Epidemiology of rare breast cancer predisposing pathogenic gene variants in high hereditary breast cancer risk of population of Latvia, initial results

Genetic testing plays an invaluable role in hereditary breast cancer management. Massively parallel sequencing technology known as next-generation sequencing have been discovered and implemented in clinical oncology. Because of the large costs of extensive gene testing, there is a necessity for optimisation. The aim of the study is to establish the spectrum of rare breast cancer predisposing (non-BRCA) mutations in particular ethnic group. Multigene panel testing was carried out in women with increased risk of hereditary breast cancer selected according to Manchester Scoring System and/or NCCN criteria from population of Latvia. Clinical and genomic data were reviewed on 70 individuals tested on a panels of up to 38 genes. Tested genes include moderate to high-penetrance BRCA1, BRCA2, PALB2, PTEN, TP53, CHEK2, ATM, CDH1, NBN, NF1, STK11, RAD50, RAD51C, RAD51D, BARD1 and low-penetrance MUTH1, MCPH1, BAP, MSH, BRIP1, MLH1, MSH2, MSH6, PMS2, EPCAM, APC, BMPR1A, CDKN2A, MEN1, POLD1, POLE, RET, SMAD4, VHL, BLM, FAM175A, MRE11A, XRCC2. Informed Consent was obtained from all participants in this study. Germline pathogenic variants (PVs) were detected in 22 of 70 probands (31%)- 15 BRCA and 7 non-BRCA. Six cases of pathogenic CHEK2 variants were observed, including 2 repeated pathogenic variants c.470t>C (p.Ile157Thr) and del5395(ex9-10del) as well single ones - c.444+1G>A and 1100delC. Eleven variants of uncertain significance (VUS) identified- 2 in BRCA and 9 in non-BRCA genes- NBN, MSH6, ATM, STK11, MUTH, CDH1, RAD50, MRE11A. Genetic evaluation is becoming an integral part of the management of  breast cancer patients and high-risk individuals. Risk assessment, early detection strategies in individuals with BRCA1,2 mutations have been extensively studied, whereas less is known about the management of other mutation carriers with hereditary breast cancer predisposing gene variants. Our initial CHEK2 mutational spectrum shows evidence of similarities with neighbouring countries and other European populations. Two repeated PVs were detected.