Analysis of GEN1 as a Breast Cancer Susceptibility Gene in Polish Women

<i>GEN1</i> is implicated in DNA damage repair, as are several other breast cancer susceptibility genes, and is included in several comprehensive next-generation sequencing (NGS) testing panels. To investigate the possible association of <i>GEN1</i> variants with breast cancer risk, we sequenced this gene in 617 Polish women with hereditary breast cancer (HBC) and 300 Polish cancer-free controls. No protein-truncating variants were detected in the conserved part of <i>GEN1</i> (first 480 codons). Two frameshift variants were detected in the last exon of <i>GEN1</i>: c.2515_2519delAAGTT (p.Lys839Glufs*2) and c.1929_1932delAAAG (p.Lys645Cysfs*29). The p.Lys839Glufs*2 variant was detected in 21.1% of 617 HBC cases and 18.4% of 300 controls (<i>p</i> = 0.38). The p.Lys645Cysfs*29 variant was rare, seen in 0.6% of 617 HBC cases and 0.3% of 300 controls. The variant was then detected in 38 (0.24%) of 15,930 unselected breast cancer cases and 8 (0.17%) of 4702 cancer-free female controls from Poland (OR = 1.40, <i>p</i> = 0.49). Clinical characteristics of breast tumors in the 38 carriers of p.Lys645Cysfs*29 and 15,892 non-carriers were similar. Survival was similar among variant carriers and non-carriers (the age-adjusted HR = 0.87, <i>p</i> = 0.76). The wild-type <i>GEN1</i> allele was retained in all five breast cancers of carriers of p.Lys645Cysfs*29. No cancer type was more frequent in the relatives of 35 p.Lys645Cysfs*29 variant carriers compared to the relatives of 14,592 non-carriers. We conclude that <i>GEN1</i> is unlikely to be a high or moderate-risk breast cancer susceptibility gene. Our study has clinical implications for genetic counseling and suggests that <i>GEN1</i> changes should be reclassified as variants of uncertain significance (VUS) when they are detected in clinical testing panels.