VCV000000816.57 - ClinVar

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

Germline

Top reviewed classifications are shown here.

Submission summary:

40 submissions

36 submitters

12 conditions

Reviewed by expert panel

Pathogenic

Feb 2023 by ClinGen InSiGH… FDA Recognized Database

for Familial adenomatous polyposis 1

Somatic

No data submitted for somatic clinical impact

Somatic

Oncogenicity

The aggregate oncogenicity classification for this variant for one or more tumor types, using the ClinGen/CGC/VICC terminology. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(1)

Stars represent the aggregate review status, or the level of review supporting the aggregate oncogenicity classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Oncogenic

criteria provided, single submitter

Variant Details

Identifiers

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

Variation ID: 816 Accession: VCV000000816.57

Type and length

Microsatellite, 5 bp

Location

Cytogenetic: 5q22.2 5: 112839515-112839519 (GRCh38) [ NCBI UCSC ] 5: 112175212-112175216 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Apr 4, 2013	Oct 8, 2024	Feb 25, 2023
Somatic - Oncogenicity	Aug 11, 2024	Aug 11, 2024	Jul 31, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000038.6:c.3927_3931del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000029.2:p.Glu1309fs	frameshift
NM_000038.6:c.3927_3931delAAAGA MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_000038.5:c.3927_3931delAAAGA
NM_001127510.3:c.3927_3931del	NP_001120982.1:p.Glu1309fs	frameshift
NM_001127511.3:c.3873_3877del	NP_001120983.2:p.Glu1291fs	frameshift
NM_001354895.2:c.3927_3931del	NP_001341824.1:p.Glu1309fs	frameshift
NM_001354896.2:c.3981_3985del	NP_001341825.1:p.Glu1327fs	frameshift
NM_001354897.2:c.3957_3961del	NP_001341826.1:p.Glu1319fs	frameshift
NM_001354898.2:c.3852_3856del	NP_001341827.1:p.Glu1284fs	frameshift
NM_001354899.2:c.3843_3847del	NP_001341828.1:p.Glu1281fs	frameshift
NM_001354900.2:c.3804_3808del	NP_001341829.1:p.Glu1268fs	frameshift
NM_001354901.2:c.3750_3754del	NP_001341830.1:p.Glu1250fs	frameshift
NM_001354902.2:c.3654_3658del	NP_001341831.1:p.Glu1218fs	frameshift
NM_001354903.2:c.3624_3628del	NP_001341832.1:p.Glu1208fs	frameshift
NM_001354904.2:c.3549_3553del	NP_001341833.1:p.Glu1183fs	frameshift
NM_001354905.2:c.3447_3451del	NP_001341834.1:p.Glu1149fs	frameshift
NM_001354906.2:c.3078_3082del	NP_001341835.1:p.Glu1026fs	frameshift
NC_000005.10:g.112839516AAAGA[1]
NC_000005.9:g.112175213AAAGA[1]
NG_008481.4:g.151996AAAGA[1]
LRG_130:g.151996AAAGA[1]
LRG_130t1:c.3927_3931del

... more HGVS ... less HGVS

Protein change

E1149fs, E1208fs, E1250fs, E1268fs, E1319fs, E1026fs, E1183fs, E1291fs, E1218fs, E1281fs, E1284fs, E1309fs, E1327fs

Other names

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

Canonical SPDI

NC_000005.10:112839514:AAAAGAAAAGA:AAAAGA

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

loss_of_function_variant; Sequence Ontology [ SO:0002054]

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

ClinGen: CA008769 OMIM: 611731.0023 dbSNP: rs121913224 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
APC		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	14981	15119

