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Mismatch repair gene pathogenic germline variants in a population-based cohort of breast cancer


The advent of gene panel testing is challenging the previous practice of using clinically defined cancer family syndromes to inform single-gene genetic screening. Individual and family cancer histories that would have previously indicated testing of a single gene or a small number of related genes are now, increasingly, leading to screening across gene panels that contain larger numbers of genes. We have applied a gene panel test that included four DNA mismatch repair (MMR) genes (MLH1, MSH2, MSH6 and PMS2) to an Australian population-based case–control-family study of breast cancer. Altogether, eight pathogenic variants in MMR genes were identified: six in 1421 case-families (0.4%, 4 MSH6 and 2 PMS2) and two in 833 control-families (0.2%, one each of MLH1 and MSH2). This testing highlights the current and future challenges for clinical genetics in the context of anticipated gene panel-based population-based screening that includes the MMR genes. This testing is likely to provide additional opportunities for cancer prevention via cascade testing for Lynch syndrome and precision medicine for breast cancer treatment.

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This work was supported by the U.S. National Institute of Health (Grant Number RO1CA159868). The ABCFR was supported in Australia by the National Health and Medical Research Council, the New South Wales Cancer Council, the Victorian Health Promotion Foundation, the Victorian Breast Cancer Research Consortium, Cancer Australia, and the National Breast Cancer Foundation. The six sites of the Breast Cancer Family Registry (BCFR) were supported by grant UM1 CA164920 from the U.S. National Cancer Institute. The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the BCFR, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government or the BCFR. TN-D a National Breast Cancer Foundation (Australia) Career Development Fellow (ECF-17-001). BJP is the recipient of a Victorian Health and Medical Research Fellowship. MCS is a National Health and Medical Research Council (NMHRC, Australia) Senior Research Fellow (APP1155163). This work was supported by an NHMRC Program grant (APP1074383), The National Breast Cancer Foundation (BRA-STRAP; NT-15-016), NHMRC European Union Collaborative Research Grant (APP1101400) and Monash University, Melbourne, Australia. We thank all the participants in this study, the entire team of Australian Breast Cancer Family Registry (BCFR-AU) and past and current investigators. We thank Dr Bryony Thompson, Royal Melbourne Hospital, Melbourne Australia, for input into MMR gene variant classification.

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Correspondence to Melissa C. Southey.

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Nguyen-Dumont, T., Steen, J.A., Winship, I. et al. Mismatch repair gene pathogenic germline variants in a population-based cohort of breast cancer. Familial Cancer 19, 197–202 (2020).

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  • Familial cancer
  • Breast cancer predisposition
  • Gene panel testing
  • Lynch syndrome
  • DNA mismatch repair