Considerations for using population frequency data in germline variant interpretation: Cancer syndrome genes as a model

2021 ◽  
Vol 42 (5) ◽  
pp. 530-536
Author(s):  
Aimee L. Davidson ◽  
Conrad Leonard ◽  
Lambros T. Koufariotis ◽  
Michael T. Parsons ◽  
Georgina E. Hollway ◽  
...  
Keyword(s):  
Variant Interpretation ◽  
Frequency Data ◽  
Cancer Syndrome ◽  
Population Frequency ◽  
Germline Variant

scholarly journals Evolution of the open-access CIViC knowledgebase is driven by the needs of the cancer variant interpretation community

2021 ◽  
Author(s):  
Kilannin Krysiak ◽  
Arpad M Danos ◽  
Susanna Kiwala ◽  
Joshua F McMichael ◽  
Adam C Coffman ◽  
...  
Keyword(s):  
Clinical Utility ◽  
Drug Response ◽  
Structured Data ◽  
Variant Interpretation ◽  
Single Institution ◽  
Cancer Management ◽  
Germline Variant ◽  
Clinical Variant ◽  
New Evidence ◽  
Widespread Dissemination

CIViC (Clinical Interpretation of Variants in Cancer; civicdb.org) is a crowd-sourced, public domain knowledgebase composed of literature-derived evidence characterizing the clinical utility of cancer variants. As clinical sequencing becomes more prevalent in cancer management, the need for cancer variant interpretation has grown beyond the capability of any single institution. With nearly 300 contributors, CIViC contains peer-reviewed, published literature curated and expert-moderated into structured data units (Evidence Items) that can be accessed globally and in real time, reducing barriers to clinical variant knowledge sharing. We have extended CIViC's functionality to support emergent variant interpretation guidelines, increase interoperability with other variant resources, and promote widespread dissemination of structured curated data. To support the full breadth of variant interpretation from basic to translational, including integration of somatic and germline variant knowledge and inference of drug response, we have enabled curation of three new evidence types (predisposing, oncogenic and functional). The growing CIViC knowledgebase distributes clinically-relevant cancer variant data currently representing >2500 variants in >400 genes from >2800 publications.

scholarly journals Full-Length Characterization of Proteins in Human Populations

2010 ◽  
Vol 56 (2) ◽  
pp. 202-211 ◽  
Author(s):  
Chad R Borges ◽  
Doug S Rehder ◽  
Jason W Jarvis ◽  
Mathew R Schaab ◽  
Paul E Oran ◽  
...  
Keyword(s):  
Population Data ◽  
Full Length ◽  
Human Populations ◽  
Frequency Data ◽  
Population Frequency ◽  
Proteomic Investigation ◽  
Human Proteins ◽  
Variant Frequency ◽  
Protein Variants

Abstract Background: Diversity in human proteins often gives rise to pluralities of structurally similar but functionally distinct proteins. Such microheterogeneity generally escapes proteomics discovery technologies, as well as conventional immunometric assays. As an intermediate between these 2 technological approaches, targeted, full-length characterization of proteins using mass spectrometry is a suitable means of defining microheterogeneity evident in human populations. Content: We describe and explore the implications of microheterogeneity using the exemplar of human vitamin D binding protein (Gc-Globulin) as observed in cohorts of 400 individuals. Our investigations yielded: (a) population frequency data comparable to genotyping; (b) population frequency data for protein variants, with and without genotype linkage; (c) reference values for the different protein variants per cohort and genotype; and (d) associations between variant, frequency, relative abundance, and diseases. Summary: With the exception of the genotype frequency, such population data are unique and illustrate a need to more fully understand the exact full-length qualitative and quantitative idiosyncrasies of individual proteins in relation to health and disease as part of the standardized biomarker development and clinical proteomic investigation of human proteins.

scholarly journals ClinGen CDH1 specifications for the ACMG/AMP guidelines: improvement of germline variant clinical assertions and updated curation guidelines

2021 ◽  
Author(s):  
Xi Luo ◽  
Jamie L Maciaszek ◽  
Bryony A Thompson ◽  
Huei San Leong ◽  
Katherine Dixon ◽  
...  
Keyword(s):  
Clinical Practice ◽  
Genetic Testing ◽  
Expert Panel ◽  
Expert Knowledge ◽  
Variant Classification ◽  
Variant Interpretation ◽  
Clinical Criteria ◽  
Germline Variant ◽  
Uncertain Significance ◽  
Development And Evolution

Purpose: The Clinical Genome Resource (ClinGen) CDH1 Variant Curation Expert Panel (VCEP) developed specifications for CDH1 variant curation with a goal to resolve variants of uncertain significance (VUS) and with ClinVar conflicting interpretations for effective medical care. In addition, the CDH1 VCEP continues to update these specifications in keeping with evolving clinical practice and variant interpretation guidelines. Methods: CDH1 variant classification specifications were modified based on updated genetic testing clinical criteria, new recommendations from ClinGen, and expert knowledge from ongoing CDH1 variant curations. Trained biocurators curated 273 variants using updated CDH1 interpretation guidelines and incorporated published and unpublished data provided by diagnostic laboratories. All variants were reviewed by the ClinGen VCEP and classifications submitted to ClinVar. Results: Updated CDH1-specific variant interpretation guidelines include eleven major modifications since the initial specifications from 2018. Using the refined guidelines, 97% (36/37) of variants with ClinVar conflicting interpretations were resolved into benign, likely benign, likely pathogenic, or pathogenic, and 35% (15/43) of VUS were resolved into benign or likely benign. Overall, 88% (239/273) of curated variants had non-VUS classifications. Conclusion: The development and evolution of CDH1-specific criteria by the expert panel results in decreased uncertain and conflicting interpretations of variants in this clinically actionable gene.

scholarly journals Pathogenic ASXL1 somatic variants in reference databases complicate germline variant interpretation for Bohring-Opitz Syndrome

2017 ◽  
Vol 38 (5) ◽  
pp. 517-523 ◽  
Author(s):  
Colleen M. Carlston ◽  
Anne H. O'Donnell-Luria ◽  
Hunter R. Underhill ◽  
Beryl B. Cummings ◽  
Ben Weisburd ◽  
...  
Keyword(s):  
Variant Interpretation ◽  
Germline Variant ◽  
Reference Databases ◽  
Opitz Syndrome
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