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Characterization of BRCA1 and BRCA2 splicing variants: a collaborative report by ENIGMA consortium members

Overview of attention for article published in Breast Cancer Research and Treatment, July 2011
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Title
Characterization of BRCA1 and BRCA2 splicing variants: a collaborative report by ENIGMA consortium members
Published in
Breast Cancer Research and Treatment, July 2011
DOI 10.1007/s10549-011-1674-0
Pubmed ID
Authors

Mads Thomassen, Ana Blanco, Marco Montagna, Thomas V. O. Hansen, Inge S. Pedersen, Sara Gutiérrez-Enríquez, Mireia Menéndez, Laura Fachal, Marta Santamariña, Ane Y. Steffensen, Lars Jønson, Simona Agata, Phillip Whiley, Silvia Tognazzo, Eva Tornero, Uffe B. Jensen, Judith Balmaña, Torben A. Kruse, David E. Goldgar, Conxi Lázaro, Orland Diez, Amanda B. Spurdle, Ana Vega

Abstract

Mutations in BRCA1 and BRCA2 predispose carriers to early onset breast and ovarian cancer. A common problem in clinical genetic testing is interpretation of variants with unknown clinical significance. The Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) consortium was initiated to evaluate and implement strategies to characterize the clinical significance of BRCA1 and BRCA2 variants. As an initial project of the ENIGMA Splicing Working Group, we report splicing and multifactorial likelihood analysis of 25 BRCA1 and BRCA2 variants from seven different laboratories. Splicing analysis was performed by reverse transcriptase PCR or mini gene assay, and sequencing to identify aberrant transcripts. The findings were compared to bioinformatic predictions using four programs. The posterior probability of pathogenicity was estimated using multifactorial likelihood analysis, including co-occurrence with a deleterious mutation, segregation and/or report of family history. Abnormal splicing patterns expected to lead to a non-functional protein were observed for 7 variants (BRCA1 c.441+2T>A, c.4184_4185+2del, c.4357+1G>A, c.4987-2A>G, c.5074G>C, BRCA2 c.316+5G>A, and c.8754+3G>C). Combined interpretation of splicing and multifactorial analysis classified an initiation codon variant (BRCA2 c.3G>A) as likely pathogenic, uncertain clinical significance for 7 variants, and indicated low clinical significance or unlikely pathogenicity for another 10 variants. Bioinformatic tools predicted disruption of consensus donor or acceptor sites with high sensitivity, but cryptic site usage was predicted with low specificity, supporting the value of RNA-based assays. The findings also provide further evidence that clinical RNA-based assays should be extended from analysis of invariant dinucleotides to routinely include all variants located within the donor and acceptor consensus splicing sites. Importantly, this study demonstrates the added value of collaboration between laboratories, and across disciplines, to collate and interpret information from clinical testing laboratories to consolidate patient management.

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Mendeley readers

The data shown below were compiled from readership statistics for 91 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
United States 2 2%
Canada 1 1%
Brazil 1 1%
Japan 1 1%
Romania 1 1%
Unknown 85 93%

Demographic breakdown

Readers by professional status Count As %
Student > Ph. D. Student 21 23%
Researcher 14 15%
Student > Doctoral Student 9 10%
Other 8 9%
Student > Postgraduate 7 8%
Other 23 25%
Unknown 9 10%
Readers by discipline Count As %
Biochemistry, Genetics and Molecular Biology 25 27%
Agricultural and Biological Sciences 24 26%
Medicine and Dentistry 18 20%
Immunology and Microbiology 2 2%
Computer Science 2 2%
Other 8 9%
Unknown 12 13%
Attention Score in Context

Attention Score in Context

This research output has an Altmetric Attention Score of 1. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 04 October 2012.
All research outputs
#18,316,001
of 22,679,690 outputs
Outputs from Breast Cancer Research and Treatment
#3,681
of 4,618 outputs
Outputs of similar age
#99,157
of 119,352 outputs
Outputs of similar age from Breast Cancer Research and Treatment
#45
of 53 outputs
Altmetric has tracked 22,679,690 research outputs across all sources so far. This one is in the 11th percentile – i.e., 11% of other outputs scored the same or lower than it.
So far Altmetric has tracked 4,618 research outputs from this source. They typically receive a little more attention than average, with a mean Attention Score of 7.2. This one is in the 11th percentile – i.e., 11% of its peers scored the same or lower than it.
Older research outputs will score higher simply because they've had more time to accumulate mentions. To account for age we can compare this Altmetric Attention Score to the 119,352 tracked outputs that were published within six weeks on either side of this one in any source. This one is in the 7th percentile – i.e., 7% of its contemporaries scored the same or lower than it.
We're also able to compare this research output to 53 others from the same source and published within six weeks on either side of this one. This one is in the 1st percentile – i.e., 1% of its contemporaries scored the same or lower than it.