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Updated: May 25, 2025
Targeted Next-generation Sequencing and Bioinformatics Pipeline to Evaluate Genetic Determinants of Constitutional Disease
Published on: April 4, 2018
PALB2 germline pathogenic variants: frequency, clinical features, and functional analysis of c.3350+5G>A variant in
1Targeted Therapy Branch, National Cancer Center, Goyang, Republic of Korea.
Background:
Germline PALB2 variants increase the risks of various cancers. However, these have not been comprehensively investigated in Korean patients with cancer. Our study aimed to evaluate the prevalence and clinical characteristics of PALB2 germline variants in Korean patients with cancer and compare these findings with existing data.
Patients And Methods:
We analyzed the clinicopathological and germline next-generation sequencing data of 3987 patients with cancer from the National Cancer Center in Korea. Additionally, we carried out functional analysis of the PALB2 splicing variant, c.3350+5G>A.
Results:
A total of 104 patients presented PALB2 germline variants with eight pathogenic variants (PVs), 14 likely pathogenic variants (LPVs), and 82 variants of uncertain significance (VUS). PALB2 PV/LPVs were detected at an overall frequency of 0.6% (22/3987) across all patients. Among patients with PV/LPVs, 95.5% were women, and 19 and 3 carriers were diagnosed with breast and ovarian cancer, respectively. Further, we reclassified c.3350+5G>A as a PV rather than VUS, according to the American College of Medical Genetics and Genomics guidelines. Patients with PALB2 PV/LPVs had a younger age at first cancer diagnosis (44.6 ± 10.1 years versus 50.2 ± 12.0 years, P = 0.019) and were more likely to have multiple primary organ cancer diagnoses (22.7% versus 8.3%, P = 0.032) compared with those without these variants.
Conclusion:
Age at first cancer diagnosis and the presence of multiple primary organ cancers are key risk factors for suspected germline PALB2 PV. Hence, strategies are required to improve adherence to the National Comprehensive Cancer Network guidelines for cancer screening and family genetic testing among Korean patients with cancer.
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