Clinical and molecular characterization of the BRCA2 p.Asn3124Ile variant reveals substantial evidence for pathogenic significance View Full Text


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Article Info

DATE

2014-06

AUTHORS

Harald Martin Surowy, Christian Sutter, Max Mittnacht, Ruediger Klaes, Dieter Schaefer, Christina Evers, Anna Lena Burgemeister, Caroline Goehringer, Nicola Dikow, Joerg Heil, Michael Golatta, Sarah Schott, Andreas Schneeweiss, Peter Bugert, Christof Sohn, Claus Rainer Bartram, Barbara Burwinkel

ABSTRACT

Variants of uncertain clinical significance (VUS) in the high-penetrance breast cancer susceptibility genes BRCA1 and BRCA2 represent a major obstacle in genetic counseling of high-risk breast cancer families. We analyzed a missense VUS located in BRCA2 (p.Asn3124Ile; HGVS: BRCA2 c.9371A > T) present in seven independent high-risk breast cancer families that were counseled and genetically tested in South-West Germany. The VUS was identified by DNA sequencing. We analyzed co-occurrence with deleterious BRCA1/2 mutations, segregation, evolutionary conservation, in silico impact prediction, and prevalence in the general population. All carriers of the VUS suffered from breast or ovarian cancer. In two families, an additional high burden of other cancers such as pancreatic, prostate, and gastric cancers was reported, one further family included two cases of male breast cancer. The VUS did not co-occur with deleterious BRCA1/2 mutations and segregated in two affected individuals of one family. In contrast to the 7/1,347 (0,5 %) tested high-risk BC families without clearly pathogenic mutations in BRCA1/2, none of 3,126 healthy population controls sharing the same ethnic and geographical background were found to carry this VUS (p = 0.0002). In-silico prediction revealed strong evolutionary conservation of the asparagine residue, residing in the C-terminal oligonucleotide-binding-fold-3 region, and a most likely damaging impact of this exchange on the protein structure. The BRCA2 p.Asn3124Ile (BRCA2 c.9371A > T) variant is a rare mutation with a damaging effect on the BRCA2 protein that is strongly associated with familial breast and ovarian cancer risk, indicating its most likely pathogenic nature and clinical relevance. More... »

PAGES

451-460

References to SciGraph publications

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  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1007/s10549-014-2943-5

    DOI

    http://dx.doi.org/10.1007/s10549-014-2943-5

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1016042485

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/24728577


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