Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000792395 | SCV000931691 | pathogenic | not provided | 2024-01-24 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Trp269*) in the NTHL1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 44 amino acid(s) of the NTHL1 protein. This variant is present in population databases (rs753029097, gnomAD 0.03%). This premature translational stop signal has been observed in individual(s) with rectal cancer or polyposis (PMID: 30753826). ClinVar contains an entry for this variant (Variation ID: 639573). This variant disrupts a region of the NTHL1 protein in which other variant(s) (p.Gln287*) have been determined to be pathogenic (PMID: 27329137, 28912133, 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 | RCV001027136 | SCV001189643 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2023-06-05 | criteria provided, single submitter | clinical testing | The p.W269* variant (also known as c.806G>A), located in coding exon 5 of the NTHL1 gene, results from a G to A substitution at nucleotide position 806. This changes the amino acid from a tryptophan to a stop codon within coding exon 5. Premature stop codons are typically deleterious in nature, however, this stop codon occurs at the 3' terminus of NTHL1, is not expected to trigger nonsense-mediated mRNA decay, and removes the last 44 amino acids of the protein. The exact functional impact of these removed amino acids is unknown at this time; however, structural analysis suggests this alteration eliminates portions of the endonuclease domain necessary for binding DNA and forming the functionally important FeS cluster (Ambry internal data). This variant has been identified in trans with a pathogenic NTHL1 mutation in an individual with colonic polyposis and extra-colonic malignancies (Grolleman JE et al. Cancer Cell, 2019 Feb;35:256-266.e5). In addition, it has also identified in conjunction with a pathogenic NTHL1 mutation in individuals with colonic polyposis and colorectal cancer; however, the phase, whether in cis or trans, was not determined (Grolleman JE et al. Cancer Cell, 2019 Feb;35:256-266.e5; Staninova-Stojovska M et al. Balkan J. Med. Genet., 2019 Dec;22:5-16). Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
| Revvity Omics, |
RCV001784408 | SCV002020171 | likely pathogenic | Familial adenomatous polyposis 3 | 2020-09-24 | criteria provided, single submitter | clinical testing | |
| Myriad Genetics, |
RCV001784408 | SCV004188363 | pathogenic | Familial adenomatous polyposis 3 | 2023-09-05 | criteria provided, single submitter | clinical testing | This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. |
| Baylor Genetics | RCV001784408 | SCV004192069 | pathogenic | Familial adenomatous polyposis 3 | 2023-10-31 | criteria provided, single submitter | clinical testing |