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1.
Taila Hartley Luca Cavallone Nelly Sabbaghian Rachel Silva-Smith Nancy Hamel Olga Aleynikova Erika Smith Valerie Hastings Pedro Pinto Marc Tischkowitz Eva Tomiak William D Foulkes 《Hereditary cancer in clinical practice》2014,12(1):19
Background
PALB2 has emerged as a breast cancer susceptibility gene. Mutations in PALB2 have been identified in almost all breast cancer populations studied to date, but the rarity of these mutations and lack of information regarding their penetrance makes genetic counseling for these families challenging. We studied BRCA1/2 -negative breast and/or ovarian cancer families to a) assess the contribution of PALB2 mutations in this series and b) identify clinical, pathological and family history characteristics that might make PALB2 screening more efficient.Methods
The coding region of the PALB2 gene was analyzed in 175 probands with family histories of breast and/or ovarian cancer ascertained from a single Canadian institution in Eastern Ontario.Results
We identified 2 probands with PALB2 mutations that are known or strongly considered to be pathogenic and 3 probands with missense mutations that are possibly pathogenic. One of the identified truncating mutations [c.3113G > A (p.Gly1000_Trp1038del – major product)], has been previously described while the other four mutations [c.3507_3508delTC (p.H1170Ffs*19), c.1846G > C (p.D616H), c.3418 T > G (p.W1140G), c.3287A > G (p.N1096S)] have not been previously reported. Loss of heterozygosity was detected in two breast tumors from one c.3507_3508delTC mutation carrier but not in other available tumors from that family or in tumors from carriers of other mutations.Conclusions
PALB2 mutation screening identifies a small, but significant number of mutations in BRCA1/2 -negative breast and/or ovarian cancer families. We show that mutations are more likely to be found in families with three or more breast cancers as well as other BRCA2-related cancers. In our cohort, both clearly pathogenic mutations were identified in premenopausal breast cancer cases (2/77, 2.6%). Testing should be preferentially offered to affected women from such families. 相似文献2.
Monne M Piras G Fancello P Santona MC Uras A Landriscina G Mastio G Gabbas A 《Familial cancer》2007,6(1):73-79
The population of Sardinia is characterized by a relatively low level of genetic heterogeneity: therefore ‘founder mutations’
can be expected to be found. We analysed 17 probands from families with high incidence of breast cancer or breast and ovarian
cancer by sequencing the full-length coding regions of BRCA1 and BRCA2 genes. A novel BRCA2 frameshift mutation, 3951del3insAT, which produces a protein truncated at codon 1258, was observed in six patients with BC from the same village. The mutation
was not found in unaffected females (matched on basis of ethnicity and age) with no family history of cancer. Haplotype analysis
strongly suggests that all affected persons had a common ancestor. The identification of this clinically significant founder
mutation may facilitate screening/testing for inherited risk of breast cancer. 相似文献
3.
J. Maksimenko A. Irmejs G. Trofimovičs D. Bērziņa E. Skuja G. Purkalne E. Miklaševičs J. Gardovskis 《Hereditary cancer in clinical practice》2018,16(1):12
Background
Pathogenic BRCA1 founder mutations (c.4035delA, c.5266dupC) contribute to 3.77% of all consecutive primary breast cancers and 9.9% of all consecutive primary ovarian cancers. Identifying germline pathogenic gene variants in patients with primary breast and ovarian cancer could significantly impact the medical management of patients. The aim of the study was to evaluate the rate of pathogenic mutations in the 26 breast and ovarian cancer susceptibility genes in patients who meet the criteria for BRCA1/2 testing and to compare the accuracy of different selection criteria for second-line testing in a founder population.Methods
Fifteen female probands and 1 male proband that met National Comprehensive Cancer Network (NCCN) criteria for BRCA1/2 testing were included in the study and underwent 26-gene panel testing. Fourteen probands had breast cancer, one proband had ovarian cancer, and one proband had both breast and ovarian cancer. In a 26-gene panel, the following breast and/or ovarian cancer susceptibility genes were included: ATM, BARD1, BLM, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, EPCAM, FAM175A, MEN1, MLH1, MRE11A, MSH2, MSH6, MUTYH, NBN, PALB2, PMS2, PTEN, RAD50, RAD51C, RAD51D, STK11, TP53, and XRCC2. All patients previously tested negative for BRCA1 founder mutations.Results
In 44% (7 out of 16) of tested probands, pathogenic mutations were identified. Six probands carried pathogenic mutations in BRCA1, and one proband carried pathogenic mutations in BRCA2. In patients, a variant of uncertain significance was found in BRCA2, RAD50, MRE11A and CDH1. The Manchester scoring system showed a high accuracy (87.5%), high sensitivity (85.7%) and high specificity (88.9%) for the prediction of pathogenic non-founder BRCA1/2 mutations.Conclusion
A relatively high incidence of pathogenic non-founder BRCA1/2 mutations was observed in a founder population. The Manchester scoring system predicted the probability of non-founder pathogenic mutations with high accuracy.4.