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Adenomatous polyposis coli with congenital cholesteatoma	Pathogenic (1)	no assertion criteria provided	Jan 1, 1999	RCV000000858.10
Gardner syndrome	Pathogenic (1)	no assertion criteria provided	Jan 1, 1999	RCV000000857.10
Familial adenomatous polyposis 1	Pathogenic (16)	reviewed by expert panel	Feb 25, 2023	RCV000000856.41
Hereditary cancer-predisposing syndrome	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Apr 20, 2023	RCV000128941.21
not provided	Pathogenic (10)	criteria provided, multiple submitters, no conflicts	Feb 2, 2024	RCV000202014.31
Adenomatous colonic polyposis Duodenal polyposis Gastric polyposis Hyperplastic colonic polyposis Intestinal polyp	Pathogenic (1)	criteria provided, single submitter	Jan 1, 2017	RCV000626570.10
Colon adenocarcinoma	Pathogenic (1)	no assertion criteria provided	Oct 25, 2017	RCV000677780.9
Carcinoma of colon	Pathogenic (1)	no assertion criteria provided	Oct 25, 2017	RCV000677779.9
Familial multiple polyposis syndrome	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Nov 10, 2016	RCV000844611.14
Colorectal cancer	Pathogenic (2)	criteria provided, single submitter	Jan 1, 2016	RCV001199306.11
Classic or attenuated familial adenomatous polyposis	Pathogenic (1)	criteria provided, single submitter	Jan 8, 2024	RCV003996072.2
APC-related disorder	Pathogenic (1)	no assertion criteria provided	Jun 1, 2024	RCV004739276.1
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Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Feb 25, 2023)	reviewed by expert panel (ClinGen InSiGHT HCCP VCEP ACMG Specifications APC V1) Method: curation	Familial adenomatous polyposis 1 (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel FDA Recognized Database Accession: SCV003836601.1 First in ClinVar: Mar 11, 2023 Last updated: Mar 11, 2023	Other databases https://erepo.clinicalgenome.org… https://erepo.clinicalgenome.org/evrepo/ui/interpretation/296f1801-94a5-465b-9e48-8c839bf73039 Comment: The c.3927_3931del (p.Glu1309Aspfs4) variant in APC is a variant predicted to cause a premature stop codon in exon 16 in a gene in which loss-of-function … (more) The c.3927_3931del (p.Glu1309Aspfs4) 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). (less)
Pathogenic (Nov 10, 2016)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Familial multiple polyposis syndrome Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000694043.1 First in ClinVar: Feb 19, 2018 Last updated: Feb 19, 2018	Publications: PubMed (3) PubMed: 14729851‚ 10768871‚ 17026565 Comment: 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 … (more) 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. (less)
Pathogenic (Jan 01, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Adenomatous colonic polyposis Duodenal polyposis Hyperplastic colonic polyposis Intestinal polyp Gastric polyposis Affected status: yes Allele origin: unknown	Centre for Mendelian Genomics, University Medical Centre Ljubljana Accession: SCV000747271.1 First in ClinVar: May 12, 2018 Last updated: May 12, 2018
Pathogenic (Sep 14, 2015)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000226389.5 First in ClinVar: Jun 28, 2015 Last updated: Dec 15, 2018	Publications: PubMed (1) PubMed: 1316610 Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=APC Number of individuals with the variant: 1 Sex: mixed
Pathogenic (Jan 09, 2012)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	Familial multiple polyposis syndrome (Autosomal dominant inheritance) Affected status: not provided Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000058712.5 First in ClinVar: May 03, 2013 Last updated: Dec 26, 2017	Publications: PubMed (4) PubMed: 20223039‚ 14523376‚ 10213492‚ 19029688 Comment: 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 … (more) 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. (less) Number of individuals with the variant: 2
Pathogenic (Dec 05, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics and Genomics, Karolinska University Hospital Accession: SCV001450375.1 First in ClinVar: Dec 12, 2020 Last updated: Dec 12, 2020	Number of individuals with the variant: 6
Pathogenic (Jan 01, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Colorectal cancer Affected status: yes Allele origin: unknown	Centre for Mendelian Genomics, University Medical Centre Ljubljana Accession: SCV001370386.2 First in ClinVar: Jul 04, 2020 Last updated: Jul 04, 2020	Comment: This variant was classified as: Pathogenic.
Pathogenic (Jun 02, 2021)	criteria provided, single submitter (Sema4 Curation Guidelines) Method: curation	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Sema4, Sema4 Accession: SCV002536193.1 First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 Comment: The APC c.3927_3931delAAAGA (p.E1309DfsX4) variant has been reported in heterozygosity in numerous individuals with familial adenomatous polyposis and/or colorectal cancer (PMID: 1316610, 23906606, 31360874, 20223039, … (more) The APC c.3927_3931delAAAGA (p.E1309DfsX4) variant has been reported in heterozygosity in numerous individuals with familial adenomatous polyposis and/or colorectal cancer (PMID: 1316610, 23906606, 31360874, 20223039, among others). It is also known as c.3927del5 and c.3921_3925delAAAAG in the literature. The variant is a well-established pathogenic variant associated with familial adenomatous polyposis (PMID: 20223039). This variant causes a frameshift at amino acid 1309 that results in premature termination 4 amino acids downstream. As this variant is not predicted to cause nonsense-mediated decay, the protein product is expected to be truncated. A functional study suggested the variant protein may act as a dominant negative allele, hindering the normal function of the wild-type protein and altering beta catenin-mediated transcription (PMID: 10213492). This variant was observed in 2/251040 chromosomes in the Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654) and has been reported in ClinVar (Variation ID: 816). Based on the current evidence available, this variant is interpreted as pathogenic. (less)	Publications: PubMed (5) PubMed: 1316610‚ 23906606‚ 31360874‚ 20223039‚ 10213492
Pathogenic (Aug 27, 2017)	criteria provided, single submitter (GenePathDx_Criteria_classificationV2) Method: clinical testing	Familial adenomatous polyposis 1 (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	GenePathDx, GenePath diagnostics Accession: SCV000616343.2 First in ClinVar: Apr 16, 2017 Last updated: Dec 11, 2022	Number of individuals with the variant: 1 Ethnicity/Population group: Indian Geographic origin: India
