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01.06.2014 | Epidemiology

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

verfasst von: 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

Erschienen in: Breast Cancer Research and Treatment | Ausgabe 2/2014

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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.

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Titel: Clinical and molecular characterization of the BRCA2 p.Asn3124Ile variant reveals substantial evidence for pathogenic significance
verfasst von: 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
Publikationsdatum: 01.06.2014
Verlag: Springer US
Erschienen in: Breast Cancer Research and Treatment / Ausgabe 2/2014
Print ISSN: 0167-6806
Elektronische ISSN: 1573-7217
DOI: https://doi.org/10.1007/s10549-014-2943-5

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

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Müde im Alter? Auch an die Nebenniere denken

Stufenschema weist Prostatakarzinom zuverlässig nach

Update Onkologie