Total submissions: 6
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000807122 | SCV000947161 | pathogenic | not provided | 2024-01-27 | criteria provided, single submitter | clinical testing | This sequence change affects a donor splice site in intron 4 of the NTHL1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs372946560, gnomAD 0.0009%). Disruption of this splice site has been observed in individual(s) with clinical features of NTHL1-related conditions (PMID: 26559593). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 218092). Studies have shown that disruption of this splice site results in multiple aberrant splice products and introduces a premature termination codon (PMID: 26559593). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. |
| Fulgent Genetics, |
RCV000202319 | SCV002808478 | likely pathogenic | Familial adenomatous polyposis 3 | 2022-01-24 | criteria provided, single submitter | clinical testing | |
| Institute for Clinical Genetics, |
RCV000807122 | SCV004025961 | pathogenic | not provided | 2022-02-11 | criteria provided, single submitter | clinical testing | PVS1, PM2_SUP, PM3 |
| Ambry Genetics | RCV003352802 | SCV004062637 | pathogenic | Hereditary cancer-predisposing syndrome | 2023-08-23 | criteria provided, single submitter | clinical testing | The c.709+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 4 of the NTHL1 gene. This mutation was confirmed in trans with another NTHL1 pathogenic variant (p.Q90*) in a patient affected with >30 colon polyps and multiple cancer diagnoses, including colon adenocarcinoma. RNA studies on this individual and her heterozygous daughter demonstrated abnormal splicing (Rivera B et al. N Engl J Med, 2015 Nov;373:1985-6). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. In addition to the clinical data presented in the literature, 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. As such, this alteration is classified as a disease-causing mutation. |
| Myriad Genetics, |
RCV000202319 | SCV004188341 | likely pathogenic | Familial adenomatous polyposis 3 | 2023-09-05 | criteria provided, single submitter | clinical testing | This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function. |
| OMIM | RCV000202319 | SCV000257324 | pathogenic | Familial adenomatous polyposis 3 | 2015-11-12 | no assertion criteria provided | literature only |