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Title of the item:

Exome Sequencing-Based Screening for BRCA1/2 Expected Pathogenic Variants Among Adult Biobank Participants.

Title :
Exome Sequencing-Based Screening for BRCA1/2 Expected Pathogenic Variants Among Adult Biobank Participants.
Authors :
Manickam K; Molecular and Human Genetics Department, Nationwide Children's Hospital, Columbus, Ohio.; Genomic Medicine Institute, Geisinger, Danville, Pennsylvania.
Buchanan AH; Genomic Medicine Institute, Geisinger, Danville, Pennsylvania.
Schwartz MLB; Genomic Medicine Institute, Geisinger, Danville, Pennsylvania.
Hallquist MLG; Genomic Medicine Institute, Geisinger, Danville, Pennsylvania.
Williams JL; Genomic Medicine Institute, Geisinger, Danville, Pennsylvania.
Rahm AK; Genomic Medicine Institute, Geisinger, Danville, Pennsylvania.
Rocha H; Genomic Medicine Institute, Geisinger, Danville, Pennsylvania.
Savatt JM; Genomic Medicine Institute, Geisinger, Danville, Pennsylvania.
Evans AE; Genomic Medicine Institute, Geisinger, Danville, Pennsylvania.
Butry LM; Genomic Medicine Institute, Geisinger, Danville, Pennsylvania.
Lazzeri AL; Genomic Medicine Institute, Geisinger, Danville, Pennsylvania.
Lindbuchler DM; Genomic Medicine Institute, Geisinger, Danville, Pennsylvania.
Flansburg CN; Genomic Medicine Institute, Geisinger, Danville, Pennsylvania.
Leeming R; Genomic Medicine Institute, Geisinger, Danville, Pennsylvania.
Vogel VG; Genomic Medicine Institute, Geisinger, Danville, Pennsylvania.
Lebo MS; Laboratory for Molecular Medicine, Partners HealthCare, Cambridge, Massachusetts.
Mason-Suares HM; Laboratory for Molecular Medicine, Partners HealthCare, Cambridge, Massachusetts.
Hoskinson DC; Laboratory for Molecular Medicine, Partners HealthCare, Cambridge, Massachusetts.
Abul-Husn NS; Regeneron Genetics Center, Tarrytown, New York.
Dewey FE; Regeneron Genetics Center, Tarrytown, New York.
Overton JD; Regeneron Genetics Center, Tarrytown, New York.
Reid JG; Regeneron Genetics Center, Tarrytown, New York.
Baras A; Regeneron Genetics Center, Tarrytown, New York.
Willard HF; Genomic Medicine Institute, Geisinger, Danville, Pennsylvania.
McCormick CZ; Genomic Medicine Institute, Geisinger, Danville, Pennsylvania.
Krishnamurthy SB; Genomic Medicine Institute, Geisinger, Danville, Pennsylvania.
Hartzel DN; Genomic Medicine Institute, Geisinger, Danville, Pennsylvania.
Kost KA; Genomic Medicine Institute, Geisinger, Danville, Pennsylvania.
Lavage DR; Genomic Medicine Institute, Geisinger, Danville, Pennsylvania.
Sturm AC; Genomic Medicine Institute, Geisinger, Danville, Pennsylvania.
Frisbie LR; Genomic Medicine Institute, Geisinger, Danville, Pennsylvania.
Person TN; Genomic Medicine Institute, Geisinger, Danville, Pennsylvania.
Metpally RP; Genomic Medicine Institute, Geisinger, Danville, Pennsylvania.
Giovanni MA; Genomic Medicine Institute, Geisinger, Danville, Pennsylvania.
Lowry LE; Genomic Medicine Institute, Geisinger, Danville, Pennsylvania.
Leader JB; Genomic Medicine Institute, Geisinger, Danville, Pennsylvania.
Ritchie MD; Genomic Medicine Institute, Geisinger, Danville, Pennsylvania.; Center for Translational Bioinformatics, University of Pennsylvania, Philadelphia.
Carey DJ; Genomic Medicine Institute, Geisinger, Danville, Pennsylvania.
Justice AE; Genomic Medicine Institute, Geisinger, Danville, Pennsylvania.
Kirchner HL; Genomic Medicine Institute, Geisinger, Danville, Pennsylvania.
Faucett WA; Genomic Medicine Institute, Geisinger, Danville, Pennsylvania.
Williams MS; Genomic Medicine Institute, Geisinger, Danville, Pennsylvania.
Ledbetter DH; Genomic Medicine Institute, Geisinger, Danville, Pennsylvania.
Murray MF; Genomic Medicine Institute, Geisinger, Danville, Pennsylvania.; Department of Genetics, Yale School of Medicine, New Haven, Connecticut.
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Source :
JAMA network open [JAMA Netw Open] 2018 Sep 07; Vol. 1 (5), pp. e182140. Date of Electronic Publication: 2018 Sep 07.
