Rs138213197

rs138213197, aka G84E, is a SNP in the homeobox transcription factor HOXB13 gene located in a cluster of HOX genes on ch 17q21&#8211;22. This gene is a member of the abdominal B subfamily, which have posterior domains of expression, including in the vertebrate urogenital system. HOXB13 maintains a relatively high level of expression in the adult prostate. G84E consists of the non-conservative replacement of a glutamic acid for a glycine at this position in the HOXB13 protein.

In early 2012, findings were published based on exome sequencing of 200 genes spanning the ch17q21-22 region of primarily Caucasian prostate cancer patients (and matched controls). Deemed a "rare but recurring mutation", rs138213197(T) was discovered and then validated in a larger case-case study. Overall, rs138213197(T) was reported to lead to a 20-fold higher risk for prostate cancer, based on having been observed in 72 of ~5,000 patients but in only 1 person out of 1400 controls (so overall odds ratio 20.1, CI: 3.5 - 803.3, p=8.5&#215;10&#8722;7).

Subsequent studies convincingly replicate this result:
 * Confirmed with odds ratio of 7.1 (CI: 4.62&#8211;10.78, p = 10e-19) based on 10,000 patients of various ethnicities (and ~60,000 controls).
 * Confirmed with odds ratio of 3.4 (CI: 2.2&#8211;5.4, p = 10e-6 or less) based on 5,000 Swedish patients. For this population, male G84E carriers have an estimated 33% cumulative risk to age 80 yr of prostate cancer, compared to 12% (CI: 11&#8211;13) among noncarriers.
 * Confirmed with odds ratio of 5.8 (CI: 1.3 - 26.5, p = .01) based on 1,800 Canadian patients.
 * Confirmed with odds ratio of 3.3 (CI: 1.21 &#8211; 8.96) in 1,300 Caucasian men.
 * Confirmed with odds ratio of 7.9 (CI: 1.8 - 34.5, p = .0062) based on 928 Caucasian patients.
 * G84E not present in 671 Chinese patients or 1,536 controls, but a novel HOXB13 SNP, G135E found by sequencing in 3 of the cases (and no controls).

Is rs138213197 also associated with breast cancer risk? Maybe, maybe not - it's too early to tell:
 * This study of 4,000+ Canadian and Polish patients indicates not; frequency of allele was 0.16%.
 * Of 877 patients, 6 women with BRCA1/2 wild-type, familial breast cancer (none Ashkenazi) Jewish ancestry had the variant, hence an odds ratio 5.7 (CI: 1-40, p=0.02).

Additional studies examining the origin of the G84E variant have determined that the haplotype background it is seen within is observed most frequently in Nordic countries, most strikingly within the Finnish population, suggesting that rs138213197 is a founder mutation that arose around the year 1800 in Northern Europe.