title: Clinical and molecular characterization of the BRCA2 p.Asn3124Ile variant reveals substantial evidence for pathogenic significance.
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.
authors.affiliation: Division Molecular Biology of Breast Cancer, Department of Gynecology and Obstetrics, University of Heidelberg, Im Neuenheimer Feld 440, 69120, Heidelberg, Germany, h.surowy@dkfz-heidelberg.de.
authors.forename: Harald Martin
authors.initials: HM
authors.lastname: Surowy
authors.forename: Christian
authors.initials: C
authors.lastname: Sutter
authors.forename: Max
authors.initials: M
authors.lastname: Mittnacht
authors.forename: Ruediger
authors.initials: R
authors.lastname: Klaes
authors.forename: Dieter
authors.initials: D
authors.lastname: Schaefer
authors.forename: Christina
authors.initials: C
authors.lastname: Evers
authors.forename: Anna Lena
authors.initials: AL
authors.lastname: Burgemeister
authors.forename: Caroline
authors.initials: C
authors.lastname: Goehringer
authors.forename: Nicola
authors.initials: N
authors.lastname: Dikow
authors.forename: Joerg
authors.initials: J
authors.lastname: Heil
authors.forename: Michael
authors.initials: M
authors.lastname: Golatta
authors.forename: Sarah
authors.initials: S
authors.lastname: Schott
authors.forename: Andreas
authors.initials: A
authors.lastname: Schneeweiss
authors.forename: Peter
authors.initials: P
authors.lastname: Bugert
authors.forename: Christof
authors.initials: C
authors.lastname: Sohn
authors.forename: Claus Rainer
authors.initials: CR
authors.lastname: Bartram
authors.forename: Barbara
authors.initials: B
authors.lastname: Burwinkel
mesh_terms: D019943:Amino Acid Substitution; D019313:BRCA1 Protein / Q000235:genetics; D024682:BRCA2 Protein / Q000737:chemistry / Q000235:genetics*; D001943:Breast Neoplasms / Q000235:genetics*; D018567:Breast Neoplasms, Male / Q000235:genetics; D016022:Case-Control Studies; D003198:Computer Simulation; D005260:Female; D020022:Genetic Predisposition to Disease; D005858:Germany; D006801:Humans; D008297:Male; D009154:Mutation; D020125:Mutation, Missense; D010051:Ovarian Neoplasms / Q000235:genetics; D010375:Pedigree
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D024682:BRCA2 Protein; C551750:BRCA2 protein, human