Background: The clinical significance of CRC risk imparted by prevalent recessive mutations MUTYH-G396D and Y179C (Caucasian carrier rate 1/50) and the low-penetrance APC-I1307K mutation (Ashkenazi Jewish carrier rate ~1/15) is debated. Evidence supporting differential mutational spectrum, immune biology, and clinical outcomes in tumors that arise in carriers could lend support to their relevance. We characterized CRC carriers of MUTYH-G396D/Y179C and APC-I1307K, as well as those with concurrent second-hit mutations, in comparison to MUTYH or APC wild-type (WT) tumors. Methods: Retrospective review of patient samples (n = 13,896) submitted to a CLIA-certified laboratory (Caris Life Sciences, Phoenix, AZ) for next-generation sequencing (NGS) of DNA (592-gene or whole exome) and RNA (whole transcriptome). Deficient mismatch repair/high microsatellite instability (dMMR/MSI-H) was assessed by IHC/NGS. PD-L1 expression was tested by IHC (SP142; positive (+): ≥2+, ≥%5). Immune cell infiltration was estimated by RNA deconvolution using quanTIseq (Finotello, 2019). Presumed monoallelic (mMut) and biallelic mutations (bMut) included those with or without, respectively, a mutation or variant allele frequency ≥60%. Statistical significance determined by Fisher’s-Exact/Mann Whitney/X² tests. *indicates raw p-value that was not significant after correction for multiple comparisons. Real world overall survival was obtained from insurance claims data, with Kaplan-Meier estimates used for comparison. Results: MUTYH-G396D/Y179C (119, 26 bMut) and APC-I1307K (11 mMut, ) alterations were identified, with all 3 founders being more common among male patients and associated with slightly increased median age at time of biopsy. MUTYH bMut had higher rates of genomic vs mMut 6.0%, p=0.02*; WT 11.0%, p=0.05*), and increased dendritic cell (p=0.04) and CD4 T-cell (p=0.007) proportions. APC bMut tumors were less frequently dMMR/MSI-H (2.6% vs mMut 18.%, p=0.11*; WT 15.5%, p=0.03*), TMB-H (2.6% vs mMut 27.3%, p=0.03*; WT 17.3%, p=0.02*), and PD-L1+ (0% vs mMut 18.2%, p=0.05*; WT 9.4%, p=0.04*), with enrichment of the canonical CMS2 subtype (44% vs 9% mMut, p<0.01; WT 11%, p<0.0001). In pMMR/MSS CRC, the prognosis of MUTYH founder carriers was superior to MUTYH WT tumors (HR 0.44, CI 0.25-0.78, p=0.004), with a non-significant trend toward greater sensitivity (HR 0.50, CI 0.21-1.2, p=0.). The prognosis of APC I1307K carriers was superior to APC WT tumors (HR 0.51, CI 0.34-0.76, p<0.001). Conclusions: Carrier status of MUTYH-G396D/Y179C and APC-I3017K founders may positively impact prognosis in patients with pMMR/MSS tumors. Differences may derive from distinct molecular signatures in tumors from MUTYH and APC founder mutations and warrant further investigation of these biomarkers in CRC.