Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV002338043 | SCV002635065 | likely pathogenic | Hereditary cancer-predisposing syndrome; Cardiovascular phenotype | 2020-09-29 | criteria provided, single submitter | clinical testing | The c.1186-2A>C intronic variant results from an A to C substitution two nucleotides upstream from coding exon 11 in the NF1 gene. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNA decay; however, direct evidence is unavailable. The exact functional effect of the missing amino acids is unknown. Other alterations impacting this same splice acceptor site have been identified in individuals with clinical diagnoses of neurofibromatosis type 1, however. Additionally, RNA data indicates three such variants (c.1186-2A>T, c.1186-2A>G, and c.1186-1G>C) result in the same abnormally spliced transcript as is predicted to result from c.1186-2A>C (Pros E et al. Hum. Mutat., 2008 Sep;29:E173-93; Brekelmans C et al. Hum. Mutat., 2019 10;40:1760-1767; Melloni G et al. Cancers (Basel), 2019 11;11:). The c.1186-2A>C variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |