Exome Sequencing–Based Screening for <i>BRCA1/2</i> Expected Pathogenic Variants Among Adult Biobank Participants

Manickam, Kandamurugu; Buchanan, Adam H.; Schwartz, Marci; Hallquist, Miranda L. G.; Williams, Janet L.; Rahm, Alanna Kulchak; Rocha, Heather; Savatt, Juliann M.; Evans, Alyson E.; Butry, Loren; Lazzeri, Amanda L.; Lindbuchler, D’Andra M.; Flansburg, Carroll N.; Leeming, Rosemary; Vogel, Victor G.; Lebo, Matthew S.; Mason‐Suares, Heather; Hoskinson, Derick; Abul‐Husn, Noura S.; Dewey, Frederick E.; Overton, John D.; Reid, Jeffrey G.; Baras, Aris; Willard, Huntington F.; McCormick, Cara Z.; Krishnamurthy, Sarathbabu; Hartzel, Dustin N.; Kost, Korey A.; Lavage, Daniel R.; Sturm, Amy C.; Frisbie, Lauren R.; Person, Thomas N.; Metpally, Raghu; Giovanni, Monica A.; Lowry, Lacy E.; Leader, Joseph B.; Ritchie, Marylyn D.; Carey, David J.; Justice, Anne E.; Kirchner, H. Lester; Faucett, W. Andrew; Williams, Marc S.; Ledbetter, David H.; Murray, Michael F.

doi:10.1001/jamanetworkopen.2018.2140

Cited by 181 publications

(212 citation statements)

References 42 publications

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“…The overall prevalence of expected pathogenic BRCA1/2 variants in our population was higher than previous estimates (5,6,13), and may be partly explained by the large number of founder variants detected. The highest prevalence was 1 in 49 (2.1%) in individuals with AJ genetic ancestry, which is similar to the previously established prevalence of 1 in 42 (2.3%) in this population (7,8).…”

Section: Discussioncontrasting

confidence: 90%

“…As with previous studies, there was a higher rate of relevant cancers in BRCA1 variant positive individuals than in BRCA2, and in women than in men (13,33,34). Over one-third of the variant positive females in our study had a documented current or prior diagnosis of a HBOC-related cancer.…”

Section: Discussionsupporting

confidence: 84%

“…Founder variants in other populations have also been described, including Icelandic, French Canadian, and Puerto Rican populations, and others (9). Recent unselected population-based genomic screening efforts have demonstrated a higher than expected prevalence of BRCA1/2 pathogenic variants in predominantly European-ancestry individuals, approximately 1 in 190, with only half of these individuals meeting current guidelines for genetic testing (10)(11)(12) and only 18% having prior knowledge of their BRCA1/2 status through clinical genetic testing (13).…”

Section: Introductionmentioning

confidence: 99%

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Exome Sequencing Reveals a High Prevalence ofBRCA1andBRCA2Founder Variants in a Diverse Population-Based Biobank

Abul‐Husn

Soper

Odgis

et al. 2019

Preprint

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Word Count: 340 Manuscript Word Count: 4214Abstract Pathogenic variants in BRCA1 and BRCA2 (BRCA1/2) lead to increased risk of breast, ovarian, and other cancers, but most variant positive individuals in the general population are unaware of their risk, and little is known about the prevalence of pathogenic BRCA1/2 variants in non-European populations.We investigated BRCA1/2 prevalence and impact using exome sequencing and electronic health record (EHR) data from 30,223 adult participants of the BioMe Biobank in New York City. There were 218 (0.7%) individuals harboring expected pathogenic variants, resulting in an overall prevalence of 1 in 139. In subpopulations defined by genetic ancestry, the highest prevalence was in individuals of Ashkenazi Jewish (AJ; 1 in 49), Filipino and Southeast Asian (1 in 81), and Non-AJ European (1 in 103) descent. Among 218 variant positive individuals, 112 (51.4%) harbored known founder variants: 80 had AJ founder variants (BRCA1 c.5266dupC and c.68_69delAG, and BRCA2 c.5946delT), 7 had a Puerto Rican founder variant (BRCA2 c.3922G>T), and 25 had one of 19 other founder variants. Non-European populations were more likely to harbor BRCA1/2 variants that were not classified in ClinVar, or that had uncertain or conflicting evidence for pathogenicity. Within mixed ancestry populations, such as Hispanic/Latinos with genetic ancestry from Africa, Europe, and the Americas, there was a strong correlation between the proportion African genetic ancestry and the likelihood of harboring a BRCA1/2 variant with uncertain or conflicting evidence for pathogenicity. Based on EHR and participant questionnaire data, ~28% of variant positive individuals had a personal history, and ~45% a personal or family history of BRCA1/2-associated cancers.Approximately 27% of variant positive individuals had evidence of prior clinical genetic testing for BRCA1/2. However, individuals with AJ founder variants were twice as likely to have had a clinical test (38%) than those with other pathogenic variants (19%). These findings deepen our knowledge about BRCA1/2 variants and associated cancer risk in diverse populations, indicate a gap in knowledge about potential cancer-related variants in non-European populations, and suggest that genomic screening in diverse patient populations may be an effective tool to identify at-risk individuals.

