Prevalence and founder effect of the BRCA1 p.(Val1833Met) variant in the
Greek population, with further evidence for pathogenicity and risk
modification
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