ClinVar Miner

Submissions for variant NM_000038.6(APC):c.5826_5829del (p.Asp1942fs) (rs864622228)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000206426 SCV000259788 pathogenic Familial adenomatous polyposis 1 2020-07-05 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 2020-08-07 criteria provided, single submitter clinical testing The c.5826_5829delCAGA pathogenic mutation, located in coding exon 15 of the APC gene, results from a deletion of 4 nucleotides at nucleotide positions 5826 to 5829, causing a translational frameshift with a predicted alternate stop codon (p.D1942Efs*27). This alteration occurs at the 3' terminus of the APC gene and is not expected to trigger nonsense-mediated mRNA decay. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data).<span style="color:rgb(255, 0, 0)"> This alteration was identified in an infant with Gardner fibroma and in this individual's sister who had hepatoblastoma; other family members had a history of colon polyposis and colorectal cancer (Vieira J et al. Eur. J. Hum. Genet., 2015 May;23:715-8). In addition, this alteration was detected in a family that included ten individuals with >100 colon adenomas (Bisgaard ML et al. Hum. Mutat., 2004 May;23:522). Epidermoid cysts, osteomas, duodenal adenomas and desmoid tumors were also reported in this family (Bisgaard ML et al. Hum. Mutat., 2004 May;23:522). In another study, this alteration (referred to as a 4 bp deletion at nucleotides 5844&ndash;5847 (codon 1962)) was detected in three unrelated families that had at least two individuals with desmoid tumors with otherwise variable presentation of colorectal polyposis and colorectal cancer (Scott RJ et al. Hum. Mol. Genet., 1996 Dec;5:1921-4). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000323095 SCV000888750 pathogenic not provided 2018-02-28 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001287089 SCV001473734 pathogenic none provided 2019-11-25 criteria provided, single submitter clinical testing The APC c.5826_5829delCAGA; p.Asp1942fs variant (rs864622228), also known as 5824delGACA and 5844_5847del4, is reported in the literature in multiple individuals and several large families affected with familial adenomatous polyposis (Bisgaard 2004, Lamlum 2000, Scott 1996, Vieira 2015). This variant is reported in ClinVar (Variation ID: 219743), and is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant results in a premature termination codon in the last exon of the APC gene. While this may not lead to nonsense-mediated decay, it is expected to create a truncated protein missing the last 902 amino acids. Based on available information, this variant is considered to be pathogenic. References: Bisgaard ML et al. Mutation analysis of the adenomatous polyposis coli (APC) gene in Danish patients with familial adenomatous polyposis (FAP). Hum Mutat. 2004 May;23(5):522. Lamlum H et al. Germline APC variants in patients with multiple colorectal adenomas, with evidence for the particular importance of E1317Q. Hum Mol Genet. 2000 Sep 22;9(15):2215-21. Scott RJ et al. Familial infiltrative fibromatosis (desmoid tumours) (MIM135290) caused by a recurrent 3' APC gene mutation. Hum Mol Genet. 1996 Dec;5(12):1921-4. Vieira J et al. Identification of previously unrecognized FAP in children with Gardner fibroma. Eur J Hum Genet. 2015 May;23(5):715-8.
OMIM RCV000000861 SCV000021011 pathogenic Desmoid disease, hereditary 1996-12-01 no assertion criteria provided literature only
Mayo Clinic Laboratories, Mayo Clinic RCV000323095 SCV000691758 pathogenic not provided no assertion criteria provided clinical testing

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