title: The BRCA2 polymorphic stop codon: stuff or nonsense?
abstract: BACKGROUND
  Despite classification of the BRCA2c.9976A>T, p.(Lys3326Ter) variant as a polymorphism, it has been associated with increased risks of pancreatic, lung, oesophageal and breast cancer.
  
  
  METHODS
  We have noticed multiple co-occurrences of the BRCA2 c.9976A>T variant with the pathogenic BRCA2c.6275_6276delTT frameshift mutation p.(Leu2092ProfsTer7) and using a cohort study have assessed if this might account for these tumour risk associations.
  
  
  RESULTS
  We identified 52 families with BRCA2c.6275_6276delTT, all of which occur in cis with the BRCA2c.9976A>T variant allele as demonstrated by co-segregation in all family members tested. Of 3245 breast/ovarian cancer samples sequenced for BRCA2, only 43/3245 (1.3%) carried BRCA2 c.9976A>T alone, after excluding individuals with BRCA2c.6275_6276delTT (n=22) or other BRCA1 (n=3) or BRCA2 (n=2) pathogenic mutations. The resultant frequency (1.3%) after removal of co-occurring mutations is lower than the 1.7% and 1.67% frequencies from two control populations for BRCA2 c.9976A>T, but similar to the 1.39% seen in the Exome Aggregation Consortium database. We did not identify increased frequencies of oesophageal, pancreatic or lung cancer in families with just BRCA2 c.9976A>T using person-years at risk analysis.
  
  
  CONCLUSIONS
  It is likely that the previous associations of increased cancer risks due to BRCA2c.9976A>T represent reporting bias and are contributed to because the variant is in LD with BRCA2c.6275_6276delTT.
authors.affiliation: Manchester Centre for Genomic Medicine, Manchester Academic Health Sciences Centre, Institute of Human Development, University of Manchester and Central Manchester Foundation Trust, Manchester, UK.
authors.forename: J E
authors.initials: JE
authors.lastname: Higgs
authors.affiliation: Centre for Imaging Sciences, Institute for Population Health, University of Manchester, Manchester, UK.
authors.forename: E F
authors.initials: EF
authors.lastname: Harkness
authors.affiliation: Manchester Centre for Genomic Medicine, Manchester Academic Health Sciences Centre, Institute of Human Development, University of Manchester and Central Manchester Foundation Trust, Manchester, UK.
authors.forename: N L
authors.initials: NL
authors.lastname: Bowers
authors.affiliation: Manchester Centre for Genomic Medicine, Manchester Academic Health Sciences Centre, Institute of Human Development, University of Manchester and Central Manchester Foundation Trust, Manchester, UK.
authors.forename: E
authors.initials: E
authors.lastname: Howard
authors.affiliation: Manchester Centre for Genomic Medicine, Manchester Academic Health Sciences Centre, Institute of Human Development, University of Manchester and Central Manchester Foundation Trust, Manchester, UK.
authors.forename: A J
authors.initials: AJ
authors.lastname: Wallace
authors.affiliation: Manchester Centre for Genomic Medicine, Manchester Academic Health Sciences Centre, Institute of Human Development, University of Manchester and Central Manchester Foundation Trust, Manchester, UK.
authors.forename: F
authors.initials: F
authors.lastname: Lalloo
authors.affiliation: Manchester Centre for Genomic Medicine, Manchester Academic Health Sciences Centre, Institute of Human Development, University of Manchester and Central Manchester Foundation Trust, Manchester, UK.
authors.forename: W G
authors.initials: WG
authors.lastname: Newman
authors.affiliation: Manchester Centre for Genomic Medicine, Manchester Academic Health Sciences Centre, Institute of Human Development, University of Manchester and Central Manchester Foundation Trust, Manchester, UK Genesis Breast Cancer Prevention Centre and Nightingale Breast Screening Centre, University Hospital of South Manchester, Manchester, UK.
authors.forename: D G
authors.initials: DG
authors.lastname: Evans
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics; D018388:Codon, Terminator; D004938:Esophageal Neoplasms / Q000235:genetics; D005060:Europe; D005260:Female; D016368:Frameshift Mutation; D024522:Genes, BRCA2; D020022:Genetic Predisposition to Disease; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics; D008297:Male; D010190:Pancreatic Neoplasms / Q000235:genetics; D020641:Polymorphism, Single Nucleotide
chemical_list: D018388:Codon, Terminator
keywords: BRCA2 polymorphic stop codon; Cancer: breast; Cancer: lung; Cancer: oesophageal; Cancer: pancreatic