Mutations In Breast Cancer Patients Research Articles

Screening of 185DelAG, 1014DelGT and 3889DelAG BRCA1 Mutations in Breast Cancer Patients from North-East India

Around 1.35 million people of worldwide suffer from breast cancer each year, whereas in India, 1 in every 17 women develops the disease. Mutations of the Breast Cancer 1 (BRCA1) gene account for the majority of breast/ ovarian cancer families. The purpose of study was to provide a prevalence of BRCA1 germline mutations in the North-East Indian population. In relation to the personal and family history with the breast cancer, we found mutations in 6.25% and 12.5% respectively. Three mutations, 185DelAG, 1014DelGT and 3889DelAG, were observed in our North-East Indian patients in exons 2 and 11, resulting in truncation of the BRCA1 protein by forming stop codons individually at amino acid positions 39, 303 and 1265. Our results point to a necessity for an extensive mutation screening study of high risk breast cancer cases in our North-East Indian population, which will provide better decisive medical and surgical preventive options.

Analysis of the Novel Fanconi Anemia GeneSLX4/FANCPin Familial Breast Cancer Cases

SLX4/FANCP is a recently discovered novel disease gene for Fanconi anemia (FA), a rare recessive disorder characterized by chromosomal instability and increased cancer susceptibility. Three of the 15 FA genes are breast cancer susceptibility genes in heterozygous mutation carriers--BRCA2, PALB2, and BRIP1. To investigate if defects in SLX4 also predispose to breast cancer, the gene was sequenced in a cohort of 729 BRCA1/BRCA2-negative familial breast cancer cases. We identified a single splice site mutation (c.2013+2T>A), which causes a frameshift by skipping of exon 8. We also identified 39 missense variants, four of which were selected for functional testing in a Mitomycin C-induced growth inhibition assay, and appeared indistinguishable from wild type. Although this is the first study that describes a truncating SLX4 mutation in breast cancer patients, our data indicate that germline mutations in SLX4 are very rare and are unlikely to make a significant contribution to familial breast cancer.

Recurrent BRCA1 and BRCA2 mutations in breast cancer patients of African ancestry

Recurrent mutations constituted nearly three quarters of all BRCA1 mutations and almost half of all BRCA2 mutations identified in the first cohort of the Nigerian Breast Cancer Study. To further characterize breast/ovarian cancer risks associated with BRCA1/BRCA2 mutations in the African diaspora, we genotyped recurrent mutations among Nigerian, African American, and Barbadian breast cancer patients. A replication cohort of 356 Nigerian breast cancer patients was genotyped for 12 recurrent BRCA1/2 mutant alleles (Y101X, 1742insG, 4241delTG, M1775R, 4359insC, C64Y, 1623delTTAAA, Q1090X, and 943ins10 from BRCA1, and 1538delAAGA, 2630del11, and 9045delGAAA from BRCA2) by means of SNaPshot followed by direct sequencing or by direct sequencing alone. In addition, 260 African Americans and 118 Barbadians were genotyped for six of the recurrent BRCA1 mutations by SNaPshot assay. Of all the BRCA1/2 recurrent mutations we identified in the first cohort, six were identified in 11 patients in the replication study. These mutation carriers constitute 3.1 % [95 % Confidence Interval (CI) 1.6-5.5 %] of the replication cohort. By comparison, 6.9 % (95 % CI 4.7-9.7 %) of the discovery cohort carried BRCA1/2 recurrent mutations. For the subset of recurrent mutations we tested in breast cancer cases from Barbados or the United States, only two 943ins10 carriers were identified in African Americans. Nigerian breast cancer patients from Ibadan carry a broad and unique spectrum of BRCA1/2 mutations. Our data suggest that BRCA1/2 mutation testing limited to recurrent mutations is not sufficient to understand the BRCA1/2-associated breast cancer risk in African populations in the diaspora. As the cost of Sanger sequencing is considerably reduced, deploying innovative technologies such as high throughput DNA sequencing of BRCA1/2 and other cancer susceptibility genes will be essential for identifying high-risk individuals and families to reduce the burden of aggressive early onset breast cancer in low-resource settings.

