Total submissions: 5
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Ambry Genetics | RCV000218609 | SCV000277498 | pathogenic | Hereditary cancer-predisposing syndrome | 2022-02-08 | criteria provided, single submitter | clinical testing | The p.W1049* pathogenic mutation (also known as c.3147G>A), located in coding exon 15 of the APC gene, results from a G to A substitution at nucleotide position 3147. This changes the amino acid from a tryptophan to a stop codon within coding exon 15. This alteration occurs at the 3' terminus of theAPC gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 1793 amino acids of the protein. However, premature stop codons are typically deleterious in nature and a significant portion of the protein is affected (Ambry internal data). This alteration has been identified in an individual with colorectal polyposis (Friedl W, et al. Hered Cancer Clin Pract 2005 ; 3(3):95-114). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |
Labcorp Genetics |
RCV004562421 | SCV001235805 | pathogenic | Familial adenomatous polyposis 1 | 2021-11-27 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. A different truncation (p.Tyr2645Lysfs*14) that lies downstream of this variant has been determined to be pathogenic (PMID: 9824584, 1316610, 27081525, 8381579, 22135120, Invitae). This suggests that deletion of this region of the APC protein is causative of disease. This variant is expected to disrupt the EB1 and HDLG binding sites, which mediate interactions with the cytoskeleton (PMID: 15311282, 17293347). While functional studies have not been performed to directly test the effect on APC protein function, this suggests that disruption of the C-terminal portion of the protein is functionally important. ClinVar contains an entry for this variant (Variation ID: 217964). This premature translational stop signal has been observed in individual(s) with clinical features of familial adenomatous polyposis (PMID: 11247896, 12010888, 15311282, 17293347, 20223039, 20685668, 20924072, 21110124). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Trp1049*) in the APC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1795 amino acid(s) of the APC protein. |
Myriad Genetics, |
RCV004562421 | SCV004044050 | pathogenic | Familial adenomatous polyposis 1 | 2023-05-05 | 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. |
Mayo Clinic Laboratories, |
RCV000202067 | SCV000256967 | pathogenic | not provided | no assertion criteria provided | research | ||
Department of Pathology and Laboratory Medicine, |
RCV000202067 | SCV001549896 | uncertain significance | not provided | no assertion criteria provided | clinical testing |