Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000657490 | SCV000779225 | likely pathogenic | not provided | 2018-03-16 | criteria provided, single submitter | clinical testing | This deletion of one nucleotide in BRCA2 is denoted c.9711delG at the cDNA level and p.Lys3238SerfsX11 (K3238SfsX11) at the protein level. The normal sequence, with the base that is deleted in brackets, is AAAG[delG]AAGT. The deletion causes a frameshift which changes a Lysine to a Serine at codon 3238, and creates a premature stop codon at position 11 of the new reading frame. Although this variant has not, to our knowledge, been reported in the literature, it is predicted to cause loss of normal protein function through protein truncation, as the last 181 amino acids are lost and replaced with 10 incorrect amino acids. The disrupted region at the end of the gene impacts the NLS1 and NLS2 domains, the RAD51 and Cyclin A binding domains, the Serine residue phosphorylated by CDK1/2, and the Threonine residue phosphorylated by CHEK1/2 (Esashi 2005, Bahassi 2008, Borg 2010, Roy 2012). This frameshift occurs in the last exon of the gene and results in truncation near a well-known BRCA2 nonsense polymorphism (K3326X). On one hand, any large truncation such as this would generally be pathogenic. However, because of the well-published downstream nonsense polymorphism, we know that loss of the end of the BRCA2 protein is not disease-causing. Based on currently available evidence, we consider this deletion to be a likely pathogenic variant. |