Publication Type :
Journal Article; Research Support, Non-U.S. Gov't
Language :
English
Imprint Name(s) :
Original Publication: Chicago, IL : American Medical Association, [2018]-
MeSH Terms :
BRCA1 Protein/*analysis
BRCA2 Protein/*analysis
Whole Exome Sequencing/*methods
Adult ; Aged ; Aged, 80 and over ; BRCA1 Protein/genetics ; BRCA2 Protein/genetics ; Biological Specimen Banks/statistics & numerical data ; Biomarkers, Tumor/analysis ; Biomarkers, Tumor/blood ; Cross-Sectional Studies ; Early Detection of Cancer/methods ; Exome/genetics ; Female ; Humans ; Male ; Middle Aged ; Pennsylvania ; Virulence/genetics ; Whole Exome Sequencing/statistics & numerical data
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Substance Nomenclature :
0 (BRCA1 Protein)
0 (BRCA1 protein, human)
0 (BRCA2 Protein)
0 (BRCA2 protein, human)
0 (Biomarkers, Tumor)
Entry Date(s) :
Date Created: 20190116 Date Completed: 20190924 Latest Revision: 20200309
Update Code :
20210914
PubMed Central ID :
PMC6324494
DOI :
10.1001/jamanetworkopen.2018.2140
PMID :
30646163
Academic Journal
Importance: Detection of disease-associated variants in the BRCA1 and BRCA2 (BRCA1/2) genes allows for cancer prevention and early diagnosis in high-risk individuals.
Objectives: To identify pathogenic and likely pathogenic (P/LP) BRCA1/2 variants in an unselected research cohort, and to characterize the features associated with P/LP variants.
Design, Setting, and Participants: This is a cross-sectional study of adult volunteers (n = 50 726) who underwent exome sequencing at a single health care system (Geisinger Health System, Danville, Pennsylvania) from January 1, 2014, to March 1, 2016. Participants are part of the DiscovEHR cohort and were identified through the Geisinger MyCode Community Health Initiative. They consented to a research protocol that included sequencing and return of actionable test results. Clinical data from electronic health records and clinical visits were correlated with variants. Comparisons were made between those with (cases) and those without (controls) P/LP variants in BRCA1/2.
Main Outcomes: Prevalence of P/LP BRCA1/2 variants in cohort, proportion of variant carriers not previously ascertained through clinical testing, and personal and family history of relevant cancers among BRCA1/2 variant carriers and noncarriers.
Results: Of the 50 726 health system patients who underwent exome sequencing, 50 459 (99.5%) had no expected pathogenic BRCA1/2 variants and 267 (0.5%) were BRCA1/2 carriers. Of the 267 cases (148 [55.4%] were women and 119 [44.6%] were men with a mean [range] age of 58.9 [23-90] years), 183 (68.5%) received clinically confirmed results in their electronic health record. Among the 267 participants with P/LP BRCA1/2 variants, 219 (82.0%) had no prior clinical testing, 95 (35.6%) had BRCA1 variants, and 172 (64.4%) had BRCA2 variants. Syndromic cancer diagnoses were present in 11 (47.8%) of the 23 deceased BRCA1/2 carriers and in 56 (20.9%) of all 267 BRCA1/2 carriers. Among women, 31 (20.9%) of 148 variant carriers had a personal history of breast cancer, compared with 1554 (5.2%) of 29 880 noncarriers (odds ratio [OR], 5.95; 95% CI, 3.88-9.13; P < .001). Ovarian cancer history was present in 15 (10.1%) of 148 variant carriers and in 195 (0.6%) of 29 880 variant noncarriers (OR, 18.30; 95% CI, 10.48-31.4; P < .001). Among 89 BRCA1/2 carriers without prior testing but with comprehensive personal and family history data, 44 (49.4%) did not meet published guidelines for clinical testing.
Conclusions and Relevance: This study found that compared with previous clinical care, exome sequencing-based screening identified 5 times as many individuals with P/LP BRCA1/2 variants. These findings suggest that genomic screening may identify BRCA1/2-associated cancer risk that might otherwise remain undetected within health care systems and may provide opportunities to reduce morbidity and mortality in patients.

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