Al-Joharah Alhuqail Areej Alzahrani Hannah Almubarak Sarah Al-Qadheeb Lamyaa Alghofaili Nisreen Almoghrabi Hamed Alhussaini Ben Ho Park Dilek Colak Bedri Karakas 《Breast cancer research and treatment》2018,168(3):695-702
Purpose
The BRCA1 and BRCA2 (BRCA) genes are heavily involved in mammalian cell DNA repair processes. Germline pathogenic mutations in BRCA increase the lifetime risk of developing breast and/or ovarian cancer in women. In the Arabian Peninsula, most breast and ovarian cancers are diagnosed as early-onset cases, some of which may be due to germline variants in BRCA genes. To identify the BRCA germline mutation frequency and spectrum in the Arab breast and ovarian cancers, we have sequenced the protein-coding exons of these genes.Methods
All BRCA coding exons were sequenced using genomic DNA isolated from lymphocytes in 173 Arab breast and ovarian cancer patients by a massively parallel sequencing technology and verified by Sanger sequencing.Results
We identified a total of 17 distinct pathogenic mutations, of which four were novel, in 28 patients; nine out of 108 breast (8.3%) and 19 out of 65 ovarian cancer (29.2%) patients. Thirteen of the 17 mutations were detected in BRCA1 and four mutations were found in BRCA2 gene. Four pathogenic BRCA1 mutations (c.1140dupG, c.4136_4137delCT, c.5095C>T, and c.5530delC) accounted for 54% of all the mutations detected in our patient cohort. Additionally, we identified a likely pathogenic BRCA1 missense variant in two of 108 breast (1.9%) and a BRCA2 missense variant in one of 65 ovarian cancer (1.5%) patients.Conclusions
The overall frequencies of the BRCA germline mutations were 10.2% in breast and 30.7% in ovarian cancer patients. These data shed new light into the prevalence of BRCA mutations in the Arab women population.5.
Histopathological features of breast tumours in <Emphasis Type="Italic">BRCA1</Emphasis>, <Emphasis Type="Italic">BRCA2</Emphasis> and mutation-negative breast cancer families 下载免费PDF全文
Introduction
Histopathological features of BRCA1 and BRCA2 tumours have previously been characterised and compared with unselected breast tumours; however, familial non-BRCA1/2 tumours are less well known. The aim of this study was to characterise familial non-BRCA1/2 tumours and to evaluate routine immunohistochemical and pathological markers that could help us to further distinguish families carrying BRCA1/2 mutations from other breast cancer families.Methods
Breast cancer tissue specimens (n = 262) from 25 BRCA1, 20 BRCA2 and 74 non-BRCA1/2 families were studied on a tumour tissue microarray. Immunohistochemical staining of oestrogen receptor (ER), progesterone receptor (PgR) and p53 as well as the histology and grade of these three groups were compared with each other and with the respective information on 862 unselected control patients from the archives of the Pathology Department of Helsinki University Central Hospital. Immunohistochemical staining of erbB2 was also performed among familial cases.Results
BRCA1-associated cancers were diagnosed younger and were more ER-negative and PgR-negative, p53-positive and of higher grade than the other tumours. However, in multivariate analysis the independent factors compared with non-BRCA1/2 tumours were age, grade and PgR negativity. BRCA2 cases did not have such distinctive features compared with non-BRCA1/2 tumours or with unselected control tumours. Familial cases without BRCA1/2 mutations had tumours of lower grade than the other groups.Conclusions
BRCA1 families differed from mutation-negative families by age, grade and PgR status, whereas ER status was not an independent marker.6.
