tumour cells in seven of eight cases showed weak to focally strong, cytoplasmic blush to fine granular staining, in > 80% of cells. The remaining case in the initial block showed variably strong non-granular cytoplasmic staining with globular perinuclear accentuation throughout, only subtly distinct from the staining pattern of non-neoplastic cells. SDHB-IHC performed on two additional blocks in this latter case revealed significant intratumoral heterogeneity, including convincing areas of complete loss. CONCLUSIONS: When evaluating SDHB-IHC, care should be taken to distinguish true retained expression from aberrant cytoplasmic expression, which may be difficult to appreciate. Sometimes this may require additional molecular testing.
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Neoplasias , Paraganglioma , Mutação em Linhagem Germinativa , Humanos , Imuno-Histoquímica , Mutação , Paraganglioma/diagnóstico , Paraganglioma/genética , Coloração e Rotulagem , Succinato Desidrogenase/genética , Succinato Desidrogenase/metabolismoRESUMO
The NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic focus primarily on assessment of pathogenic or likely pathogenic variants associated with increased risk of breast, ovarian, and pancreatic cancer and recommended approaches to genetic testing/counseling and management strategies in individuals with these pathogenic or likely pathogenic variants. This manuscript focuses on cancer risk and risk management for BRCA-related breast/ovarian cancer syndrome and Li-Fraumeni syndrome. Carriers of a BRCA1/2 pathogenic or likely pathogenic variant have an excessive risk for both breast and ovarian cancer that warrants consideration of more intensive screening and preventive strategies. There is also evidence that risks of prostate cancer and pancreatic cancer are elevated in these carriers. Li-Fraumeni syndrome is a highly penetrant cancer syndrome associated with a high lifetime risk for cancer, including soft tissue sarcomas, osteosarcomas, premenopausal breast cancer, colon cancer, gastric cancer, adrenocortical carcinoma, and brain tumors.
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Neoplasias da Mama , Neoplasias Ovarianas , Neoplasias Pancreáticas , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/genética , Feminino , Genes BRCA1 , Genes BRCA2 , Aconselhamento Genético , Predisposição Genética para Doença , Testes Genéticos , Humanos , Masculino , Mutação , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/genética , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/genéticaRESUMO
The NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic provide recommendations for genetic testing and counseling for hereditary cancer syndromes, and risk management recommendations for patients who are diagnosed with syndromes associated with an increased risk of these cancers. The NCCN panel meets at least annually to review comments, examine relevant new data, and reevaluate and update recommendations. These NCCN Guidelines Insights summarize the panel's discussion and most recent recommendations regarding criteria for high-penetrance genes associated with breast and ovarian cancer beyond BRCA1/2, pancreas screening and genes associated with pancreatic cancer, genetic testing for the purpose of systemic therapy decision-making, and testing for people with Ashkenazi Jewish ancestry.
