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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_3931del(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

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

APC
NM_000038.6 frameshift

Scores

Not classified

Clinical Significance

Pathogenic reviewed by expert panel P:36U:1O:1

Conservation

PhyloP100: 6.22
Variant links:
Genes affected
APC (HGNC:583): (APC regulator of WNT signaling pathway) This gene encodes a tumor suppressor protein that acts as an antagonist of the Wnt signaling pathway. It is also involved in other processes including cell migration and adhesion, transcriptional activation, and apoptosis. Defects in this gene cause familial adenomatous polyposis (FAP), an autosomal dominant pre-malignant disease that usually progresses to malignancy. Mutations in the APC gene have been found to occur in most colorectal cancers, where disease-associated mutations tend to be clustered in a small region designated the mutation cluster region (MCR) and result in a truncated protein product. [provided by RefSeq, Jun 2022]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 454 pathogenic variants in the truncated region.
PP5
Variant 5-112839514-TAAAAG-T is Pathogenic according to our data. Variant chr5-112839514-TAAAAG-T is described in ClinVar as [Pathogenic]. Clinvar id is 816.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr5-112839514-TAAAAG-T is described in Lovd as [Pathogenic]. Variant chr5-112839514-TAAAAG-T is described in Lovd as [Pathogenic]. Variant chr5-112839514-TAAAAG-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
APCNM_000038.6 linkuse as main transcriptc.3927_3931del p.Glu1309AspfsTer4 frameshift_variant 16/16 ENST00000257430.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
APCENST00000257430.9 linkuse as main transcriptc.3927_3931del p.Glu1309AspfsTer4 frameshift_variant 16/165 NM_000038.6 P1P25054-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000797
AC:
2
AN:
251040
Hom.:
0
AF XY:
0.00000737
AC XY:
1
AN XY:
135676
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000882
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.00000821
AC:
12
AN:
1461874
Hom.:
0
AF XY:
0.00000550
AC XY:
4
AN XY:
727238
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000809
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.000113
Hom.:
0

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:36Uncertain:1Other:1
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Familial adenomatous polyposis 1 Pathogenic:14Uncertain:1Other:1
Pathogenic, no assertion criteria providedliterature onlyOMIMJan 01, 1999- -
Pathogenic, criteria provided, single submitterclinical testingInvitaeJan 16, 2024This 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. -
Pathogenic, no assertion criteria providedclinical testingPathway GenomicsJul 24, 2014- -
Likely pathogenic, no assertion criteria providedresearchCancer Diagnostics Division, Gene SolutionsJan 03, 2018Carriers of this heterozygous deletion develop classic FAP at young age (18-24). -
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsJul 07, 2023- -
Pathogenic, criteria provided, single submitterclinical testingUniversity of Science and Technology Houari Boumediene, Laboratory of Molecular and Cellular Biology (LBCM)-- -
Pathogenic, reviewed by expert panelcurationClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert PanelFeb 25, 2023The 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). -
Pathogenic, criteria provided, single submitterclinical testingMyriad Genetics, Inc.Feb 23, 2023This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -
Pathogenic, criteria provided, single submitterclinical testingLaboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert EinsteinOct 14, 2021ACMG classification criteria: PVS1 strong, PS4 strong, PM2 moderate -
Pathogenic, criteria provided, single submitterclinical testingCounsylApr 28, 2016- -
Pathogenic, criteria provided, single submitterclinical testingDepartment of Molecular Diagnostics, Institute of Oncology LjubljanaJun 27, 2019- -
Pathogenic, criteria provided, single submitterclinical testingGenePathDx, GenePath diagnosticsAug 27, 2017- -
Pathogenic, criteria provided, single submitterclinical testingNeuberg Centre For Genomic Medicine, NCGM-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. -
not provided, no classification providedliterature onlyGeneReviews-- -
Uncertain significance, criteria provided, single submitterclinical testingCenter for Genomic Medicine, King Faisal Specialist Hospital and Research CenterMar 25, 2024- -
Pathogenic, criteria provided, single submitterclinical testingKCCC/NGS Laboratory, Kuwait Cancer Control CenterJul 07, 2023This 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. -
not provided Pathogenic:9
Pathogenic, no assertion criteria providedclinical testingMayo Clinic Laboratories, Mayo Clinic-- -
Pathogenic, criteria provided, single submitterclinical testingClinical Genetics and Genomics, Karolinska University HospitalDec 05, 2017- -
Pathogenic, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Sep 14, 2015- -
Pathogenic, no assertion criteria providedclinical testingDiagnostic Laboratory, Department of Genetics, University Medical Center Groningen-- -
Pathogenic, criteria provided, single submitterclinical testingRevvity Omics, RevvitySep 24, 2022- -
Pathogenic, no assertion criteria providedclinical testingDepartment of Pathology and Laboratory Medicine, Sinai Health System-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. -
Pathogenic, criteria provided, single submitterclinical testingGeneDxJun 27, 2023Observed 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) -
Pathogenic, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Pathogenic, criteria provided, single submitterclinical testingQuest Diagnostics Nichols Institute San Juan CapistranoSep 12, 2020This 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. -
Hereditary cancer-predisposing syndrome Pathogenic:3
Pathogenic, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthApr 20, 2023This 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. -
Pathogenic, criteria provided, single submittercurationSema4, Sema4Jun 02, 2021- -
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsMay 02, 2022The 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
Pathogenic, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineJan 09, 2012The 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. -
Pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpNov 10, 2016Variant 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:2
Pathogenic, criteria provided, single submitterclinical testingCentre for Mendelian Genomics, University Medical Centre LjubljanaJan 01, 2016This variant was classified as: Pathogenic. -
Pathogenic, no assertion criteria providedresearchGenome Sciences Centre, British Columbia Cancer AgencyJul 11, 2016- -
Carcinoma of colon Pathogenic:1
Pathogenic, no assertion criteria providedclinical testing3DMed Clinical Laboratory IncOct 25, 2017- -
Intestinal polyp;C0236048:Gastric polyposis;C0578477:Duodenal polyposis;C1868071:Adenomatous colonic polyposis;C4023010:Hyperplastic colonic polyposis Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingCentre for Mendelian Genomics, University Medical Centre LjubljanaJan 01, 2017- -
Adenomatous polyposis coli with congenital cholesteatoma Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMJan 01, 1999- -
Classic or attenuated familial adenomatous polyposis Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingAll of Us Research Program, National Institutes of HealthJan 08, 2024This 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. -
Colon adenocarcinoma Pathogenic:1
Pathogenic, no assertion criteria providedclinical testing3DMed Clinical Laboratory IncOct 25, 2017- -
Gardner syndrome Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMJan 01, 1999- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs121913224; hg19: chr5-112175211; API