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ESRRG is implicated in breast cancer risk through its role in estrogen signaling and metabolism. Several studies have evaluated polymorphisms in estrogen metabolizing enzymes, with ESRRG emerging as a candidate gene from multi‐patient association studies. In these studies, large cohorts of breast cancer patients and controls were genotyped, revealing modest associations with breast cancer risk that appear to be influenced by menopausal status (PMID:19415745) and lifestyle factors (PMID:35092367).
The overall clinical validity of the ESRRG–breast cancer association is best characterized as Moderate. Two independent case–control studies, one including 570 breast cancer patients (PMID:19415745) and another with 390 patients (PMID:35092367), supported an altered risk for breast cancer linked to ESRRG variants. Although segregation data are limited, the replication of association signals across distinct cohorts strengthens the confidence in this moderate level of evidence.
Genetic evidence primarily arises from evaluations of single nucleotide polymorphisms within ESRRG. In one study, a variant in ESRRG (rs1857407) was associated with a decreased risk (OR = 0.72 with 95% CI: 0.55–0.96) in a mixed population, while another study incorporated an ESRRG SNP (rs17043393) in a polygenic risk score model that further stratified risk when combined with traditional breast cancer risk factors. Together, these findings support a moderate level of genetic evidence for the gene–disease relationship (PMID:19415745; PMID:35092367).
Functional evidence from in vitro studies provides mechanistic insight into the role of ESRRG in transcriptional regulation. Specifically, targeted mutagenesis replacing Asp-273 with lysine in ESRRG (c.819G>A (p.Asp273Lys)) resulted in a complete loss of constitutive transcriptional activity due to impaired interaction with p160 coactivators. This experiment confirms the functional importance of this residue in maintaining the active conformation of the receptor and supports the pathogenic role of ESRRG alteration in breast cancer risk (PMID:16326832).
No significant conflicting evidence was reported in these studies, although the modest effect sizes observed in the genetic studies warrant further investigation. Integration of the genetic and functional data suggests that ESRRG variants contribute to breast cancer risk through a mechanism involving altered transcriptional regulation. Additional evidence exists beyond the maximal scoring limits of ClinGen, highlighting the potential utility of ESRRG testing for refining risk stratification in breast cancer.
Key Take‑home: ESRRG alterations, through both genetic predisposition and demonstrable functional impairment, represent a moderate level of evidence for contributing to breast cancer risk, underscoring its potential for clinical utility in risk assessment and diagnostic decision‑making.
Gene–Disease AssociationModerateTwo independent case–control studies (570 and 390 patients, respectively PMID:19415745; PMID:35092367) support an association, complemented by functional data confirming mechanistic disruption (PMID:16326832). Genetic EvidenceModerateCase–control analyses identified ESRRG variants with modest risk modifications (e.g., OR = 0.72), and inclusion in a polygenic risk score further supports its contributory role (PMID:19415745; PMID:35092367). Functional EvidenceModerateIn vitro mutagenesis (c.819G>A (p.Asp273Lys)) demonstrated loss of transcriptional activity due to impaired coactivator binding, confirming the mechanistic role of ESRRG in modulating estrogen receptor function (PMID:16326832). |