Abstract 3599: Expression and function of HFE in mammary gland iron homeostasis and its relevance to breast cancer

Abstract Emerging evidences on the role of iron-regulatory proteins in tumor growth provide new insights into the role of iron in cancer. Iron, though essential for normal cellular function, is toxic if present in excess. Hemochromatosis is an autosomal recessive disease of iron overload linked to mutations in HFE gene [Histocompatability leukocyte antigen class I-like protein involved in iron (FE) homeostasis]. HFE interacts with transferrin receptors, TfR1 and TfR2, and inhibits cellular iron uptake. The prevalence of the disease is very high with homozygosity incidence of ∼1 in 300 and heterozygosity incidence of ∼1 in 10. The disease manifests with liver cirrhosis/cancer, cardiomyopathy, diabetes, and arthritis. Several studies have shown increased prevalence of HFE mutations in breast cancer patients across all races. There is also evidence of increased levels of iron in breast cancer tissue. Although excessive iron and oxidative stress have been postulated to play a role in breast cancer, the expression/function of HFE in mammary gland iron homeostasis and how mutations in HFE affect breast cancer progression have not been studied directly. Here we demonstrate the expression of HFE mRNA in mouse mammary gland and primary mammary epithelial cells. The mRNA was absent in HFE-/- mice. Immunohistochemistry showed localization of HFE protein in luminal and myoepithelial cells. Similar staining was also seen in primary mammary epithelial cells from wild type mice but not from HFE-/- mice. We then examined the physiological role of HFE in mammary gland. Ferritin is a cytoplasmic protein involved in iron storage, and increase in intracellular iron levels results in increased level of ferritin. Recently, ferritin has also been shown to promote angiogenesis. Western blot and immunohistochemical analysis revealed that mammary tissue from HFE-/- mice had increased ferritin levels in an age-dependent manner. Thus, for the first time we show that HFE-/- mice have increased iron accumulation in the mammary gland. Immunostaining with antibody against 4-hydroxynonenal, one of the byproducts of lipid peroxidation, showed that HFE-/- mammary tissue have oxidative stress mediated by iron accumulation. MTT assay and thymidine incorporation showed that primary mammary epithelial cells from HFE-/- mice proliferate faster than the cells from HFE+/+ mice. Increase in histone deacetylase (HDAC) activity has been implicated in many cancers. We found that mammary tissue from HFE-/- mice has increased HDAC activity compared to wild type tissue. This shows that functional loss of HFE in mammary tissue can also promote cell cycle progression via epigenetic mechanisms. Based on these data, we hypothesize that tissue iron is an important modifier of breast cancer progression and that mutations in HFE (heterozygosity as well as homozygosity) may enhance the incidence and/or progression of breast cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3599. doi:1538-7445.AM2012-3599

Detection ofBRCA1/2mutations in breast cancer patients from Thailand and Pakistan

Detection of<i>BRCA1/2</i>mutations in breast cancer patients from Thailand and Pakistan

The R337H mutation in TP53 and breast cancer in Brazil

BackgroundGermline mutations in p53 are associated with the Li-Fraumeni Syndrome which is characterized by childhood cancers, including pediatric adrenal cortical carcinomas and early onset breast cancer. The high incidence of adrenal cortical carcinomas in southern Brazil is mostly attributed to the R337H mutation in TP53. The relatively high population frequency of this mutation in southern Brazil, along with the clustering of early onset breast cancer in Li-Frameni families, suggests this mutation may also be a low-penetrance breast cancer susceptibility polymorphism.MethodsWe undertook this study to evaluate the frequency of the R337H mutation in breast cancer patients from Rio de Janeiro, Brazil. R337H mutation status was determined in 390 unselected breast cases and 324 controls identified from clinics in Rio de Janeiro, Brazil using a PCR-based assay.ResultsTwo of the breast cancer cases (0.5%) and none of the controls carried the mutation. Both cases had an early age at diagnosis (< 40 years old) and a family history of breast and other cancers.ConclusionsThese data suggest genetic screening of young onset breast cancer patients should include testing for the R337H mutation.

