Points to consider for sharing variant-level information from clinical genetic testing with ClinVar

Azzariti, Danielle R.; Riggs, Erin Rooney; Niehaus, Annie; Rodriguez, Laura Lyman; Ramos, Erin M.; Kattman, B; Landrum, Melissa; Martin, Christa Lese; Rehm, Heidi L.

doi:10.1101/mcs.a002345

Cited by 26 publications

(34 citation statements)

References 17 publications

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“…Specifically, laboratories offering germline testing should modify their test requisition forms to indicate that de-identified phenotype and variant data will be deposited into ClinVar as part of ongoing quality assurance and improvement efforts (https://www.clinicalgenome.org/share-your-data/laboratories/). 70,71 Additional details of the ClinVar deposition process are included in Online Supplementary Figure S1.…”

Section: Discussionmentioning

confidence: 99%

How I curate: applying American Society of Hematology-Clinical Genome Resource Myeloid Malignancy Variant Curation Expert Panel rules for RUNX1 variant curation for germline predisposition to myeloid malignancies

Luo

Feurstein

et al. 2020

Haematologica

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Section: Discussionmentioning

confidence: 99%

How I curate: applying American Society of Hematology-Clinical Genome Resource Myeloid Malignancy Variant Curation Expert Panel rules for RUNX1 variant curation for germline predisposition to myeloid malignancies

Luo

Feurstein

et al. 2020

Haematologica

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“…ClinVar and DECIPHER (the Database of Genomic Variation and Phenotype in Humans Using Ensembl Resources) are two major public databases that are frequently used by laboratories for data sharing [37]. Consistent with GDPR requirements, ClinVar does not require explicit consent for sharing de-identified variant-level information obtained by laboratories during the course of fee-for-service clinical testing [38]. However, these consent requirements may change when sharing 'more specific individual-level information, such as the distinct phenotypes of each individual observed in a particular laboratory's experience with a variant' [38].…”

Section: Legal and Regulatory Contextmentioning

confidence: 99%

Rethinking the ethical principles of genomic medicine services

et al. 2019

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Clinical genome and exome sequencing is currently used in only a small fraction of patients, yet large scale genomic initiatives are becoming more embedded in clinical services. This paper examines the ethical principles that should guide regulatory processes regarding consent and data sharing in this context. We argue that a genomic dataset administered by the health system carries substantial societal benefits, and that the collective nature of this initiative means that at least those patients who benefit from genome sequencing have an ethical obligation to share their health information. This obligation is grounded in considerations of fairness. Furthermore, we argue that the use of genomic data for the advancement of medical knowledge should be permitted without explicit consent and that international and other bodies should be granted access to these data, provided certain conditions are satisfied.

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“…High penetrance (or high risk) genes are considered those which when mutated, confer a high Relative Risk of cancer development (greater than 4 times the risk of the general population). Moreover, they are included in guidelines for cancer predisposition testing and specific clinical management recommendations for patients carrying pathogenic variants have been formulated by large working groups [5][6][7]. Pathogenic variants in moderate penetrance (or moderate risk) genes confer a 2-4 times risk of cancer development compared to the general population.…”

Section: Gene Selectionmentioning

confidence: 99%

“…Low penetrance/risk genes are those related to less than 2 times risk of cancer or those with limited or yet insufficient data available concerning their association and magnitude of cancer risk. Although this categorization is constantly altered in reflection to the accumulated clinical information, based on the latest published data [3,[5][6][7][8][9][10], the genes analyzed are summarized in Table 1.…”

Section: Gene Selectionmentioning

confidence: 99%

See 1 more Smart Citation

Abstract P4-03-07: Analysis of hereditary cancer syndromes by using a panel of genes: Novel and multiple pathogenic mutations

Tsoulos¹,

Tsaousis²,

Papadopoulou³

et al. 2019

Cancer Research

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Background: Hereditary cancer predisposition syndromes are responsible for approximately 5-10% of all diagnosed cancer cases. In the past, single-gene analysis of specific high risk genes was used for the determination of the genetic cause of cancer heritability in certain families. The application of Next Generation Sequencing (NGS) technology has facilitated multigene panel analysis and is widely used in clinical practice, for the identification of individuals with cancer predisposing gene variants. The purpose of this study was to investigate the extent and nature of variants in genes implicated in hereditary cancer predisposition in individuals referred for testing in our laboratory.Methods: In total, 1197 individuals from Greece, Romania and Turkey were referred to our laboratory for genetic testing in the past 4 years. The majority of referrals included individuals with personal of family history of breast and/or ovarian cancer. The analysis of genes involved in hereditary cancer predisposition was performed using a NGS approach. Genomic DNA was enriched for targeted regions of 36 genes and sequencing was carried out using the Illumina NGS technology. The presence of large genomic rearrangements (LGRs) was investigated by computational analysis and Multiplex Ligation-dependent Probe Amplification (MLPA). Results: A pathogenic variant was identified in 264 of 1197 individuals (22.1%) analyzed while a variant of uncertain significance (VUS) was identified in 34.8% of cases. Clinically significant variants were identified in 29 of the 36 genes analyzed. Concerning the mutation distribution among individuals with positive findings, 43.6% were located in the BRCA1/2 genes whereas 21.6, 19.9, and 15.0% in other high, moderate and low risk genes respectively. Notably, 25 of the 264 positive individuals (9.5%) carried clinically significant variants in two different genes and 6.1% had a LGR. Conclusions:In our cohort, analysis of all the genes in the panel allowed the identification of 4.3 and 8.1% additional pathogenic variants in other high or moderate/low risk genes, respectively, enabling personalized management decisions for these individuals and supporting the clinical significance of multigene panel analysis in hereditary cancer predisposition.

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Points to consider for sharing variant-level information from clinical genetic testing with ClinVar

Cited by 26 publications

References 17 publications

How I curate: applying American Society of Hematology-Clinical Genome Resource Myeloid Malignancy Variant Curation Expert Panel rules for RUNX1 variant curation for germline predisposition to myeloid malignancies

How I curate: applying American Society of Hematology-Clinical Genome Resource Myeloid Malignancy Variant Curation Expert Panel rules for RUNX1 variant curation for germline predisposition to myeloid malignancies

Rethinking the ethical principles of genomic medicine services

Abstract P4-03-07: Analysis of hereditary cancer syndromes by using a panel of genes: Novel and multiple pathogenic mutations

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