Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV001025282 | SCV001187443 | uncertain significance | Hereditary cancer-predisposing syndrome | 2024-01-24 | criteria provided, single submitter | clinical testing | The c.645+2T>C intronic variant results from a T to C substitution two nucleotides after coding exon 4 in the AIP gene. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay; however, +2T>C alterations are capable of generating wild-type transcripts in some genomic contexts and should be interpreted with caution (Lin JH et al. Hum Mutat. 2019 10;40:1856-1873). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis for this alteration is inconclusive; however, RNA studies have demonstrated that this alteration does not result in abnormal splicing in the set of samples tested (Ambry internal data). Based on the available evidence, the clinical significance of this alteration remains unclear. |
| Labcorp Genetics |
RCV001862318 | SCV002253892 | uncertain significance | not provided | 2025-01-08 | criteria provided, single submitter | clinical testing | This sequence change affects a donor splice site in intron 4 of the AIP gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in AIP are known to be pathogenic (PMID: 23321498, 26186299). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with AIP-related conditions. ClinVar contains an entry for this variant (Variation ID: 826413). Studies have shown that disruption of this splice site is associated with inconclusive levels of altered splicing (internal data). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. |
| Gene |
RCV001862318 | SCV004023427 | uncertain significance | not provided | 2023-02-06 | criteria provided, single submitter | clinical testing | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this variant does not alter splicing; Has not been previously published as pathogenic or benign to our knowledge |
| Juno Genomics, |
RCV004796352 | SCV005416916 | likely pathogenic | Somatotroph adenoma | criteria provided, single submitter | clinical testing | PM2_Supporting+PVS1_Strong+PP4 |