Up to 5% of all colorectal cancers (CRC) are due to the well characterised inherited syndromes, including Lynch syndrome, caused by germline mutations in the DNA mismatch repair (MMR) genes. Tumour mismatch repair (MMR) deficiency, determined by immunohistochemical loss of MMR protein expression, is used diagnostically to identify individuals with CRC likely to be caused by Lynch syndrome. However, for a high proportion of CRC tumours with MMR-deficiency the individual does not have an identifiable germline mutation in a MMR gene; this is categorised as ‘suspected Lynch syndrome’. We have used whole genome sequencing and tumour profiling to identify additional causes of MMR-deficient CRC tumours through the identification of new susceptibility genes and bi-allelic somatic mutations in the MMR genes, respectively. This has enabled the stratification of suspected Lynch syndrome CRCs into groups for clinical management. Recently, germline mutations in the polymerase proofreading genes POLE and POLD1 have been identified in CRC and polyposis affected families, however, the age- and sex-specific CRC risks for carriers have not yet been quantified. We will present the prevalence and spectrum of POLE and POLD1 variants/mutations among familial CRCs and the first estimates of both relative and absolute risks of CRC for POLE and POLD1 mutation carriers. Furthermore, tumour profiling has enabled the identification of a hypermutated tumour phenotype in POLE or POLD1 mutation carriers that can be used to aid the diagnosis of carriers and genetic variant classification. Finally, we provide an update of our work describing new CRC susceptibility genes identified from whole genome and whole exome sequencing of 203 CRC-affected individuals from 90 families from the Australasian Colorectal Cancer Family Registry.