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Síndromes Neoplásicas Hereditárias/diagnóstico , Síndromes Neoplásicas Hereditárias/genética , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/genética , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/genética , Biomarcadores Tumorais , Feminino , Estudos de Associação Genética , Aconselhamento Genético , Predisposição Genética para Doença , Testes Genéticos , Humanos , Síndromes Neoplásicas Hereditárias/terapia , Penetrância , Neoplasias PancreáticasRESUMO
Hereditary leiomyomatosis and renal cell carcinoma syndrome (HLRCC), caused by a germline mutation in the fumarate hydratase (FH) gene, predisposes patients to uterine and cutaneous smooth muscle tumors and an aggressive type of renal cell carcinoma. Almost all women with HLRCC develop symptomatic uterine leiomyomas resulting in surgery at young ages, presenting an ideal opportunity for early detection of these patients and the implementation of surveillance measures for renal cell carcinoma. FH-deficient uterine leiomyomas can show characteristic morphologic features (FH-d morphology) that have been previously described. Immunohistochemistry (IHC) for FH can also be helpful in detecting FH deficiency in leiomyomas, which manifests as complete loss of staining for FH. However, the distribution and topography of FH-d morphology and FH loss by IHC in the context of multiple leiomyomas in patients with HLRCC has not been evaluated. The aim of this study is to describe in detail the clinical and pathologic characteristics of uterine leiomyomas from women with HLRCC. Six patients with proven FH germline mutations were included. All available slides were reviewed and FH IHC staining was performed on multiple blocks when possible. Clinical data were extracted from online medical records. All 6 patients presented with symptomatic uterine fibroids and underwent myomectomy (age 24 to 36 y), followed by hysterectomy in 2 patients (age 31 and 40 y). Specimens showed conventional leiomyomas, cellular leiomyomas and leiomyomas with bizarre nuclei. FH-d morphology was present in leiomyomas from all patients and was typically observed as a diffuse finding in the majority of slides across different leiomyoma types. FH-d morphology was absent in some leiomyoma sections from one patient and the morphologic features were focal and subtle in leiomyomas from 2 patients. Both hysterectomy specimens were also notable for showing scattered irregular tongues and nodules of smooth muscle proliferation (leiomyomatosis-like) in the background myometrium. Immunohistochemical staining of multiple slides per patient for FH showed either retained staining in all sections (2/6 cases), loss of staining in all sections (1 case) or variable staining across different leiomyomas (3 cases). In conclusion, patients with HLRCC undergo surgery at young ages for highly symptomatic uterine leiomyomas. FH-d morphology is usually a diffuse and well developed finding across different leiomyomas but may be absent or focal and subtle. FH IHC can show variable results and presence of retained FH staining should not be used to exclude the possibility of HLRCC. Referral for genetic counselling and testing should be considered in a young patient with uterine leiomyomas showing FH-d morphology even if immunohistochemical staining for FH is retained.
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Fumarato Hidratase/biossíntese , Leiomiomatose/metabolismo , Leiomiomatose/patologia , Síndromes Neoplásicas Hereditárias/metabolismo , Síndromes Neoplásicas Hereditárias/patologia , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Neoplasias Uterinas/metabolismo , Neoplasias Uterinas/patologia , Útero/metabolismo , Útero/patologia , Adulto , Feminino , Fumarato Hidratase/análise , Fumarato Hidratase/deficiência , Humanos , Histerectomia , Imuno-Histoquímica , Erros Inatos do Metabolismo , Hipotonia Muscular , Transtornos Psicomotores , Miomectomia UterinaRESUMO
Pathology-based screening of uterine smooth muscle tumors (uSMT) for morphology suggestive of fumarate hydratase deficiency (FH-d morphology) has been proposed as a method to identify women at increased risk for hereditary leiomyomatosis renal cell carcinoma (HLRCC) syndrome. For 5 years our clinical diagnostic practice has evaluated all women with any type of uSMT for FH-d morphology (defined, at low magnification, as staghorn shaped blood vessels and alveolar pattern edema and, at high magnification, as tumor macronucleoli surrounded by a halo and cytoplasmic eosinophilic globules) and, when present, used the pathology report to advise genetic counseling to further evaluate for HLRCC syndrome. We now report the results of this prospective screening strategy, with emphasis on the incidence and clinicopathologic features of FH-d morphology in uSMT, the rate of patient uptake of referral to genetic counseling, and the results of genetic testing for FH germline mutation. Among 2060 women with a uSMT, FH-d morphology was reported in 1.4% (30 women). Ten women elected to undergo FH genetic testing and 6 of 10 (60%) had a FH germline mutation: 5 were pathogenic mutations and 1 was a mutation variant of unknown significance. Therefore, the screening program led to a confirmed genetic diagnosis of HLRCC syndrome in 0.24% of all women with any type of uSMT. The women with a pathogenic mutation were ages 24 to 40 years. Although the majority of leiomyoma with bizarre nuclei exhibited FH-d morphology, the uSMT were conventional leiomyomas with FH-d morphology in 2 of 5 women found to have a pathogenic FH germline mutation. Relying on an abnormal FH immunostain result to trigger genetic counseling referral would have resulted in 2 of 5 (40%) cases with pathogenic FH germline mutation but normal FH immunoexpression going undetected, both of which were missense type mutations. There was no difference in the incidence of pathogenic FH germline mutation between FH-d morphology uSMT with an abnormal versus a normal FH immunostain result. Overall, this study demonstrates that prospective morphology-based screening, integrated with referral for genetic counseling, can result in the diagnosis of HLRCC syndrome in otherwise unselected women with uSMT. We conclude that this strategy should be incorporated in the routine pathologic examination of all uterine smooth muscle tumors.
