Constitutional heterozygous mutations in CHEK2 gene have been associated with hereditary cancer risk. To date, only a few homozygous CHEK2 mutations have been reported in families with cancer susceptibility. Here, we report two unrelated individuals with a personal and familial cancer history in whom biallelic CHEK2 alterations were identified. The first case resulted homozygous for the CHEK2 c.793-1 G > A (p.Asp265Thrfs*10) variant, and the second one was found to be compound heterozygous for the c.1100delC (p.Thr367Metfs*15) and the c.1312 G > T (p.Asp438Tyr) variants. Multiple cytogenetic anomalies were demonstrated on peripheral lymphocytes of both patients. A literature revision showed that a single other CHEK2 homozygous variant was previously associated to a constitutional randomly occurring multi-translocation karyotype from peripheral blood in humans. We hypothesize that, at least some biallelic CHEK2 mutations might be associated with a novel disorder, further expanding the group of chromosome instability syndromes. Additional studies on larger cohorts are needed to confirm if chromosomal instability could represent a marker for CHEK2 constitutionally mutated recessive genotypes, and to investigate the cancer risk and the occurrence of other anomalies typically observed in chromosome instability syndromes.
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The authors thank all the patients for participating in this study.
This study was funded by the Experimental Medicine Department, Sapienza University of Rome.
The authors declare no competing interests.
Informed consent was obtained from all subjects, and study procedures were compliant with the revised Helsinki Declaration of 2000. The study, part of a research project about genetic disorders, was approved by the San Camillo Forlanini Hospital Ethics Board.
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Bottillo, I., Savino, E., Majore, S. et al. Two unrelated cases with biallelic CHEK2 variants:a novel condition with constitutional chromosomal instability?. Eur J Hum Genet (2022). https://doi.org/10.1038/s41431-022-01270-z