Although with varying frequency, gastrointestinal cancers are associated with constitutional, and therefore inheritable, genetic variants. The detection of pathogenic variants associated with the development of gastrointestinal cancers has dual implications. On the one hand, it can have both a prognostic and predictive impact on the response to cancer treatment, while on the other, it can be of great relevance for establishing preventive and therapeutic strategies, both for the individual and for their relatives. All these implications should be assessed on an individual basis within a genetic counselling process, including systematic collection of personal and family history, pre-test information on possible outcomes, population view, future risks and preventive strategies which can be recommended to the individual and their relatives.

In recent decades, the introduction of Next Generation Sequencing (NGS) technology has revolutionised the identification of pathogenic variants in DNA, simplifying and reducing the cost of analysis and considerably increasing the information obtained in the same test compared to previous technologies. This technology has also been introduced into the routine practice of screening for suspected hereditary cancer, using gene panels. The use of these panels enables the simultaneous sequencing of several genes potentially involved in the phenotype observed, but also makes it challenging to interpret the results, as it multiplies the number of genetic variants detected. According to the recommendations of the American College of Medical Genetics (ACMG),1 constitutional variants detectable in a genetic analysis can be classified into five categories: benign (class 1); likely benign (class 2); uncertain or unknown clinical significance (VUS) (class 3); likely pathogenic (class 4); and pathogenic (class 5). Benign and likely benign variants have no disease implications and may be very common in the general population. For practical purposes, likely pathogenic variants are often treated as if they were pathogenic. To simplify the reading of the text, the likely pathogenic variants will be grouped with the pathogenic variants throughout the document. In the case of VUS, it is recommended to periodically review their classification in case new scientific information emerges that allows them to be reclassified as pathogenic or benign. Another factor to take into account in the genetic counselling process is that not all genetic variants carry the same risk of developing disease, as they can be of low, moderate or high penetrance. In addition, the simultaneous analysis of several genes can sometimes provide incidental or secondary findings, such as the detection of pathogenic variants not clearly related to the suspicion being assessed. This is the case, for example, for pathogenic variants in the BRCA1 or BRCA2 genes in patients with familial clustering of colorectal cancer. Incidental findings are defined as findings that may or may not have potential health implications and clinical significance, but are not related to the disease symptoms for which the test was requested (for example, individual with suspected Lynch syndrome where the exome was sequenced in order to analyse a virtual panel for hereditary cancer, and a pathogenic variant was detected in MYH7, not contained in the virtual panel and associated with hypertrophic cardiomyopathy). Meanwhile, secondary findings are those intentionally sought and secondary to the target for which the sequencing was requested (for example, same individual and same test as in the previous example, but in which a pathogenic variant in CDH1 is detected, contained in the virtual panel, but associated with diffuse gastric cancer [GC] and lobular breast cancer).2

The aim of this document is to establish recommendations on the use of gene panels in the evaluation of hereditary syndromes associated with gastrointestinal cancer. We specifically aim to:

Define the clinical scenarios in which genetic analysis is indicated for the identification of hereditary syndromes associated with gastrointestinal cancers.

Determine which genes are currently recommended for testing in each clinical scenario.

Establish indications for genetic testing in healthy mucosa in cases of non-informative genetic testing, to screen for mosaicism.

Establish indications for genetic testing in healthy tissue or healthy relatives if the index case is not available.

Establish indications for constitutional genetic testing based on pathogenic variants detected in the sequencing of gastrointestinal cancers.

It is beyond the scope of this document to propose strategies for uncertain situations such as the evaluation of genetic variants of uncertain clinical significance, genes of low penetrance and genes not associated with the observed suspicion of hereditary cancer (phenotype-genotype dissociation).