Endocrine Metabolic Disorders in Patients with Breast Cancer, Carriers of BRCA1 Gene Mutations

Two groups of breast cancer patients (53±2 years) in clinical remission receiving no specific therapy were examined: group 1, with BRCA1 gene mutations (N=11) and group 2, without mutations of this kind (N=11). The two groups did not differ by insulinemia and glycemia, insulin resistance index, blood levels of thyrotropic hormone, sex hormone-binding globulin, insulin-like growth factor-1, triglycerides, or lipoproteins. In group 1, blood estradiol level was higher. Intensive glucose-induced generation of reactive oxygen species in these patients was associated with a decrease of cholesterolemia, of the C-peptide/insulin proportion, and a trend to higher urinary excretion of 4-hydroxyestrone, one of the most genotoxic catecholestrogens. BRCA1 gene mutations in breast cancer patients were associated with signs of estrogenization and a pro-genotoxic shift in the estrogen and glucose system, which could modulate the disease course and requires correction.

Common BRCA1 and BRCA2 mutations in breast cancer families: a meta-analysis from systematic review

A number of molecular epidemiological studies have been conducted the screening for BRCA1 and BRCA2 mutations in breast cancer patients with a positive family history of breast and/or ovarian cancer and reported many common mutations in BRCA1 and BRCA2 associated in breast cancer in different population and different ethnicity. However, it's still lack of a systematic analysis on these mutations. To comprehensively evaluate the frequency and distribution of common BRCA1 and BRCA2 mutations which associated with breast cancer risk, we address this issue through system review and meta-analysis on 29 relevant published studies by conducting a literature search on PubMed and CNKI. 20 common founder germline mutations were identified from all 29 studies and 4 of BRCA1 (5382insC, 185delAG, 3819del5 and 4153delA) and 2 of BRCA2 (4075delGT, 5802del4) mutations were repeatedly reported twice or more in different articles, respectively. For the BRCA1, after conducting meta-analysis, we found that the overall frequency of 5382insC was 0.09 (95% CI 0.06-0.12), the frequency of 185delAG was 0.07 (95% CI 0.01-0.13), the frequency of 3819del5 was 0.02 (95% CI 0.01-0.04) and the frequency of 4153delA was 0.06 (95% CI 0.03-0.09). For the BRCA2, the overall frequency of 4075delGT was 0.02 (95% CI 0.00-0.03) and the frequency of 5802del4 was 0.07 (95% CI 0.04-0.11). This article provides a set of common mutations for BRCA1 and BRCA2 mutation carriers and the results may help to explore frequencies of BRCA1 and BRCA2 mutations in a given population and will be of significance both for diagnostic testing and for epidemiological studies.

StatBite BRCA Mutations in Breast Cancer Patients Under Age 50 Tested for Mutations

StatBite BRCA Mutations in Breast Cancer Patients Under Age 50 Tested for Mutations

Absence of the K303R estrogen receptor α mutation in breast cancer patients exhibiting different responses to aromatase inhibitor anastrozole neoadjuvant treatment

Aromatase inhibitors, such as anastrozole, are established in the treatment of hormone-dependent breast cancer. However, approximately 20% of patients treated with anastrozole do not respond, and it remains impossible to accurately predict sensitivity. Thus, novel markers to predict response are required. The K303R estrogen receptor (ER)α mutation confers resistance to tamoxifen treatment. Moreover, K303R-expressing MCF-7 cells, transfected with an aromatase expression vector and stimulated with androstenedione (an aromatase substrate), were found to be resistant to the inhibitory effect of anastrozole. The aim of this study was to verify whether the presence of the K303R ERα mutation is associated with response to 3-month neoadjuvant treatment with anastrozole (Arimidex) in a cohort of post-menopausal breast cancer patients. Of 37 patients with ER(+) tumors, 19 showed a clinical response to anastrozole and 18 were resistant. Biopsies were obtained from tumors responding to the therapy or from non-responding tumors. None carried the K303R ERα mutation. To our knowledge, this is the first study to search for K303R ERα mutations in tumors clinically responsive or resistant to an aromatase inhibitor. Lack of the mutation leads us to believe that this mutation has in vivo biological significance in only a subset of breast cancers.

Mutations of p53 gene in breast cancer in the Egyptian Province of Dakahliya

Breast cancer is the most common malignancy among females worldwide. Molecular analysis of p53 is likely to have value in diagnosis, prognosis, and treatment of breast cancer. To study the frequency and spectrum of p53 gene mutations in breast cancer patients residing Al Dakahliya district in the north of Egypt. Thirty patients with cancer breast as well as 10 controls were evaluated for p53 status by flow-cytometry, PCR-SSCP, and sequencing analysis. P53 mutations were evident in five breast cancer patients (17%) including two missense mutations (A218 T and R279 G) in exon 6, 8; nonsense mutations (S297stop and Y159stop) in exon 8, 5, respectively, and frame shift mutation (M133 fs) in exon 5. p53 mutations were associated with invasive ductal carcinoma, large tumor size, and advanced disease stage p53 gene mutations is potentially responsible for pathogenesis and clinical aggressiveness of breast cancer in our locality.

