LAUSR

PURPOSE Multiple lines of evidence have suggested a likely causative role in breast/ovarian cancer (BrCa/OvCa) predisposition for the BRCA1 p.(Val1833Met) variant, predominantly found among Greek patients. Our aim was to study the variant's prevalence and founder effect on the Greek population, while providing additional data for its pathogenicity. METHODS We genotyped 3531 BrCa/OvCa patients using Sanger and next generation sequencing, as well as 1558 healthy, age-matched females with real-time PCR. Carriers underwent haplotype analysis to determine a founder effect. A co-segregation analysis was applied to estimate the likelihood ratio for pathogenicity. RESULTS In total, 27 BrCa/OvCa patients (0.77%; 27/3531) were found to carry the p.(Val1833Met) variant. No carriers were identified in the control group diagnosis. A common shared haplotype, spanning 2.76 Mb on chromosome 17 was demonstrated among carriers, establishing the founder effect. BRCA1, p.(Val1833Met) is possibly a disease-associated variant, supported by a likelihood ratio of 1.88, while a correlation to ovarian cancer is suspected. CONCLUSIONS Altogether, BRCA1, p.(Val1833Met) variant is a Greek founder and is very likely to predispose for BrCa/OvCa. Therefore, such carriers should be counselled accordingly, with clinical recommendations supporting surveillance and risk-reduction strategies, while providing the option for targeted therapeutic interventions.