Reacción a "The proportion of people with genetic variants associated with cancer may be higher than expected, according to a study"

With more than 400,000 individuals studied, it is, to date, the largest study conducted on a population not selected for their possible predisposition to hereditary cancer.

It highlights that the number of pathogenic variants in genes related to hereditary cancer predisposition is probably higher than was thought years ago and that personal/family criteria for genetic testing may in some cases exclude patients who could be carriers. Although in the case of alterations in genes with low/moderate penetrance, it could also lead to unnecessary overdiagnosis if there is a total absence of personal or family history related to the predisposition in question.

This is no cause for alarm, but it does highlight the importance of adequate awareness among the professionals involved and adequate genetic counselling regarding possible incidental or secondary findings when conducting a genetic study.

[Regarding possible limitations] I believe that the most important limitation may be that the selection of pathogenic variants has not been sufficiently adequate, as it is not based on an evidence-based classification system and apparently uses classifications published in the ClinVar database, which contains careful classifications made by committees and other much more dubious ones not based on evidence. This has undoubtedly had an impact on the article and could explain some curious percentages that stand out or appear, for example, pathogenic point mutations in the EPCAM gene, when to date only large deletions affecting its last exons have been reported as associated with cancer predisposition.

Genes of dubious clinical actionability have also been included, either because their association with predisposition is not entirely clear or because it is so limited that, for the time being, it is not considered to have an impact on the clinical management of carriers.