7.
BRCA1 mutations predispose to early-onset breast cancer. We previously reported an association between absence of the common IGF1 19 CA-repeat allele (IGF1-19/-19) and being a BRCA1 mutation carrier in young women from breast cancer high-risk families. Others have reported a four-fold risk of premenopausal breast cancer in women with a family history and the IGF1-19/-19 genotype. The aim of this study was to investigate whether the IGF1-19/-19 genotype was associated with being a BRCA1 mutation carrier among women from BRCA1 families. DNA was available from 268 women with known BRCA1 status from the South Swedish Health Care Region. IGF1 genotyping was successfully performed with fragment analysis in 211 women from 96 families. The IGF1-19/-19 genotype was significantly more common among BRCA1 mutation carriers (14.2%) than among non-carriers (4.8%), OR 3.3 (95%CI 1.11-9.78, P = 0.03) adjusted for family clustering. We confirmed our previous finding of an association between the IGF1-19/-19 genotype and BRCA1 mutation status. Since the IGF1-19/-19 genotype in combination with OC use or multiparity confers an increased risk for early onset breast cancer in high-risk women and in women from the general population, future studies are needed to elucidate the importance of the IGF1-19/-19 genotype concerning the variability in breast cancer risk among BRCA1 mutation carriers. 相似文献
8.
Choi DH Cho DY Lee MH Park HS Ahn SH Son BH Haffty BG 《Breast cancer research and treatment》2008,112(3):569-573
The germline CHEK2 1100delC mutation is a low penetrance breast cancer susceptibility allele, frequently observed in patient with family history
of breast cancer and/or young age and the frequency varied according to race or ethnicity. In this study, we evaluated the
significance of CHEK2 1100delC in predisposition to breast cancer by assessing its frequency in a material of 493 Korean breast cancer patients
who had been screened for BRCA1 and BRCA2 mutations (42 patients had deleterious mutation of BRCA1/2). Mutation detection of CHEK2 1100delC was based upon analysis of primer extension products generated for previously amplified genomic DNA using a chip
based MALDI-TOP mass spectrometry platform. After overall measurement automatically, assays which had bad peaks were checked
again manually. None of the 493 Korean patients with breast cancer who were candidate for BRCA1 and BRCA2 test carried the 1100delC mutation observed in Caucasians with limited frequency. In the previous studies, we observed higher
or comparable prevalence of BRCA1 and BRCA2 mutations in Korean patients with breast cancer compared to Caucasian breast cancer population. In the present study, we
evaluated the role of a CHEK2 1100delC as a susceptibility mutation of breast cancer in the Korean population. However, our results suggest that this mutation
is absent or may be very infrequent in Korean patients with breast cancer who have high risk of BRCA1 and BRCA2 mutation, making its screening irrelevant from the practical point view. 相似文献
9.
Tomasz Kluz Andrzej Jasiewicz Elżbieta Marczyk Robert Jach Anna Jakubowska Jan Lubiński Steven A. Narod Jacek Gronwald 《Hereditary cancer in clinical practice》2018,16(1):6
Background
Causative variants in BRCA1 and BRCA2 are well-established risk factors for breast and ovarian cancer. In Poland, the causative founder variants in the BRCA1 are responsible for a significant proportion of ovarian cancer cases, however, regional differences in the frequencies of various mutations may exist. The spectrum and frequency of BRCA1/2 mutations between ovarian cancer patients have not yet been studied in the region of South-East Poland.Methods
We examined 158 consecutive unselected cases of ovarian cancer patients from the region of Podkarpacie. We studied 13 Polish causative founder variants in BRCA1 (c.5266dupC, c.4035delA, c.5251C?>?T, c.181 T?>?G, c.676delT, c.68_69delAG, c.3700_3704delGTAAA, c.1687C?>?T, c.3756_3759delGTCT) and in BRCA2 (c.658_659delGT, c.7910_7914delCCTTT, c.3847_3848delGT, c.5946delT).Results
A BRCA1 causative founder variants were detected in 10 of the 158 (6.3%) ovarian cancer cases. BRCA2 causative founder variants were not observed. The c.5266dupC mutation was detected in 6 patients, c.181 T?>?G mutation in 3 patients and the c.676delT mutation in 1 patient. The median age of diagnosis of the 10 hereditary ovarian cancers was 55.5 years of age.Conclusions
The frequency of 13 causative founder variants in Podkarpacie was lower than in other regions of Poland. Testing of three BRCA1 mutations (c.5266dupC, c.181 T?>?G, c.676delT) should be considered a sensitive test panel.10.