Pathogenic (Feb 23, 2023)	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023)) Method: clinical testing	Familial adenomatous polyposis 1 Affected status: unknown Allele origin: unknown	Myriad Genetics, Inc. Accession: SCV004018827.1 First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023	Comment: This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Pathogenic (Sep 12, 2020)	criteria provided, single submitter (Quest Diagnostics criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Quest Diagnostics Nichols Institute San Juan Capistrano Accession: SCV000600092.5 First in ClinVar: Sep 28, 2017 Last updated: Jan 06, 2024	Publications: PubMed (24) PubMed: 1316610‚ 14734220‚ 23906606‚ 24664542‚ 26422110‚ 28975465‚ 29367705‚ 30092803‚ 30172912‚ 30340471‚ 30511453‚ 31360874‚ 31447099‚ 31744909‚ 32388397‚ 33769591‚ 8395941‚ 19029688‚ 25317407‚ 29406563‚ 25980754‚ 23561487‚ 30730459‚ 20223039 Comment: 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) … (more) 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. (less)
Pathogenic (Sep 24, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV003815510.2 First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024
Uncertain significance (Mar 25, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial adenomatous polyposis 1 Affected status: unknown Allele origin: germline	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center Accession: SCV004806294.1 First in ClinVar: Apr 06, 2024 Last updated: Apr 06, 2024
Pathogenic (Jan 08, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Classic or attenuated familial adenomatous polyposis (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	All of Us Research Program, National Institutes of Health Accession: SCV004837854.1 First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 Comment: This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more) This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)	Publications: PubMed (29) PubMed: 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 Comment: 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. … (more) 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. (less) Number of individuals with the variant: 2
Pathogenic (May 27, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics Laboratory, Skane University Hospital Lund Accession: SCV005197786.1 First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024
Pathogenic (Jun 27, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial adenomatous polyposis 1 Affected status: yes Allele origin: germline	Department of Molecular Diagnostics, Institute of Oncology Ljubljana Accession: SCV000930652.1 First in ClinVar: Aug 14, 2019 Last updated: Aug 14, 2019
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial adenomatous polyposis 1 (Autosomal dominant inheritance) Affected status: yes Allele origin: de novo, germline	University of Science and Technology Houari Boumediene, Laboratory of Molecular and Cellular Biology (LBCM) Accession: SCV002102565.2 First in ClinVar: Mar 12, 2022 Last updated: Apr 02, 2022	Publications: PubMed (1) PubMed: 35142982 DOI: 10.1158/1538-7445.AM2019-655 DOI: 10.1158/1538-7445.AM2019-655 Observation 1: Age: 20-29 years Sex: female Geographic origin: Algeria Observation 2: Age: 40-49 years Sex: male Geographic origin: Algeria Observation 3: Age: 30-39 years Sex: female Geographic origin: Algeria Observation 4: Age: 10-19 years Sex: female Geographic origin: Algeria
Pathogenic (Oct 14, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial adenomatous polyposis 1 Affected status: yes Allele origin: germline	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein Accession: SCV002512747.1 First in ClinVar: May 21, 2022 Last updated: May 21, 2022	Comment: ACMG classification criteria: PVS1 strong, PS4 strong, PM2 moderate Geographic origin: Brazil
Pathogenic (Apr 28, 2016)	criteria provided, single submitter (Counsyl Autosomal Dominant Disease Classification criteria (2015)) Method: clinical testing	Familial adenomatous polyposis 1 Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000488559.2 First in ClinVar: Dec 06, 2016 Last updated: Dec 24, 2022	Publications: PubMed (8) PubMed: 24664542‚ 25980754‚ 8395941‚ 1316610‚ 25317407‚ 16088911‚ 23561487‚ 17963004
Pathogenic (Jul 07, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial adenomatous polyposis 1 Affected status: yes Allele origin: unknown	KCCC/NGS Laboratory, Kuwait Cancer Control Center Accession: SCV004015236.1 First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023	Comment: This sequence change results in a premature translational stop signal in the APC gene (p.Glu1309Aspfs4). While this is not anticipated to result in nonsense mediated … (more) This sequence change results in a premature translational stop signal in the APC gene (p.Glu1309Aspfs4). 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. (less)
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial adenomatous polyposis 1 (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Neuberg Centre For Genomic Medicine, NCGM Accession: SCV004047962.1 First in ClinVar: Oct 28, 2023 Last updated: Oct 28, 2023	Comment: 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 … (more) 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. (less) Clinical Features: Colorectal polyposis (present)
Pathogenic (Jul 07, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial adenomatous polyposis 1 Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004203925.1 First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023
Pathogenic (Jan 16, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Familial adenomatous polyposis 1 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000260059.12 First in ClinVar: Jun 28, 2015 Last updated: Feb 14, 2024	Publications: PubMed (11) PubMed: 28492532‚ 1316610‚ 20223039‚ 23159591‚ 24664542‚ 15311282‚ 17293347‚ 9824584‚ 27081525‚ 8381579‚ 22135120 Comment: This sequence change creates a premature translational stop signal (p.Glu1309Aspfs4) in the APC gene. While this is not anticipated to result in nonsense mediated decay, … (more) This sequence change creates a premature translational stop signal (p.Glu1309Aspfs4) 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. (less)
