Bridging the gap with an ileocolonic graft after extensive colorectal resections.

BACKGROUND: Ileocecal interposition (ICI) for first-line reconstruction after low anterior colorectal resection was introduced by von Flüe and Harder in 1994 (Dis Colon Rectum 37:1160-1162, 1994). We report our experience using this technique to bridge colonic gaps after significant loss of bowel length. PATIENTS AND METHODS: Between 1999 and 2009 the left-sided colon was too short for traditional isoperistaltic reconstruction in six patients treated in our hospital. Reasons for extensive bowel loss were a deficient (n = 3) or torn (n = 1) marginal artery with ischemia or repeat colorectal resections (n = 2). An ICI was done to bridge the gap and enable restoration of intestinal continuity. RESULTS: No patient died. Whenever performing a coloanal anastomosis (4/6) a loop ileostomy was raised. One patient with colonic diversion experienced graft-related complications: ischemic colitis of the interposed colonic segment, anastomotic stenosis, and a presacral sinus were observed and managed nonoperatively. Subsequent closure of the stoma was possible in all cases. A median Vaizey incontinence score of 9 (range: 4-14) was recorded in the patient with coloanal anastomosis. The average number of bowel movements per day was 1.5 (range: 0.5-6). CONCLUSIONS: When the descending colon does not reach the rectal stump or anal canal in reoperative cases or after vascular complication, ICI is a useful salvage procedure resulting in good bowel function.

Breast cancer risks in individuals testing negative for a known family mutation in BRCA1 or BRCA2.

Genetic testing for BRCA1 and BRCA2 mutations in family members of individuals with known deleterious mutations can distinguish between patients at high risk of disease and those who are not. Some studies have suggested that individuals testing negative for known familial mutations (true negatives), may still have a higher risk of breast cancer (BC) than the general population. We have examined a prospectively followed cohort of true negative women in the US. Subjects were close relatives of known BRCA1 and BRCA2 mutation carriers who had undergone genetic testing, were negative for the known familial mutation, and were unaffected at the time of genetic testing. Standardized incidence ratios (SIR) and 95% confidence intervals (CI) were calculated using SEER incidence rates. Among 375 true negatives, two invasive and two in situ BC and no ovarian cancers were diagnosed with mean follow up of 4.9 years (total of 1,962 person years).Four invasive BC were expected, whereas two were observed, for an age-adjusted SIR of 0.52 (95% CI 0.13-2.09). We observed more cases of in situ BC (n = 2) than were expected (n = 0.9; SIR = 2.30; 95% CI 0.57-9.19).There were no cases of ovarian cancer observed; 0.4 case was expected. In this prospective study of women who were unaffected at the time of genetic testing and who were negative for the known familial mutation in BRCA1/2, no excess risk of invasive BC was observed. Our data suggest that such women in the US should adhere to population based guidelines for breast cancer screening.

Prospective study of breast MRI in BRCA1 and BRCA2 mutation carriers: effect of mutation status on cancer incidence.

Annual MRI screening is recommended as an adjunct to mammography for BRCA1 and BRCA2 mutation carriers. Prophylactic oophorectomy has been shown to decrease breast cancer risk in BRCA1/2 mutation carriers. Here, we aimed to examine the combined effects of MRI and oophorectomy. For this purpose, 93 BRCA1/2 mutation carriers were screened with yearly mammograms and yearly MRI scans. Study endpoints were defined as date of breast cancer diagnosis, date of prophylactic mastectomy, or date of most recent contact. Of 93 women, with a median age of 47, 80 (86%) had prophylactic oophorectomy. Fifty-one women (55%) had BRCA1 mutations. A total of 283 MRI scans were performed. Eleven breast cancers (9 invasive, 2 ductal carcinoma in situ) were detected in 93 women (12%) with a median follow-up of 3.2 years (incidence 40 per 1,000 person-years). Six cancers were first detected on MRI, three were first detected by mammogram, and two were "interval cancers." All breast cancers occurred in BRCA1 mutation carriers (incidence 67 per 1,000 person-years). Apart from BRCA1 vs. BRCA2 mutation status, there were no other significant predictors of breast cancer incidence. Most invasive breast cancers were estrogen receptor negative (7 of 9) and lymph node negative (7 of 9). There have been no systemic recurrences with a median follow-up of 19 months after cancer diagnosis. Finally, it was concluded that all breast cancers occurred in BRCA1 mutation carriers, in most cases despite oophorectomy. These data suggest that surveillance and prevention strategies may have different outcomes in BRCA1 and BRCA2 mutation carriers.