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Biomarcadores Tumorais/genética , Análise Mutacional de DNA , Fumarato Hidratase/genética , Aconselhamento Genético , Mutação em Linhagem Germinativa , Leiomiomatose/genética , Síndromes Neoplásicas Hereditárias/genética , Neoplasias Cutâneas/genética , Neoplasias Uterinas/genética , Adulto , Idoso , Biópsia , Feminino , Predisposição Genética para Doença , Hereditariedade , Humanos , Leiomiomatose/enzimologia , Leiomiomatose/patologia , Leiomiomatose/terapia , Pessoa de Meia-Idade , Síndromes Neoplásicas Hereditárias/enzimologia , Síndromes Neoplásicas Hereditárias/patologia , Síndromes Neoplásicas Hereditárias/terapia , Aceitação pelo Paciente de Cuidados de Saúde , Linhagem , Fenótipo , Valor Preditivo dos Testes , Prognóstico , Estudos Prospectivos , Encaminhamento e Consulta , São Francisco , Neoplasias Cutâneas/enzimologia , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/terapia , Fatores de Tempo , Neoplasias Uterinas/enzimologia , Neoplasias Uterinas/patologia , Neoplasias Uterinas/terapia , Adulto JovemRESUMO
OBJECTIVE: We sought to characterize referral patterns for genetic counseling for women with ovarian cancer and hypothesized that differences in referral and testing rates are shaped by socioeconomic factors. METHODS: Patients were identified by pathology reports from August 2012 to January 2016 containing the words "serous" or "ovarian." Patient information was obtained via electronic medical record. Primary outcomes were placement of a genetics referral and completion of counseling. A secondary outcome was completion of genetic testing. RESULTS: We identified 246 women with a diagnosis of ovarian cancer. Ten were previously counseled and excluded. 53% of patients were referred for counseling with mean time from diagnosis to counseling of 4.6months. Age and family history were not associated with referral, however rates differed by race with 61% of Caucasian and 40%, 38% and 33% of Asian, Latina and Black women, respectively, referred (p=0.035). Overall, 36% of patients diagnosed underwent counseling, and 33% were tested. English language (p<0.0001), high-grade serous histology (p=<0.0001) and private or Medicare insurance (p<0.0001) were significantly associated with referral. CONCLUSION: We have not yet reached the Society of Gynecologic Oncology recommendation for referral to genetics. Women of color and those with public insurance have lower referral rates. This disparity in care impacts cancer treatment options and prevents appropriate screening for other hereditary malignancies. To provide comprehensive oncology care, including genetic assessment, we recommend focusing on these barriers including improving outreach and interpreter services.