GST Polymorphisms: Bonassi et al. Respond

We thank Vodicka et al. for drawing attention to a critical issue—the role of genetic polymorphisms in the induction of chromosomal damage. First, we would like to clarify that our study (Rossi et al. 2009) was not designed to evaluate the influence of glutathione S-transferase (GST) polymorphisms on the frequency of chromosomal aberrations (CAs). Instead, we aimed to identify any possible susceptibility alleles that would increase the strength of the relationship between CAs and risk of cancer in subgroups of genetically variant individuals. The specific purpose of this case–control study explains the relative small size: We planned to obtain data on both CAs and enetic polymorphisms in the same individuals, with all subjects at ages appropriate to allow for an informative follow-up. The interesting data reported by Vodicka et al. in their letter confirm the extreme heterogeneity of findings when the frequency of chromosome damage is associated with polymorphisms in genes that influence several pathways. In fact, the lack of association in the whole database described by Vodicka et al. contrasts with the significant results reported in exposure-specific subsets, such as the highest frequency of CAs in GSTT1-null smokers working in the tire industry (Musak et al. 2008). This interpretation is also supported by the study of Iarmarcovai et al. (2008a), who reviewed 72 population studies reporting a significant effect of GSTM1, EPHX (microsomal epoxide hydrolase), and GSTT1 on micronucleus frequency. These authors also reported that the effect observed in specific pathways—such as ALDH2 in connection to chromosome damage due to alcohol consumption, BRCA1 and BRCA2 mutations in breast cancer patients, and MTHFR depending on folate levels—was much more pronounced. A great deal of information about the role of genetic polymorphisms in the induction of chromosomal damage will stem from genome-wide association studies, when enough resources will be available in the field to explore the genetic determinants of chromosome damage using a whole genome scan. Nevertheless, classical association studies are still valid assuming that specific pathways are identified, possibly a priori, linking genotoxic exposure to polymorphisms of genes involved in the correspondent pathway We would also like to address future strategies for exploring the link between the frequency of chromosome damage and the risk of cancer (and other diseases). We fully agree with Vodicka et al.’s recommendation that possible modifying effects of lifestyle, occupational factors, and genetic poly morphisms be taken into account. However, after finding negative results concerning the role of occupational exposure to genotoxic agents and smoking habit (Bonassi et al. 2000), and polymorphisms of metabolic genes (Rossi et al. 2009), we believe that the remaining factor to be investigated is diet. Many studies have reported on the role of various food items and nutrients as modulators of chromosome stability (Fenech 2007); therefore, this parameter now has top priority, although reliable data are difficult to collect retrospectively. The other recommendation from Vodicka et al. seems less promising, because measuring the frequency of chromosome damage in cancer patients (besides the classical discussion about whether the damage is a cause or a consequence of the disease) is possibly more a marker of progression than a predictive marker (Iarmarcovai et al. 2008b).

Contribution of BRCA1 and BRCA2 mutations to breast cancer in Tunisia

e22191 Background: Hereditary breast cancer accounts for 3–8% of all breast cancers. It was recently estimated that a combination of BRCA1 and BRCA2 genes mutations is responsible for 30% of hereditary breast cancer cases. Methods: To investigate the prevalence of BRCA1 and BRCA2 gene mutations in breast cancer patients with affected relatives in Tunisia, 36 patients who had at least one first degree relative affected with breast and/or ovarian cancer were analysed. Thirty three patients are suggestive of BRCA1 mutation and 3 are suggestive of BRCA2 mutation. Results: Four mutations in BRCA1 gene were described among which, one novel splice site mutation (330 dupA) and 3 frameshift mutations including the 4160 delAG, the 2789 delG and the 5385 insC. Our study is the first to describe the 5385 insC mutation which was described only among Jewish Ashkenazi population. Two frameshift mutations (1537 del4 and 5909 insA) were screened in BRCA2 gene. Nineteen percent (7/36) of the familial cases were altered on BRCA1 or BRCA2 genes with deleterious mutations at heterozygous state and 55% (20/36) by mutation with uncertain value (UV) or by single nucleotide polymorphisms (SNPs). Conclusions: Almost all the cases mutated by deleterious mutations on BRCA1 gene reported a family history of breast and/or ovarian cancer in the index case or in their relatives. On the contrary, patients with an UV mutation or SNPs have no history of ovarian cancer in their corresponding families. Our data are the first to contribute to information on mutation spectrum of BRCA genes and offer a recommended screening mode for clinical genetic testing policy in Tunisia. No significant financial relationships to disclose.