Pathogenic (Apr 20, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Color Diagnostics, LLC DBA Color Health Accession: SCV000681641.4 First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024	Publications: PubMed (29) PubMed: 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 Comment: 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. … (more) 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. (less)
Pathogenic (May 02, 2022)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000172816.10 First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024	Publications: PubMed (8) PubMed: 1316610‚ 20223039‚ 23906606‚ 24664542‚ 26422110‚ 29406563‚ 8162022‚ 8187091 Comment: 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 … (more) 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. (less)
Pathogenic (Feb 02, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000490405.8 First in ClinVar: Nov 20, 2015 Last updated: Sep 16, 2024	Comment: 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 … (more) 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) (less)
Pathogenic (Jul 11, 2016)	no assertion criteria provided Method: research	Malignant Colorectal Neoplasm Affected status: yes Allele origin: somatic	Genome Sciences Centre, British Columbia Cancer Agency Study: Personalized OncoGenomics Accession: SCV000693731.1 First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018	Number of individuals with the variant: 1 Sex: male
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001964019.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021
Pathogenic (Jun 01, 2024)	no assertion criteria provided Method: clinical testing	APC-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV005361348.1 First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024	Comment: The APC c.3927_3931del5 variant is predicted to result in a frameshift and premature protein termination (p.Glu1309Aspfs4). This variant has been reported in many individuals with … (more) The APC c.3927_3931del5 variant is predicted to result in a frameshift and premature protein termination (p.Glu1309Aspfs4). 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. (less)
Pathogenic (Jan 01, 1999)	no assertion criteria provided Method: literature only	GARDNER SYNDROME Affected status: not provided Allele origin: unknown	OMIM Accession: SCV000021007.1 First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013	Publications: PubMed (4) PubMed: 8162051‚ 8281160‚ 8929955‚ 9890479 Comment on evidence: In 9 patients with severe FAP1 (175100), Gayther et al. (1994) identified a 5-bp deletion at codon 1309 of the APC gene. The 5-bp deletion … (more) In 9 patients with severe FAP1 (175100), Gayther et al. (1994) identified a 5-bp deletion at codon 1309 of the APC gene. The 5-bp deletion extends from the last base of codon 1309 to the first base of codon 1311; some refer to it as the 'codon 1309' APC mutation. This mutation may account for 9% of FAP due to mutations in the APC gene. The mutation tends to be associated with more severe and earlier onset disease and the presence of congenital hypertrophy of the retinal pigmented epithelium (CHRPE). Bapat et al. (1993) identified a 5-bp deletion at codon 1309 in an FAP patient with periampullary adenomas. Two different somatic mutations in the APC gene (611731.0019; 611731.0020) were identified in 2 distinct adenomas from this patient. Distante et al. (1996) described a 5-year-old girl with the mutation who presented with rectal bleeding from extensive polyposis of the colon; her father had had a colectomy for FAP at the age 23. Shaoul et al. (1999) described a 6-year-old boy with FAP and congenital cholesteatoma (see 604183). They suggested that cholesteatoma represents a tumor-like lesion with biologic characteristics resembling other alimentary lesions of FAP. The patient first came to medical attention at the age of 4 years because of intermittent painless hematochezia. Colonoscopy at the age of 6 years showed multiple polyps of the colon. Eye examination showed hyperpigmented retinal lesions in the temporal retina of each eye, but radiographic studies of the mandible and maxilla showed no changes. The cholesteatoma was detected at the age of 4 years because of unilateral conductive hearing loss. Polyps had been detected in the patient's mother at the age of 25 years and a subtotal colectomy was performed. In both the mother and the child, DNA analysis identified a 5-bp deletion (GAAAG) at codons 1309-1311 in exon 15 of the APC gene. Shaoul et al. (1999) commented that mutations at codon 1309 have been associated with early development of adenomatous polyps and a greater risk of malignancies at an early age. Furthermore, the same mutations are strongly associated with the presence of congenital hypertrophy of the retinal pigment epithelium. (less)
Pathogenic (Jan 01, 1999)	no assertion criteria provided Method: literature only	ADENOMATOUS POLYPOSIS COLI WITH CONGENITAL CHOLESTEATOMA Affected status: not provided Allele origin: unknown	OMIM Accession: SCV000021008.1 First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013	Publications: PubMed (4) PubMed: 8162051‚ 8281160‚ 8929955‚ 9890479 Comment on evidence: In 9 patients with severe FAP1 (175100), Gayther et al. (1994) identified a 5-bp deletion at codon 1309 of the APC gene. The 5-bp deletion … (more) In 9 patients with severe FAP1 (175100), Gayther et al. (1994) identified a 5-bp deletion at codon 1309 of the APC gene. The 5-bp deletion extends from the last base of codon 1309 to the first base of codon 1311; some refer to it as the 'codon 1309' APC mutation. This mutation may account for 9% of FAP due to mutations in the APC gene. The mutation tends to be associated with more severe and earlier onset disease and the presence of congenital hypertrophy of the retinal pigmented epithelium (CHRPE). Bapat et al. (1993) identified a 5-bp deletion at codon 1309 in an FAP patient with periampullary adenomas. Two different somatic mutations in the APC gene (611731.0019; 611731.0020) were identified in 2 distinct adenomas from this patient. Distante et al. (1996) described a 5-year-old girl with the mutation who presented with rectal bleeding from extensive polyposis of the colon; her father had had a colectomy for FAP at the age 23. Shaoul et al. (1999) described a 6-year-old boy with FAP and congenital cholesteatoma (see 604183). They suggested that cholesteatoma represents a tumor-like lesion with biologic characteristics resembling other alimentary lesions of FAP. The patient first came to medical attention at the age of 4 years because of intermittent painless hematochezia. Colonoscopy at the age of 6 years showed multiple polyps of the colon. Eye examination showed hyperpigmented retinal lesions in the temporal retina of each eye, but radiographic studies of the mandible and maxilla showed no changes. The cholesteatoma was detected at the age of 4 years because of unilateral conductive hearing loss. Polyps had been detected in the patient's mother at the age of 25 years and a subtotal colectomy was performed. In both the mother and the child, DNA analysis identified a 5-bp deletion (GAAAG) at codons 1309-1311 in exon 15 of the APC gene. Shaoul et al. (1999) commented that mutations at codon 1309 have been associated with early development of adenomatous polyps and a greater risk of malignancies at an early age. Furthermore, the same mutations are strongly associated with the presence of congenital hypertrophy of the retinal pigment epithelium. (less)
