The APC gene plays a crucial role in colorectal cancer (CRC) susceptibility. Most pathogenic variants in APC affect Wnt signaling by promoting β-catenin accumulation, leading to polyposis. However, the APC I1307K variant (NM_000038.6: c.3920T > A) functions differently. Although located in the β-catenin binding domain, it doesn’t disrupt Wnt signaling, as the protein structure remains mostly intact. This single-nucleotide change extends an AAATAAAA sequence into eight adenosine nucleotides, making it prone to replication slippage and DNA polymerase errors. This variant increases the risk of somatic truncating variants on this allele and localized genomic instability, subtly elevating cancer risk without significantly increasing the polyp burden [18, 19].

Despite extensive study of the I1307K variant across different populations, disagreements persist in literature. First, the I1307K variant is interpreted differently across laboratories, with classifications ranging from “pathogenic” to “variant of uncertain significance” [20]. It has to be noted that the widely used variant interpretation criteria are developed for Mendelian diseases and not for low/moderate penetrant variants, as also discussed in the APC-specific variant interpretation criteria [21, 22]. As such, the ClinGen Low Penetrance/Risk Allele Working Group recommend the term “risk allele” [23].

Another key area of debate is the impact of the carrier’s ancestry on cancer risk. These differences have led to a variability in clinical recommendations for carriers and their families. Table 1 outlines the variant classifications and screening recommendations from three leading organizations. This review aims to summarize the pathogenicity data across different ethnicities and explain the basis for the differing recommendations.

Table 1 Summary of clinical recommendations for APC I1307K variant carriers

Before reviewing the clinical implications of the I1307K variant based on different ancestries, we want to shed light on relevant ethnic groups by exploring historical and contemporary factors that are pertinent to genetic discourse and may influence surveillance strategies for carriers and their families.

Jewish history has been marked by numerous events that led to the migration of Jewish populations from Jerusalem and its surrounding areas, resulting in their dispersion across various regions all over the world. This resulted in distinct ethnic groups with shared ancestral origins and unique genetic traits influenced by host populations.

Research into the genetic anthropology of the I1307K variant suggests that the variant arose before the beginning of the Jewish diaspora (586BC) [26]. Thus, the observation that the variant is found in both Ashkenazi and non-Ashkenazi individuals is consistent with this timeline. However, the significantly higher prevalence of this variant in the Ashkenazi population still requires further explanation. European Jewish communities migrated within the continent, particularly during the late Middle Ages, due to religious persecution, and established Ashkenazi communities in Eastern Europe [27,28,29].

In 1648–1649, these communities faced dramatic population declines due to the Cossack massacres. The small remaining communities expanded rapidly between 1765 and 1900, growing from 560,000 to 5 million. This expansion from a small founder population led to a high prevalence of certain genetic variants, including I1307K, through genetic drift [30].

Extensive research over the past two decades has linked the I1307K variant to increased CRC risk in Ashkenazi Jews (AJ). A meta-analysis by Valle et al., covering 19 studies, found that 11.5% of AJ CRC patients carry the I1307K variant, compared to 7.2% of AJs without CRC, with an odds ratio (OR) of 1.68 (95% CI 1.50–1.87; p < 0.00001) [24]. However, carriers do not show a higher propensity for multiple adenomas, and the age at first adenoma diagnosis is consistent across both groups [31,32,33]. One study noted that, after age adjustment, I1307K carriers are more likely to have colorectal polyps than non-carriers (51.3% vs. 33.6%; p = 0.03), but the number of polyps did not significantly differ [34].

In contrast to AJ, the definition of Sephardi Jews (SJ) is not based on ethnicity, but on cultural and religious background. SJ, used to live in Spain and Portugal until their expulsion in the late 15th century to North Africa, Western Asia, Southern Europe, and parts of America. Today, many reside in Israel [35]. Data on SJ alone is limited, with most studies grouping all non-AJ together, composed mainly of SJ and Yemenite Jews. Valle et al., based on five case-control studies and three without a control group, found the prevalence of I1307K to be 2.5% (16/651) in non-AJ Jewish CRC patients and 1.8% (20/1097) in controls, showing no significant CRC risk association (OR 1.36, 95% CI 0.65–2.78, p = 0.39) [24].

The data summarized above primarily links the increased CRC risk associated with the I1307K variant to AJ populations, aligning with the InSiGHT recommendation for CRC screening focused on AJ carriers [24]. However, we propose several points for consideration in this context, which may support the approach suggesting high-quality colonoscopy every five years for all Jewish carriers.

