Breast Cancer Research and Treatment

, Volume 151, Issue 2, pp 475–476 | Cite as

Interpretation of genomic variation and disease association: the great missense mutation challenge!

  • Tú Nguyen-Dumont
  • Ingrid Winship
  • Melissa C. Southey
Letter to the Editor

To the Editor,

The recent report from Downs et al. (April 2, 2015) illustrates the enormous challenge faced by researchers who are trying to identify germline genetic variants associated with breast cancer risk from the vast array of human genetic variation that is identified via whole exome capture and massively parallel sequencing (or similar). We are concerned that the current report lacks adequate attention to the detail required for genomic data filtering and interpretation in a study of this nature and has led to the overstatement that the two reported missense variants in PALB2, namely c.2014G>C p.E672Q and c.2993G>A p.G998E, are associated with breast cancer risk.

Despite the text describing them as “novel”, these variants have been reported in a number of previous studies at a frequency highly unlikely to be compatible with an autosomal dominantly inherited breast cancer genetic risk factor. Indeed, at an observed MAF of 0.024 and 0.018 for c.2014G>C and c.2993G>A,...


Breast Cancer Breast Cancer Risk Missense Mutation BRCA1 Mutation Carrier Missense Variant 
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  1. 1.
    Nguyen-Dumont T, Hammet F, Mahmoodi M et al (2015) Mutation screening of PALB2 in clinically ascertained families from the Breast Cancer Family Registry. Breast Cancer Res Treat 149(2):547–554. doi: 10.1007/s10549-014-3260-8 CrossRefPubMedGoogle Scholar
  2. 2.
    Antoniou AC, Casadei S, Heikkinen T et al (2014) Breast-cancer risk in families with mutations in PALB2. N Engl J Med 371(6):497–506. doi: 10.1056/NEJMoa1400382 CrossRefPubMedCentralPubMedGoogle Scholar
  3. 3.
    Southey MC, Park DJ, Nguyen-Dumont T et al (2013) COMPLEXO: identifying the missing heritability of breast cancer via next generation collaboration. Breast Cancer Res 15(3):402. doi: 10.1186/bcr3434 PubMedCentralPubMedGoogle Scholar
  4. 4. Accessed 16 April 2015

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Tú Nguyen-Dumont
    • 1
  • Ingrid Winship
    • 2
    • 3
  • Melissa C. Southey
    • 1
  1. 1.Genetic Epidemiology Laboratory, Department of PathologyThe University of MelbourneMelbourneAustralia
  2. 2.Department of MedicineThe University of MelbourneMelbourneAustralia
  3. 3.The Royal Melbourne HospitalParkvilleAustralia

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