Genome-wide association studies have revealed many breast cancer (BC) risk-associated genetic variants that might functionally interact with other molecular determinants of BC. We analysed the association of 21 known risk-associated single-nucleotide variants (SNVs) with recurrent somatic variants in two cohorts of 77 and 754 oestrogen receptor α-positive BCs. Four SNVs located at 5q11.2 were found to be associated with the somatic PIK3CA variant status in the pilot cohort of 77 cases with odds ratio (OR) up to 6.5 indicating strong effects, and were selected for the validation phase. Two of these SNVs, rs252913 and rs331499, located in the MAP3K1/SETD9 gene boundary, were confirmed to be associated with somatic PIK3CA variants in the large cohort with OR 2.97 (1.17-7.75) and 1.76 (1.11-2.77), respectively, notably higher than their BC risk-associated values, both around 1.1. In the presence of the SNV or of somatic PIK3CA variants, cancers express significantly elevated levels of MAP3K1 and SETD9, with synergy of SNV and PIK3CA variants in MAP3K1 gene overexpression, consistent with a preferential PIK3CA-dependent regulation of the variant alleles.