Henriette Roed Nielsen Janne Petersen Lotte Krogh Mef Nilbert Anne-Bine Skytte 《Familial cancer》2016,15(4):523-528
In families screened for mutations in the BRCA1 or BRCA2 genes and found to have a segregating mutation the breast cancer risk for women shown not to carry the family-specific mutation might be at above “average” risk. We assessed the risk of breast cancer in a clinic based cohort of 725 female proven noncarriers in 239 BRCA1 and BRCA2 families compared with birth-matched controls from the Danish Civil Registration System. Prospective analysis showed no significantly increased risk for breast cancer in noncarriers with a hazard ratio of 0.67 [95 % confidence interval (CI) 0.32–1.42, p = 0.29] for all family members who tested negative and 0.87 (95 % CI 0.38–1.97, p = 0.73) for non-carries who were first-degree relatives of mutation carriers. Proven noncarriers from BRCA1 and BRCA2 families have no markedly increased risk for breast cancer compared to the general population, and our data do not suggest targeted breast cancer surveillance for noncarriers from BRCA1 and BRCA2 families. 相似文献
11.
Zhang J Fackenthal JD Zheng Y Huo D Hou N Niu Q Zvosec C Ogundiran TO Hennis AJ Leske MC Nemesure B Wu SY Olopade OI 《Breast cancer research and treatment》2012,134(2):889-894
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. 相似文献
12.
<Emphasis Type="Italic">BRCA1</Emphasis> and <Emphasis Type="Italic">BRCA2</Emphasis> mutations in a population-based study of male breast cancer 下载免费PDF全文
Victoria?M?Basham Julian?M?Lipscombe Joanna?M?Ward Simon?A?Gayther Bruce?AJ?Ponder Douglas?F?Easton Paul?DP?Pharoah
Background
The contribution of BRCA1 and BRCA2 to the incidence of male breast cancer (MBC) in the United Kingdom is not known, and the importance of these genes in the increased risk of female breast cancer associated with a family history of breast cancer in a male first-degree relative is unclear.Methods
We have carried out a population-based study of 94 MBC cases collected in the UK. We screened genomic DNA for mutations in BRCA1 and BRCA2 and used family history data from these cases to calculate the risk of breast cancer to female relatives of MBC cases. We also estimated the contribution of BRCA1 and BRCA2 to this risk.Results
Nineteen cases (20%) reported a first-degree relative with breast cancer, of whom seven also had an affected second-degree relative. The breast cancer risk in female first-degree relatives was 2.4 times (95% confidence interval [CI] = 1.4–4.0) the risk in the general population. No BRCA1 mutation carriers were identified and five cases were found to carry a mutation in BRCA2. Allowing for a mutation detection sensitivity frequency of 70%, the carrier frequency for BRCA2 mutations was 8% (95% CI = 3–19). All the mutation carriers had a family history of breast, ovarian, prostate or pancreatic cancer. However, BRCA2 accounted for only 15% of the excess familial risk of breast cancer in female first-degree relatives.Conclusion
These data suggest that other genes that confer an increased risk for both female and male breast cancer have yet to be found.13.
