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Cancer is a genomic disease, with driver mutations contributing to tumorigenesis. These potentially heritable variants influence risk and underlie familial breast cancer (BC). This study evaluated associations between BC risk and 13 SNPs in driver genes <i>MAP3K1</i>, <i>SF3B1</i>, <i>SMAD4</i>, <i>ARID2</i>, <i>ATR</i>, <i>KMT2C</i>, <i>MAP3K13</i>, <i>NCOR1</i>, and <i>TBX3</i>, in <i>BRCA1/2</i>-negative Chilean families. SNPs were genotyped using TaqMan Assay in 492 cases and 1285 controls. There were no associations between rs75704921:C>T (<i>ARID2</i>); rs2229032:A>C (<i>ATR</i>); rs3735156:C>G (<i>KMT2C</i>); rs2276738:G>C, rs2293906:C>T, rs4075943T:>A, rs13091808:C>T (<i>MAP3K13</i>); rs178831:G>A (<i>NCOR1</i>); or rs3759173:C>A (<i>TBX3</i>) and risk. The <i>MAP3K1</i> rs832583 A allele (C/A+A/A) showed a protective effect in families with moderate BC history (OR = 0.7 [95% CI 0.5–0.9] <i>p</i> = 0.01). <i>SF3B1</i> rs16865677-T (G/T+T/T) increased risk in sporadic early-onset BC (OR = 1.4 [95% CI 1.0–2.0] <i>p</i> = 0.01). <i>SMAD4</i> rs3819122-C (A/C+C/C) increased risk in cases with moderate family history (OR = 2.0 [95% CI 1.3–2.9] <i>p</i> ≤ 0.0001) and sporadic cases diagnosed ≤50 years (OR = 1.6 [95% CI 1.1–2.2] <i>p</i> = 0.006). <i>SMAD4</i> rs12456284:A>G increased BC risk in G-allele carriers (A/G + G/G) in cases with ≥2 BC/OC cases and early-onset cases (OR = 1.2 [95% CI 1.0–1.6] <i>p</i> = 0.04 and OR = 1.4 [95% CI 1.0–1.9] <i>p</i> = 0.03, respectively). Our study suggests that specific germline variants in driver genes <i>MAP3K1</i>, <i>SF3B1</i>, and <i>SMAD4</i> contribute to BC risk in Chilean population.