Grant Details
Grant Number: |
1U01CA242954-01 Interpret this number |
Primary Investigator: |
Cline, Melissa |
Organization: |
University Of California Santa Cruz |
Project Title: |
Eliminating Variants of Uncertain Significance in BRCA1, Brca2 and Beyond |
Fiscal Year: |
2019 |
Abstract
Abstract
By current evidence, roughly one-third of all cancers are driven in part by germline variation. Genetic testing
now enables individuals and their doctors to better understand and manage their genetic cancer risk.
However, the effectiveness of these tests is limited by the many gaps in our knowledge about the clinical
impact of individual variants. Even in the well-studiedBRCA1 and BRCA2 genes, 7280 of the 17156 variants
currently in ClinVar are listed as “Variants of Uncertain Significance” (VUS). VUS test reports leave patients
with anxiety, and often lead to clinical mismanagement: many doctors frequently recommend bilateral
mastectomies for patients with uncertain variants, even though many of those variants will turn out to be
benign. Genetic testing will not reach its potential while VUS test reports are still frequent, yet with global data
sharing, novel functional screens, and integrative data analysis methods, we can envisage eliminating the VUS
problem. We will produce methods for secure data sharing, and integrative analysis that leverages highly
predictive modern functional assays. We will demonstrate these approaches on BRCA1 and BRCA2, while
outlining their application to other high-penetrance cancer susceptibility genes. We will develop APIs to
integrate this new knowledge into the ClinGen and CIViC repositories, to benefit the larger research
community. Finally, we will extend the integrative data visualization of BRCA Exchange to additional genes
implicated in breast, ovarian and colorectal cancers, which will ultimately benefit tens of thousands of cancer
patients and previvors.
Publications
Mapping MAVE data for use in human genomics applications.
Authors: Arbesfeld J.A.
, Da E.Y.
, Stevenson J.S.
, Kuzma K.
, Paul A.
, Farris T.
, Capodanno B.J.
, Grindstaff S.B.
, Riehle K.
, Saraiva-Agostinho N.
, et al.
.
Source: Biorxiv : The Preprint Server For Biology, 2024-06-30 00:00:00.0; , .
EPub date: 2024-06-30 00:00:00.0.
PMID: 38979347
Related Citations
Federated Analysis for Privacy-Preserving Data Sharing: A Technical and Legal Primer.
Authors: Casaletto J.
, Bernier A.
, McDougall R.
, Cline M.S.
.
Source: Annual Review Of Genomics And Human Genetics, 2023-08-25 00:00:00.0; 24, p. 347-368.
EPub date: 2023-05-30 00:00:00.0.
PMID: 37253596
Related Citations
An Atlas of Variant Effects to understand the genome at nucleotide resolution.
Authors: Fowler D.M.
, Adams D.J.
, Gloyn A.L.
, Hahn W.C.
, Marks D.S.
, Muffley L.A.
, Neal J.T.
, Roth F.P.
, Rubin A.F.
, Starita L.M.
, et al.
.
Source: Genome Biology, 2023-07-03 00:00:00.0; 24(1), p. 147.
EPub date: 2023-07-03 00:00:00.0.
PMID: 37394429
Related Citations
Development and application of a computable genotype model in the GA4GH Variation Representation Specification.
Authors: Goar W.
, Babb L.
, Chamala S.
, Cline M.
, Freimuth R.R.
, Hart R.K.
, Kuzma K.
, Lee J.
, Nelson T.
, Prlić A.
, et al.
.
Source: Pacific Symposium On Biocomputing. Pacific Symposium On Biocomputing, 2023; 28, p. 383-394.
PMID: 36540993
Related Citations
Modeling the impact of data sharing on variant classification.
Authors: Casaletto J.
, Cline M.
, Shirts B.
.
Source: Journal Of The American Medical Informatics Association : Jamia, 2022-11-30 00:00:00.0; , .
EPub date: 2022-11-30 00:00:00.0.
