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The BRCA1 c. 5096G>A p.Arg1699Gln (R1699Q) intermediate risk variant: breast and ovarian cancer risk estimation and recommendations for clinical management from the ENIGMA consortium

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  • Setareh Moghadasi
  • Huong D Meeks
  • Maaike Pg Vreeswijk
  • Linda Am Janssen
  • Åke Borg
  • Hans Ehrencrona
  • Ylva Paulsson-Karlsson
  • Barbara Wappenschmidt
  • Christoph Engel
  • Andrea Gehrig
  • Norbert Arnold
  • Thomas Van Overeem Hansen
  • Mads Thomassen
  • Uffe Birk Jensen
  • Torben A Kruse
  • Bent Ejlertsen
  • Anne-Marie Gerdes
  • Inge Søkilde Pedersen
  • Sandrine M Caputo
  • Fergus Couch
  • Emily J Hallberg
  • Ans Mw van den Ouweland
  • Margriet J Collée
  • Erik Teugels
  • Muriel A Adank
  • Rob B van der Luijt
  • Arjen R Mensenkamp
  • Jan C Oosterwijk
  • Marinus J Blok
  • Nicolas Janin
  • Kathleen Bm Claes
  • Kathy Tucker
  • Valeria Viassolo
  • Amanda Ewart Toland
  • Diana E Eccles
  • Peter Devilee
  • Christie J Van Asperen
  • Amanda B Spurdle
  • David E Goldgar
  • Encarna Gómez García
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BACKGROUND: We previously showed that the BRCA1 variant c.5096G>A p.Arg1699Gln (R1699Q) was associated with an intermediate risk of breast cancer (BC) and ovarian cancer (OC). This study aimed to assess these cancer risks for R1699Q carriers in a larger cohort, including follow-up of previously studied families, to further define cancer risks and to propose adjusted clinical management of female BRCA1*R1699Q carriers.

METHODS: Data were collected from 129 BRCA1*R1699Q families ascertained internationally by ENIGMA (Evidence-based Network for the Interpretation of Germline Mutant Alleles) consortium members. A modified segregation analysis was used to calculate BC and OC risks. Relative risks were calculated under both monogenic model and major gene plus polygenic model assumptions.

RESULTS: In this cohort the cumulative risk of BC and OC by age 70 years was 20% and 6%, respectively. The relative risk for developing cancer was higher when using a model that included the effects of both the R1699Q variant and a residual polygenic component compared with monogenic model (for BC 3.67 vs 2.83, and for OC 6.41 vs 5.83).

CONCLUSION: Our results confirm that BRCA1*R1699Q confers an intermediate risk for BC and OC. Breast surveillance for female carriers based on mammogram annually from age 40 is advised. Bilateral salpingo-oophorectomy should be considered based on family history.

Original languageEnglish
JournalJournal of Medical Genetics
Issue number1
Pages (from-to)15-20
Publication statusPublished - 2018

    Research areas

  • Journal Article

ID: 52152339