Identification of two or more pathogenic/likely pathogenic (P/LP) variants in cancer
susceptibility genes carried by the same patient have important consequences for patient
management. We have limited information about the effect of double heterozygosity
(DH) in cancer susceptibility genes. The prevalence of DH among Hungarian cancer patients
referred to oncogenetic counselling, and comparison of their phenotypes to single
variant carriers were performed. In total, 2050 patients were analysed by multigene
panel sequencing. Variants of 48 established cancer predisposition genes by ACMG guidelines
were evaluated. In overall, P/LP variants were found in 19.8% of cases. DH was observed
in 16 cases, amount to 0.8% of all patients, and to 4.0% of positive cases. Appearance
of multiple primary tumours was not associated with DH compared to non-P/LP and single
P/LP carriers (p = 0.71 and p = 0.54, respectively). Within a cohort of patients referred
with suspected HBOC syndrome, earlier tumour formation was observed when DH cases
were compared to non-P/LP carriers (p = 0.01), but difference between single and DH
carriers was not statistically significant (p = 0.19; Bonferroni corrected alpha =
0.017). Our observations provide information about the incidence of DH status among
Hungarian hereditary cancer patients and suggest that DH did not increase the risk
of cancer compared to individuals with single P/LP mutation.
