The effects of BRCA1 missense variants V1804D and M1628T on transcriptional activity

Cancer Genetics and Cytogenetics
Kimberly Laskie OstrowRichard A DiCioccio

Abstract

Many families with multiple cases of ovarian cancer, breast cancer, or both segregate inherited mutations in one allele of the tumor suppressor gene BRCA1. Genetic testing is used to assess cancer risk; however, testing can detect missense DNA alterations, called unclassified variants, of unknown functional and biological significance with uncertain risk implications. Some missense variants at the transcriptional activation domain of BRCA1 of cancer patients inactivate transcriptional activity of BRCA1, providing evidence that they are deleterious. We identified the variants V1804D and M1628T at the transcriptional activation domain of BRCA1 of two ovarian cancer patients without a family history of ovarian or breast cancer. To test if these residues are critical for transcriptional activation, we created V1804D and M1628T independently in BRCA1 cDNA via site-directed mutagenesis in a mammalian expression vector, pcDNA3.1. Wild-type, mutant, and empty vector constructs were tested in human kidney 293 cells using a p53-responsive luciferase reporter. M1628T had the same transcriptional activity as wild-type BRCA1 but V1804D and the empty vector control showed a 60% reduction. This indicates that V1804D is deleterious but M1628T ...Continue Reading

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Citations

Jan 10, 2012·Breast Cancer Research and Treatment·Michelle G RathBarbara Burwinkel
Jun 1, 2005·Journal of Medical Genetics·P K LovelockUNKNOWN kConFab Investigators
Oct 20, 2015·Molecular Diagnosis & Therapy·Elisabete Weiderpass, Jerzy E Tyczynski
Feb 21, 2006·Cancer Research·Georgia Chenevix-TrenchUNKNOWN kConFab Investigators

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