ClinVar Miner

Submissions for variant NM_000038.6(APC):c.3927_3931del (p.Glu1309fs) (rs121913224)

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Total submissions: 25
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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.
Ambry Genetics RCV000128941 SCV000172816 pathogenic Hereditary cancer-predisposing syndrome 2019-04-26 criteria provided, single submitter clinical testing The c.3927_3931delAAAGA pathogenic mutation, located in coding exon 15 of the APC gene, results from a deletion of 5 nucleotides at nucleotide positions 3927 to 3931, causing a translational frameshift with a predicted alternate stop codon (p.E1309Dfs*4). This alteration is one of the most frequently observed pathogenic mutations in individuals and families with familial adenomatous polyposis (FAP) (Mandl M et al. Hum. Mol. Genet. 1994 Jan;3:181-4; Miyaki M et al. Cancer Res. 1994 Jun;54:3011-20; Friedl W et al. Hered. Cancer Clin. Pract. 2005 Sep;3:95-114; Yanus GA et al. Clin. Genet. 2018 May;93:1015-1021). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation. As such, this alteration is interpreted as a disease-causing mutation.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000202014 SCV000226389 pathogenic not provided 2015-09-14 criteria provided, single submitter clinical testing
Invitae RCV000000856 SCV000260059 pathogenic Familial adenomatous polyposis 1 2020-10-19 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.
Counsyl RCV000000856 SCV000488559 pathogenic Familial adenomatous polyposis 1 2016-04-28 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000202014 SCV000600092 pathogenic not provided 2020-09-12 criteria provided, single submitter clinical testing The variant results in a shift of the reading frame, and is therefore predicted to result in the loss of a functional protein. Found in at least one patient with expected phenotype for this gene, and found in general population data at a frequency that is consistent with pathogenicity.
GenePathDx,Causeway Health Care Private Ltd RCV000000856 SCV000616343 pathogenic Familial adenomatous polyposis 1 2017-08-27 criteria provided, single submitter clinical testing
Color Health, Inc RCV000128941 SCV000681641 pathogenic Hereditary cancer-predisposing syndrome 2020-10-19 criteria provided, single submitter clinical testing This variant deletes 5 nucleotides in exon 16 of the APC gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with familial adenomatous polyposis (PMIDs: 8187091, 9950360, 12007223, 14961559, 15024739, 15108288, 16088911, 16134147, 17411426, 17486639, 17963004, 18433509, 19029688, 19531215, 20223039, 20564245, 20649969, 20685668, 20924072, 21078199, 21110124, 21643010, 21779980, 21901162, 22987206, 23159591, 25317407, 26163615, 26625971). This variant has been identified in 2/251040 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of APC function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000844611 SCV000694043 pathogenic Familial multiple polyposis syndrome 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.
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
Department of Molecular Diagnostics, Institute of Oncology Ljubljana RCV000000856 SCV000930652 pathogenic Familial adenomatous polyposis 1 2019-06-27 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001199306 SCV001370386 pathogenic Colorectal cancer 2016-01-01 criteria provided, single submitter clinical testing This variant was classified as: Pathogenic.
Clinical Genetics Karolinska University Hospital,Karolinska University Hospital RCV000202014 SCV001450375 pathogenic not provided 2017-12-05 criteria provided, single submitter 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
GeneReviews RCV000000856 SCV000040393 pathogenic Familial adenomatous polyposis 1 2017-02-02 no assertion criteria provided literature only
Pathway Genomics RCV000000856 SCV000189857 pathogenic Familial adenomatous polyposis 1 2014-07-24 no assertion criteria provided clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000202014 SCV000256981 pathogenic not provided no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000202014 SCV000591161 pathogenic not provided no assertion criteria provided clinical testing The p.Glu1309AspfsX4 deletion variant has been previously reported numerous times in the literature. In a small selection of publications, the variant was reported in 45 of 996 proband chromosomes in individuals with familial adenomatous polyposis from various ethnic backgrounds (Polish, Czech, Greek, Norwegian, Chinese), and it was absent in the 202 control chromosomes evaluated (Andresen 2009, Sheng 2010, Schwarzova 2012, Plawski 2008, Fostira 2010). This deletion is one of the more frequent known mutations in the APC gene. Its frequency varies in FAP patients from 0% in southwest Spain, 2.4% in the Australian population, 5% in the Dutch population, 7% in the Israeli population, and up to 16% in Italian FAP patients (Plawski 2008). Notably, a particular severe phenotype, involving a higher number of polyps and an earlier onset of colorectal cancer, has been observed in patients carrying mutations at this codon (1309) of the APC gene (Fostira 2010). It is listed in the dbSNP database as coming from a "clinical source" (ID#: rs12193224) but no frequency information. It has also been observed in the UMD database (238X). This variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1309 and leads to a premature stop codon 4 codons downstream. This alteration is predicted to lead to a truncated or absent protein and loss of function. Loss of function of the APC gene is an established disease mechanism in FAP. In summary, based on the above information, this variant is classified as Pathogenic.
Genome Sciences Centre, British Columbia Cancer Agency RCV000589212 SCV000693731 pathogenic Malignant Colorectal Neoplasm 2016-07-11 no assertion criteria provided research
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).
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 Colon adenocarcinoma 2017-10-25 no assertion criteria provided clinical testing

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