Failure to identify high impact pathogenic mutations in all affected family members prompted extended analysis for functional polymorphisms (minor allele frequency > 1%) in the folate pathway genes, methionine synthase (MTR) and methionine synthase reductase (MTRR). These genes are included in the Ion AmpliSeqTM Comprehensive Cancer Panel used to identify the RAD50 and MUC1 rare variants. This evidence concerns the gene MTR and cancer.