ClinVar Miner

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

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Total submissions: 8
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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 The c.2547_2550delTAGA pathogenic mutation, located in coding exon 15 of the APC gene, results from a deletion of 4 nucleotides at nucleotide positions 2547 to 2550, causing a translational frameshift with a predicted alternate stop codon (p.D849Efs*11). This mutation was seen as a confirmed de novo mutation in one individual with histologically verified polyposis (Ripa R et al. Eur. J. Hum. Genet. 2002 Oct;10(10):631-7). This mutation was also seen in two alleles from a cohort of 1166 unrelated German individuals with a clinical diagnosis of either FAP or AFAP (Friedl W et al. Hered. Cancer Clin. Pract. 2005 Sep;3(3):95-114). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000779727 SCV000916491 pathogenic Familial multiple polyposis syndrome 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.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001002166 SCV001160025 pathogenic not specified 2018-10-09 criteria provided, single submitter clinical testing The APC c.2547_2550delTAGA; p.Asp849fs variant (rs398123118) has been described in several individuals and families affected with familial adenomatous polyposis (FAP; Friedl 2005, Miyaki 1994, Ripa 2002). It is reported as pathogenic by several laboratories in ClinVar (Variation ID: 92342) and is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. This variant causes a frameshift by deleting 4 nucleotides, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Additionally, the vast majority of pathogenic APC variants are truncating nonsense or frameshift variants (see InSiGHt, Kerr 2013). Based on available information, this variant is considered pathogenic. REFERENCES Link to InSiGHt: Friedl W et al. Familial adenomatous polyposis: experience from a study of 1164 unrelated german polyposis patients. Hered Cancer Clin Pract. 2005 Sep 15;3(3):95-114. Kerr SE et al. APC germline mutations in individuals being evaluated for familial adenomatous polyposis: a review of the Mayo Clinic experience with 1591 consecutive tests. J Mol Diagn. 2013 Jan;15(1):31-43. Miyaki M et al. Characteristics of somatic mutation of the adenomatous polyposis coli gene in colorectal tumors. Cancer Res. 1994 Jun 1;54(11):3011-20. Ripa R et al. De novo mutations in familial adenomatous polyposis (FAP). Eur J Hum Genet. 2002 Oct;10(10):631-7.
Invitae RCV001389824 SCV001591314 pathogenic Familial adenomatous polyposis 1 2020-08-31 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the APC gene (p.Asp849Glufs*11). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1995 amino acids of the APC protein. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with clinical features of familial adenomatosis polyposis (PMID: 17963004, 12357334, 30897307, 20685668, 29406563, 20223039, Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 92342). This variant is expected to disrupt the EB1 and HDLG binding sites, which mediate interactions with the cytoskeleton (PMID: 15311282, 17293347). While functional studies have not been performed to directly test the effect on APC protein function, this suggests that disruption of the C-terminal portion of the protein is functionally important. A different truncation (p.Tyr2645Lysfs*14) that lies downstream of this variant has been determined to be pathogenic (PMID: 9824584, 1316610, 27081525, 8381579, 22135120, Invitae). 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.
Mayo Clinic Laboratories, Mayo Clinic RCV000077984 SCV000256950 pathogenic not provided no assertion criteria provided research
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000077984 SCV001553831 uncertain significance not provided no assertion criteria provided clinical testing

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