LAUSR

Simple Summary The Finnish population has evolved through multiple reductions in the population size, which have caused decreased genetic diversity in the population. This may affect the risk variant spectrum in diseases such as breast cancer (BC) so that a few variants may cover most of the pathogenic variation found in the risk genes. A dozen recurrent pathogenic variants have been identified in the moderate-risk BC susceptibility genes in Finnish BC patients. To evaluate the spectrum and frequency of the risk variants more comprehensively, we have, here, studied all variants in 1769 patients and copy number changes in 1511 patients both in the moderate-risk genes as well as in the high-risk BRCA1 and BRCA2 genes. While the overall pathogenic variant frequency was comparable to other populations, just a few variants accounted for most of the pathogenic burden in the risk genes. These results could be utilized in population screening strategies in Finland. Abstract Recurrent pathogenic variants have been detected in several breast and ovarian cancer (BC/OC) risk genes in the Finnish population. We conducted a gene-panel sequencing and copy number variant (CNV) analysis to define a more comprehensive spectrum of pathogenic variants in BRCA1, BRCA2, PALB2, CHEK2, ATM, BARD1, RAD51C, RAD51D, BRIP1, and FANCM genes in Finnish BC patients. The combined frequency of pathogenic variants in the BRCA1/2 genes was 1.8% in 1356 unselected patients, whereas variants in the other genes were detected altogether in 8.3% of 1356 unselected patients and in 12.9% of 699 familial patients. CNVs were detected in 0.3% of both 1137 unselected and 612 familial patients. A few variants covered most of the pathogenic burden in the studied genes. Of the BRCA1/2 carriers, 70.8% had 1 of 10 recurrent variants. In the other genes combined, 92.1% of the carrier patients had at least 1 of 11 recurrent variants. In particular, PALB2 c.1592delT and CHEK2 c.1100delC accounted for 88.9% and 82.9%, respectively, of the pathogenic variation in each gene. Our results highlight the importance of founder variants in the BC risk genes in the Finnish population and could be used in the designing of population screening for the risk variants.