ClinVar Miner

Submissions for variant NM_000038.6(APC):c.5936_5939del (p.Asn1979fs) (rs587781330)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129077 SCV000183780 pathogenic Hereditary cancer-predisposing syndrome 2012-12-19 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),Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation
GeneDx RCV000202142 SCV000209573 pathogenic not provided 2017-04-04 criteria provided, single submitter clinical testing This deletion of 4 nucleotides in APC is denoted c.5936_5939delACAA at the cDNA level and p.Asn1979ThrfsX64 (N1979TfsX64) at the protein level. Using alternate nomenclature, this variant would be defined as APC 5934_5937delAAAC. The normal sequence, with the bases that are deleted in brackets, is GAAA[delACAA]CAAT. The deletion causes a frameshift, which changes an Asparagine to a Threonine at codon 1979, and creates a premature stop codon at position 64 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.5936_5939delACAA has been observed in multiple families with a history of polyposis and colorectal cancer (Brensinger 1998, Castellsague 2010). We consider this variant to be pathogenic.
Invitae RCV000168219 SCV000218886 pathogenic Familial adenomatous polyposis 1 2018-12-30 criteria provided, single submitter clinical testing This sequence change deletes 4 nucleotides from exon 16 of the APC mRNA (c.5936_5939delACAA), causing a frameshift at codon 1979. This creates a premature translational stop signal in the last exon of the APC mRNA (p.Asn1979Thrfs*64). While this is not anticipated to result in nonsense mediated decay, it is expected to result in a truncated APC protein. Loss-of-function variants in APC are known to be pathogenic. This particular variant has been reported in the literature in families affected with attenuated familial adenomatous polyposis (PMID: 20434453, 9824584), and an individual affected with a history of colon polyps (PMID: 26681312). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000825610 SCV000966955 pathogenic Familial multiple polyposis syndrome 2018-04-06 criteria provided, single submitter clinical testing The p.Asn1979fs variant in APC has been reported in at least 5 individuals with attenuated familial adenomatous polyposis (AFAP; Brensinger 1998, Castellsague 2 010), 5 that have been referred for APC clinical testing (Kerr 2013), and 1 ind ividual with a personal history of colonic polyps (Susswein 2015). The variant s egregated with AFAP in at least 5 affected relatives from 1 family (Brensinger 1 998). This variant has also been reported by other clinical laboratories in Clin Var (Variation ID: 140863) and was absent from large population studies, though the ability of these studies to accurately detect indels may be limited. This va riant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at position 1979 and leads to a premature termination codon 6 4 amino acids downstream. This termination codon occurs within the last exon and is more likely to escape nonsense mediated decay (NMD) and result in a truncate d protein. An in vitro protein assay from patient RNA confirmed that this varian t leads to a truncated protein (Brensinger 1998). Truncating variants in the las t exon of APC have been reported in individuals with FAP. In summary, this vari ant meets criteria to be classified as pathogenic for APC-associated polyposis c onditions in an autosomal dominant manner based upon presence in multiple affect ed individuals, segregation studies, absence from the general population, and th e predicted impact on protein. ACMG/AMP Criteria applied (Richards 2015): PS4; P P1_Moderate; PM2; PM4.
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000202142 SCV000257019 pathogenic not provided no assertion criteria provided clinical testing

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