title: Reevaluation of RINT1 as a breast cancer predisposition gene.
abstract: Rad50 interactor 1 (RINT1) has recently been reported as an intermediate-penetrance (odds ratio 3.24) breast cancer susceptibility gene, as well as a risk factor for Lynch syndrome. The coding regions and exon-intron boundaries of RINT1 were sequenced in 2024 familial breast cancer cases previously tested negative for BRCA1, BRCA2, and PALB2 mutations and 1886 population-matched cancer-free controls using HaloPlex Targeted Enrichment Assays. Only one RINT1 protein-truncating variant was detected in a control. No excess was observed in the total number of rare variants (truncating and missense) (28, 1.38 %, vs. 27, 1.43 %. P > 0.999) or in the number of variants predicted to be pathogenic by various in silico tools (Condel, Polyphen2, SIFT, and CADD) in the cases compared to the controls. In addition, there was no difference in the incidence of classic Lynch syndrome cancers in RINT1 rare variant-carrying families compared to RINT1 wild-type families. This study had 90 % power to detect an odds ratio of at least 2.06, and the results do not provide any support for RINT1 being a moderate-penetrance breast cancer susceptibility gene, although larger studies will be required to exclude more modest effects. This study emphasizes the need for caution before designating a cancer predisposition role for any gene based on very rare truncating variants and in silico-predicted missense variants.
authors.affiliation: Cancer Genetics Laboratory, Research Division, Peter MacCallum Cancer Centre, 305 Grattan Street, Melbourne, VIC, 3000, Australia.|Cancer Biology Medical Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
authors.forename: Na
authors.initials: N
authors.lastname: Li
authors.affiliation: Cancer Genetics Laboratory, Research Division, Peter MacCallum Cancer Centre, 305 Grattan Street, Melbourne, VIC, 3000, Australia.|Department of Pathology, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.
authors.forename: Ella R
authors.initials: ER
authors.lastname: Thompson
authors.affiliation: Cancer Genetics Laboratory, Research Division, Peter MacCallum Cancer Centre, 305 Grattan Street, Melbourne, VIC, 3000, Australia.
authors.forename: Simone M
authors.initials: SM
authors.lastname: Rowley
authors.affiliation: Familial Cancer Centre, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.
authors.forename: Simone
authors.initials: S
authors.lastname: McInerny
authors.affiliation: Cancer Genetics Laboratory, Research Division, Peter MacCallum Cancer Centre, 305 Grattan Street, Melbourne, VIC, 3000, Australia.|LifePool, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.
authors.forename: Lisa
authors.initials: L
authors.lastname: Devereux
authors.affiliation: Cancer Genetics Laboratory, Research Division, Peter MacCallum Cancer Centre, 305 Grattan Street, Melbourne, VIC, 3000, Australia.|Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia.
authors.forename: David
authors.initials: D
authors.lastname: Goode
authors.affiliation: LifePool, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.
authors.affiliation: Discipline of Medical Genetics and Centre for Information-Based Medicine, The University of Newcastle and Hunter Medical Research Institute, Newcastle, Australia.
authors.forename: Michelle W
authors.initials: MW
authors.lastname: Wong-Brown
authors.affiliation: Discipline of Medical Genetics and Centre for Information-Based Medicine, The University of Newcastle and Hunter Medical Research Institute, Newcastle, Australia.|Division of Molecular Medicine, Pathology North, Newcastle, NSW, Australia.
authors.forename: Rodney J
authors.initials: RJ
authors.lastname: Scott
authors.affiliation: Cancer Genetics Laboratory, Research Division, Peter MacCallum Cancer Centre, 305 Grattan Street, Melbourne, VIC, 3000, Australia.|Familial Cancer Centre, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.|Department of Pathology, University of Melbourne, Melbourne, VIC, Australia.
authors.forename: Alison H
authors.initials: AH
authors.lastname: Trainer
authors.affiliation: Cancer Genetics Laboratory, Research Division, Peter MacCallum Cancer Centre, 305 Grattan Street, Melbourne, VIC, 3000, Australia.|Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia.
authors.forename: Kylie L
authors.initials: KL
authors.lastname: Gorringe
authors.affiliation: Cancer Genetics Laboratory, Research Division, Peter MacCallum Cancer Centre, 305 Grattan Street, Melbourne, VIC, 3000, Australia.|Familial Cancer Centre, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.|Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia.|Department of Pathology, University of Melbourne, Melbourne, VIC, Australia.
authors.forename: Paul A
authors.initials: PA
authors.lastname: James
authors.affiliation: Cancer Genetics Laboratory, Research Division, Peter MacCallum Cancer Centre, 305 Grattan Street, Melbourne, VIC, 3000, Australia. ian.campbell@petermac.org.|Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia. ian.campbell@petermac.org.|Department of Pathology, University of Melbourne, Melbourne, VIC, Australia. ian.campbell@petermac.org.
authors.forename: Ian G
authors.initials: IG
authors.lastname: Campbell
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001943:Breast Neoplasms / Q000235:genetics*; D018797:Cell Cycle Proteins / Q000235:genetics*; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D059645:Mutation Rate; D019683:Penetrance; D017422:Sequence Analysis, DNA / Q000379:methods*; D044465:White People / Q000235:genetics; D055815:Young Adult
chemical_list: D018797:Cell Cycle Proteins; C422909:RINT1 protein, human
keywords: Breast cancer; Cancer predisposition; Germline mutation; RINT1