ClinVar Miner

Submissions for variant NM_000038.6(APC):c.4474del (p.Ala1492fs)

dbSNP: rs1131691144
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000494331 SCV000581425 pathogenic Hereditary cancer-predisposing syndrome 2013-10-01 criteria provided, single submitter clinical testing ​The c.4474delG pathogenic mutation, located in coding exon 15 of the APC gene, results from a deletion of one nucleotide at position 4474, causing a translational frameshift with a predicted alternate stop codon. Since frameshifts are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294).
Invitae RCV003651940 SCV001582844 pathogenic Familial adenomatous polyposis 1 2020-08-20 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. This variant disrupts the C-terminus of the APC protein. Other variant(s) that disrupt this region (p.Tyr2645Lysfs*14) have been determined to be pathogenic (PMID: 9824584, 1316610, 27081525, 8381579, 22135120, Invitae). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. This variant has not been reported in the literature in individuals with APC-related conditions. ClinVar contains an entry for this variant (Variation ID: 429057). This variant is not present in population databases (ExAC no frequency). This sequence change results in a premature translational stop signal in the APC gene (p.Ala1492Profs*15). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1352 amino acids of the APC protein. 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.
Myriad Genetics, Inc. RCV002523998 SCV004043417 pathogenic Familial adenomatous polyposis 1 2023-05-11 criteria provided, single submitter clinical testing This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.

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