BRCA1 and cancer: Constitutional epimutations may be classified as primary epimutations (methylation in absence of any genetic aberration) or secondary epimutations that are associated with rare germline genetic variants.10,24 Secondary epimutations have been detected in only a few cases associated with the Lynch syndrome–associated MLH1 gene, but also BRCA1. 24,25 In such cases, the fraction of methylated alleles is typically around 50% (ie, 100% of cells carrying the epigenetic variant in a heterozygous individual), and cancer penetrance is high.