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, 129, 99-120

THE GORDON WILSON LECTURE: CANCER GENE VARIANT (RE)CLASSIFICATION: FROM TRUTHINESS TO TRUTH

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THE GORDON WILSON LECTURE: CANCER GENE VARIANT (RE)CLASSIFICATION: FROM TRUTHINESS TO TRUTH

Theodora Ross. Trans Am Clin Climatol Assoc.

Abstract

The new genetics, defined as that which followed the completion of the human genome project and includes development of rapid and cheaper next-generation sequencing (NGS), is impacting our medical world in several ways (1). As is the case in any new area of medicine, the field is infused with "truthiness," where instead, what is needed for good patient care and scientific rigor is an effort to close in on the truth. Today, I'll discuss how variation in the human genome is being evaluated and re-evaluated as we sequence more and more of our patients' genes.

Conflict of interest statement

Potential Conflicts of Interest: None disclosed.

Figures

Fig. 1
Fig. 1
Difficult conversations about test results. “No, you were not adopted.” Cartoon from xkcd.com.
Fig. 3
Fig. 3
TFI to TMI: Too few ideas to too many ideas. Each dot is a gene plotted to represent how variant it is in each population. Shaded area has genes with rare variations in the BRCA control cohort. Being in the grey area means it’s a gene with VUSs. Big data and bias conspire to hide the truth. How do we find hidden broken genes? One variant at a time.
Fig. 2
Fig. 2
A flood of sequence variations in disease genes. PPV, potentially pathogenic variants.
Fig. 4
Fig. 4
Rorschach test. It’s obvious that there are two horses, their emperor and two dragons. Copyright Can Stock Photo, Inc.
Fig. 5
Fig. 5
Leaving the grey zone with only loss-of-function variations. Gene variance plot of ClinVar genes with loss-of-function variants clarifies the analysis.
Fig. 6
Fig. 6
Reclassification timeline is variable and can take years. Genetic testing is a process, not an event.

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