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Breast Cancer Risk Related to Pathogenic BRCA1 Mutation May Be Modified by Repeats

A team at the Beckman Research Institute City of Hope, the University of California, San Diego, and other centers in the US and Israel describe potential breast cancer risk modifiers in individuals carrying a form of BRCA1 marked by the pathogenic 185delAG deletion, a founder mutation linked to the Ashkenazi Jewish population. As they report in the European Journal of Human Genetics, the investigators used targeted capture sequencing and a VNTR genotyping method called adVNTR to profile more than 300 variable number tandem repeats (VNTRs) in 347 women the pathogenic BRCA1 185delAG variant, unearthing four VNTRs that appeared to impact the BRCA1 mutation carriers' lifetime risk of developing breast cancer. In a broader set of eight risk-modifying VNTRs, they note that all but one risk allele was linked to younger breast cancer diagnoses in those with the same BRCA1 mutation. "[I]dentification of VNTRs significantly associated with risk of developing breast cancer in this genetically and ethnically homogeneous population is encouraging," the authors suggest, adding that "[s]imilar to SNPs, VNTRs significantly associated with the disease of interest could be incorporated into polygenic risk scores (PRS) to test for improved risk assessment and clinical applicability."