Conflicting interpretations of genetic variants and cancer risk: time to speak the same language

Important advances in next-generation whole-genome sequencing for precision oncology have led to the development of multiplex panel testing for the molecular diagnosis of inherited cancer susceptibility. While such progress must be celebrated as we collectively seek to translate genomic testing results into benefits for patients by both identifying specific molecular risk factors and gauging the potential efficacy of specific agents for individual patients, there are still several hurdles that must be overcome in order to improve prediction of cancer susceptibility, diagnostic efficiency and clinical decision making based on genomic-driven insights.

One such hurdle, as highlighted in a recent study* led by Judith Balmaña, Principal Investigator of VHIO´s High Risk and Cancer Prevention Group, Medical Oncologist at the Vall d´Hebron University Hospital (HUVH), and a visiting scholar at Penn Medicine (Philadelphia, USA) at the time of the study, concerns the lack of consistency in genetic variant interpretation in the context of shared data.

Published this month in the Journal of Clinical Oncology, first author Judith Balmaña, in collaboration with experts from several US-based cancer research centers of excellence, explored the conflicting classification of genetic variants and associated cancer risk reported by commercial clinical laboratories in the web-based Prospective Registry of Multiplex Testing (PROMPT).

“Thanks to our increased understanding of the cellular hallmarks of cancer, expanding suite of powerful technologies and approaches, as well as the construction of a high-resolution atlas of the genomic landscape of cancer-related mutations, we are better equipped than ever to advance personalized approaches to cancer treatment. The predictive value of data generated by genome sequencing in establishing cancer risk is not progressing at the same pace,”
says Judith Balmaña.

Despite the various guidelines that have been put drawn up to help standardize variant classification, the subsequent interpretation of these recommendations varies immensely among laboratories and providers. The accumulation of pooled data in public registries has revealed that the classification of sequence variants and cancer risk prediction are often conflicting and may therefore have a detrimental effect on cancer care and clinical decision making.

Importantly, Balmaña and colleagues found that one quarter of the clinical genetic results from commercially available multiplex cancer panels reported in the PROMPT registry, had conflicting interpretations. This discordance was identified thanks to the existence of data sharing among laboratories into public databases and the collaboration between academic research consortia and commercial laboratories. Based on these findings, initiatives aimed at further harmonizing variant interpretation in the context of shared data should be widely embraced and supported.

The study´s authors highlight the need for testing laboratories to submit their findings to public databases, describing the evidence upon which their clinical interpretations are based. This course of action may help to promote strategies aimed at standardizing clinical variant curation algorithms.

“Multiplex panel testing aimed at establishing inherited cancer susceptibility include high-penetrance genes and less prevalent moderate ones that still lack robust evidence of their association with the exact magnitude of cancer risk. Some variants are classified as having uncertain clinical significance by some laboratories and as pathogenic variants by others. We must all work in concert to resolve these inconsistencies – especially those that might seriously impact on the medical management of our patients,
she concludes.


To consult this open access Original Report, published in JCO ahead of print, 12 September 2016, please click here.

For more information please contact: Amanda Wren, Director of Communications, Vall d´Hebron Institute of Oncology (VHIO), Tel: +34 695 207 886, Email:


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