Pathogenic (Jan 01, 1999)	no assertion criteria provided Method: literature only	FAMILIAL ADENOMATOUS POLYPOSIS 1 Affected status: not provided Allele origin: unknown	OMIM Accession: SCV000021006.1 First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013	Publications: PubMed (4) PubMed: 8162051‚ 8281160‚ 8929955‚ 9890479 Comment on evidence: In 9 patients with severe FAP1 (175100), Gayther et al. (1994) identified a 5-bp deletion at codon 1309 of the APC gene. The 5-bp deletion … (more) In 9 patients with severe FAP1 (175100), Gayther et al. (1994) identified a 5-bp deletion at codon 1309 of the APC gene. The 5-bp deletion extends from the last base of codon 1309 to the first base of codon 1311; some refer to it as the 'codon 1309' APC mutation. This mutation may account for 9% of FAP due to mutations in the APC gene. The mutation tends to be associated with more severe and earlier onset disease and the presence of congenital hypertrophy of the retinal pigmented epithelium (CHRPE). Bapat et al. (1993) identified a 5-bp deletion at codon 1309 in an FAP patient with periampullary adenomas. Two different somatic mutations in the APC gene (611731.0019; 611731.0020) were identified in 2 distinct adenomas from this patient. Distante et al. (1996) described a 5-year-old girl with the mutation who presented with rectal bleeding from extensive polyposis of the colon; her father had had a colectomy for FAP at the age 23. Shaoul et al. (1999) described a 6-year-old boy with FAP and congenital cholesteatoma (see 604183). They suggested that cholesteatoma represents a tumor-like lesion with biologic characteristics resembling other alimentary lesions of FAP. The patient first came to medical attention at the age of 4 years because of intermittent painless hematochezia. Colonoscopy at the age of 6 years showed multiple polyps of the colon. Eye examination showed hyperpigmented retinal lesions in the temporal retina of each eye, but radiographic studies of the mandible and maxilla showed no changes. The cholesteatoma was detected at the age of 4 years because of unilateral conductive hearing loss. Polyps had been detected in the patient's mother at the age of 25 years and a subtotal colectomy was performed. In both the mother and the child, DNA analysis identified a 5-bp deletion (GAAAG) at codons 1309-1311 in exon 15 of the APC gene. Shaoul et al. (1999) commented that mutations at codon 1309 have been associated with early development of adenomatous polyps and a greater risk of malignancies at an early age. Furthermore, the same mutations are strongly associated with the presence of congenital hypertrophy of the retinal pigment epithelium. (less)
Pathogenic (Jul 24, 2014)	no assertion criteria provided Method: clinical testing	Adenomatous polyposis coli Affected status: unknown Allele origin: germline	Pathway Genomics Accession: SCV000189857.1 First in ClinVar: Oct 19, 2014 Last updated: Oct 19, 2014	Publications: PubMed (5) PubMed: 1316610‚ 7906810‚ 11247896‚ 12172928‚ 23159591
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV000256981.2 First in ClinVar: Nov 20, 2015 Last updated: Sep 28, 2017
Likely pathogenic (Jan 03, 2018)	no assertion criteria provided Method: research	Familial adenomatous polyposis 1 Affected status: yes, no Allele origin: germline	Cancer Diagnostics Division, Gene Solutions Accession: SCV000803435.1 First in ClinVar: May 26, 2018 Last updated: May 26, 2018	Comment: Carriers of this heterozygous deletion develop classic FAP at young age (18-24). Observation 1: Clinical Features: Classic familial adenomatous polyposis (present) Age: 20-29 years Observation 2: Clinical Features: Classic familial adenomatous polyposis (present) Age: 20-29 years Observation 3: Clinical Features: Classic familial adenomatous polyposis (present) Age: 10-19 years Observation 4: Age: 0-9 years Comment on evidence: No diagnosis was made due to young age (4 years of age)
Pathogenic (Oct 25, 2017)	no assertion criteria provided (ACMG Guidelines, 2015) Method: clinical testing	Carcinoma of colon Affected status: yes Allele origin: germline	3DMed Clinical Laboratory Inc Accession: SCV000803935.1 First in ClinVar: Aug 27, 2018 Last updated: Aug 27, 2018
Pathogenic (Oct 25, 2017)	no assertion criteria provided (ACMG Guidelines, 2015) Method: clinical testing	Adenocarcinoma of the colon Affected status: yes Allele origin: germline	3DMed Clinical Laboratory Inc Accession: SCV000803936.1 First in ClinVar: Aug 27, 2018 Last updated: Aug 27, 2018
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: unknown	Department of Pathology and Laboratory Medicine, Sinai Health System Additional submitter: Franklin by Genoox Study: The Canadian Open Genetics Repository (COGR) Accession: SCV000591161.3 First in ClinVar: Aug 28, 2017 Last updated: Apr 13, 2021	Comment: 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 … (more) 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. (less) Number of individuals with the variant: 11
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001963412.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021
not provided (-)	no classification provided Method: literature only	Familial adenomatous polyposis 1 Affected status: unknown Allele origin: germline	GeneReviews Accession: SCV000040393.3 First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022	Publications: PubMed (5) PubMed: 20301519‚ 8281160‚ 8929955‚ 8162051‚ 9890479 BookShelf: NBK1345 BookShelf: NBK1345
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Comment:

