title: Screening for the BRCA1-ins6kbEx13 mutation: potential for misdiagnosis. Mutation in brief #964. Online.
abstract: Misdiagnosis of a germline mutation associated with an inherited disease syndrome can have serious implications for the clinical management of patients. A false negative diagnosis (mutation missed by genetic screening) limits decision making about intervention strategies within families. More serious is the consequence of a false positive diagnosis (genetic test suggesting a mutation is present when it is not). This could lead to an individual, falsely diagnosed as a mutation carrier, undergoing unnecessary clinical intervention, possibly involving risk-reducing surgery. As part of screening 283 ovarian cancer families for BRCA1 mutations, we used two different methods (mutation specific PCR and multiplex ligation-dependent probe amplification) to screen for a known rearrangement mutation L78833.1:g.44369_50449dup (ins6kbEx13). We found false positive and false negative results in several families. We then tested 61 known carriers or non-carriers from an epidemiological study of BRCA1 and BRCA2 mutation carriers (the EMBRACE study). These data highlight the need for caution when interpreting analyses of the ins6kbEx13 mutation and similar mutations, where characterising the exact sequence alteration for a deleterious mutation is not a part of the routine genetic test.
authors.affiliation: Translational Research Laboratory, Institute for Women's Health, University College London, United Kingdom. s.ramus@ucl.ac.uk
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Ramus
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Harrington
authors.forename: Carole
authors.initials: C
authors.lastname: Pye
authors.forename: Susan
authors.initials: S
authors.lastname: Peock
authors.forename: Margaret R
authors.initials: MR
authors.lastname: Cook
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Cox
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Jacobs
authors.forename: Richard A
authors.initials: RA
authors.lastname: DiCioccio
authors.forename: Alice S
authors.initials: AS
authors.lastname: Whittemore
authors.forename: M Steven
authors.initials: MS
authors.lastname: Piver
authors.lastname: EMBRACE
authors.forename: Douglas F
authors.initials: DF
authors.lastname: Easton
authors.forename: Bruce A J
authors.initials: BA
authors.lastname: Ponder
authors.forename: Paul D P
authors.initials: PD
authors.lastname: Pharoah
authors.forename: Simon A
authors.initials: SA
authors.lastname: Gayther
mesh_terms: D005188:False Negative Reactions; D005189:False Positive Reactions; D005260:Female; D019398:Genes, BRCA1; D006580:Genetic Carrier Screening; D005820:Genetic Testing; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D010051:Ovarian Neoplasms / Q000235:genetics; D010375:Pedigree; D016133:Polymerase Chain Reaction