1.

(1) Studies on SJ have low participant numbers, only 10% of those in AJ I1307K studies, necessitating more data to confirm non-significant results.

2.

(2) Post-Holocaust demographic shifts led to increased migration and intermarriage among Jewish communities. In Israel, intermarriage rates between AJ and non-AJ increased from 9% in the 1950s to 25% and continue to rise, blurring distinctions between populations [36].

Only few studies report the association between CRC and I1307K in non-Jewish populations. In four small cohort studies from European countries (Croatia, Sweden, and England), only one CRC participant carried the variant [37,38,39,40], and no CRC was found in another cohort (including Italian, Finnish, and Hawaiian-Japanese individuals) [41]. Conflicting results were seen in population-based case-control studies. Based on Spanish exome array data, Valle et al. cited in their review that the I1307K variant was found to be 0.17% in CRC patients and 0.15% in controls (OR = 1.18, 95% CI 0.34–4.03, p = NS) [24]. On the other hand, Forkosh et al. found the variant in 0.24% of CRC patients and 0.12% of controls among non-Ashkenazi white (NAW) individuals, leading to an OR of 1.95, (95% CI 1.39–2.73, p < 0.01) [42]. Pooling data from studies in NAW shows a higher prevalence in CRC patients (0.23%) than controls (0.12%), with an OR of 1.88. However, the results are mainly based on Forkosh’s study and may not apply to all NAW. Three studies assessed the prevalence of I1307K in Israeli Arabs and Egyptians [34, 43, 44], with reported prevalence in CRC patients ranging from 3.1% (Israeli Arabs with CRC in north Israel) [34] to 33% (Israeli Arabs younger than 60 years at a single center) [43].

InSiGHT recommends CRC screening only for AJ I1307K carriers due to lack of conclusive evidence in other ethnicities [24]. On the other hand, the NCCN recommends screening regardless of ethnicity, as some individuals may be unaware of their Ashkenazi heritage. Moreover, as shown, there might be an increased CRC risk in other ethnicities. Further studies are needed to make a definite recommendation. Meanwhile, screening regardless of ethnicity should be considered.

Another controversy between the NCCN and InSiGHT concerns the age to begin screening. The NCCN recommends starting colonoscopy at age 40 (or 10 years before CRC diagnosis in a first-degree relative), while InSiGHT suggests starting at 45–50. Since no evidence exists of early-onset CRC among I1307K carriers, beginning screening at the same age of average risk population sounds reasonable [24].

Data on the effect of I1307K on extracolonic cancer risk are limited. Two Israeli studies showed an increased overall extracolonic cancer risk but did not mention ethnicity [45, 46]. Only two studies assessed this risk in AJ [42, 47], with a meta-analysis finding no increased risk (7% both in extracolonic cancer patients and in controls). Most included patients were from one study [42]. Several studies examined the effect of I1307K on specific cancer types among different ethnicities. Valle et al. found no increased risk for breast, prostate, and pancreatic cancer among AJ carriers, though there was a trend towards a higher prevalence of pancreatic cancer (9.2% in cases vs. 7% in controls, OR 1.36, 95% CI 0.97–1.89, p = 0.06) [24]. One large population-based study found higher prevalence for renal cancer (both sexes) and melanoma (males only) among AJ carriers compared to healthy individuals (renal cancer: OR 1.64, 95% CI 1.04–2.47; melanoma: OR 2.04, 95% CI 1.24–3.22, p < 0.05) [42]. Data on non-Jewish populations are scarce, with two small studies from Turkey [48, 49] and one large study from the US and Europe [42] indicating higher I1307K rates in melanoma patients (OR 2.54, 95% CI 1.57–3.98, p < 0.01), as well as in breast (female only) and prostate (male only) cancer patients (OR 1.73, 95% CI 1.18–2.65, p < 0.01; OR 2.42, 95% CI 1.45–3.94, p < 0.01, respectively). All three organizations (Table 1) agree that data on extracolonic cancer are controversial and scarce, so currently screening is not recommended.

In summary, strong evidence links the I1307K variant to increased CRC risk in AJ. More data is needed to assess its pathogenicity in non-AJ populations(Jewish and non-Jewish) and its impact on cancer onset and prognosis across different ethnicities. Resolving these issues will clarify screening recommendations for non-AJ populations and the appropriate age to begin screening.