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J Med Genet. 2007 August; 44(8): e88.
PMCID: PMC2597936

Response to correspondence on “Phenocopies in BRCA1 and BRCA2 families: evidence for modifier genes and implications for screening”

We wish to reply to the interesting comments concerning our paper on phenocopies in families positive for mutations in BRCA1/2 genes since its electronic publication in October 2006.1 We understand the reservations about changing practice in reassuring individuals who test negative for a family mutation based on one largely retrospective analysis of families, and clearly there is a need to confirm our results in other large series. We were particularly careful to obviate potential biases in our analyses.

We would prefer that the interpretation of our article is based on the final detailed analysis of type A1 phenocopies, which yielded a relative risk of three‐fold, equivalent to a doubling of lifetime risk. We would not suggest screening before the age of 35 years for individuals in this category, and certainly not as early as suggested in one response.2 We agree that ultimately our study needs to be confirmed in prospective analysis, before widespread change in practice. However, we are convinced that two potential biases do not contribute substantially to our original figures.2,3,4

We were also concerned that identification of families for mutation testing could have occurred because high‐risk selection finds more families with chance breast cancers.2,3 If this were the case, the ratio of first‐degree relatives (FDR) with breast cancer who tested negative for the family mutation should be higher before family ascertainment than afterwards. We have carried out an analysis of our enhanced dataset, now containing 52 breast cancer phenocopies. The ratio of phenocopies amongst FDR remains constant at 17% both before and after family ascertainment and after a mutation has been identified in the family. We also do not believe that extra mammography has made a substantial contribution;4 the majority of phenocopy cancers were not detected by screening mammography. In particular, after genetic testing women were discharged from extra mammographic surveillance, which may have had the opposite effect by removing the lead time to diagnosis (if involved in screening there would be a delay to diagnosis if screening is stopped). More detailed analysis is under way in order to help determine which family structures are likely to contain phenocopies and where the extra risk pertains.3


Competing interests: None declared.


1. Smith A, Moran A, Boyd M C, Bulman M, Shenton A, Smith L, Iddenden I, Woodward E, Lalloo F, Rahman N, Maher E R, Evans D G R. The trouble with phenocopies: are those testing negative for a family BRCA1/2 mutation really at population risk? J Med Genet 2007. 4410–15.15 [PMC free article] [PubMed]
2. Tilanus‐Linthorst M. No screening yet after a negative test for the family mutation. J Med Genet 2007. 44e79 [PMC free article] [PubMed]
3. Goldgar D, Venne V, Conner T, Buys S. BRCA phenocopies or ascertainment bias? J Med Genet 2007. 44e86 [PMC free article] [PubMed]
4. Eisinger F. Phenocopies: actual risk or self‐fulfilling prophecy? J Med Genet 2007. 44e87 [PMC free article] [PubMed]

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