Submission Details

RINT1 (RAD50 Interactor 1) encodes a protein first identified for its ability to interact with the RAD50 double strand break repair protein, with the resulting interaction implicated in the regulation of cell cycle progression and telomere length. RINT1 also plays a role in trafficking of cellular cargo from the endosome to the trans-Golgi network. Biallelic RINT1 mutations are associated with Infantile liver failure syndrome 3. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we describe curation for hereditary breast cancer (refute the association with breast cancer) in this curation. Evidence refuting this gene-disease relationship includes case-control data, while experimental data supports the role of RINT1 in cell cycle regulation.

Summary of Case-Control Data: 0.5 POINTS

This gene-disease relationship has been studied in at least 5 case-control studies at the aggregate variant level. In 2021, two large case-control studies [CARRIERS (PMID: 33471974) and BCAC (PMID: 33471991); both with more than 32 thousand cases and controls] did not identify a significant association of aggregate loss of function (LOF) variants in RINT1 and breast cancer. Likewise, two more case-control studies with smaller case and control sizes did not find significant association of breast cancer with pathogenic RINT1 variant (PMID:35884425) and missense RINT1 variants (PMID:27544226). However, a case-control study with small population size including 29 missense and 2 in-frame deletion RINT1 variants showed significant associations to breast cancer (0.5 points, PMID: 25050558).

Summary of Experimental Data: 3 POINTS

While major case-control studies did not support the gene-disease association, experimental data reported the physical interaction of RINT1 and RAD50, which further regulate cell cycle (0.5 points, PMID:11096100). Rint1-deficient fibroblasts showed a significant increase in chromosomal aberrations such as sister chromatid fusion (0.5 points, PMID:26383973). Rint-1 heterozygous mice also developed mammary gland adenocarcinoma (2 points, PMID:17470549).

Overall Summary:

In summary, given the lack of significant association in large breast cancer case-control studies to date, there is convincing evidence refuting the association between RINT1 and autosomal dominant hereditary breast cancer, which significantly outweighs the evidence supporting the association. This gene-disease pair was originally evaluated as disputed by the Breast/Ovarian Cancer GCEP on 9/26/2016. This re-curation was approved by the ClinGen Hereditary Diseases GCEP on 2/17/2023 (SOP Version 9).