ClinVar Miner

Submissions for variant NM_000038.6(APC):c.5822_5825CAGA[1] (p.Asp1942fs) (rs864622228)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000206426 SCV000259788 pathogenic Familial adenomatous polyposis 1 2016-10-12 criteria provided, single submitter clinical testing This sequence change deletes 4 nucleotides from exon 16 of the APC mRNA (c.5826_5829delCAGA), causing a frameshift at codon 1942. This creates a premature translational stop signal in the last exon of the APC mRNA (p.Asp1942Glufs*27). While this is not anticipated to result in nonsense mediated decay, it is expected to delete the last 902 amino acids of the APC protein. Loss-of-function variants in APC are known to be pathogenic. This particular variant has been reported in the literature in individuals with a personal or family history of desmoid tumors (PMID: 8968744), and a personal or family history of familial adenomatous polyposis (PMID: 15108286, 11001924). This variant has been also been reported in an infant affected with Gardner fibroma with suspected desmoid tumor (PMID: 25074465). In this family, the variant was also observed in the proband's father, who had polyposis. The proband's paternal grandfather, affected with polyposis and colon cancer, is an obligate carrier. Sequencing of the proband's tumor revealed a somatic pathogenic APC mutation (p.Lys560*). This variant is also known as 5824delGACA and 5844_5847del4 in the literature. For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000323095 SCV000329773 pathogenic not provided 2016-08-25 criteria provided, single submitter clinical testing The c.5826_5829delCAGA variant in the APC gene has been reported previously in several families with familial adenomatous polyposis (Scott et al., 1996; Lamlum et al., 2000; Bisgaard et al., 2004; Vieira et al., 2015). Note that alternate nomenclature c.5844_5847delCAGA was used by Scott et al. (1996) and codon 1942 frameshift (5824delGACA) was used by Lamlum et al. (2000). The c.5826_5829delCAGA variant causes a frameshift starting with codon Aspartic Acid 1942, changes this amino acid to a Glutamic Acid residue, and creates a premature Stop codon at position 27 of the new reading frame, denoted p.Asp1942GlufsX27. This variant is predicted to cause loss of normal protein function through protein truncation. The c.5826_5829delCAGA variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret c.5826_5829delCAGA as a pathogenic variant
Ambry Genetics RCV000491422 SCV000579836 pathogenic Hereditary cancer-predisposing syndrome 2014-10-25 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)
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000323095 SCV000888750 pathogenic not provided 2018-02-28 criteria provided, single submitter clinical testing
OMIM RCV000000861 SCV000021011 pathogenic Desmoid disease, hereditary 1996-12-01 no assertion criteria provided literature only
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000323095 SCV000691758 pathogenic not provided no assertion criteria provided clinical testing

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