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Testes Genéticos/estatística & dados numéricos , Neoplasias Ovarianas/etnologia , Neoplasias Ovarianas/genética , Povo Asiático/genética , Povo Asiático/estatística & dados numéricos , População Negra/genética , População Negra/estatística & dados numéricos , Feminino , Testes Genéticos/normas , Disparidades em Assistência à Saúde , Hispânico ou Latino/genética , Hispânico ou Latino/estatística & dados numéricos , Humanos , Pessoa de Meia-Idade , Neoplasias Ovarianas/economia , Encaminhamento e Consulta/estatística & dados numéricos , Estudos Retrospectivos , Programa de SEER , Estados Unidos/epidemiologia , População Branca/genética , População Branca/estatística & dados numéricosRESUMO
OBJECTIVES: To characterize the post-operative care of BRCA1 and BRCA2 mutation carriers who undergo risk-reducing salpingo-oophorectomy (RRSO). METHODS: BRCA1 and BRCA2 mutation carriers from our Cancer Risk Program who elected RRSO were sent questionnaires regarding their post-surgical surveillance and treatment for menopause symptoms, primary peritoneal cancer and bone loss. RESULTS: In 51 mutation carriers who were surveyed a median of 6 years after RRSO, 24 (47%) received dual-energy X-ray absorptiometry (DXA) testing, yearly CA-125 serum testing and yearly pelvic examination. Three women received none of these examinations in follow-up. Respondents reported an average of 3.5 menopausal symptoms (range 0-9). The mean number of menopausal symptoms reported by respondents using HRT was 2.8, compared to 3.9 symptoms reported by women not using HRT (p=0.06). Six of 10 (60%) subjects who reported no history of DXA bone scan, and 10 of 15 (67%) subjects who reported no post-surgical CA-125 serum monitoring noted that their physicians "did not recommend" testing. Two out of six symptomatic women who were younger than 50 (33%) who had no other contraindication to the use of HRT reported their non-use was because their care providers "advised against" HRT use. CONCLUSION: We believe that the lack of post-RRSO health care guidelines has resulted in inconsistent care for this cohort of patients. We proposed that national guidelines be developed to standardize care with the goal of optimizing long term survival in this unique cohort of young cancer previvors.
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Tubas Uterinas/cirurgia , Genes BRCA1 , Genes BRCA2 , Heterozigoto , Mutação , Neoplasias Ovarianas/prevenção & controle , Ovariectomia , Adulto , Idoso , Densidade Óssea , Antígeno Ca-125/sangue , Terapia de Reposição de Estrogênios , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , SobreviventesRESUMO
Genetic counseling and testing for heritable susceptibility to breast cancer caused by mutations in BRCA genes are largely unavailable to underserved women in the United States. Starting in 2002 the UCSF Cancer Risk Program offered this service free of charge to poor and medically indigent women at San Francisco General Hospital (SFGH). One recruitment strategy was a single-page questionnaire in four languages administered to women waiting for mammograms at SFGH. This report analyzes our first 3 years of experience with the recruitment questionnaire and compares the patient demographics and BRCA test results at SFGH with a more typical population undergoing genetic counseling and testing at UCSF's Mt. Zion Hospital (MZH). To our knowledge this is the first comprehensive clinical service for hereditary breast cancer in a U.S. public hospital. The ethnic mix of all 350 patients counseled was Caucasian 49% (approximately 20% of Caucasians reported Ashkenazi Jewish ancestry), Latina, 26%; African American, 13%; and Asian/other, 12%. Compared to the MZH population, SFGH patients were more ethnically diverse, less educated and more likely to be unemployed. Of 72 patients tested for BRCA mutations, 51 (71%) were negative, 5 were BRCA1 positive, and 12 were BRCA2 positive. Four (1 Caucasian, 1 Latina, 2 African American) had a total of 13 BRCA variants of unknown significance (VUS). The ratio of BRCA1/BRCA2 positive SFGH patients (5/12) was reversed compared to MZH (119/91). We evaluated 4573 recruitment questionnaires and 280 (6%) were judged to represent a high risk of heritable cancer. After additional screening and referral negotiation, 74 were scheduled for counseling. We judged the recruitment questionnaire to be a feasible, efficient, and reasonably cost-effective way to identify women at high risk of hereditary cancer in a traditionally underserved population. Underserved populations present special challenges for genetic counselors because of large, geographically dispersed families, cultural taboos about cancer diagnoses, and social marginalization. Despite these complexities, the clinical service at SFGH has been well accepted by patients and staff. Our successful venture can serve as a model for other public hospitals contemplating this clinical service.