ClinVar

Description

The c.12_13delCGinsTT variant, located in coding exon 1 of the RAD50 gene, results from an in-frame deletion of CG and insertion of TT at nucleotide positions 12 to 13. This changes the amino acid at codon 5 from a glutamic acid to a stop codon. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. However, the RAD50 gene contains a second methionine encoding an initiation sequence 21 nucleotides (seven amino acids) downstream of the canonical start site. This has the potential to function as an alternate translation initiation site, resulting in the removal of the first six amino acids from the protein; however, direct evidence is unavailable. Other variants that impact the p.M1 initiation codon, p.M1? (c.1A>G) and p.M1? (c.3G>A), are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame, and are interpreted as likely pathogenic. Based on the majority of available evidence to date, this variant is likely to be pathogenic.