title: Functional analysis of BRCA1 missense variants of uncertain significance in Japanese breast cancer families.
abstract: Germline mutations in the tumor suppressor genes BRCA1 and BRCA2 are responsible for a large proportion of familial breast cancer cases, and therefore, BRCA1 and BRCA2 genetic testing has become increasingly common in clinical practice. However, variants of uncertain significance (VUS) have been detected in 16.3% of Japanese patients suspected of having hereditary breast and ovarian cancers. The clinical importance of VUS is unknown, and their incidence has led to issues in risk counseling, assessment and treatment of cancer patients. In the present study, we performed functional analyses of two VUS in BRCA1, A1752G and Y1853C that were detected in two independent breast cancer patients who were suspected of having hereditary breast cancer. Segregation analysis revealed that Y1853C, but not A1752G, was cosegregated in affected family members. Conservation, transcription and structure analyses also supported the pathogenic potential of Y1853C. Detailed segregation and in silico and in vitro analyses will enhance our understanding of VUS and improve the management of cancer patients and their families.
authors.affiliation: Department of Medical Genetics, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
authors.forename: Shogo
authors.initials: S
authors.lastname: Kawaku
authors.forename: Rieko
authors.initials: R
authors.lastname: Sato
authors.forename: Hao
authors.initials: H
authors.lastname: Song
authors.forename: Yuko
authors.initials: Y
authors.lastname: Bando
authors.forename: Tadao
authors.initials: T
authors.lastname: Arinami
authors.forename: Emiko
authors.initials: E
authors.lastname: Noguchi
mesh_terms: D044466:Asian People; D001943:Breast Neoplasms / Q000208:ethnology / Q000235:genetics*; D005260:Female; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D020022:Genetic Predisposition to Disease; D006801:Humans; D008875:Middle Aged; D020125:Mutation, Missense; D010051:Ovarian Neoplasms / Q000235:genetics; D012307:Risk Factors