Confirming a diagnosis of “hereditary colorectal cancer” through genetic testing is crucial for the healthcare of affected families. Nevertheless, many of the genetic variants found in known genes are not yet conclusively classified regarding their role in cancer development. An international research team, led by the University Hospital Bonn (UKB) and the University of Bonn, has re-evaluated the medical significance of many ambiguous variants, resulting in a substantial decrease in their numbers. The findings of this research have recently been published in the American Journal of Human Genetics.
Families with hereditary cancer syndromes face heightened risks for certain types of cancers, like colon and breast cancer. Fortunately, there are now highly effective screening programs and preventative measures available for many of these hereditary syndromes. Therefore, prompt detection and accurate diagnosis of a hereditary predisposition are incredibly vital for affected families.
As genetic testing becomes more comprehensive, an increasing number of genetic variants are being discovered within relevant genes, many of which do not have a clear connection to tumor development. Such variants are termed variants of uncertain significance (VUS). In fact, more than 50 percent of some genes in public databases, particularly ClinVar, are now categorized as VUS. “These variants are not suitable for diagnostic purposes or for screening healthy individuals who may be at risk; they often lead to confusion, as those carrying a VUS might have an elevated cancer risk,” explains Dr. Isabel Spier, co-senior author from the Institute of Human Genetics.
Many gene variants lack significance for tumor development
The team at UKB’s Center for Hereditary Tumor Syndromes has dedicated years to uncovering new genetic factors behind hereditary tumor diseases. To address the challenges of interpreting VUS, the Institute of Human Genetics has established special classification criteria aimed at enhancing the evaluation of variants in the APC gene. Inherited mutations in this gene lead to familial adenomatous polyposis (FAP), a common cause of hereditary colorectal cancer and gastrointestinal polyp diseases. In collaboration with an international panel of experts under the Hereditary Colorectal Cancer / Polyposis Variant Curation Expert Panel (VCEP), Prof. Stefan Aretz’s research group is working together with the International Society for Gastrointestinal Hereditary Tumors (InSiGHT) and the Clinical Genome Resource (ClinGen). “Our gene-specific classification criteria have enabled us to reclassify a considerable number of VUS related to the APC gene into clinically relevant categories,” states Prof. Aretz, who is also part of the Transdisciplinary Research Area (TRA) “Life & Health” at the University of Bonn.
The research team analyzed all over 10,000 germline variants of the APC gene documented in the public databases ClinVar and LOVD. Among the variants initially classified as benign or pathogenic, around 95 percent retained their original classification. Conversely, 41 percent of the VUS recorded in ClinVar and 61 percent in LOVD were reclassified into clinically significant categories, with most being deemed benign. The study also highlighted that extensive data mining — the thorough search for all global genetic and clinical information linked to a particular genetic variant — significantly aids in achieving better classifications. Overall, the number of VUS was reduced by 37 percent. “Our ability to categorize a large percentage of VUS as benign variants brings peace of mind to all individuals worldwide carrying these variants,” says co-senior author Prof. Aretz, who acknowledges the close collaboration with Dr. Xiaoyu Yin from Melbourne, who contributed significantly during her six-month tenure as a visiting scientist at UKB. This research also showcases the potential for effectively classifying variants in large datasets, which could serve as a model for interpreting variants in other genes in the future.
