Assessment of the prevalence of de novo mutations in the BRCA1 and BRCA2 genes

Zhang, L; Fleischut, MH; Kohut, Kelly; Spencer, Stuart; Wong, Kah Keng; Stadler, ZK; Kauff, Noah D.; Offit, Kenneth

doi:10.1111/j.1399-0004.2011.01691.x

Cited by 7 publications

(3 citation statements)

References 7 publications

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“…A few cases of de novo constitutional BRCA1 or BRCA2 have previously been described, but most were detected in a heterozygous form in constitutional DNA and were not mosaic ( Tesoriero et al , 1999 ; Robson et al , 2002 ; Hansen et al 2008 ; Edwards et al , 2009 ; Marshall et al , 2009 ; Garcia-Casado et al , 2011 ; Kwong et al , 2011 ; Zhang et al , 2011 ) or detected at a high frequency of >70% of cells ( Delon et al , 2013 ). The per cent of hereditary breast ovarian cancer cases that can be attributed to low-level constitutional mosaicism is not known at this time.…”

Section: Discussionmentioning

confidence: 99%

Low-level constitutional mosaicism of a de novoBRCA1 gene mutation

et al. 2015

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Background:Pathogenic BRCA1 mutations are usually inherited. Constitutional low-level BRCA1 mosaicism has never been reported.Methods:Next-generation sequencing (NGS) of cancer gene panel of germline and tumour DNA in a patient with early onset, triple-negative breast cancer.Results:Constitutional de novo mosaicism (5%) for a pathogenic (c.1953dupG; p.Lys652Glufs*21) BRCA1mutation was detected in leukocytes, buccal tissue and normal breast tissue DNA, with ∼50% mutation in tumorous breast tissue.Conclusion:This is the first reported case of low-level, multiple tissue, constitutional mosaicism in BRCA1, and highlights the need to consider deep sequencing in affected individuals clinically suspected of having cancer predisposition whose tumours display a BRCA mutation.

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Section: Discussionmentioning

confidence: 99%

Low-level constitutional mosaicism of a de novoBRCA1 gene mutation

et al. 2015

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“…40 , 41 It is also important to emphasize that the likelihood of a de novo mutation occurring in BRCA1 and BRCA2 genes is very low. 42 …”

Section: Discussionmentioning

confidence: 99%

Germline mutations in BRCA1, BRCA2, CHEK2 and TP53 in patients at high-risk for HBOC: characterizing a Northeast Brazilian Population

et al. 2014

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Considering the importance of BRCA1, BRCA2, CHEK2 and TP53 in the development of hereditary early-onset breast and ovarian cancer and that the genetic susceptibility profile of the Northeast population from Brazil has never been analyzed, this study aimed to verify the frequency of mutations of clinical significance in these genes in high-risk hereditary breast and ovarian cancer (HBOC) syndrome patients from that region. DNA samples from 106 high-risk unrelated patients mostly from Bahia, the biggest state in the Northeast region, were analyzed. These patients underwent full BRCA1 gene sequencing, screening for common founder mutations in the BRCA2, CHEK2 and TP53 genes and genetic ancestry analysis with nine ancestry informative markers. The positive results were confirmed by two sequencing reactions. Three mutations of clinical significance were found: BRCA1 p.R71G (4.71%), 3450del4 (3.77%) and TP53 p.R337H (0.94%). The genetic ancestry analysis showed a high European ancestry contribution (62.2%) as well as considerable African (31.2%) and Amerindian (6.6%) ancestry contributions (r2=0.991); this degree of heterogeneity was also significant in the population structure analysis (r=0.604). This population is highly admixed with a different spectrum of genetic susceptibility, with the Galician founder mutation BRCA1 p.R71G accounting for 50% of all identified mutations in high-risk HBOC patients. TP53 p.R337H was also significantly frequent; thus, the combined screening of BRCA1/2 and TP53 should be offered to high-risk HBOC patients from Northeast Brazil.

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“…One study was designed to assess the prevalence of de novo BRCA1/2 mutations in a cohort of BRCA1/2-mutated patients but no de novo BRCA1/2 mutation was detected among 45 families. 20 (2) An important factor of mutagenesis is the abundance of CpG dinucleotides, promoting C4T or G4A transitions. 21 BRCA1 and BRCA2 mutation spectra do not seem to be highly influenced by the CpG dinucleotide content, as most recurrent mutations are not transitions but small insertions/deletions.…”

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confidence: 99%

Breast and ovarian cancer predisposition due to de novo BRCA1 and BRCA2 mutations

et al. 2015

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BRCA1 and BRCA2 are the two major genes predisposing to breast and ovarian cancer. Whereas high de novo mutation rates have been demonstrated for several genes, only 11 cases of de novo BRCA1/2 mutations have been reported to date and the BRCA1/2 de novo mutation rate remains unknown. The present study was designed to fill this gap based on a series of 12 805 consecutive unrelated patients diagnosed with breast and/or ovarian cancer who met the inclusion criteria for BRCA1/2 gene analysis according to French guidelines. BRCA1/2 mutations were detected in 1527 (12%) patients, and three BRCA1 mutations and one BRCA2 mutation were de novo. The BRCA1/2 de novo mutation rate was estimated to be 0.3% (0.1%; 0.7%). Although rare, it may be useful to take the possibility of de novo BRCA1/2 mutation into account in genetic counseling of relatives and to improve the understanding of complex family histories of breast and ovarian cancers.

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Assessment of the prevalence of de novo mutations in the BRCA1 and BRCA2 genes

Cited by 7 publications

References 7 publications

Low-level constitutional mosaicism of a de novoBRCA1 gene mutation

Low-level constitutional mosaicism of a de novoBRCA1 gene mutation

Germline mutations in BRCA1, BRCA2, CHEK2 and TP53 in patients at high-risk for HBOC: characterizing a Northeast Brazilian Population

Breast and ovarian cancer predisposition due to de novo BRCA1 and BRCA2 mutations

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