The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer

Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes <i>BRCA1</i>, <i>BRCA2</i>, <i>PALB2</i>, <i>ATM</i>, and <i>CHEK2</i> are associated with breast cancer risk. <i>FANCM</i>, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants <i>FANCM</i>:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of <i>BRCA1</i> or <i>BRCA2</i>. These three variants were also studied functionally by measuring survival and chromosome fragility in <i>FANCM</i> ^<i>-/-</i> patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that <i>FANCM</i>:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, <i>P</i> = 0.034 and OR = 3.79; <i>P</i> = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for <i>FANCM</i>:p.Arg658* and found that also <i>FANCM</i>:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; <i>P</i> = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with <i>FANCM</i>:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare <i>FANCM</i> deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat <i>FANCM</i>-associated tumors.