Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001220484 | SCV001392476 | pathogenic | not provided | 2023-10-03 | criteria provided, single submitter | clinical testing | This sequence change affects a donor splice site in intron 5 of the NTHL1 gene. While this variant is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with NTHL1-related conditions. ClinVar contains an entry for this variant (Variation ID: 949095). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts a region of the NTHL1 protein in which other variant(s) (p.Gln287*) have been determined to be pathogenic (PMID: 27329137, 30552997, 30753826; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. |
| Ambry Genetics | RCV002418757 | SCV002679576 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-12-22 | criteria provided, single submitter | clinical testing | The c.815+2T>C intronic variant results from a T to C substitution two nucleotide after coding exon 5 of the NTHL1 gene. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and may result in the creation or strengthening of a novel splice donor site; however, direct evidence is insufficient at this time (Ambry internal data). 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). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Baylor Genetics | RCV003462750 | SCV004192129 | likely pathogenic | Familial adenomatous polyposis 3 | 2023-09-06 | criteria provided, single submitter | clinical testing |