Identification of Variants in Breast Cancer Susceptibility Genes and Determination of Functional and Clinical Significance of Novel Mutations
Annual rept. 30 Sep 2013-29 Sep 2014
TRUSTEES OF PENNSYLVANIA UNIV PHILADELPHIA PA
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Purpose Clinical testing for germline variation in multiple cancer susceptibility genes is available using massively parallel sequencing. Limited information is available for pre-test genetic counseling regarding the spectrum of mutations and variants of uncertain significance VUSs in defined patient populations. Methods We performed massively parallel sequencing using targeted capture of 22 cancer susceptibility genes in 278 BRCA12 negative patients with early onset breast cancer diagnosed under age 40. Results Thirty-one patients 11 were found to have at least one deleterious or likely deleterious variant. Seven patients 2.5 overall were found to have deleterious or likely deleterious variants in genes for which clinical guidelines exist for management, namely TP53 4, CDKN2A 1 MSH2 1, and MUTYH double heterozygote. Twenty-four patients 8.6 had deleterious or likely deleterious variants in a cancer susceptibility gene for which clinical guidelines are lacking, such as CHEK2 and ATM. Fifty-four patients 19 had at least one VUS, and six patients were heterozygous for a variant in MUTYH. Conclusion These data demonstrate that massively parallel sequencing identifies reportable variants in known cancer susceptibility genes in over 30 of patients with early onset breast cancer. However, only rare patients 2.5 have definitively actionable mutations given current clinical management guidelines.
- Genetic Engineering and Molecular Biology
- Medicine and Medical Research