Screening for BRCA1 and BRCA2 mutations in breast cancer patients from mexico: the public health perspective

Genetic testing for mutations in BRCA1 and BRCA2 has potentially important public health implications. Through judicious testing of women believed to be at high risk for early-onset breast cancer and for ovarian cancer, it is possible to identify highly-predisposed women prior to the development of cancer. Current preventive options include preventive mastectomy, preventive oophorectomy, tamoxifen and oral contraceptives. The ability to offer genetic testing in Mexico on a widespread level is enhanced if the common founder mutations in the two genes can be discovered or if the cost of genetic sequencing is reduced. It is important that a genetic testing service be a multi-disciplinary effort with co-ordinated follow-up.

Evidence for an ancient BRCA1 mutation in breast cancer patients of yoruban ancestry

BRCA1 recurrent mutations have rarely been assessed in non-founder populations. Still, identifying such mutations could be important for designing genetic testing strategies for high-risk breast/ovarian cancer families in non-founder populations. To determine whether the recurrent BRCA1 Y101X mutation identified in Yoruban breast cancer patients represents a single historical mutation event, and determine the prevalence of this mutation in a hospital based cohort. 365 breast cancer patients and 177 controls of Yoruban ancestry from Nigeria, unselected for age of onset or family history were screened for the BRCA1 Y101X mutation. The haplotypes on which the Y101X mutation occurred were characterized using microsatellite markers and single-nucleotide polymorphisms (SNPs). Phase ambiguity was resolved using allele-specific PCR. The BRCA1 Y101X mutation was detected in four Yoruban patients with no documented family history of breast cancer among a cohort of 365 (1.1, 95% C.I. = 0.43-2.78%) unrelated Yoruban breast cancer patients. This study reveals the four Y101X mutations occur on a single, rare haplotype. Further characterization in a patient of European ancestry with a strong family history of breast/ovarian cancer revealed the same Y101X mutation on the same haplotype as those in the Yoruban carriers. These observations suggest the Y101X mutations identified in the Yoruban patients may have originated from a single mutation event. BRCA1 Y101X is the first reported recurrent mutation occurring in patients of African ancestry for which prevalence has been determined. Identification of this mutation in a woman of European ancestry with strong family history of breast/ovarian suggests further that this mutation occurred once, probably many generations ago.

Prevalence of BRCA1 and BRCA2 mutations in breast cancer patients from Cuba

The contribution of BRCA1 and BRCA2 to breast cancer incidence in Cuba has not yet been explored. In order to estimate the proportion of breast cancers due to BRCA1 and BRCA2 mutations in Cuba, and to identify possible Cuban founder mutations, we conducted a study of unselected breast cancer patients from Havana, Cuba. We enrolled 336 women with breast cancer from a large public hospital in the city. A family history of cancer was obtained from each patient and a blood sample was processed for DNA analysis. Mutations in BRCA1 and BRCA2 were sought using a combination of techniques, but all mutations were confirmed by direct sequencing. We were able to successfully complete testing on samples from 307 women. Among these, eight mutations were identified (seven in BRCA2 and one in BRCA1) representing 2.6% of the total, including 10% of familial cases and 10% of cases under age forty. One BRCA2 mutation (c.3394C > T) was found in two women, but no clear example of a founder mutation was identified. In summary, BRCA1 and BRCA2 mutations are not uncommon in Cuban women with breast cancer, but the absence of founder mutations precludes the development of a rapid and inexpensive clinical screening test.