Anticipated versus actual emotional reactions to disclosure of results of genetic tests for cancer susceptibility: findings from p53 and BRCA1 testing programs.

PURPOSE: We examined the ability of individuals undergoing genetic testing for cancer susceptibility in two structured research protocols to accurately anticipate emotional reactions to disclosure of their test result. We explored whether accuracy of emotional anticipation was associated with postdisclosure psychologic adjustment. METHODS: Data from 65 individuals were analyzed; 24 members of Li-Fraumeni cancer syndrome families were tested for p53 mutations (all 24 were unaffected), and 41 subjects with hereditary breast-ovarian cancer susceptibility were tested for BRCA1 mutations (34 were unaffected and seven were affected). Subjects were from families in which a germline mutation had been previously identified. At the pretest session, subjects rated the extent to which they anticipated feeling each of six emotional states (relief, happiness, sadness, guilt, anger, and worry) after disclosure that they did or did not carry the familial mutation. After receiving their test result, they rated their feelings on the same scale of emotions for the appropriate condition. Extent of accuracy and association with psychologic distress at 6 months, as assessed with standardized measures, were evaluated. RESULTS: Overall, mean levels of emotional reactions after receiving test results were not different from those anticipated before result disclosure. However, affected BRCA1 carriers experienced higher levels of anger and worry than they had anticipated. Underestimation of subsequent distress emotions related to test result was associated with a significant increase in general psychologic distress at 6 months. CONCLUSION: Unaffected individuals in cancer-predisposition testing programs are generally accurate in anticipating emotional reactions to test results. However, cancer patients may underestimate their distress after disclosure of positive results and could benefit from intervention strategies.

Factors associated with decisions about clinical BRCA1/2 testing.

Testing for mutations in BRCA1 and BRCA2 can provide important information about breast and ovarian cancer risk to a small but identifiable subgroup of women. Women who test positive for a BRCA1/2 mutation can pursue more aggressive cancer surveillance and prevention regimens. Among families with known mutations, women who test negative may avoid unnecessary interventions. Currently, little is known about the factors associated with the use of clinical BRCA1/2 testing. The objective of this study was to determine the factors associated with decisions about clinical BRCA1/2 testing among women undergoing clinical BRCA1/2 counseling through a retrospective cohort study of women who participated in a university-based clinic offering breast cancer risk assessment, genetic counseling, and BRCA1/2 testing between January 1996 and April 1998. From the 251 eligible women who responded to a follow-up survey, 125 (50%) had undergone or were undergoing BRCA1/2 testing, 86 (34%) had decided not to undergo testing, and 40 (16%) were undecided about testing. After multivariate adjustment, we found that women who chose to undergo BRCA1/2 testing were more likely to have a known familial mutation [odds ratio (OR), 7.46; 95% confidence interval (CI), 0.97-62.16], more likely to be Ashkenazi Jewish (OR, 6.37; 95% CI, 2.68-15.12), more likely to want cancer risk information for family members (OR, 1.93; 95% CI, 0.99-4.14), more likely to want information about ovarian cancer risk (OR, 1.69; 95% CI, 1.18-3.69), and less likely to be concerned about insurance or job discrimination (OR, 0.45; 95% CI, 0.21-0.94). These associations were also found in the subgroup of women with a predicted probability of a BRCA1 mutation of 25%. Our study suggests that approximately half of eligible women choose to undergo clinical BRCA1/2 testing after participating in counseling. Women who have the highest risk of carrying a mutation, and thus the greatest probability of gaining some useful information from the test results, are most likely to undergo testing. Women who undergo testing are also more interested in ovarian cancer risk information and less concerned about job and insurance discrimination.

Comprehensive 4-year follow-up on a case of maternal heterodisomy for chromosome 16.

