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

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 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 (first 480 codons). Two frameshift variants were detected in the last exon of : c.2515_2519delAAGTT (p.Lys839Glufs2) and c.1929_1932delAAAG (p.Lys645Cysfs29). The p.Lys839Glufs2 variant was detected in 21.1% of 617 HBC cases and 18.4% of 300 controls ( = 0.38). The p.Lys645Cysfs29 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, = 0.49). Clinical characteristics of breast tumors in the 38 carriers of p.Lys645Cysfs29 and 15,892 non-carriers were similar. Survival was similar among variant carriers and non-carriers (the age-adjusted HR = 0.87, = 0.76). The wild-type allele was retained in all five breast cancers of carriers of p.Lys645Cysfs29. 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 is unlikely to be a high or moderate-risk breast cancer susceptibility gene. Our study has clinical implications for genetic counseling and suggests that changes should be reclassified as variants of uncertain significance (VUS) when they are detected in clinical testing panels.