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The cancer precision medicine knowledge base for structured clinical-grade mutations and interpretations

View Article: PubMed Central - PubMed

ABSTRACT

Objective:: This paper describes the Precision Medicine Knowledge Base (PMKB; https://pmkb.weill.cornell.edu), an interactive online application for collaborative editing, maintenance, and sharing of structured clinical-grade cancer mutation interpretations.

Materials and methods:: PMKB was built using the Ruby on Rails Web application framework. Leveraging existing standards such as the Human Genome Variation Society variant description format, we implemented a data model that links variants to tumor-specific and tissue-specific interpretations. Key features of PMKB include support for all major variant types, standardized authentication, distinct user roles including high-level approvers, and detailed activity history. A REpresentational State Transfer (REST) application-programming interface (API) was implemented to query the PMKB programmatically.

Results:: At the time of writing, PMKB contains 457 variant descriptions with 281 clinical-grade interpretations. The EGFR, BRAF, KRAS, and KIT genes are associated with the largest numbers of interpretable variants. PMKB’s interpretations have been used in over 1500 AmpliSeq tests and 750 whole-exome sequencing tests. The interpretations are accessed either directly via the Web interface or programmatically via the existing API.

Discussion:: An accurate and up-to-date knowledge base of genomic alterations of clinical significance is critical to the success of precision medicine programs. The open-access, programmatically accessible PMKB represents an important attempt at creating such a resource in the field of oncology.

Conclusion:: The PMKB was designed to help collect and maintain clinical-grade mutation interpretations and facilitate reporting for clinical cancer genomic testing. The PMKB was also designed to enable the creation of clinical cancer genomics automated reporting pipelines via an API.

No MeSH data available.


Diagram of the variant description data types.
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ocw148-F1: Diagram of the variant description data types.

Mentions: We developed a system for variant description that incorporates existing standards such as those of the Human Genome Variation Society (HGVS)8 (Figure 1). At the highest level, a variant is described by the gene it is associated with and a variant category. Variant categories include small, localized mutations (single nucleotide variants, indels), copy number alterations, and gene fusions. Descriptions of small, localized mutations such as single nucleotide variants and indels can be broken down into 2 groups: a specific mutation described using HGVS protein-change and DNA-change notation, and a gene region–based description. Gene regions can be further divided into specific codons, specific exons, and the entire gene (Figure 1). The variant type, eg, deletion, insertion, missense, nonsense, etc., must be specified. Fusions are described as a pair consisting of the primary gene and the partner gene. Copy number alterations are described as either a gain or loss of copy number, pertaining to either a gene or a chromosome region, using arm and cytoband notation, eg, 17p13.1. When variants are entered, PMKB automatically retrieves specific gene region information from Ensembl, based on Ensembl’s canonical transcript for a gene and its GRCh37-based API.9Figure 1.


The cancer precision medicine knowledge base for structured clinical-grade mutations and interpretations
Diagram of the variant description data types.
© Copyright Policy - cc-by-nc
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5391733&req=5

ocw148-F1: Diagram of the variant description data types.
Mentions: We developed a system for variant description that incorporates existing standards such as those of the Human Genome Variation Society (HGVS)8 (Figure 1). At the highest level, a variant is described by the gene it is associated with and a variant category. Variant categories include small, localized mutations (single nucleotide variants, indels), copy number alterations, and gene fusions. Descriptions of small, localized mutations such as single nucleotide variants and indels can be broken down into 2 groups: a specific mutation described using HGVS protein-change and DNA-change notation, and a gene region–based description. Gene regions can be further divided into specific codons, specific exons, and the entire gene (Figure 1). The variant type, eg, deletion, insertion, missense, nonsense, etc., must be specified. Fusions are described as a pair consisting of the primary gene and the partner gene. Copy number alterations are described as either a gain or loss of copy number, pertaining to either a gene or a chromosome region, using arm and cytoband notation, eg, 17p13.1. When variants are entered, PMKB automatically retrieves specific gene region information from Ensembl, based on Ensembl’s canonical transcript for a gene and its GRCh37-based API.9Figure 1.

View Article: PubMed Central - PubMed

ABSTRACT

Objective:: This paper describes the Precision Medicine Knowledge Base (PMKB; https://pmkb.weill.cornell.edu), an interactive online application for collaborative editing, maintenance, and sharing of structured clinical-grade cancer mutation interpretations.

Materials and methods:: PMKB was built using the Ruby on Rails Web application framework. Leveraging existing standards such as the Human Genome Variation Society variant description format, we implemented a data model that links variants to tumor-specific and tissue-specific interpretations. Key features of PMKB include support for all major variant types, standardized authentication, distinct user roles including high-level approvers, and detailed activity history. A REpresentational State Transfer (REST) application-programming interface (API) was implemented to query the PMKB programmatically.

Results:: At the time of writing, PMKB contains 457 variant descriptions with 281 clinical-grade interpretations. The EGFR, BRAF, KRAS, and KIT genes are associated with the largest numbers of interpretable variants. PMKB’s interpretations have been used in over 1500 AmpliSeq tests and 750 whole-exome sequencing tests. The interpretations are accessed either directly via the Web interface or programmatically via the existing API.

Discussion:: An accurate and up-to-date knowledge base of genomic alterations of clinical significance is critical to the success of precision medicine programs. The open-access, programmatically accessible PMKB represents an important attempt at creating such a resource in the field of oncology.

Conclusion:: The PMKB was designed to help collect and maintain clinical-grade mutation interpretations and facilitate reporting for clinical cancer genomic testing. The PMKB was also designed to enable the creation of clinical cancer genomics automated reporting pipelines via an API.

No MeSH data available.