In this study we have performed whole-exome sequencing on germline DNA from 55 mismatch repair-proficient early-onset CRC cases and identified multiple potentially damaging variants in two colon-expressed genes: PTPN12 and LRP6. The germline variants identified in these genes appeared to affect highly conserved amino acids and were absent, or present at extremely low frequencies, in control populations. Here, LRP6 is linked to colorectal carcinoma.