ClinVar Miner

Submissions for variant NM_000038.6(APC):c.1999C>T (p.Gln667Ter) (rs876660130)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000213199 SCV000277302 pathogenic Hereditary cancer-predisposing syndrome 2015-07-17 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Invitae RCV000548322 SCV000647214 pathogenic Familial adenomatous polyposis 1 2018-08-06 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the last exon of the APC mRNA at codon 667 (p.Gln667*). While this is not anticipated to result in nonsense mediated decay, it is expected to delete the last 2,176 amino acids of the APC protein. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the literature in individuals affected with familial adenomatous polyposis (FAP) (PMID: 26414517, 20685668) and has been reported to segregate with FAP in one family (PMID: 22164339). 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. 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. For these reasons, this variant has been classified as Pathogenic.

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