The predictive ability of the 313 variant-based polygenic risk score for contralateral breast cancer risk prediction in women of European ancestry with a heterozygous BRCA1 or BRCA2 pathogenic variant

Inge M. M. Lakeman, Alexandra J. van den Broek, Julien A. M. Vos, Daniel R. Barnes, Julian Adlard, Irene L. Andrulis, Adalgeir Arason, Norbert Arnold, Banu K. Arun, Judith Balmana, Daniel Barrowdale, Javier Benitez, Ake Borg, Trinidad Caldes, Maria A. Caligo, Wendy K. Chung, Kathleen B. M. Claes, J. Margriet Collee, Fergus J. Couch, Mary B. DalyJoe Dennis, Mallika Dhawan, Susan M. Domchek, Ros Eeles, Christoph Engel, D. Gareth Evans, Lidia Feliubadalo, Lenka Foretova, Eitan Friedman, Debra Frost, Patricia A. Ganz, Judy Garber, Simon A. Gayther, Anne-Marie Gerdes, Andrew K. Godwin, David E. Goldgar, Eric Hahnen, Christopher R. Hake, Ute Hamann, Frans B. L. Hogervorst, Maartje J. Hooning, John L. Hopper, Peter J. Hulick, Evgeny N. Imyanitov, Claudine Isaacs, Louise Izatt, Anna Jakubowska, Paul A. James, Ramunas Janavicius, Uffe Birk Jensen, GEMO Study Collaborators, EMBRACE Collaborators, OCGN Investigators, HEBON Investigators, Marinus Blok, Encarna Gomez Garcia, KConFab Investigators, Marjanka K. Schmidt*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

5 Citations (Web of Science)


Purpose To evaluate the association between a previously published 313 variant-based breast cancer (BC) polygenic risk score (PRS313) and contralateral breast cancer (CBC) risk, in BRCA1 and BRCA2 pathogenic variant heterozygotes. Methods We included women of European ancestry with a prevalent first primary invasive BC (BRCA1 = 6,591 with 1,402 prevalent CBC cases; BRCA2 = 4,208 with 647 prevalent CBC cases) from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), a large international retrospective series. Cox regression analysis was performed to assess the association between overall and ER-specific PRS313 and CBC risk. Results For BRCA1 heterozygotes the estrogen receptor (ER)-negative PRS313 showed the largest association with CBC risk, hazard ratio (HR) per SD = 1.12, 95% confidence interval (CI) (1.06-1.18), C-index = 0.53; for BRCA2 heterozygotes, this was the ER-positive PRS313, HR = 1.15, 95% CI (1.07-1.25), C-index = 0.57. Adjusting for family history, age at diagnosis, treatment, or pathological characteristics for the first BC did not change association effect sizes. For women developing first BC < age 40 years, the cumulative PRS313 5th and 95th percentile 10-year CBC risks were 22% and 32% for BRCA1 and 13% and 23% for BRCA2 heterozygotes, respectively. Conclusion The PRS313 can be used to refine individual CBC risks for BRCA1/2 heterozygotes of European ancestry, however the PRS313 needs to be considered in the context of a multifactorial risk model to evaluate whether it might influence clinical decision-making.

Original languageEnglish
Pages (from-to)1726-1737
Number of pages12
JournalGenetics in Medicine
Issue number9
Publication statusPublished - Sept 2021



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