PMID: 36451272
Related Citations
Federated analysis of BRCA1 and BRCA2 variation in a Japanese cohort.
Authors: Casaletto J.
, Parsons M.
, Markello C.
, Iwasaki Y.
, Momozawa Y.
, Spurdle A.B.
, Cline M.
.
Source: Cell Genomics, 2022-03-09 00:00:00.0; 2(3), .
PMID: 35373174
Related Citations
U.S. Adult Perspectives on Facial Images, DNA, and Other Biometrics.
Authors: Katsanis S.H.
, Claes P.
, Doerr M.
, Cook-Deegan R.
, Tenenbaum J.D.
, Evans B.J.
, Lee M.K.
, Anderton J.
, Weinberg S.M.
, Wagner J.K.
.
Source: Ieee Transactions On Technology And Society, 2022 Mar; 3(1), p. 9-15.
EPub date: 2021-10-18 00:00:00.0.
PMID: 35360665
Related Citations
Closing the gap: Systematic integration of multiplexed functional data resolves variants of uncertain significance in BRCA1, TP53, and PTEN.
Authors: Fayer S.
, Horton C.
, Dines J.N.
, Rubin A.F.
, Richardson M.E.
, McGoldrick K.
, Hernandez F.
, Pesaran T.
, Karam R.
, Shirts B.H.
, et al.
.
Source: American Journal Of Human Genetics, 2021-12-02 00:00:00.0; 108(12), p. 2248-2258.
EPub date: 2021-11-17 00:00:00.0.
PMID: 34793697
Related Citations
GA4GH: International policies and standards for data sharing across genomic research and healthcare.
Authors: Rehm H.L.
, Page A.J.H.
, Smith L.
, Adams J.B.
, Alterovitz G.
, Babb L.J.
, Barkley M.P.
, Baudis M.
, Beauvais M.J.S.
, Beck T.
, et al.
.
Source: Cell Genomics, 2021-11-10 00:00:00.0; 1(2), .
PMID: 35072136
Related Citations
International federation of genomic medicine databases using GA4GH standards.
Authors: Thorogood A.
, Rehm H.L.
, Goodhand P.
, Page A.J.H.
, Joly Y.
, Baudis M.
, Rambla J.
, Navarro A.
, Nyronen T.H.
, Linden M.
, et al.
.
Source: Cell Genomics, 2021-11-10 00:00:00.0; 1(2), .
PMID: 35128509
Related Citations
The GA4GH Variation Representation Specification: A computational framework for variation representation and federated identification.
Authors: Wagner A.H.
, Babb L.
, Alterovitz G.
, Baudis M.
, Brush M.
, Cameron D.L.
, Cline M.
, Griffith M.
, Griffith O.L.
, Hunt S.E.
, et al.
.
Source: Cell Genomics, 2021-11-10 00:00:00.0; 1(2), .
PMID: 35311178
Related Citations
A survey of U.S. public perspectives on facial recognition technology and facial imaging data practices in health and research contexts.
Authors: Katsanis S.H.
, Claes P.
, Doerr M.
, Cook-Deegan R.
, Tenenbaum J.D.
, Evans B.J.
, Lee M.K.
, Anderton J.
, Weinberg S.M.
, Wagner J.K.
.
Source: Plos One, 2021; 16(10), p. e0257923.
EPub date: 2021-10-14 00:00:00.0.
PMID: 34648520
Related Citations
Recommendations for the collection and use of multiplexed functional data for clinical variant interpretation.
Authors: Gelman H.
, Dines J.N.
, Berg J.
, Berger A.H.
, Brnich S.
, Hisama F.M.
, James R.G.
, Rubin A.F.
, Shendure J.
, Shirts B.
, et al.
.
Source: Genome Medicine, 2019-12-20 00:00:00.0; 11(1), p. 85.
EPub date: 2019-12-20 00:00:00.0.
PMID: 31862013
Related Citations