ClinVar Miner

Submissions for variant NM_000038.6(APC):c.3922_3926AAAGA[1] (p.Glu1309fs) (rs121913224)

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Total submissions: 23
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
3DMed Clinical Laboratory Inc RCV000677779 SCV000803935 pathogenic Carcinoma of colon 2017-10-25 no assertion criteria provided clinical testing
3DMed Clinical Laboratory Inc RCV000677780 SCV000803936 pathogenic Adenocarcinoma of the colon 2017-10-25 no assertion criteria provided clinical testing
Ambry Genetics RCV000128941 SCV000172816 pathogenic Hereditary cancer-predisposing syndrome 2018-03-12 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,Rarity in general population databases (dbsnp, esp, 1000 genomes)
Cancer Diagnostics Division,Gene Solutions RCV000000856 SCV000803435 likely pathogenic Familial adenomatous polyposis 1 2018-01-03 no assertion criteria provided research Carriers of this heterozygous deletion develop classic FAP at young age (18-24).
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000626570 SCV000747271 pathogenic Gastric polyposis; Duodenal polyposis; Adenomatous colonic polyposis; Intestinal polyp; Hyperplastic colonic polyposis 2017-01-01 criteria provided, single submitter clinical testing
Color RCV000128941 SCV000681641 pathogenic Hereditary cancer-predisposing syndrome 2017-01-03 criteria provided, single submitter clinical testing
Counsyl RCV000000856 SCV000488559 pathogenic Familial adenomatous polyposis 1 2016-04-28 criteria provided, single submitter clinical testing
Department of Molecular Diagnostics,Institute of Oncology RCV000000856 SCV000930652 pathogenic Familial adenomatous polyposis 1 2019-06-27 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000503175 SCV000591161 pathogenic Familial adenomatous polyposis 2015-03-27 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000202014 SCV000226389 pathogenic not provided 2015-09-14 criteria provided, single submitter clinical testing
GeneDx RCV000202014 SCV000490405 pathogenic not provided 2018-10-16 criteria provided, single submitter clinical testing This deletion of five nucleotides in APC is denoted c.3927_3931delAAAGA at the cDNA level and p.Glu1309AspfsX4 (E1309DfsX4) at the protein level. The normal sequence, with the bases that are deleted in brackets, is AAGA[delAAAGA]TTGG. The deletion causes a frameshift, which changes a Glutamic Acid to an Aspartic Acid at codon 1309 and creates a premature stop codon at position 4 of the new reading frame. It is predicted to cause loss of normal protein function through protein truncation as the last 1535 amino acids are lost and replaced with 3 incorrect amino acids. The disrupted region at the end of the gene includes the EB1 and hDLG binding domains and a portion of the basic domain (Azzopardi 2008). APC c.3927_3931delAAAGA is a common pathogenic variant that has been observed in numerous families with Familial Adenomatous Polyposis (Miyoshi 1992, Aretz 2004, Friedl 2005, Papp 2015). We consider this variant to be pathogenic.
GenePathDx,Causeway Health Care Private Ltd RCV000000856 SCV000616343 pathogenic Familial adenomatous polyposis 1 2017-08-27 criteria provided, single submitter clinical testing
GeneReviews RCV000000856 SCV000040393 pathologic Familial adenomatous polyposis 1 2011-10-27 no assertion criteria provided curation Converted during submission to Pathogenic.
Genome Sciences Centre,British Columbia Cancer Agency RCV000589212 SCV000693731 pathogenic Malignant Colorectal Neoplasm 2016-07-11 no assertion criteria provided research
Integrated Genetics/Laboratory Corporation of America RCV000503175 SCV000694043 pathogenic Familial adenomatous polyposis 2016-11-10 criteria provided, single submitter clinical testing Variant summary: The APC c.3927_3931delAAAGA (p.Glu1309Aspfs) variant results in a premature termination codon, predicted to cause a truncated or absent APC protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. This variant is absent in 121054 control chromosomes. The variant has been reported in numerous affected families and individuals in the literature from various countries/ethnicities. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Invitae RCV000000856 SCV000260059 pathogenic Familial adenomatous polyposis 1 2018-12-16 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the APC gene (p.Glu1309Aspfs*4). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1535 amino acids of the APC protein. This variant is present in population databases (rs763847228, ExAC 0.01%). This variant has been reported in numerous individuals and families affected with familial adenomatous polyposis (FAP) (PMID: 20223039, 1316610, 23159591, 24664542), and is the most frequently observed APC pathogenic variant in individuals with FAP (PMID: 20223039). ClinVar contains an entry for this variant (Variation ID: 816). Numerous pathogenic truncating variants have been reported downstream of this variant (PMID: 8940264, 11247896, 20434453), suggesting that deletion of this region of the APC protein is causative of disease. For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000844611 SCV000058712 pathogenic Familial multiple polyposis syndrome 2012-01-09 criteria provided, single submitter clinical testing The p.Glu1309fs variant in APC has been seen in over 100 individuals with famili al adenomatous polyposis (FAP) and is the most common pathogenic APC variant in patients with FAP (Aretz 2004, Friedl 2005, Plawski 2008, GeneReviews). It has b een shown to occur de novo and to segregate with disease in multiple families (A retz 2004). This variant has also been reported by other clinical laboratories i n ClinVar (Variation ID# 816). In vitro functional studies provide some evidence that the p.Glu1309fs variant may impact protein function (Dihlmann 2009). This variant has been identified in 2/111348 European chromosomes by the Genome Aggre gation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs80338757). Th is variant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at position 1309 and leads to a premature termination co don 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 trun cated protein. Downstream nonsense and frameshift variants at the 3' end of the gene have been reported in individuals with APC and lead to a non-functional pro tein. In summary, this variant meets criteria to be classified as pathogenic for FAP in an autosomal dominant manner based upon presence in multiple affected in dividuals, segregation studies, low frequency in the general population and de n ovo occurrence. ACMG/AMP Criteria applied (Richards 2015): PS2_VeryStrong; PS4; PM2; PM4; PP1; PS3_Supporting.
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000202014 SCV000256981 pathogenic not provided no assertion criteria provided clinical testing
OMIM RCV000000856 SCV000021006 pathogenic Familial adenomatous polyposis 1 1999-01-01 no assertion criteria provided literature only
OMIM RCV000000857 SCV000021007 pathogenic Gardner syndrome 1999-01-01 no assertion criteria provided literature only
OMIM RCV000000858 SCV000021008 pathogenic Adenomatous polyposis coli with congenital cholesteatoma 1999-01-01 no assertion criteria provided literature only
Pathway Genomics RCV000000856 SCV000189857 pathogenic Familial adenomatous polyposis 1 2014-07-24 no assertion criteria provided clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000202014 SCV000600092 pathogenic not provided 2015-06-12 criteria provided, single submitter clinical testing

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