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

dbSNP: rs121913224

Total submissions: 36

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel	RCV000000856	SCV003836601	pathogenic	Familial adenomatous polyposis 1	2023-02-25	reviewed by expert panel	curation	The c.3927_3931del (p.Glu1309Aspfs*4) variant in APC is a variant predicted to cause a premature stop codon in exon 16 in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant has been reported in more than 400 probands, resulting in a total phenotype score of 33 (PS4_VeryStrong, GeneDx, Ambry, Invitae, Catalan Institute of Oncology, University Hospital of Bonn, Leiden University Medical Center internal data). It has also been identified as a de novo occurrence with unconfirmed parental relationships in 63 individuals on LOVD and in 4 individuals from Barcelona internal data, the total points scored based on available phenotypic information is 17.5 (PM6_VeryStrong, LOVD, Catalan Institute of Oncology internal data). The highest allele frequency of this variant gnomAD v2.1.1 (non-cancer) is 0.000008456, which is higher than the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel (HCCP VCEP) threshold of 0.000003 for PM2_Supporting (PM2_Supporting not met) and lower than the threshold (0.00001) for BS1 (BS1 not met). It is the most common pathogenic APC variant in APC InSiGHT LOVD (www.lovd.nl/APC; 331 / 5700 = 5.8%; retrieved on 06/01/2023), thus the occurrence in gnomAD is compatible with a pathogenic variant. In summary, this variant meets the criteria to be classified as Pathogenic for FAP based on the ACMG/AMP criteria applied, as specified by the HCCP VCEP: PVS1, PS4_VeryStrong, and PM6_VeryStrong (VCEP specifications version 1; date of approval: 12/12/2022).
Laboratory for Molecular Medicine, Mass General Brigham 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	2022-05-02	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 occurs at the 3' terminus of theAPC gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 1535 amino acids of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). 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). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Eurofins Ntd Llc (ga)	RCV000202014	SCV000226389	pathogenic	not provided	2015-09-14	criteria provided, single submitter	clinical testing
Invitae	RCV003534303	SCV000260059	pathogenic	Familial adenomatous polyposis 1	2024-01-16	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu1309Aspfs*4) in the APC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1535 amino acid(s) of the APC protein. This variant is present in population databases (rs763847228, gnomAD 0.002%). This premature translational stop signal has been observed in individuals with familial adenomatous polyposis (FAP), and is one of the most frequently observed APC pathogenic variant in patients with FAP (PMID: 1316610, 20223039, 23159591, 24664542). ClinVar contains an entry for this variant (Variation ID: 816). 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.
Counsyl	RCV000000856	SCV000488559	pathogenic	Familial adenomatous polyposis 1	2016-04-28	criteria provided, single submitter	clinical testing
GeneDx	RCV000202014	SCV000490405	pathogenic	not provided	2023-06-27	criteria provided, single submitter	clinical testing	Observed in numerous families with Familial Adenomatous Polyposis referred for genetic testing at GeneDx and in the published literature (Miyoshi et al., 1992; Aretz et al., 2004; Friedl and Aretz, 2005; Papp et al., 2015); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 1316610, 24664542, 20223039, 8162051, 25318681, 26422110, 26161710, 26309368, 33769591, 25317407, 19728755, 19029688, 14523376, 12894596, 23115482, 23970361, 17963004, 23159591, 25832318, 26446593, 26981152, 26625971, 25980754, 28533537, 23906606, 8395941, 28975465, 29367705, 30340471, 30092803, 30511453, 30272267, 29954149, 31101557, 30730459, 31360874, 30172912, 14734220, 31744909, 31447099, 32388397, 36225625, 34873480, 35418818, 35189564, 35142982)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000202014	SCV000600092	pathogenic	not provided	2020-09-12	criteria provided, single submitter	clinical testing	This frameshift variant causes the premature termination of APC protein synthesis. In addition, it has been reported in multiple individuals with Familial Adenomatous Polyposis (FAP) in the published literature and has been reported to be one of the most commonly observed mutations in the APC gene in FAP patients (PMID: 30730459 (2019), 29406563 (2017), 25980754 (2015), 25317407 (2014), 23561487 (2013), 19029688 (2008), 20223039 (2005)). Based on the available information, this variant is classified as pathogenic.
GenePathDx, GenePath diagnostics	RCV000000856	SCV000616343	pathogenic	Familial adenomatous polyposis 1	2017-08-27	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000128941	SCV000681641	pathogenic	Hereditary cancer-predisposing syndrome	2023-04-20	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 in the last coding exon. This variant is predicted to escape nonsense-mediated decay and be expressed as a truncated protein. Although functional studies have not been reported, this variant is expected to disrupt the Beta-catenin binding, EB1 binding and HDLG binding domains; and NLS domains. 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 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 and Genomics, Karolinska University Hospital	RCV000202014	SCV001450375	pathogenic	not provided	2017-12-05	criteria provided, single submitter	clinical testing
Laboratory of Molecular and Cellular Biology, University of Science and Technology Houari Boumediene	RCV000000856	SCV002102565	pathogenic	Familial adenomatous polyposis 1		criteria provided, single submitter	clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000000856	SCV002512747	pathogenic	Familial adenomatous polyposis 1	2021-10-14	criteria provided, single submitter	clinical testing	ACMG classification criteria: PVS1 strong, PS4 strong, PM2 moderate
Sema4, Sema4	RCV000128941	SCV002536193	pathogenic	Hereditary cancer-predisposing syndrome	2021-06-02	criteria provided, single submitter	curation
Revvity Omics, Revvity	RCV000202014	SCV003815510	pathogenic	not provided	2022-09-24	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000000856	SCV004015236	pathogenic	Familial adenomatous polyposis 1	2023-07-07	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 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. Therefore, this variant has been classified as Pathogenic.
Myriad Genetics, Inc.	RCV000000856	SCV004018827	pathogenic	Familial adenomatous polyposis 1	2023-02-23	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine	RCV003338376	SCV004047962	pathogenic	Familial adenomatous polyposis 1		criteria provided, single submitter	clinical testing	The frameshift c.3927_3931del (p.Glu1309AspfsTer4) variant has been observed in individuals with familial adenomatous polyposis (FAP), and is one of the most frequently observed APC pathogenic variant in patients with FAP (Miyoshi Y et al, Kerr SE et al). This p.Glu1309AspfsTer4 variant has allele frequency of 0.0007967% in the gnomAD and novel (not in any individuals) in 1000 genome database. This variant has been reported to the ClinVar database as Pathogenic. This variant causes a frameshift starting with codon Glutamic Acid 1309, changes this amino acid to Aspartic Acid residue, and creates a premature Stop codon at position 4 of the new reading frame, denoted p.Glu1309AspfsTer4. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000000856	SCV004203925	pathogenic	Familial adenomatous polyposis 1	2023-07-07	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	not provided	Familial adenomatous polyposis 1		no assertion 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	RCV001199306	SCV000693731	pathogenic	Colorectal cancer	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
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000202014	SCV001963412	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000202014	SCV001964019	pathogenic	not provided		no assertion criteria provided	clinical testing