Germline POT1 Variants: A Critical Perspective on POT1 Tumor Predisposition Syndrome

The Protection of Telomere 1 ( ) gene was identified as a melanoma predisposition candidate nearly 10 years ago. Thereafter, various cancers have been proposed as associated with germline variants in the context of the so-called Predisposition Tumor Syndrome (POT1-TPD). While the key role, and related risks, of the alterations in in melanoma are established, the correlation between germline variants and the susceptibility to other cancers partially lacks evidence, due also to the rarity of POT1-TPD. Issues range from the absence of functional or segregation studies to biased datasets or the need for a revised classification of variants. Furthermore, a proposal of a surveillance protocol related to the cancers associated with pathogenic variants requires reliable data to avoid an excessive, possibly unjustified, burden for variant carriers. We propose a critical perspective regarding data published over the last 10 years that correlate variants to various types of cancer, other than cutaneous melanoma, to offer food for thought for the specialists who manage cancer predisposition syndromes and to stimulate a debate on the grey areas that have been exposed.