Comprehensive Pan-Cancer Assessment of the APC I1307K Variant Reveals Ancestry-Independent Colorectal Cancer Risk
Annual Clinical Genetics Meeting, March 2026
Maksym Misyura, PhD, FACMG, Clinical molecular geneticist, Memorial Sloan Kettering Cancer Center, Chuan Gao, PhD, Zarina Yelskaya, MA, Kanika Arora, MS, Diana Mandelker, MD, PhD
Introduction: The APC I1307K germline variant is a well-established risk factor for colorectal cancer (CRC) among individuals of Ashkenazi Jewish (ASJ) ancestry. However, its contribution to oncogenesis across other tumor types and ancestral backgrounds remains unclear.
Methods: We analyzed germline and somatic sequencing data from 50,849 cancer patients who underwent clinical tumor–normal sequencing between May 2015 and November 2025, including carriers of the APC I1307K variant. Somatic data were examined to identify truncating alterations occurring in-cis and within the homopolymer tract created by APC I1307K in order to estimate the proportion of cancers directly attributable to this risk allele. Ancestry was inferred from MSK-IMPACT sequencing data to determine ASJ ancestry.
Results: We identified 521 carriers of APC I1307K across multiple cancer types. Based on SNP-inferred ancestry analysis, 420 carriers were of ASJ origin, while 99 were not ASJ (ancestry could not be inferred for two individuals). Across all carriers, 41 truncating alterations were detected in-cis with the APC I1307K risk allele within the resulting homopolymer region, and all occurred exclusively in CRC samples. Overall, 6.7% (95% CI: 4.4–9.5%; 26/394) and 17.9% (95% CI: 10.4–27.8%; 15/84) of cancers were attributable to the APC I1307K variant among risk allele carriers of ASJ and non-ASJ ancestry, respectively. The higher proportion observed among non-ASJ carriers suggests that the pathogenic mechanism associated with APC I1307K also confers elevated CRC risk in non-ASJ populations, extending beyond the ancestry group currently recognized by clinical guidelines.
Conclusion: These findings demonstrate that APC I1307K confers increased risk specifically for colorectal cancer across diverse ancestries. While consistent with the tissue specificity described in prior studies, the comparable and even higher proportion of CRCs attributable to this variant in non-ASJ individuals challenges current recommendations limiting genetic testing to ASJ populations. In light of the Position statement of the International Society for Gastrointestinal Hereditary Tumours (InSiGHT) on APC I1307K and cancer risk, our results provide emerging evidence to support considering targeted testing and surveillance for non-ASJ carriers as well.
