Oncogenic point mutations in exon 20 of the RB1 gene in families showing incomplete penetrance and mild expression of the retinoblastoma phenotype.

The retinoblastoma-predisposition gene, RB1, segregates as an autosomal dominant trait with high (90%) penetrance.
Certain families, however, show an unusual low-penetrance phenotype with many individuals being unaffected, unilaterally affected, or with evidence of spontaneously regressed tumors.
We have used single-strand conformation polymorphism analysis and PCR sequencing to study two such families.
Mutations were found in exon 20 of RB1 in both cases.
In one family a C----T transition in codon 661 converts an arginine (CGG) to a tryptophan (TGG) codon.
In this family, incomplete penetrance and mild phenotypic expression were observed in virtually all patients, possibly indicating that single amino acid changes may modify protein structure/function such that tumorigenesis is not inevitable.
In the second family the mutation in codon 675 is a G----T transversion that converts a glutamine (GAA) to a stop (TAA) codon.
However, this mutation also occurs near a potential cryptic splice acceptor site, raising the possibility of alternative splicing resulting in a less severely disrupted protein.. 