Uniparental disomy for chromosome 16 has been previously identified in fetal deaths and newborn infants with limited follow-up. Thus there is a lack of information about the long-term effects of maternal uniparental disomy 16 on growth and development. We present a case of maternal heterodisomy for chromosome 16 and a comprehensive 4-year physical and cognitive evaluation. Cytogenetic analysis of chorionic villus obtained at 10 weeks gestation for advanced maternal age showed trisomy 16. At 15 weeks, amniocentesis demonstrated low level mosaicism 47,XY,+16[1]/46,XY[25]. Decreased fetal growth was noted in the last 2 months of pregnancy and the infant was small for gestational age at birth. Molecular studies revealed only maternal alleles for chromosome 16 in a peripheral blood sample from the child, consistent with maternal uniparental heterodisomy 16. Although short stature remains a concern, there appears to be no major cognitive effects of maternal disomy 16. Clinical evaluation and follow-up on additional cases should further clarify the role of placental mosaicism and maternal disomy 16 in intrauterine growth retardation and its effects on long-term growth in childhood.

Role of the genetic counselor in familial cancer.

Increased knowledge about inherited susceptibility for cancer and the identification of genes associated with cancer risk has increased the need for individuals with training in genetics to work closely with oncology professionals in the familial cancer arena. Genetic counselors can provide a variety of useful services: They may function as clinical coordinators of a family cancer risk counseling (FCRC) program and serve as study coordinatiors on research teams. In the oncology practice setting, genetic counselors who are trained to do cancer risk counseling can help ascertain and evaluate familial clusters of cancers. In the context of FCRC, the genetic counselor can educate family members about risk factors for cancer and the significance of a positive family history, assess psychosocial functioning and provide psychosocial support and referrals. Genetic susceptibility testing should be offered only with appropriate genetic counseling.

Characterization of two novel BRCA1 germ-line mutations involving splice donor sites.

Deleterious BRCA1 mutations have significant clinical implications for the patients that carry them. Point mutations in critical functional domains and frameshift mutations that lead to early termination of protein translation are associated with a 60-80% risk of breast cancer and a 20-40% risk of ovarian cancer. In contrast, the significance of mutations located in intronic regions of BRCA1, even in the setting of a family history of breast and ovarian cancer, is not always clear. Some of these mutations occur in splice donor/acceptor consensus sites. These mutations can affect heteronuclear RNA (hnRNA) processing, leading to the loss of functional BRCA1 protein and thus may be disease-associated. However, it is important to verify the effect of these mutations, because splicing alterations cannot be predicted from genomic sequence alone. We report here the characterization of two novel BRCA1 mutations identified in families seen in our cancer risk evaluation clinic that alter splice donor sites of BRCA1. We show that both mutations alter transcript splicing and result in truncated BRCA1. IVS17 + 1G --> T leads to inclusion of part of intron 17 after the coding sequence of exon 17, resulting in early termination of BRCA1 protein following codon 1692. 252del5insT abolishes the splice donor site in exon 3, leading to the skipping of exon 5 and BRCA1 protein truncation following codon 45. Thus, both mutations result in loss of BRCA1 function, and carriers of these mutations should be counseled in the same manner as carriers of other truncating BRCA1 mutations.

Is penile atherosclerosis the link between erectile dysfunction and cardiovascular risk? An autopsy study.

Erectile dysfunction (ED) is increasingly linked to coronary heart disease risk. Aim of this study was to test the hypothesis whether this association is due to penile atherosclerosis. We evaluated the prevalence and severity of penile atherosclerosis in relation to coronary and peripheral atherosclerosis. Between January and June 2010, a consecutive series of 31 men underwent an autopsy at the Department of Pathology at the Medical University Vienna. Atherosclerosis at the following localizations were histologically classified: right coronary artery, left coronary artery, left circumflex artery, internal iliac artery, dorsal penile artery and deep penile artery (bilateral). Coronary and peripheral atherosclerosis was present in 87.1 and 77.4% of cases. Atherosclerosis of penile arteries was detectable in only 4 men (12.9%). The only factor linked to penile atherosclerosis was diabetes (P=0.03). All other parameters as assessed according to medical history, general finding from autopsy or histological results regarding arterial lesions in general were not correlated to penile arterial lesions. In contrast to the high prevalence of atherosclerosis in general, penile arterial lesions are rarely present.

Non-cancer endpoints in BRCA1/2 carriers after risk-reducing salpingo-oophorectomy.

