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RPAP1 has emerged as a candidate gene associated with breast cancer through multi‐patient genetic association studies. Two independent case‑control studies have interrogated markers in DNA repair and modification pathway genes, and RPAP1 was identified in the proximity of one of the replicated single‑nucleotide polymorphisms ([PMID:22258532]). The first study employed a two‑stage design with an initial cohort of 302 cases and 321 controls ([PMID:22258532]), followed by a replication cohort of 1178 cases and 1314 controls, altogether providing evidence from 3115 subjects ([PMID:22258532]). These data offer a statistically significant, albeit modest, association with breast cancer susceptibility.
The overall clinical validity for the RPAP1–breast cancer association is rated as Limited. While the replication across independent cohorts strengthens the finding, the modest effect sizes and the lack of classical segregation data limit the strength of the association ([PMID:22258532], [PMID:23755158]). The genetic signal is derived from common variants identified in genome‑wide association approaches rather than from rare, high‑penetrance mutations.
In terms of genetic evidence, the significant SNP near RPAP1 (rs2297381) contributed to SNP‑SNP interaction findings in the second study, which investigated 2795 cases and 4505 controls ([PMID:23755158]). No coding sequence variant meeting the strict HGVS criteria was reported in these studies. Thus, the variant evidence is limited to association signals and does not include an HGVS‑format variant for direct clinical interpretation.
The current studies predominantly utilized a case‑control design without evidence of familial segregation. There is no additional data on affected relatives, and the mode of inheritance remains complex rather than following a simple Mendelian pattern. Consequently, the inheritance of RPAP1‐associated breast cancer risk is best described as a complex trait, reflecting the polygenic nature of breast cancer susceptibility ([PMID:22258532], [PMID:23755158]).
Functional evidence supporting the pathogenicity of RPAP1 in breast cancer is notably absent. No in vitro assays, animal models, or mechanistic studies directly linking RPAP1 dysfunction to breast tumorigenesis were provided. This lack of functional data further underscores the current categorization of the gene–disease relationship as limited in clinical utility.
In summary, while replicated genome‑wide association studies have identified a statistically significant association between markers near RPAP1 and breast cancer risk, the modest effect sizes and absence of robust segregation or functional data confine the clinical interpretation to a limited level of evidence. Nonetheless, the reproducible association suggests that RPAP1 may contribute to polygenic risk and could be considered in broader risk‐assessment models in the future.
Gene–Disease AssociationLimitedThe association is based on replicated case‑control data (stage 1: 302 cases, 321 controls [PMID:22258532]; stage 2: 1178 cases, 1314 controls [PMID:22258532]; additional study: 2795 cases, 4505 controls [PMID:23755158]), but the modest effect sizes and absence of familial segregation data limit the strength of evidence. Genetic EvidenceLimitedGenetic evidence is provided solely through common variant associations (e.g., the SNP near RPAP1, rs2297381) with significant statistical signals in two independent studies, without any reported HGVS‑formatted coding variant. Functional EvidenceLimitedThere are no functional or mechanistic studies reported to support the role of RPAP1 in breast cancer, leaving a gap in experimental evidence. |