Recurrent missense variants in clonal hematopoiesis-related genes present in the general population

Clonal hematopoiesis (CH) consists in an abnormal expansion of a hematopoietic stem cell bearing an advantageous somatic variant. A survey of known recurrent somatic missense variants in DNMT3A, SF3B1, SRSF2, and TP53, some of the most prominent genes underlying CH of indeterminate potential (CHIP), in gnomAD noncancer database shows the presence of 73 variants. Many of them reach frequencies higher than 0.01% in various populations and, in many cases, are enriched in specific populations. Consistent with a potential involvement in CHIP, we found that the age distribution of the carriers is shifted towards old ages. Moreover, the variant allele frequencies are on average lower than 50%, expected for germline heterozygous variants. The pervasive presence of some of such variants in blood DNA from elder individuals is compatible with CHIP of somatic origin. On practical grounds, CHIP can lead to misclassification of somatic variants in cancer-predisposition genes as inherited, which bear consequences for the affected individuals and their families.

Automated summary

Clonal hematopoiesis refers to the abnormal expansion of a hematopoietic stem cell with advantageous somatic variants. A survey found that some common gene mutations have higher frequencies in various populations and are enriched in specific populations. The age distribution of individuals with these variants suggests a potential involvement in clonal hematopoiesis, and the variant allele frequencies in blood DNA of elderly individuals are lower than expected. This can result in misclassification of somatic variants in cancer-predisposition genes, which has consequences for affected individuals and their families.