Contribution of the BRCA1 and BRCA2 mutations to breast cancer in Tunisia

Hereditary breast cancer accounts for 3-8% of all breast cancers, with mutations in the BRCA1 and BRCA2 genes responsible for up to 30% of these. To investigate the prevalence of BRCA1 and BRCA2 gene mutations in breast cancer patients with affected relatives in Tunisia, we studied 36 patients who had at least one first degree relative with breast and/or ovarian cancer Thirty-four 34 patients were suggestive of the BRCA1 mutation and two were suggestive of the BRCA2 mutation, based on the presence of male breast cancer detected in their corresponding pedigrees. Four mutations in BRCA1 were detected, including a novel frame-shift mutation (c.211dupA) in two unrelated patients and three other frameshift mutations--c.4041delAG, c.2551delG and c.5266dupC. Our study is the first to describe the c.5266dupC mutation in a non-Jewish Ashkenazi population. Two frameshift mutations (c.1309del4 and c.5682insA) were observed in BRCA2. Nineteen percent (7/36) of the familial cases had deleterious mutations of the BRCA1 or BRCA2 genes. Almost all patients with deleterious mutations of BRCA1 reported a family history of breast and/or ovarian cancer in the index case or in their relatives. Our data are the first to contribute to information on the mutation spectrum of BRCA genes in Tunisia, and we give a recommendation for improving clinical genetic testing policy.

Novel BRCA1 gene mutations in breast cancer patients from St. Petersburg

Screening of patients with familial breast cancer from St. Petersburg for BRCA1 gene mutations resulted in identification of three mutations (414del3, 276delA, and A622V) and two polymorphisms (P871L and S1436S). Mutations 4146del3 and 276delA are novel, never previously described elsewhere. Deletion 2761delA produces a reading frame shift, premature protein synthesis termination and can cause predisposition for breast cancer. Deletion 414de13 does not cause a frame shift, but can result both in the disappearance of amino acid residue (D1343del) in the BRCA1 protein and in alteration of folding of the protein, entailing loss of its functional activity. Two variants of nucleotide sequence observed in the number of patients were classified as DNA polymorphisms (P871L and S1436S) rather than mutations as they were not tightly associated with the increased risk of breast cancer.

Prevalence of BRCA1 and BRCA2 mutations in breast cancer patients from Brazil

The contribution of BRCA1 and BRCA2 to breast cancer incidence in Brazil has not yet been explored. In order to estimate the proportion of breast cancers due to BRCA1 and BRCA2 mutations in Brazil, we conducted a study of unselected breast cancer patients from Rio de Janeiro, Brazil. We enrolled 402 women with breast cancer from a large public hospital and two private medical clinics in the city. A detailed family history was obtained from each patient and a blood sample was obtained for DNA analysis. Mutations in BRCA1 and BRCA2 were sought using a combination of techniques, but all mutations were confirmed by direct sequencing. Overall, nine mutations were identified (six in BRCA1 and three in BRCA2) representing 2.3% of the total. The most common mutation, 5382insC in BRCA1, was seen five times and accounted for 56% of all identified mutations. A second mutation, in BRCA2 (6633del5) was seen in two unrelated women. In summary, BRCA1 and BRCA2 mutations are not uncommon in Brazilian women with breast cancer. It appears that a small number of founder mutations may be predominant. Moreover, a small number of founder mutations may be prevalent in Brazil, raising the possibility that a rapid and inexpensive genetic test may be developed to screen for inherited susceptibility to breast cancer in Brazil.

A prospective study on predictive factors linked to the presence of BRCA1 and BRCA2 mutations in breast cancer patients

We prospectively screened a hospital-based population of 1000 successive breast cancer patients receiving adjuvant radiotherapy for predictive factors associated with the presence of BRCA1 and BRCA2 mutations. We offered genetic counseling and DNA analysis to selected patients. About 52% of patients showed at least one presumed predictive factor. Hundred and thirty-seven patients underwent DNA analysis. We identified 14 deleterious mutations (10.2%, 95% CI: 5.2–15.3%): 8 BRCA1 mutations and 6 BRCA2 mutations and 14 variants of uncertain clinical significance. Ovarian cancer in the family history was the only factor significantly associated with the presence of a disease-causing mutation ( P < 0.01). Eight of the 14 (57%) mutation carriers had no affected first-degree relatives and in 4 of these there was no family history of breast or ovarian cancer. Clinicians should offer genetic counseling and DNA testing to breast cancer patients from families with breast and ovarian cancer, and to patients who are younger than 45 years when they are diagnosed with breast cancer.