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Section: Discussioncontrasting

confidence: 90%

Section: Discussionsupporting

confidence: 84%

Section: Introductionmentioning

confidence: 99%

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Exome Sequencing Reveals a High Prevalence ofBRCA1andBRCA2Founder Variants in a Diverse Population-Based Biobank

Abul‐Husn

Soper

Odgis

et al. 2019

Preprint

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“…24 Approximately 0.2% to 0.5% of women carry a pathogenic BRCA variant. 49,50 This varies by population; in Ashkenazi Jewish women up to 2.5% have a pathogenic BRCA variant and 29% to 41% of ovarian cancer is attributed to one of three BRCA founder variants (c.68_69delAG and c.5266dupC in BRCA1 and c.5946delT in BRCA2) compared to 10% in the overall outbred ovarian cancer population. 51 In Iceland, the BRCA2 variant c.999del5 carries an odds ratio (OR) of 20.7 and accounts for 6.0% to 7.9% of ovarian cancer in that country.…”

Section: Brca Genes Brcaness and Methylationmentioning

confidence: 99%

Epithelial ovarian cancer risk: A review of the current genetic landscape

et al. 2019

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Ovarian cancer is the fourth most common cause of cancer-related death in women in the developed world, and one of the most heritable cancers. One of the most significant risk factors for epithelial ovarian cancer (EOC) is a family history of breast and/or ovarian cancer. Combined risk factors can be used in models to stratify risk of EOC, and aid in decisions regarding risk-reduction strategies. Germline pathogenic variants in EOC susceptibility genes including those involved in homologous recombination and mismatch repair pathways are present in approximately 22% to 25% of EOC. These genes are associated with an estimated lifetime risk of EOC of 13% to 60% for BRCA1 variants and 10% to 25% for BRCA2 variants, with lower risks associated with remaining genes. Genome-wide association studies have identified single nucleotide polymorphisms (SNPs) thought to explain an additional 6.4% of the familial risk of ovarian cancer, with 34 susceptibility loci identified to date. However, an unknown proportion of the genetic component of EOC risk remains unexplained.This review comprises an overview of individual genes and SNPs suspected to contribute to risk of EOC, and discusses use of a polygenic risk score to predict individual cancer risk more accurately. K E Y W O R D SBRCA, genetic risk, homologous recombination, mismatch repair, ovarian cancer, polygenic risk score, SNPs

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“…Thus, early identification of individuals with a pathogenic variant in BRCA1/2 has the potential to reduce cancer morbidity and mortality in this population. The exact general population prevalence of BRCA pathogenic variants is not known, and has previously been estimated to be approximately 1 in 350 (Drohan, Roche, Cusack, & Hughes, ); however, a recent publication suggested that the general population prevalence might be as high as 1 in 200 (Manickam et al, ). The prevalence among individuals with a personal and/or family history of breast and/or ovarian cancer is higher, and guidelines for BRCA1/2 testing exist (Moyer, ; National Comprehensive Cancer Network (NCCN), ), but these consensus guidelines are constantly changing based on evolving evidence.…”

Section: Introductionmentioning

confidence: 99%

Knowledge and opinions regarding BRCA1 and BRCA2 genetic testing among primary care physicians

Dekanek

Thull

Massart

et al. 2019

Journal of Genetic Counseling

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BRCA1 and BRCA2 (BRCA1/2) testing is standard for individuals with personal and/or family history suggestive of hereditary breast and ovarian cancer syndrome. The indications for testing have been expanding. To accommodate the need, incorporation of cancer genetic services into the practice of non‐genetic healthcare providers should be considered. We carried out a survey to evaluate the knowledge and opinions regarding BRCA1/2 testing among primary care providers. The survey was sent to 245 Obstetrics/Gynecology and 97 Family Medicine physicians in the UPMC network. Eighty‐six completed the survey between July 2015 and September 2015. The average correct responses to knowledge questions was 73%. A few respondents reported being completely confident, and ~50% reported being somewhat confident, in providing BRCA1/2‐related information. Respondents selected genetic specialists and oncologists as the most qualified to provide cancer genetic services. Several perceived barriers and motivating factors to the implementation of BRCA1/2 testing in primary care were identified. The findings from this study suggested that primary care providers were not uniformly ready to provide BRCA1/2 genetic testing. Availability of professional society guidelines and evidence of testing's usefulness might motivate the incorporation of BRCA1/2 genetic testing into primary care practices. These findings would help guide future educational efforts to promote provision of cancer genetic services by non‐genetic professionals.

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

Cited by 181 publications

References 42 publications

Exome Sequencing Reveals a High Prevalence ofBRCA1andBRCA2Founder Variants in a Diverse Population-Based Biobank

Exome Sequencing Reveals a High Prevalence ofBRCA1andBRCA2Founder Variants in a Diverse Population-Based Biobank

Epithelial ovarian cancer risk: A review of the current genetic landscape

Knowledge and opinions regarding BRCA1 and BRCA2 genetic testing among primary care physicians

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