ClinVar Miner

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

dbSNP: rs587781330
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Total submissions: 7
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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 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, the impacted region is critical for protein function, and a significant portion of the protein is affected (Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
GeneDx RCV000202142 SCV000209573 pathogenic not provided 2022-07-12 criteria provided, single submitter clinical testing Frameshift variant predicted to result in protein truncation in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26681312, 24763289, 23159591, 31447099, 20434453, 17088437, 9824584, 1316610, 27081525, 22135120, 8381579)
Invitae RCV003534369 SCV000218886 pathogenic Familial adenomatous polyposis 1 2023-10-27 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Asn1979Thrfs*64) in the APC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 865 amino acid(s) of the APC protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of APC-related conditions (PMID: 9824584, 20434453, 26681312). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 140863). This variant disrupts a region of the APC protein in which other variant(s) (p.Tyr2645Lysfs*14) have been determined to be pathogenic (PMID: 1316610, 8381579, 9824584, 22135120, 27081525; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham 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.
Myriad Genetics, Inc. RCV002514709 SCV004044631 pathogenic Familial adenomatous polyposis 1 2023-05-15 criteria provided, single submitter clinical testing This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Baylor Genetics RCV002514709 SCV004208062 pathogenic Familial adenomatous polyposis 1 2021-11-18 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000202142 SCV000257019 pathogenic not provided no assertion criteria provided clinical testing

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