rs121913224
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_000038.6(APC):c.3927_3931delAAAGA(p.Glu1309AspfsTer4) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000821 in 1,461,874 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★).
Frequency
Consequence
NM_000038.6 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| APC | ENST00000257430.9 | c.3927_3931delAAAGA | p.Glu1309AspfsTer4 | frameshift_variant | Exon 16 of 16 | 5 | NM_000038.6 | ENSP00000257430.4 | ||
| ENSG00000258864 | ENST00000520401.1 | n.228+10549_228+10553delAAAGA | intron_variant | Intron 3 of 7 | 3 | ENSP00000454861.1 |
Frequencies
GnomAD3 genomes
GnomAD3 exomes AF: 0.00000797 AC: 2AN: 251040Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135676
GnomAD4 exome AF: 0.00000821 AC: 12AN: 1461874Hom.: 0 AF XY: 0.00000550 AC XY: 4AN XY: 727238
GnomAD4 genome
ClinVar
Submissions by phenotype
Familial adenomatous polyposis 1 Pathogenic:14Uncertain:1Other:1
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ACMG classification criteria: PVS1 strong, PS4 strong, PM2 moderate -
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This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -
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). -
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. -
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Carriers of this heterozygous deletion develop classic FAP at young age (18-24). -
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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. -
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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, internal data). 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. -
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not provided Pathogenic:12
PP1_strong, PP5, PS2, PS4_very_strong, PVS1 -
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The APC c.3927_3931del; p.Glu1309AspfsTer4 variant (rs121913224) is reported in the literature in several unrelated individuals with familial adenomatous polyposis (Ishida 2013, Lozynska 2015, Miyoshi 1992, Torrezan 2013). This variant is also reported in ClinVar (Variation ID: 816) and is only observed on two alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant causes a frameshift by deleting five nucleotides, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Ishida H et al. Identification of APC gene mutations in jejunal carcinomas from a patient with familial adenomatous polyposis. Jpn J Clin Oncol. 2013 Sep;43(9):929-34. PMID: 23906606. Lozynska MR et al. Rare case of intraintestinal stromal tumors in the patient with familial adenomatous polyposis. Exp Oncol. 2015 Sep;37(3):227-30. PMID: 26422110. Miyoshi Y et al. Germ-line mutations of the APC gene in 53 familial adenomatous polyposis patients. Proc Natl Acad Sci U S A. 1992 May 15;89(10):4452-6. PMID: 1316610. Torrezan GT et al. Mutational spectrum of the APC and MUTYH genes and genotype-phenotype correlations in Brazilian FAP, AFAP, and MAP patients. Orphanet J Rare Dis. 2013 Apr 5;8:54. PMID: 23561487. -
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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 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, 35988656) -
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The APC c.3927_3931del (p.Glu1309Aspfs*4) variant alters the translational reading frame of the APC mRNA and causes the premature termination of APC protein synthesis. This variant has been reported in the published literature in multiple individuals with familial adenomatous polyposis (PMID: 33769591 (2021), 30730459 (2019), 30092803 (2018), 29406563 (2018), 25980754 (2015), 25317407 (2014), 23561487 (2013), 20223039 (2005), 19029688 (2008), 8395941 (1993), 1316610 (1992)). The frequency of this variant in the general population, 0.000008 (2/251040 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic. -
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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. -
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APC: PS4, PVS1:Strong, PM2 -
Hereditary cancer-predisposing syndrome Pathogenic:3
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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 domain, SAMP-repeats, basic domain, and the EB1 binding and HDLG binding domains (PMID: 11257105). This variant has been reported in many 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. -
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. -
Familial multiple polyposis syndrome Pathogenic:2
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. -
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. -
Colorectal cancer Pathogenic:1Other:1
This variant was classified as: Pathogenic. -
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Gastric cancer;C0346629:Colorectal cancer;C1851124:Desmoid disease, hereditary;C2239176:Hepatocellular carcinoma;C2713442:Familial adenomatous polyposis 1;C4749917:Gastric adenocarcinoma and proximal polyposis of the stomach Pathogenic:1
PVS1_Strong+PM2_Supporting+PS4+PM6_VeryStrong -
Intestinal polyp;C0236048:Gastric polyposis;C0578477:Duodenal polyposis;C1868071:Adenomatous colonic polyposis;C4023010:Hyperplastic colonic polyposis Pathogenic:1
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Carcinoma of colon Pathogenic:1
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Adenomatous polyposis coli with congenital cholesteatoma Pathogenic:1
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Classic or attenuated familial adenomatous polyposis Pathogenic:1
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. -
Gardner syndrome Pathogenic:1
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Colon adenocarcinoma Pathogenic:1
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APC-related disorder Pathogenic:1
The APC c.3927_3931del5 variant is predicted to result in a frameshift and premature protein termination (p.Glu1309Aspfs*4). This variant has been reported in many individuals with familial adenomatous polyposis coli (Aretz et al. 2004. PubMed ID: 14523376; Plawski et al. 2008. PubMed ID: 19029688; Friedl et al. 2005. PubMed ID: 20223039; Lee et al. 2022. PubMed ID: 35189564). It has been shown to segregate with disease in multiple families as well as occurring frequently de novo (Aretz et al. 2004. PubMed ID: 14523376). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/816/). Frameshift variants in APC are expected to be pathogenic. Although this variant occurs in the terminal exon of APC, pathogenic truncating variants have been reported downstream of this variant (Friedl et al. 2005. PubMed ID: 20223039; Kerr et al. 2013. PubMed ID: 23159591). This variant is interpreted as pathogenic. -
Neoplasm Other:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at