RINT1 – hereditary breast carcinoma

Germline RINT1 has been proposed as an intermediate‐penetrance breast cancer predisposition gene based on rare protein‐damaging variants (PDAVs) identified in 1 of 54 BRCA1/2‐negative familial BC probands ([PMID:30947698]) and a single pathogenic RINT1 variant detected among 36 multigene panel–tested patients ([PMID:39831988]). However, a large case–control sequencing study of 2024 familial BC cases versus 1886 controls found no significant excess of truncating or rare missense RINT1 variants (28 cases vs. 27 controls; p>0.999) and no difference in Lynch syndrome cancer incidence in variant carriers, negating a moderate‐penetrance role ([PMID:27544226]). Segregation data are lacking and burden analyses failed to demonstrate statistical enrichment or locus‐specific loss of heterozygosity. No functional assays directly link RINT1 variant effects to breast tumorigenesis, and experimental models have not recapitulated a BC phenotype. Collectively, the genetic findings are inconsistent and the negative well‐powered case–control data refute a causal association of RINT1 with hereditary breast carcinoma. Key Take‐home: Current evidence does not support clinical testing of RINT1 for hereditary breast cancer risk.

References

• BMC cancer • 2019 • Identification of candidate cancer predisposing variants by performing whole-exome sequencing on index patients from BRCA1 and BRCA2-negative breast cancer families. PMID:30947698
• Surgery today • 2025 • Germline variants detected by multigene panel testing in patients with suspected hereditary breast cancer. PMID:39831988
• Breast cancer research and treatment • 2016 • Reevaluation of RINT1 as a breast cancer predisposition gene. PMID:27544226

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