Absence of genomic BRCA1 and BRCA2 rearrangements in Ashkenazi breast and ovarian cancer families

Stadler, Zsofia K.; Saloustros, Emmanouil; Hansen, Nichole; Schluger, A.; Kauff, Noah D.; Offit, Kenneth

doi:10.1007/s10549-010-0818-y

Cited by 16 publications

(8 citation statements)

References 38 publications

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“…Large rearrangements were not identified in the BRCA1/2 genes (n=26) in our cohort of AJ individuals testing negative for founder and non-founder point mutations, which is consistent with previous reports (Palma et al 2008;Stadler et al 2010). These data are consistent with prior studies showing that founder mutations continue to account for the vast majority of all mutations in this population and suggest that routine screening for large rearrangements does not seem to be warranted in AJ individuals.…”

Section: Practice Implicationssupporting

confidence: 92%

“…The prevalence of these three mutations is between 1.1 and 2.7 % in AJ populations unselected for personal or family cancer history (Metcalfe et al 2010;Neuhausen et al 1996;Roa et al 1996;Struewing et al 1997), and 10.2 % for AJ individuals with a family history of breast or ovarian cancer (Malone et al 2006). Of those who do not carry one of the three founder mutations, approximately 0.6-4.0 % have been found to harbor a nonfounder BRCA1/2 mutation (Frank et al 2002;Kauff et al 2002;Phelan et al 2002), and large genomic rearrangements in AJ individuals are reported to be rare (Palma et al 2008;Stadler et al 2010;Distelman-Menachem et al 2009;Walsh et al 2006).…”

Section: Introductionmentioning

confidence: 99%

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To Reflex or Not: Additional BRCA1/2 Testing in Ashkenazi Jewish Individuals Without Founder Mutations

Petrucelli

Mange

Fulbright

et al. 2014

Journal of Genetic Counseling

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This study determined the prevalence of non-Ashkenazi Jewish BRCA1/2 mutations in the Ashkenazi Jewish population in the state of Michigan, current provider testing practices, and the use of mutation probability models in determining which Ashkenazi Jewish individuals should be offered further analysis following negative BRCA1/2 founder testing. Testing patterns, mutation probabilities, and testing results were assessed for 327 Ashkenazi Jewish individuals seen for BRCA1/2 counseling in the state of Michigan who underwent testing for the Ashkenazi Jewish founder mutations. Only one (0.6 %) Ashkenazi Jewish individual with sequencing after negative founder analysis was found to have a non-founder mutation; no rearrangements were identified. Testing patterns varied by clinic, with the proportion of Ashkenazi Jewish individuals undergoing additional sequencing ranging from 22.2 to 92.9 %. In Ashkenazi Jewish individuals with a pre-test BRCAPRO risk calculation, the mean risk was significantly higher in those with follow-up sequencing compared to those who did not pursue additional testing. The low prevalence of non-founder BRCA1/2 mutations in Ashkenazi Jewish individuals does not warrant automatically reflexing to full analysis after negative mutation testing. Increased use of mutation probability models may aid in determining which cases warrant additional testing.

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Section: Practice Implicationssupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

To Reflex or Not: Additional BRCA1/2 Testing in Ashkenazi Jewish Individuals Without Founder Mutations

Petrucelli

Mange

Fulbright

et al. 2014

Journal of Genetic Counseling

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“…In addition, the presence of pathogenic alterations that escape most of the current gene sequencing-based diagnostic approaches were proposed, including partial or complete exon losses or duplications resulting in an out-of-frame translation and a mutant peptide with abnormal structure and/or function ( Petrij-Bosch et al , 1997 ; Ewald et al , 2009 ). Several reports confirmed that BRCA rearrangements, particularly in BRCA1 , are indeed quite frequent in HBOC families from selected countries ( Preisler-Adams et al , 2006 ; Hansen et al , 2008 ; Kang et al , 2010 ; Ratajska et al , 2008 ; Stadler et al , 2010 ; Rudnicka et al , 2013 ; Pal et al , 2014 ). These mutations are scattered throughout the gene and although most of them are deletions, duplications and triplications, as well as combined deletion/insertion events have also been described.…”