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).

Comment:

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.

Comment:

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.

Comment:

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.

Comment:

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.

Comment:

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.

Comment:

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.

Comment:

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.

Comment:

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.

Comment:

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)

Comment:

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.

Comment:

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.

Germline Functional Evidence

Functional Help The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence	Method Help A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter.	Result Help A brief description of the result of this method for this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
loss_of_function_variant (SO:0002054)			University of Science and Technology Houari Boumediene, Laboratory of Molecular and Cellular Biology (LBCM) Accession: SCV002102565.2	Publications PubMed (1) DOI: 10.1158/1538-7445.AM2019-655

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Germline mutations of the adenomatous polyposis coli (APC) gene in Algerian familial adenomatous polyposis cohort: first report.	Khider F	Molecular biology reports	2022	PMID: 35142982
APC-Associated Polyposis Conditions.	Adam MP	-	2022	PMID: 20301519
Mutational screening through comprehensive bioinformatics analysis to detect novel germline mutations in the APC gene in patients with familial adenomatous polyposis (FAP).	Ghadamyari F	Journal of clinical laboratory analysis	2021	PMID: 33769591
Double mutation of APC and BRCA1 in an Italian family.	Vietri MT	Cancer genetics	2020	PMID: 32388397
Genomic and transcriptomic profiling of carcinogenesis in patients with familial adenomatous polyposis.	Li J	Gut	2020	PMID: 31744909
Harmonizing Clinical Sequencing and Interpretation for the eMERGE III Network.	eMERGE Consortium. Electronic address: [email protected]	American journal of human genetics	2019	PMID: 31447099
Detection of Pathogenic Germline Variants Among Patients With Advanced Colorectal Cancer Undergoing Tumor Genomic Profiling for Precision Medicine.	You YN	Diseases of the colon and rectum	2019	PMID: 30730459
Atypical presentation of a germline APC mutation in a child with supratentorial primitive neuroectodermal tumor.	Aguiar TF	Pediatric blood & cancer	2019	PMID: 30511453
Tubulopapillary adrenocortical adenoma in a patient with familial adenomatous polyposis: a morphologic, ultrastructural, and molecular study.	Huang H	Human pathology	2019	PMID: 30172912
Germline Pathogenic Variants in Homologous Recombination and DNA Repair Genes in an Asian Cohort of Young-Onset Colorectal Cancer.	Toh MR	JNCI cancer spectrum	2018	PMID: 31360874
Detection of a heterozygous germline APC mutation in a three-generation family with familial adenomatous polyposis using targeted massive parallel sequencing in Vietnam.	Giang H	BMC medical genetics	2018	PMID: 30340471
Additional germline findings from a tumor profiling program.	Stjepanovic N	BMC medical genomics	2018	PMID: 30092803
Molecular characterization of ERBB2-amplified colorectal cancer identifies potential mechanisms of resistance to targeted therapies: a report of two instructive cases.	Owen DR	Cold Spring Harbor molecular case studies	2018	PMID: 29438965
Spectrum of APC and MUTYH germ-line mutations in Russian patients with colorectal malignancies.	Yanus GA	Clinical genetics	2018	PMID: 29406563
Somatic APC mosaicism and oligogenic inheritance in genetically unsolved colorectal adenomatous polyposis patients.	Ciavarella M	European journal of human genetics : EJHG	2018	PMID: 29367705
Expanding the spectrum of germline variants in cancer.	Siraj AK	Human genetics	2017	PMID: 28975465
Novel and reported APC germline mutations in Chinese patients with familial adenomatous polyposis.	Zhang S	Gene	2016	PMID: 26625971
Attenuated familial adenomatous polyposis with desmoids caused by an APC mutation.	Ikenoue T	Human genome variation	2015	PMID: 27081525
Rare case of intraintestinal stromal tumors in the patient with familial adenomatous polyposis.	Lozynska MR	Experimental oncology	2015	PMID: 26422110
Analysis of Small Fragment Deletions of the APC gene in Chinese Patients with Familial Adenomatous Polyposis, a Precancerous Condition.	Chen QW	Asian Pacific journal of cancer prevention : APJCP	2015	PMID: 26163615
Identification of a Variety of Mutations in Cancer Predisposition Genes in Patients With Suspected Lynch Syndrome.	Yurgelun MB	Gastroenterology	2015	PMID: 25980754
Frameshift Mutations (Deletion at Codon 1309 and Codon 849) in the APC Gene in Iranian FAP Patients: a Case Series and Review of the Literature.	Kashfi SM	International journal of molecular and cellular medicine	2014	PMID: 25317407
Two Chinese pedigrees for adenomatous polyposis coli: new mutations at codon 1309 and predisposition to phenotypic variations.	Liao DX	Familial cancer	2014	PMID: 24664542
Identification of APC gene mutations in jejunal carcinomas from a patient with familial adenomatous polyposis.	Ishida H	Japanese journal of clinical oncology	2013	PMID: 23906606
Mutational spectrum of the APC and MUTYH genes and genotype-phenotype correlations in Brazilian FAP, AFAP, and MAP patients.	Torrezan GT	Orphanet journal of rare diseases	2013	PMID: 23561487
APC germline mutations in individuals being evaluated for familial adenomatous polyposis: a review of the Mayo Clinic experience with 1591 consecutive tests.	Kerr SE	The Journal of molecular diagnostics : JMD	2013	PMID: 23159591
Novel mutations of the APC gene and genetic consequences of splicing mutations in the Czech FAP families.	Schwarzová L	Familial cancer	2013	PMID: 22987206
Prevalence of skin lesions in familial adenomatous polyposis: a marker for presymptomatic diagnosis?	Burger B	The oncologist	2011	PMID: 22135120
Molecular genetic analysis of 103 sporadic colorectal tumours in Czech patients.	Vasovcak P	PloS one	2011	PMID: 21901162
A survey of APC mutations in Quebec.	Jarry J	Familial cancer	2011	PMID: 21779980
Inactivation of promoter 1B of APC causes partial gene silencing: evidence for a significant role of the promoter in regulation and causative of familial adenomatous polyposis.	Rohlin A	Oncogene	2011	PMID: 21643010
Mutation analysis of the APC gene in unrelated Korean patients with FAP: four novel mutations with unusual phenotype.	Han SH	Familial cancer	2011	PMID: 21110124
Clinical and genetic characterization of classical forms of familial adenomatous polyposis: a Spanish population study.	Rivera B	Annals of oncology : official journal of the European Society for Medical Oncology	2011	PMID: 20924072