Risk-reducing salpingo-oophorectomy (RRSO) significantly reduces the risk of ovarian cancer and breast cancer in pre-menopausal women with BRCA1 and BRCA2 (B1/2) mutations. Despite its clear benefits, little is known about non-cancer endpoints in this population. Medical records were examined in 226 B1/2 mutation carriers, who had previously undergone RRSO with a focus on bone health as well as the frequency of hypertension, hyperlipidemia, coronary artery disease (CAD), myocardial infarction (MI), diabetes, hypothyroidism and depression. From the medical records, DEXA scans, medications and medical conditions were recorded. Of the 226 patient records examined, 16% (36/226) had hypertension, 17% (39/226) hyperlipidemia, 2% (5/226) CAD or MI, 2% (4/226) diabetes, 13% (29/226) hypothyroidism and 14% (31/226) depression. DEXA results were available in 152 women. Of those DEXA scans, 71% (108/152) were abnormal (57% osteopenia and 14% osteoporosis). Among women who underwent RRSO prior to age 50, 71% (62/88) had osteopenia/osteoporosis. Although there was no difference in osteopenia/osteoporosis in women with RRSO prior to age 50 compared to those RRSO > 50, the age at follow up in these two groups differs greatly (mean age 44.7 vs. 60.6), suggesting that both current age and age at RRSO contribute to bone health assessment. In summary, here, we report the prevalence of non-cancer endpoints in a cohort of B1/2 mutation carriers and note a particularly high rate of osteopenia and osteoporosis in B1/2 with breast cancer undergoing RRSO prior to 50. Despite the risk reduction RRSO offers, attention should be paid to non-cancer endpoints, particularly bone health, in this population.

Exercise lowers estrogen and progesterone levels in premenopausal women at high risk of breast cancer.

Experimental and clinical data support a role for estrogens in the development and growth of breast cancer, and lowered estrogen exposure reduces breast cancer recurrence and new diagnoses in high-risk women. There is varied evidence that increased physical activity is associated with breast cancer risk reduction in both pre- and postmenopausal women, perhaps via lowered estrogen levels. The purpose of this study was to assess whether exercise intervention in premenopausal women at increased breast cancer risk reduces estrogen or progesterone levels. Seven healthy premenopausal women at high risk for breast cancer completed a seven-menstrual-cycle study. The study began with two preintervention cycles of baseline measurement of hormone levels via daily first-morning urine collection, allowing calculation of average area under the curve (AUC) hormone exposure across the menstrual cycle. Participants then began five cycles of exercise training to a maintenance level of 300 min per week at 80-85% of maximal aerobic capacity. During the last two exercise cycles, urinary estradiol and progesterone levels were again measured daily. Total estrogen exposure declined by 18.9% and total progesterone exposure by 23.7%. The declines were mostly due to decreased luteal phase levels, although menstrual cycle and luteal phase lengths were unchanged. The study demonstrated the feasibility of daily urine samples and AUC measurement to assess hormone exposure in experimental studies of the impact of interventions on ovarian hormones. The results suggest value in exercise interventions to reduce hormone levels in high-risk women with few side effects and the potential for incremental benefits to surgical or pharmacologic interventions.

Effect of genetic counseling and testing for BRCA1 and BRCA2 mutations in African American women: a randomized trial.

BACKGROUND: Limited empirical data are available on the effects of genetic counseling and testing among African American women. OBJECTIVE: To evaluate the effects of genetic counseling and testing in African American women based on different levels of exposure: (a) women who were randomized to culturally tailored (CTGC) and standard genetic counseling (SGC) to women who declined randomization (non-randomized group), (b) participants and non-participants in genetic counseling, and (c) BRCA1 and BRCA2 (BRCA1/2) test result acceptors and decliners. DESIGN: Randomized trial of genetic counseling conducted from February 2003 to November 2006. MEASURES: We evaluated changes in perceived risk of developing breast cancer and cancer worry. RESULTS: Women randomized to CTGC and SGC did not differ in terms of changes in risk perception and cancer worry compared to decliners. However, counseling participants had a significantly greater likelihood of reporting reductions in perceived risk compared to non-participants (p = 0.03). Test result acceptors also had a significantly greater likelihood of reporting decreases in cancer worry (p = 0.03). However, having a cancer history (p = 0.03) and a BRCA1/2 prior probability (p = 0.04) were associated with increases in cancer worry. CONCLUSIONS: Although CTGC did not lead to significant improvements in perceived risk or psychological functioning, African American women may benefit from genetic counseling and testing. Continued efforts should be made to increase access to genetic counseling and testing among African American women at increased risk for hereditary disease. But, follow-up support may be needed for women who have a personal history of cancer and those with a greater prior probability of having a BRCA1/2 mutation.

