ClinVar Miner

Submissions for variant NM_000038.6(APC):c.2547_2550del (p.Asp849fs) (rs398123118)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 5
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000115074 SCV000148983 pathogenic Hereditary cancer-predisposing syndrome 2014-03-25 criteria provided, single submitter clinical testing This variant is denoted APC c.2547_2550delTAGA at the cDNA level and p.Asp849GlufsX11 (D849EfsX11) at the protein level. The normal sequence, with the bases that are deleted in brackets, is AAGA{TAGA}AGTT. The deletion causes a frameshift, which changes an Aspartic Acid to a Glutamic Acid at codon 849 in exon 16, and creates a premature stop codon at position 11 of the new reading frame. This mutation is predicted to cause loss of normal protein function through protein truncation. APC 2547_2550delTAGA, previously reported as 2547del4, has been observed in association with Familial Adenomatous Polyposis (Ripa 2002, Friedl 2005). We therefore consider this mutation to be pathogenic. and is indicative of a Familial Adenomatous Polyposis (FAP)-associated condition, which includes classic FAP and attenuated FAP (AFAP). These autosomal dominant conditions predispose individuals to the development of many polyps, colorectal cancer, and other cancers. AFAP is distinguished from classic FAP primarily by the difference in polyp burden and age at presentation. Individuals with classic FAP may develop hundreds to thousands of adenomatous polyps by age 35 and, on average, are diagnosed with colon cancer by the age of 39. The age-related risk for colon cancer in untreated individuals is 7% by age 21, 87% by age 45, and 93% by age 50 (Jasperson 2010). Individuals with AFAP develop an average of about 30 polyps and are typically diagnosed with colon cancer between ages 50 and 55. Other cancer risks in individuals with FAP and AFAP include 5% risk for duodenal or periampullary cancer, and in FAP less than or equal to a 2% risk for stomach, thyroid, pancreatic, brain (typically medulloblastoma), and liver (hepatoblastoma) cancers, while AFAP has less than or equal to a 2% risk for stomach, thyroid, and pancreatic cancers (Jasperson 2012). Upper gastrointestinal tract polyps and fundic gland polyps are present in most cases of classic FAP and AFAP; other findings include desmoid tumors, osteomas, epidermoid cysts, and fibromas. Approximately 20-25% of individuals with an APC mutation have a de novo, rather than inherited, mutation. The variant is found in APC panel(s).
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000077984 SCV000226396 pathogenic not provided 2013-01-17 criteria provided, single submitter clinical testing
Ambry Genetics RCV000115074 SCV000672515 pathogenic Hereditary cancer-predisposing syndrome 2018-01-12 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Other ACMG-defined mutation (i.e. initiation codon or gross deletion),Confirmed de novo alteration in the setting of a new disease (appropriate phenotype) in the family,Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Rarity in general population databases (dbSNP, ESP, 1000 Genomes),Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Integrated Genetics/Laboratory Corporation of America RCV000779727 SCV000916491 pathogenic Familial adenomatous polyposis 2018-06-22 criteria provided, single submitter clinical testing Variant summary: APC c.2547_2550delTAGA (p.Asp849GlufsX11) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 245936 control chromosomes (in gnomAD). c.2547_2550delTAGA has been reported in the literature in multiple individuals affected with Familial Adenomatous Polyposis (Miyaki 1994, Friedl 2005, Rohlin 2011), segregation with the disease was also described (Ripa 2002). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000077984 SCV000256950 pathogenic not provided no assertion criteria provided research

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.