ClinVar Miner

Submissions for variant NM_000038.6(APC):c.1970_1971GA[1] (p.Glu658fs) (rs863225322)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000233179 SCV000282708 pathogenic Familial adenomatous polyposis 1 2019-01-05 criteria provided, single submitter clinical testing This sequence change deletes 4 nucleotides from exon 16 of the APC mRNA (c.1972_1975delGAGA), causing a frameshift at codon 658. This creates a premature translational stop signal in the last exon of the APC mRNA (p.Glu658Thrfs*11). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the 11 amino acids that follow this variant and delete the last 2175 amino acids (~76%) of the APC protein. This variant has been reported in an individual with several colorectal polyps (PMID: 25604157), and in individuals with familial adenomatous polyposis (PMID: 2068568, 23159591, 20564245). ClinVar contains an entry for this variant (Variation ID: 217940). Several truncating variants downstream of this variant have been determined to be pathogenic (PMID: 20223039, 11247896, 1316610). 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.
GeneDx RCV000202030 SCV000293371 pathogenic not provided 2015-11-04 criteria provided, single submitter clinical testing This deletion of 4 nucleotides in APC is denoted c.1972_1975delGAGA at the cDNA level and p.Glu658ThrfsX11(E658TfsX11) at the protein level. The normal sequence, with the bases that are deleted in braces, is AAGA[GAGA]ACAA. The deletion causes a frameshift, which changes a Glutamic Acid to a Threonine at codon 658, and creates a premature stop codon at position 11 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. APC c.1972_1975delGAGA has been reported in individuals with familial adenomatous polyposis (Lagarde 2010, Miclea 2010, Kerr 2013). We consider this variant to be pathogenic.
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000202030 SCV000256938 pathogenic not provided no assertion criteria provided research

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