rs7167936 — CYP19A1 CYP19A1 intronic variant

CYP19A1 rs7167936 — A Regulatory-Zone Intronic Variant Linked to Breast Cancer Prognosticators

Aromatase¹¹ Aromatase
the enzyme encoded by CYP19A1 that catalyzes the conversion of androgens to estrogens, the final step in estrogen biosynthesis is expressed in the ovaries, adipose tissue, breast, bone, and brain. Local aromatase activity determines the estrogen microenvironment in hormone-sensitive tissues, and variants that alter CYP19A1 transcription or regulatory activity can shift the androgen-to-estrogen balance in ways relevant to cancer biology, reproductive function, and bone health. rs7167936 sits at chromosome 15 position 51,207,348 (GRCh38) — approximately 709 bp upstream of the annotated CYP19A1 transcription start site and within an intron of the neighboring non-coding RNA gene MIR4713HG. It maps to the CYP19A1 RefSeqGene (NG_007982.1:g.136251T>C), placing it squarely in the regulatory zone that governs aromatase expression in peripheral tissues.

The Mechanism

rs7167936 is classified as an intron variant in the MIR4713HG host gene transcript but lies within the broader CYP19A1 genomic locus. The CYP19A1 gene is on the minus strand of chromosome 15, meaning that the plus-strand coordinate 51,207,348 is upstream of the 3' (coding) end of the gene and near the region containing tissue-specific promoter elements. CYP19A1 is unusual in that it uses at least ten different tissue-specific promoters spread over ~93 kb of upstream sequence, with different promoter elements driving expression in the ovary, adipose tissue, bone, and brain. Variants in this regulatory region can alter which tissues express aromatase, at what level, and in response to which hormonal signals — without changing the protein itself.

rs7167936 has not been directly characterized for transcription factor binding or allele-specific expression, unlike the better-studied rs1062033 (CEBPβ binding) or rs700518 (splicing-related). Its functional significance is inferred from population-level association signals rather than from direct mechanistic studies.

The Evidence

The primary evidence for rs7167936 comes from Darabi et al. 2011²² Darabi et al. 2011
Breast Cancer Research and Treatment — 1,569 Swedish breast cancer patients; rs7167936 associated with histological grade (p=0.010) and tumor size (p=0.005; 1-sided). The study examined genetic variation across the androgen-to-estrogen conversion pathway in relation to tumor characteristics. rs7167936 associations with grade and size persisted when restricted to ER-positive tumors (p=0.008 and p=0.011), consistent with an estrogen-pathway mechanism influencing tumor biology rather than an off-target effect. rs4646 showed the strongest single-SNP associations in the same study, with the common CYP19A1 allele linked to low histological grade and smaller tumor size.

The variant has not been independently replicated for the specific associations with histological grade and tumor size. The evidence base is therefore limited to a single cohort and qualifies as emerging rather than strong. No ClinVar submissions exist, and no pharmacogenomics guidelines reference this variant. The broader CYP19A1 locus harbors multiple variants with stronger and better-replicated associations — rs727479, rs4646, rs10046, rs700518, and rs1062033 — with which rs7167936 may be in partial linkage disequilibrium, though formal LD data are not readily available.

Glubb et al. 2017³³ Glubb et al. 2017
review of CYP19A1 variation and aromatase inhibitor outcomes concluded that rs727479 best captures the CYP19A1 signal for circulating estradiol and that rs4646 (in LD with rs727479) was the only variant replicating across studies for aromatase inhibitor treatment outcomes. The position of rs7167936 near the CYP19A1 regulatory zone suggests it may tag this same haplotype block, though this requires formal confirmation.

Practical Actions

For carriers of the G allele (one or two copies), the evidence base is currently too limited to support specific clinical recommendations independent of the variant's broader CYP19A1 haplotype context. The primary actionable implication is awareness for women with a personal or family history of hormone receptor-positive breast cancer: the Darabi cohort data suggest this locus tags a biological signal influencing breast cancer tumor behavior, though the association is from a single study and the allele-specific direction requires clarification from the full text of the original paper.

Women undergoing surveillance for hormone-sensitive cancers or those with known CYP19A1 haplotype risk should discuss this variant alongside the better-characterized SNPs at the same locus (rs4646, rs10046, rs700518) with their clinician, as haplotype context may provide more interpretive power than any single variant in isolation.

Interactions

rs7167936 resides within the broader CYP19A1 regulatory zone that contains rs700518 (~12 kb upstream), rs1062033 (~12 kb upstream), rs10046 (in the 3'UTR), and rs4646 (in intron 4). These variants form multiple haplotype blocks and their combined effect on aromatase expression has been studied in bone, breast, and endometrium. The association of rs7167936 with breast tumor characteristics in the Darabi cohort was studied in the context of all these variants simultaneously; it is plausible that rs7167936 tags a haplotype shared with one or more of these better-characterized variants, though formal LD mapping at this position is needed.