title: Strong evidence that the common variant S384F in BRCA2 has no pathogenic relevance in hereditary breast cancer.
abstract: BACKGROUND
  Unclassified variants (UVs) of unknown clinical significance are frequently detected in the BRCA2 gene. In this study, we have investigated the potential pathogenic relevance of the recurrent UV S384F (BRCA2, exon 10).
  
  
  METHODS
  For co-segregation, four women from a large kindred (BN326) suffering from breast cancer were analysed. Moreover, paraffin-embedded tumours from two patients were analysed for loss of heterozygosity. Co-occurrence of the variant with a deleterious mutation was further determined in a large data set of 43,029 index cases. Nature and position of the UV and conservation among species were evaluated.
  
  
  RESULTS
  We identified the unclassified variant S384F in three of the four breast cancer patients (the three were diagnosed at 41, 43 and 57 years of age). One woman with bilateral breast cancer (diagnosed at ages 32 and 50) did not carry the variant. Both tumours were heterozygous for the S384F variant, so loss of the wild-type allele could be excluded. Ser384 is not located in a region of functional importance and cross-species sequence comparison revealed incomplete conservation in the human, dog, rodent and chicken BRCA2 homologues. Overall, the variant was detected in 116 patients, five of which co-occurred with different deleterious mutations. The combined likelihood ratio of co-occurrence, co-segregation and loss of heterozygosity revealed a value of 1.4 x 10-8 in favour of neutrality of the variant.
  
  
  CONCLUSIONS
  Our data provide conclusive evidence that the S384F variant is not a disease causing mutation.
authors.affiliation: Department of Obstetrics and Gynaecology, University Hospital of Cologne, Cologne, Germany. barbara.wappenschmidt@uk-koeln.de
authors.forename: B
authors.initials: B
authors.lastname: Wappenschmidt
authors.forename: R
authors.initials: R
authors.lastname: Fimmers
authors.forename: K
authors.initials: K
authors.lastname: Rhiem
authors.forename: M
authors.initials: M
authors.lastname: Brosig
authors.forename: E
authors.initials: E
authors.lastname: Wardelmann
authors.forename: A
authors.initials: A
authors.lastname: Meindl
authors.forename: N
authors.initials: N
authors.lastname: Arnold
authors.forename: P
authors.initials: P
authors.lastname: Mallmann
authors.forename: R K
authors.initials: RK
authors.lastname: Schmutzler
mesh_terms: D000328:Adult; D019943:Amino Acid Substitution; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology*; D020090:Chromosome Segregation; D004273:DNA, Neoplasm / Q000235:genetics; D005260:Female; D007839:Functional Laterality; D014644:Genetic Variation; D018095:Germ-Line Mutation; D006801:Humans; D019656:Loss of Heterozygosity; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide
chemical_list: D004273:DNA, Neoplasm