PALB2 Variants Extend the Mutational Profile of Hungarian Patients with Breast and Ovarian Cancer

SIMPLE SUMMARY: PALB2 is the third most important breast cancer susceptibility gene after BRCA1 and BRCA2, presenting with varying prevalence and mutational profiles in different populations. We prospectively evaluated the prevalence of germline PALB2 genetic variants in 1848 (1280 breast and 568 non-breast) consecutive Hungarian cancer patients between 2021 September and 2023 March. In addition, 191 young (<33 years, yBC) breast cancer cases were also tested. These data were compared with data of 134,187 non-cancer individuals retrieved from the Genome Aggregation Database. Twenty-one breast cancer (1.4%) and one non-breast cancer patient (0.17%) carried pathogenic/likely pathogenic PALB2 variants. One particular variant (NM_024675.4:c.509_510delGA) was relatively common, presented in one-third of the cases among Hungarian patients with PALB2 variants. Including PALB2 in the routine molecular genetic testing of breast cancer patients is recommended because it is associated with high cancer risk, and preventive and screening programs in PALB2 carriers may improve their life expectancy similarly to BRCA1/2 carriers. ABSTRACT: Background: The pathogenic/likely pathogenic (P/LP) variant detection rate and profile of PALB2, the third most important breast cancer gene, may vary between different populations. Methods: PALB2 was analyzed in peripheral blood samples of three independent cohorts: prospectively between September 2021 and March 2023 (i) in 1280 consecutive patients with breast and/or ovarian cancer (HBOC), (ii) in 568 patients with other cancers (controls), and retrospectively, (iii) in 191 young breast cancer (<33 years, yBC) patients. These data were compared with data of 134,187 non-cancer individuals retrieved from the Genome Aggregation Database. Results: Altogether, 235 cases (235/1280; 18.3%) carried at least one P/LP variant in one of the HBOC susceptibility genes. P/LP PALB2 variants were identified in 18 patients (1.4%; 18/1280) in the HBOC and 3 cases (1.5%; 3/191) in the yBC group. In the control group, only one patient had a disease-causing PALB2 variant (0.17%; 1/568) as a secondary finding not related to the disease, which was similar (0.15%; 205/134,187) in the non-cancer control group. The NM_024675.4:c.509_510delGA variant was the most common among our patients (33%; 6/18). We did not find a significant difference in the incidence of PALB2 disease-causing variants according to age; however, the median age of tumor onset was lower in PALB2 P/LP carriers versus wild-type patients (44 vs. 48 years). In our cohort, the odds ratio for breast cancer risk in women with PALB2 P/LP variants was between 8.1 and 9.3 compared to non-HBOC cancer patients and the non-cancer population, respectively. Conclusions: PALB2 P/LP variants are not uncommon among breast and/or ovarian cancer patients. Their incidence was the same in the two breast cancer cohorts studied but may occur rarely in patients with non-breast/ovarian cancer. The c.509_510delGA variant is particularly common in the studied Hungarian patient population.