rs9383935 — CCDC170

3' UTR variant in CCDC170 at the 6q25.1 estrogen-signaling locus; the T allele confers breast cancer risk (OR 1.38 in Chinese women); the same locus independently confers endometriosis susceptibility

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CCDC170 3' UTR

At chromosome 6q25.1, the estrogen receptor alpha gene ESR1 sits next to CCDC170 (Coiled-Coil Domain Containing 170), a gene whose protein organizes the Golgi apparatus and its microtubule connections inside cells. This locus is one of the most intensively studied regions in cancer and reproductive genetics — it has been implicated in breast cancer, endometriosis, and bone mineral density across dozens of GWAS studies spanning multiple ancestries.

rs9383935 is a variant in the 3' untranslated region (3' UTR) of CCDC170. The variant is in high linkage disequilibrium11 linkage disequilibrium
variants in LD tend to be inherited together; r² = 0.86 here means they co-occur ~86% of the time with the classic GWAS sentinel rs2046210 upstream of ESR1, but shows a strong independent effect in conditional analysis.

The Mechanism

rs9383935 sits at GRCh38 position chr6:151,618,713 in the 3' UTR of CCDC170, the last segment of CCDC170 mRNA that is not translated into protein. This region typically contains binding sites for microRNAs — small RNAs that bind mRNAs and regulate how much protein is made.

Luciferase reporter assays in MCF-7 and BT-474 breast cancer cell lines22 Luciferase reporter assays in MCF-7 and BT-474 breast cancer cell lines
Wang et al. Breast Cancer Research, 2014 demonstrated that constructs carrying the T allele had significantly lower reporter activity than the C allele constructs.

CCDC170 protein localizes to the Golgi apparatus and organizes perinuclear microtubule networks33 perinuclear microtubule networks
microtubules radiating from the Golgi help polarize cells and direct protein secretion; when disrupted, cells lose the ability to migrate in an organized, directional way. In cancer-associated truncation models, loss of CCDC170 Golgi localization drives increased cell motility and anchorage-independent growth — processes that contribute to tumor cell invasion and metastasis.

The Evidence

The primary evidence for rs9383935 comes from a 2014 study of 1,064 breast cancer cases and 1,073 controls in Chinese women44 2014 study of 1,064 breast cancer cases and 1,073 controls in Chinese women
Wang et al. Breast Cancer Research. Breast cancer risk was significantly associated with rs9383935-T with an odds ratio of 1.38 (95% CI 1.20–1.57, P = 2.21×10⁻⁶). This effect was identified by conditional analysis as independent of rs2046210. The study is moderately sized for GWAS standards, and the evidence level is moderate pending replication in larger multi-ethnic cohorts for rs9383935 specifically.

The broader locus has been comprehensively characterized. Fine-mapping in more than 118,000 subjects55 Fine-mapping in more than 118,000 subjects
Dunning et al. Nature Genetics, 2016 identified at least five independent causal variants at 6q25, each regulating ESR1, RMND1, or CCDC170 through distinct enhancer elements. The CCDC170/ESR1 locus is also one of the most robustly replicated endometriosis susceptibility regions: a meta-analysis of 17,045 cases and 191,596 controls66 meta-analysis of 17,045 cases and 191,596 controls
Sapkota et al. Nature Communications, 2017 and the largest endometriosis GWAS to date in 60,674 cases77 largest endometriosis GWAS to date in 60,674 cases
Rahmioglu et al. Nature Genetics, 2023 both confirm genome-wide significance for this region in endometriosis.

The T allele of rs9383935 is notably more common in East Asian populations (~30%) than in Europeans (~8%) or Africans (~5%), consistent with the stronger breast cancer associations initially detected in Chinese cohorts.

Practical Actions

For breast cancer risk, CT and TT carriers at this locus have elevated susceptibility. Proactive surveillance — staying current with breast cancer screening guidelines and discussing cumulative polygenic risk with a clinician — is the primary actionable step.

Interactions

rs9340799 (ESR1 XbaI): The classical ESR1 polymorphism rs9340799, characterized in the reproductive_hormones and endometriosis categories, is also at 6q25.1.

Genotype Interpretations

What each possible genotype means for this variant.

CC Normal

Common genotype — baseline breast cancer risk at this locus

You carry two copies of the C allele at rs9383935, the most common genotype globally. About 84% of the global population carries this genotype; it is most common in Europeans and Africans (>90%) and somewhat less frequent in East Asian populations (~49%).

Your breast cancer risk from this particular variant is at baseline.

CT Intermediate

One copy of the T allele — modestly elevated breast cancer risk at this locus

The Wang et al. (2014) study (PMID 25116933) demonstrated that the T allele reduces CCDC170 reporter gene activity in both MCF-7 (luminal A) and BT-474 (HER2+) breast cancer cell lines.

Because rs9383935 is in high LD (r² = 0.86) with the GWAS sentinel rs2046210, they tend to co-occur — meaning CT carriers here are likely to also carry the AG genotype at rs2046210. However, conditional regression analysis shows rs9383935 retains independent statistical significance after accounting for rs2046210.

The endometriosis connection at this locus is established for the broader 6q25.1 region, but rs9383935's independent contribution to endometriosis susceptibility has not been separately validated.

TT High Risk

Two copies of the T allele — highest breast cancer risk at this locus

You carry two copies of the T allele at rs9383935. The 2014 Wang et al. study in Chinese women reported an odds ratio of 1.38 (95% CI 1.20–1.57) for the T variant allele; homozygous TT carriers fall at the highest-effect end of this additive genetic model. TT genotype is rare globally (~1% average), but reaches approximately 9% frequency in East Asian populations where the T allele is most common (~30%).

Two copies of the T allele represent the highest burden at this specific locus for breast cancer susceptibility.