Sequencing-based functional assays for classification of BRCA2 variants in mouse ESCs

Author:

Biswas,Kajal

Mitrophanov,Alex

Sahu,Sounak

Sullivan,Teresa

Southon,Eileen

Nousome,Darryl

Reid, Susan

Narula, Sakshi

Smolen, Julia

Sengupta, Trisha

Riedel-Topper, Maximilian

Kapoor, Medha

Babbar, Anav

Stauffer,Stacey

Cleveland, Linda

Tandon, Mayank

Malys,Tyler

Sharan,Shyam
Author Address

Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA., Statistical Consulting and Scientific Programming, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA., Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA; Leidos Biomed Research Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA., Biomedical Informatics and Data Science, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA., Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA. Electronic address: sharans@mail.nih.gov.,

Abstract:

Sequencing of genes, such as BRCA1 and BRCA2, is recommended for individuals with a personal or family history of early onset and/or bilateral breast and/or ovarian cancer or a history of male breast cancer. Such sequencing efforts have resulted in the identification of more than 17,000 BRCA2 variants. The functional significance of most variants remains unknown; consequently, they are called variants of uncertain clinical significance (VUSs). We have previously developed mouse embryonic stem cell (mESC)-based assays for functional classification of BRCA2 variants. We now developed a next-generation sequencing (NGS)-based approach for functional evaluation of BRCA2 variants using pools of mESCs expressing 10-25 BRCA2 variants from a given exon. We use this approach for functional evaluation of 223 variants listed in ClinVar. Our functional classification of BRCA2 variants is concordant with the classification reported in ClinVar or those reported by other orthogonal assays. Published by Elsevier Inc.

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