Use of total abdominal hysterectomy and hormone replacement therapy in BRCA1 and BRCA2 mutation carriers undergoing risk-reducing salpingo-oophorectomy.

INTRODUCTION: Risk-reducing salpingo-oophorectomy (RRSO) reduces the risk of developing ovarian and breast cancer in BRCA 1 and BRCA 2 (BRCA1/2) mutation carriers. The short-term use of hormone replacement therapy (HRT) after RRSO may relieve menopausal symptoms and does not appear to affect the breast cancer risk reduction gained by RRSO. Multiple factors may influence decisions regarding whether or not total abdominal hysterectomy (TAH) is done at the time of RRSO, whether HRT is elected after surgery, and if so, which type of HRT is selected. Our investigation has been to examine factors associated with TAH and HRT use and to determine if the choice of TAH at the time of RRSO and the type of HRT that was chosen has changed since the report of data from the Women's Health Initiative (WHI) in 2002, which showed that the relative risk for breast cancer is higher in subjects who used combined estrogen-progestin HRT compared with those who used estrogen alone. METHODS: We identified 73 female BRCA1/2 mutation carriers who were known to have undergone RRSO between 1/1972 and 11/2005 who had no history of breast or ovarian cancer at the time of the surgery. Information regarding whether or not TAH was done in addition to RRSO, the type of HRT, and the subsequent diagnosis of breast cancer was collected. RESULTS: Of 73 unaffected BRCA1/2 carriers known to have had RRSO, 40 (40/73, 55%) also underwent TAH. Thirty-three of 73 (33/73, 45%) began HRT following RRSO. Of 33 HRT users, 17 (17/33, 52%) used estrogen only and 14 (14/33, 42%) used combined hormonal therapy. There was no difference in use of HRT in women with TAH (17/40, 43%) vs. those without (16/33, 48%) (P = 0.6). There was no difference in the proportion of women who underwent TAH before and after the WHI report in 2002. Use of HRT, most notably combined estrogen-progestin HRT, appears to have declined since 2002, although this result did not reach statistical significance. CONCLUSION: In this single institution study, the majority of BRCA1/2 mutation carriers undergoing RRSO also underwent TAH, and a substantial number took HRT. TAH did not increase the likelihood of taking HRT compared to RRSO alone.

Genetic counseling and clinical cancer genetics services.

Cancer genetic services, typically provided by clinicians with expertise in both oncology and genetics, include cancer risk assessment and education, facilitation of genetic testing, pre-and post-test counseling, provision of personally tailored cancer risk management options and recommendations, and psychosocial counseling and support services. All oncology providers should obtain basic information on the family cancer history of their patients to determine the likelihood of hereditary cancer risk as well as possible indications for providing brief or comprehensive cancer genetic counseling. Those who choose to provide these services themselves must be familiar with the complex issues of genetic counseling and testing, and be aware of the time and expertise required to adequately deliver these services. Genetic nurses and genetic counselors with master's degrees function as valuable members of a comprehensive cancer genetic service; they are trained to independently collect and confirm medical and family history information, perform risk assessments, offer patient education regarding cancer and genetics, and provide supportive counseling services for patients and families. It is hoped that specific risk interventions will significantly reduce morbidity and mortality from familial forms of cancer. This review outlines the process of cancer genetic counseling and defines the roles of the cancer genetic counselor and the function of the cancer genetics specialty clinic. The possible medical and legal implications for failing to obtain adequate family history information are reviewed, and the issues of genetic discrimination are discussed.

Establishing a cancer risk evaluation program.