Dorina M. van der Kolk Geertruida H. de Bock Beike K. Leegte Michael Schaapveld Marian J. E. Mourits Jakob de Vries Annemieke H. van der Hout Jan C. Oosterwijk 《Breast cancer research and treatment》2010,124(3):643-651
Accurate estimations of lifetime risks of breast and ovarian cancer are crucial for counselling women from BRCA1/2 families. We therefore determined breast and ovarian cancer penetrance in BRCA1/2 mutation families in the northern Netherlands and compared them with the incidence of cancers in the general population in
this region. We identified 1188 female mutation carriers and first-degree female relatives in 185 families with a pathogenic
BRCA1 or BRCA2 mutation. The occurrence of breast cancer, contralateral breast cancer and ovarian cancer was recorded. The cumulative incidence
of breast cancer by age 70 was 71.4% (95% CI 67.2–82.4%) in BRCA1 and 87.5% (82.4–92.6%) in BRCA2 mutation carriers. For ovarian cancer at age 70, it was 58.9% (53.5–64.3%) in BRCA1 and 34.5% (25.0–44.0%) in BRCA2 mutation carriers. For breast cancer we saw a rise of 24.2% in the cumulative incidence in the seventh decade for BRCA2 mutation carriers versus 6.3% for BRCA1. For ovarian cancer the rise in the seventh decade was 17.3% for BRCA1 mutation carriers and 15.1% for BRCA2. The 10-year risk for contralateral breast cancer was 34.2% (29.4–39.0%) in BRCA1 families and 29.2% (22.9–35.5%) in BRCA2. We show that the incidence of breast and ovarian cancer in BRCA2 mutation carriers and of ovarian cancer in BRCA1 mutation carriers is still high after 60 years. This may justify intensive breast screening as well as oophorectomy even
after age 60. The risk of contralateral breast cancer rises approximately 3% per year, which may affect preventive choices. 相似文献
14.
Ivana Ticha Zdenek Kleibl Jana Stribrna Jaroslav Kotlas Martina Zimovjanova Martin Mateju Michal Zikan Petr Pohlreich 《Breast cancer research and treatment》2010,124(2):337-347
Large genomic rearrangements (LGR) represent substantial proportion of pathogenic mutations in the BRCA1 gene, whereas the frequency of rearrangements in the BRCA2 gene is low in many populations. We screened for LGRs in BRCA1 and BRCA2 genes by multiplex ligation-dependent probe amplification (MLPA) in 521 unrelated patients negative for BRCA1/2 point mutations selected from 655 Czech high-risk breast and/or ovarian cancer patients. Besides long range PCR, a chromosome
17-specific oligonucleotide-based array comparative genomic hybridization (aCGH) was used for accurate location of deletions.
We identified 14 patients carrying 8 different LGRs in BRCA1 that accounted for 12.3% of all pathogenic BRCA1 mutations. No LGRs were detected in the BRCA2 gene. In a subgroup of 239 patients from high-risk families, we found 12 LGRs (5.0%), whereas two LGRs were revealed in a subgroup
of 282 non-familial cancer cases (0.7%). Five LGRs (deletion of exons 1–17, 5–10, 13–19, 18–22 and 21–24) were novel; two
LGRs (deletion of exons 5–14 and 21–22) belong to the already described Czech-specific mutations; one LGR (deletion of exons
1–2) was reported from several countries. The deletions of exons 1–17 and 5–14, identified each in four families, represented
Czech founder mutations. The present study indicates that screening for LGRs in BRCA1 should include patients from breast or ovarian cancer families as well as high-risk patients with non-familial cancer, in
particular cases with early-onset breast or ovarian cancer. On the contrary, our analyses do not support the need to screen
for LGRs in the BRCA2 gene. Implementation of chromosome-specific aCGH could markedly facilitate the design of primers for amplification and sequence
analysis of junction fragments, especially in deletions overlapping gene boundaries. 相似文献
15.
16.
17.
Novel mutations in the <Emphasis Type="Italic">BRCA1</Emphasis> and <Emphasis Type="Italic">BRCA2</Emphasis>genes in Iranian women with early-onset breast cancer 总被引:2,自引:0,他引:2 下载免费PDF全文
Yassaee VR Zeinali S Harirchi I Jarvandi S Mohagheghi MA Hornby DP Dalton A 《Breast cancer research : BCR》2002,4(4):R6
Background
Breast cancer is the most common female malignancy and a major cause of death in middle-aged women. So far, germline mutations in the BRCA1 and BRCA2 genes in patients with early-onset breast and/or ovarian cancer have not been identified within the Iranian population. 相似文献18.