Section: Introductionmentioning

confidence: 82%

BRCA1 and BRCA2 rearrangements in Brazilian individuals with Hereditary Breast and Ovarian Cancer Syndrome

et al. 2016

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Approximately 5-10% of breast cancers are caused by germline mutations in high penetrance predisposition genes. Among these, BRCA1 and BRCA2, which are associated with the Hereditary Breast and Ovarian Cancer (HBOC) syndrome, are the most frequently affected genes. Recent studies confirm that gene rearrangements, especially in BRCA1, are responsible for a significant proportion of mutations in certain populations. In this study we determined the prevalence of BRCA rearrangements in 145 unrelated Brazilian individuals at risk for HBOC syndrome who had not been previously tested for BRCA mutations. Using Multiplex Ligation-dependent Probe Amplification (MLPA) and a specific PCR-based protocol to identify a Portuguese founder BRCA2 mutation, we identified two (1,4%) individuals with germline BRCA1 rearrangements (c.547+240_5193+178del and c.4675+467_5075-990del) and three probands with the c.156_157insAlu founder BRCA2 rearrangement. Furthermore, two families with false positive MLPA results were shown to carry a deleterious point mutation at the probe binding site. This study comprises the largest Brazilian series of HBOC families tested for BRCA1 and BRCA2 rearrangements to date and includes patients from three regions of the country. The overall observed rearrangement frequency of 3.44% indicates that rearrangements are relatively uncommon in the admixed population of Brazil.

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“…To date, at least 81 different large genomic rearrangements have been found in BRCA1 gene and account for 8%–27% of all BRCA1 mutations. Alternatively Alu sequences are less common in BRCA2 gene, where only few large genomic rearrangements are reported, accounting for 0%–11% of all BRCA2 mutations [19-21]. …”

Section: Resultsmentioning

confidence: 99%

Analysis of BRCA1 and BRCA2 large genomic rearrangements in Sri Lankan familial breast cancer patients and at risk individuals

et al. 2014

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BackgroundMajority of mutations found to date in the BRCA1/BRCA2 genes in breast and/or ovarian cancer families are point mutations or small insertions and deletions scattered over the coding sequence and splice junctions. Such mutations and sequence variants of BRCA1 and BRCA2 genes were previously identified in a group of Sri Lankan breast cancer patients. Large genomic rearrangements have been characterized in BRCA1 and BRCA2 genes in several populations but these have not been characterized in Sri Lankan breast cancer patients.FindingsA cohort of familial breast cancer patients (N = 57), at risk individuals (N = 25) and healthy controls (N = 23) were analyzed using multiplex ligation-dependent probe amplification method to detect BRCA1 and BRCA2 large genomic rearrangements. One familial breast cancer patient showed an ambiguous deletion in exon 6 of BRCA1 gene. Full sequencing of the ambiguous region was used to confirm MLPA results. Ambiguous deletion detected by MLPA was found to be a false positive result confirming that BRCA1 large genomic rearrangements were absent in the subjects studied. No BRCA2 rearrangement was also identified in the cohort.ConclusionThus this study demonstrates that BRCA1 and BRCA2 large genomic rearrangements are unlikely to make a significant contribution to aetiology of breast cancer in Sri Lanka.

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Absence of genomic BRCA1 and BRCA2 rearrangements in Ashkenazi breast and ovarian cancer families

Cited by 16 publications

References 38 publications

To Reflex or Not: Additional BRCA1/2 Testing in Ashkenazi Jewish Individuals Without Founder Mutations

To Reflex or Not: Additional BRCA1/2 Testing in Ashkenazi Jewish Individuals Without Founder Mutations

BRCA1 and BRCA2 rearrangements in Brazilian individuals with Hereditary Breast and Ovarian Cancer Syndrome

Analysis of BRCA1 and BRCA2 large genomic rearrangements in Sri Lankan familial breast cancer patients and at risk individuals

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