Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000222879 | SCV000273154 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2016-12-23 | criteria provided, single submitter | clinical testing | The p.M1? variant (also known as c.1A>G), located in coding exon 1 of the RAD50 gene, results from an A to G substitution at nucleotide position 1. This alters the methionine residue at the initiation codon. However, the RAD50 gene contains a second methionine 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 protein, however, direct evidence is unavailable. A similar alteration at the same initiation codon, p.M1? (c.3G>A), has been reported in 1/104 Irish familial breast cancer families and 0/140 controls (Aloraifi F et al. FEBS J., 2015 Sep;282:3424-37), and has also been reported in conjunction with a BRCA2 mutation in an individual diagnosed with breast cancer at age 49 (Foley SB et al. EBioMedicine, 2015 Jan;2:74-81). In addition to the clinical data presented in the literature, since sequence variations that modify the initiation codon (ATG) are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame, the p.M1? variant is interpreted as likely pathogenic. |
| Invitae | RCV000222879 | SCV002313289 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2021-11-12 | criteria provided, single submitter | clinical testing | In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. ClinVar contains an entry for this variant (Variation ID: 229813). A different variant (c.3G>A) giving rise to the same protein effect has been determined to be pathogenic (PMID: 26023681, 26094658; Invitae). This suggests that this variant is also likely to be causative of disease. This variant is not present in population databases (gnomAD no frequency). This sequence change affects the initiator methionine of the RAD50 mRNA. The next in-frame methionine is located at codon 7. |