Identification of 5 novel germline APC mutations and characterization of clinical phenotypes in Japanese patients with classical and attenuated familial adenomatous polyposis.	Tao H	BMC research notes	2010	PMID: 21078199
Germline APC mutation spectrum derived from 863 genomic variations identified through a 15-year medical genetics service to French patients with FAP.	Lagarde A	Journal of medical genetics	2010	PMID: 20685668
Mutational spectrum of APC and genotype-phenotype correlations in Greek FAP patients.	Fostira F	BMC cancer	2010	PMID: 20649969
APC mutations are associated with increased bone mineral density in patients with familial adenomatous polyposis.	Miclea RL	Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research	2010	PMID: 20564245
Molecular analysis of the APC and MUTYH genes in Galician and Catalonian FAP families: a different spectrum of mutations?	Gómez-Fernández N	BMC medical genetics	2009	PMID: 19531215
APC gene mutations causing familial adenomatous polyposis in Polish patients.	Plawski A	Journal of applied genetics	2008	PMID: 19029688
Clinical characterization and the mutation spectrum in Swedish adenomatous polyposis families.	Kanter-Smoler G	BMC medicine	2008	PMID: 18433509
Mutational screening of the APC gene in Chilean families with familial adenomatous polyposis: nine novel truncating mutations.	De la Fuente MK	Diseases of the colon and rectum	2007	PMID: 17963004
Somatic APC mosaicism: a frequent cause of familial adenomatous polyposis (FAP).	Aretz S	Human mutation	2007	PMID: 17486639
Novel APC mutations in Czech and Slovak FAP families: clinical and genetic aspects.	Stekrova J	BMC medical genetics	2007	PMID: 17411426
Regulated binding of adenomatous polyposis coli protein to actin.	Moseley JB	The Journal of biological chemistry	2007	PMID: 17293347
Singapore familial adenomatous polyposis (FAP) patients with classical adenomatous polyposis but undetectable APC mutations have accelerated cancer progression.	Cao X	The American journal of gastroenterology	2006	PMID: 17026565
Familial adenomatous polyposis: experience from a study of 1164 unrelated german polyposis patients.	Friedl W	Hereditary cancer in clinical practice	2005	PMID: 20223039
Mutations of APC and MYH in unrelated Italian patients with adenomatous polyposis coli.	Aceto G	Human mutation	2005	PMID: 16134147
Mutation spectrum of the APC gene in 83 Korean FAP families.	Kim DW	Human mutation	2005	PMID: 16088911
EB1 and APC bind to mDia to stabilize microtubules downstream of Rho and promote cell migration.	Wen Y	Nature cell biology	2004	PMID: 15311282
First genotype characterization of Argentinean FAP patients: identification of 14 novel APC mutations.	De Rosa M	Human mutation	2004	PMID: 15108288
Molecular analysis of the APC and MYH genes in Czech families affected by FAP or multiple adenomas: 13 novel mutations.	Vandrovcová J	Human mutation	2004	PMID: 15024739
Challenging colonic polyposis pedigrees: differential diagnosis, surveillance, and management concerns.	Lynch HT	Cancer genetics and cytogenetics	2004	PMID: 14734220
Novel germline mutations in the adenomatous polyposis coli gene in Polish families with familial adenomatous polyposis.	Plawski A	Journal of medical genetics	2004	PMID: 14729851
Frequency and parental origin of de novo APC mutations in familial adenomatous polyposis.	Aretz S	European journal of human genetics : EJHG	2004	PMID: 14523376
The mutation spectrum of the APC gene in FAP patients from southern Italy: detection of known and four novel mutations.	De Rosa M	Human mutation	2003	PMID: 14961559
Preliminary results of the molecular diagnosis of familial adenomatous polyposis in Cuban families.	Cruz-Bustillo D	International journal of colorectal disease	2002	PMID: 12172928
Molecular analysis of the APC gene in 71 Israeli families: 17 novel mutations.	Gavert N	Human mutation	2002	PMID: 12007223
Can APC mutation analysis contribute to therapeutic decisions in familial adenomatous polyposis? Experience from 680 FAP families.	Friedl W	Gut	2001	PMID: 11247896
The relationship between frequencies of extracolonic manifestations and the position of APC germline mutation in patients with familial adenomatous polyposis.	Enomoto M	Japanese journal of clinical oncology	2000	PMID: 10768871
Dominant negative effect of the APC1309 mutation: a possible explanation for genotype-phenotype correlations in familial adenomatous polyposis.	Dihlmann S	Cancer research	1999	PMID: 10213492
Molecular analysis of the APC gene in 205 families: extended genotype-phenotype correlations in FAP and evidence for the role of APC amino acid changes in colorectal cancer predisposition.	Wallis YL	Journal of medical genetics	1999	PMID: 9950360
Congenital cholesteatoma in a child carrying a gene mutation for adenomatous polyposis coli.	Shaoul R	Journal of pediatric gastroenterology and nutrition	1999	PMID: 9890479
Variable phenotype of familial adenomatous polyposis in pedigrees with 3' mutation in the APC gene.	Brensinger JD	Gut	1998	PMID: 9824584
Familial adenomatous polyposis in a 5 year old child: a clinical, pathological, and molecular genetic study.	Distante S	Journal of medical genetics	1996	PMID: 8929955
Characteristics of somatic mutation of the adenomatous polyposis coli gene in colorectal tumors.	Miyaki M	Cancer research	1994	PMID: 8187091
Regionally clustered APC mutations are associated with a severe phenotype and occur at a high frequency in new mutation cases of adenomatous polyposis coli.	Gayther SA	Human molecular genetics	1994	PMID: 8162051
Frequency of common and novel inactivating APC mutations in 202 families with familial adenomatous polyposis.	Mandl M	Human molecular genetics	1994	PMID: 8162022
Familial adenomatous polyposis: mutation at codon 1309 and early onset of colon cancer.	Caspari R	Lancet (London, England)	1994	PMID: 7906810
Identical APC exon 15 mutations result in a variable phenotype in familial adenomatous polyposis.	Paul P	Human molecular genetics	1993	PMID: 8395941
Mutational analysis of patients with adenomatous polyposis: identical inactivating mutations in unrelated individuals.	Groden J	American journal of human genetics	1993	PMID: 8381579
Identification of somatic APC gene mutations in periampullary adenomas in a patient with familial adenomatous polyposis (FAP).	Bapat B	Human molecular genetics	1993	PMID: 8281160
Germ-line mutations of the APC gene in 53 familial adenomatous polyposis patients.	Miyoshi Y	Proceedings of the National Academy of Sciences of the United States of America	1992	PMID: 1316610
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=APC	-	-	-	-
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/296f1801-94a5-465b-9e48-8c839bf73039	-	-	-	-
-	-	-	-	DOI: 10.1158/1538-7445.AM2019-655
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Conditions - Somatic