Hansen Tv Jønson L Albrechtsen A Andersen MK Ejlertsen B Nielsen FC 《Breast cancer research and treatment》2009,115(2):315-323
BRCA1 and BRCA2 germ-line mutations predispose to breast and ovarian cancer. Large genomic rearrangements of BRCA1 account for 0–36% of all disease causing mutations in various populations, while large genomic rearrangements in BRCA2 are more rare. We examined 642 East Danish breast and/or ovarian cancer patients in whom a deleterious mutation in BRCA1 and BRCA2 was not detected by sequencing using the multiplex ligation-dependent probe amplification (MLPA) assay. We identified 15
patients with 7 different genomic rearrangements, including a BRCA1 exon 5–7 deletion with a novel breakpoint, a BRCA1 exon 13 duplication, a BRCA1 exon 17–19 deletion, a BRCA1 exon 3–16 deletion, and a BRCA2 exon 20 deletion with a novel breakpoint as well as two novel BRCA1 exon 17–18 and BRCA1 exon 19 deletions. The large rearrangements in BRCA1 and BRCA2 accounted for 9.2% (15/163) of all BRCA1 and BRCA2 mutations in East Denmark. Nine patients had the exon 3–16 deletion in BRCA1. By SNP analysis we find that the patients share a 5 Mb fragment of chromosome 17, including BRCA1, indicating that the exon 3–16 deletion represents a Danish founder mutation.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. 相似文献
19.
Genetic testing for BRCA1 and BRCA2 (BRCA1/2) mutations can provide important information for women who are concerned about their breast and ovarian cancer risks and need to make relevant prevention and medical management decisions. However, lifetime risks of breast cancer in individual BRCA1/2 mutation carriers have been confusing to apply in clinical decision-making. Published risk estimates vary significantly and are very dependent on the characteristics of the population under study. Recently, Begg and colleagues estimated cancer risks in a population-based study of BRCA1/2 mutation carriers. Here, we discuss the clinical decision-making implications of this research in the context of risk factors that may influence risk estimates in BRCA1/2 mutation carriers. 相似文献
20.
Henriette Roed Nielsen Mef Nilbert Janne Petersen Steen Ladelund Mads Thomassen Inge Søkilde Pedersen Thomas V. O. Hansen Anne-Bine Skytte Åke Borg Christina Therkildsen 《Familial cancer》2016,15(4):507-512
Mutations in the BRCA1 and BRCA2 genes significantly contribute to hereditary breast cancer and ovarian cancer, but the phenotypic effect from different mutations is insufficiently recognized. We used a western Danish clinic-based cohort of 299 BRCA families to study the female cancer risk in mutation carriers and their untested first-degree relatives. Founder mutations were characterized and the risk of cancer was assessed in relation to the specific mutations. In BRCA1, the cumulative cancer risk at age 70 was 35 % for breast cancer and 29 % for ovarian cancer. In BRCA2, the cumulative risk was 44 % for breast cancer and 15 % for ovarian cancer. We identified 47 distinct BRCA1 mutations and 48 distinct mutations in BRCA2. Among these, 8 founder mutations [BRCA1 c.81-?_4986+?del, c.3319G>T (p.Glu1107*), c.3874delT and c.5213G>A (p.Gly1738Glu) and BRCA2 c.6373delA, c.7008?1G>A, c.7617+1G>A and c.8474delC] were found to account for 23 % of the BRCA1 mutations and for 32 % of the BRCA2 mutations. The BRCA1 mutation c.3319G>T was, compared to other BRCA1 mutations, associated with a higher risk for ovarian cancer. In conclusion, founder mutations in BRCA1 and BRCA2 contribute to up to one-third of the families in western Denmark and among these the BRCA1 c.3319G>T mutation is potentially linked to an increased risk of ovarian cancer. 相似文献