PURPOSE: Presymptomatic genetic testing for cancer susceptibility is a new practice arena that raises many complex issues. This article presents one model of a cancer risk evaluation program that specifically addresses the unique issues associated with genetic testing for cancer risk. DESCRIPTION OF PROGRAM: The Cancer Risk Evaluation Program is designed to care for any individual concerned about his or her risk for cancer, offering predisposition genetic testing if appropriate. The program includes clinical and psychosocial assessment, education, cancer risk analysis, and genetic counseling; it offers long-term screening and surveillance and provides a forum for ongoing genetic and clinical research. RESULTS: Program evaluations from participants have shown that the program is successfully meeting the needs of the participants. This program also ensures that the University of Pennsylvania Cancer Center is delivering cancer genetic services consistent with the existing position statements on genetic testing for cancer susceptibility, which have included guidelines and indications for predisposition genetic testing and informed consent. CLINICAL IMPLICATIONS: Researchers anticipate a substantial demand for predisposition genetic testing for cancer susceptibility. However, not all individuals interested in testing are eligible or willing to undergo direct gene analysis because of the potential risks. Therefore, clinical programs must address the complex issues surrounding presymptomatic genetic testing and incorporate cancer risk assessment strategies. Additionally, healthcare providers in this new practice arena should be fully informed and current in the state of the knowledge regarding cancer risk assessment; predisposition genetic testing; and the ethical, legal, and social issues pertaining to cancer risk assessment and management.

Complexities in Cancer Risk Counseling: Presentation of Three Cases.

Complexities abound in the identification and management of families at increased risk for inherited forms of cancer. One of the ways to learn as a profession how best to provide cancer risk counseling (CRC) is to share counseling experiences. Such cases can provide insight into the issues raised by families and ways in which genetic counselors have handled complex situations. Here we describe three CRC cases initially presented at the 1995 American College of Medical Genetics meeting. The first case involves balancing the importance of informing a family of the presence of an inherited cancer syndrome with the family's right "not to know." The second case illustrates the difficulties in assisting an individual to make medical management decisions in the face of uncertain risk information. The third case describes the complex interactions with a woman before and after her decision to have prophylactic surgery.

Assessment and counseling for women with a family history of breast cancer. A guide for clinicians.

More women in all risk categories are seeking information regarding their individual breast cancer risk, and there is a need for their primary care clinicians to be able to assess familial risk factors for breast cancer, provide individualized risk information, and offer surveillance recommendations. Estimates of the number of women with a family history of breast cancer range from approximately 5% to 20%, depending on the population surveyed. Many of these women will not have a family history that suggests the presence of a highly penetrant breast cancer susceptibility gene. However, a small subset of such women will come from families with a striking incidence of breast and other cancers often associated with inherited mutations. The development and refinement of risk prediction models provide an epidemiologic basis for counseling women with a family history that does not appear related to a dominant susceptibility gene. contrast, the recent isolation of BRCA1, the localization of BRCA2, and the acknowledgement that additional breast cancer susceptibility genes must exist provide a molecular basis for counseling some high-risk women. We present a guide for primary care clinicians that may be helpful in defining families as moderate or high risk, in determining individual risk in women with a family history of breast cancer based on this distinction, and for counseling women in a setting where the data necessary to design surveillance and prevention strategies are lacking. We include criteria for selecting women who may be candidates for detection of inherited mutations in breast cancer susceptibility genes.

BRCA1 mutations in women attending clinics that evaluate the risk of breast cancer.

BACKGROUND: To define the incidence of BRCA1 mutations among patients seen in clinics that evaluate the risk of breast cancer, we analyzed DNA samples from women seen in this setting and constructed probability tables to provide estimates of the likelihood of finding a BRCA1 mutation in individual families. METHODS: Clinical information, family histories, and blood for DNA analysis were obtained from 263 women with breast cancer. Conformation-sensitive gel electrophoresis and DNA sequencing were used to identify BRCA1 mutations. RESULTS: BRCA1 mutations were identified in 16 percent of women with a family history of breast cancer. Only 7 percent of women from families with a history of breast cancer but not ovarian cancer had BRCA1 mutations. The rates were higher among women from families with a history of both breast and ovarian cancer. Among family members, an average age of less than 55 years at the diagnosis of breast cancer, the presence of ovarian cancer, the presence of breast and ovarian cancer in the same woman, and Ashkenazi Jewish ancestry were all associated with an increased risk of detecting a BRCA1 mutation. No association was found between the presence of bilateral breast cancer or the number of breast cancers in a family and the detection of a BRCA1 mutation, or between the position of the mutation in the BRCA1 gene and the presence of ovarian cancer in a family. CONCLUSIONS: Among women with breast cancer and a family history of the disease, the percentage with BRCA1 coding-region mutations is less than the 45 percent predicted by genetic-linkage analysis. These results suggest that even in a referral clinic specializing in screening women from high-risk families, the majority of tests for BRCA1 mutations will be negative and therefore uninformative.