Tumor type Help The tumor type for this variant-condition (RCV) record in ClinVar.	Clinical impact (# of submissions) Help The aggregate somatic clinical impact for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to the aggregate somatic clinical impact is shown in parentheses. The corresponding review status for the RCV record is indicated by stars. Read our rules for calculating the review status.	Oncogenicity Help The aggregate oncogenicity classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to the aggregate oncogenicity classification is shown in parentheses. The corresponding review status for the RCV record is indicated by stars. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the tumor type.	Variation/condition record Help The most recent date that a submitter evaluated this variant for the tumor type.
Neoplasm		Oncogenic criteria provided, single submitter	Jul 31, 2024	RCV004668706.1

Submissions - Somatic

Oncogenicity Help The submitted oncogenicity classification for each SCV record. (Last evaluated)	Review Status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Tumor type Help The tumor type for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the somatic clinical impact, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.

Oncogenic

(Jul 31, 2024)

(ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022)

Method: clinical testing

Neoplasm

Affected status: unknown

Allele origin: somatic

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Accession: SCV005094079.1
First In ClinVar: Aug 11, 2024
Last updated: Aug 11, 2024

Comment:

Citations for somatic classification of this variant

There are no citations for somatic classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar.

Text-mined citations for rs121913224 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 25, 2024

ClinVar Genomic variation as it relates to human health

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

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Conditions - Somatic

Submissions - Somatic

Citations for somatic classification of this variant

Text-mined citations for rs121913224 ...