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.

Mutational Signature Analysis Reveals NTHL1 Deficiency to Cause a Multi-tumor Phenotype

“…The coding regions and exon-intron boundaries (10 bp each side) of NTHL1 were amplified from germline DNA using custom designed HaloPlex Targeted Enrichment Assays (Agilent Technologies, Santa Clara, CA). Subsequently, sequencing was performed on a HiSeq2500 Genome Analyzer (Illumina, San Diego, CA), sequence alignment and variant calling was performed as described previously (Li et al, 2016). To remove likely false positives, called variants were only retained if they had quality score >60 and an overall read depth R30, with a minimum of 8 reads and 20% of all reads supporting the alternate allele, as well as no obvious bias in strand of origin.…”

Familial breast cancer and DNA repair genes: Insights into known and novel susceptibility genes from the GENESIS study, and implications for multigene panel testing

“…11 Other DNA repair genes, such as RAD51 paralogs, 12-14 RINT1 15 and genes of the MRE11A-RAD50-NBN complex 16 are also screened although replication studies conducted in independent at-risk populations are lacking or failed to replicate initial findings. 17,18 The interpretation of the genetic data is also complicated. Most of the known pathogenic variants associated with BC are LoF (i.e.…”

Non-BRCA1/2 Breast Cancer Susceptibility Genes: A New Frontier with Clinical Consequences for Plastic Surgeons

“… 1 , 5 , 8 , 37 Mutations in the genes involved in the MRN complex, including RAD50, MRE11, and NBN/NBS1, appear to yield an intermediate risk for the development of breast cancer based on pooled data for all of these genes. 1 , 8 , 9 , 13 Their prevalence in pathogenic mutations is less than 1% while relative risk for breast cancer with MRN complex mutations has been suggested to be approximately 2.5 in some studies. 4 , 11 , 37 It is notable that only specific mutations of these genes appear to increase breast cancer risk and that these mutations appear population-specific through a potential founder effect.…”

“… 1 Concurrently, advanced genetic testing for these breast cancer susceptibility genes has been refined and is now widely available and cost-effective. 1 , 4 , 7 – 9 Despite remaining controversial, the growth in genetic testing can be expected to increase the proportion of patients diagnosed with a breast cancer susceptibility gene. 4 , 5 , 8 , 10 – 15 …”