ClinVar Miner

Submissions for variant NM_000038.6(APC):c.6099_6100CT[1] (p.Asp2033_Ser2034insTer) (rs886039638)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000256071 SCV000322566 likely pathogenic not provided 2017-11-27 criteria provided, single submitter clinical testing The c.6101_6102delCT variant in the APC gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The c.6101_6102delCT variant causes a frameshift, changing codon Serine 2034 to a premature Stop codon, denoted p.Ser2034Ter. This variant is predicted to cause loss of normal protein function through protein truncation. The c.6101_6102delCT variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Therefore, based on the ACMG recommendations, c.6101_6102delCT is interpreted as an expected pathogenic sequence change.
Invitae RCV000808474 SCV000948584 pathogenic Familial adenomatous polyposis 1 2018-07-13 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the APC gene (p.Ser2034*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 810 amino acids of the APC protein. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with APC-related disease. ClinVar contains an entry for this variant (Variation ID: 265576). A different truncation (p.Tyr2645Lysfs*14) that lies downstream of this variant has been determined to be pathogenic (PMID: 9824584, 1316610, 27081525, 8381579, 22135120). 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. For these reasons, this variant has been classified as Pathogenic.

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