Pathogenic coding region mutations in BRCA1, BRCA2 and PALB2 are major contributors to hereditary breast cancer (HBC) but collectively explain less than a quarter of the families tested in clinical practice, leaving the majority with no identifiable genetic defect to inform cancer prevention strategies. Other HBC genes explain only a small fraction (5%) of families. In contrast to the intensive, but largely unsuccessful, international efforts aimed at discovering new HBC genes, little attention has been given to the possibility that many of these families are explained by known HBC genes but which are inactivated via alternative mechanisms that are not detected by current methodology. We hypothesize that a clinically important component of the uncovered inherited risk of breast cancer is due to inherited promoter hypermethylation. Promoter hypermethylation of specific genes in hereditary cancer syndromes have been reported, such as the MLH1 gene in a proportion of Lynch syndrome patients but whether the same mechanism explains some HBC families is largely unexplored. A significant limitation of the few studies that have tried to explore HBC is that most have used methods that interrogate single CpG dinucleotides rather than the entire gene promoter and few included cases with a strong cancer family history. To overcome the limitations of these previous attempts to resolve the role of inherited promoter hypermethylation we are performing targeted methylation sequencing (TWIST Bioscience) of the entire promoter regions of 13 HBC genes in germline DNA from over 1000 women from the BEACCON study (npj Breast Cancer 2021, 7:76) who have a very strong breast cancer family history but where all known genetic causes have been excluded. This represents the largest and most comprehensive study of its type to date, which will have the power to conclusively resolve the contribution of inherited promoter hypermethylation to HBC.