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NM_000038.6(APC):c.3920T>A (p.Ile1307Lys)

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Interpretation:
Conflicting interpretations of pathogenicity, risk factor​

Likely benign(1);Likely pathogenic(3);Pathogenic(1);Uncertain significance(8)

Review status:
criteria provided, conflicting interpretations
Submissions:
25 (Most recent: Sep 24, 2019)
Last evaluated:
Aug 27, 2019
Accession:
VCV000000822.5
Variation ID:
822
Description:
single nucleotide variant
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NM_000038.6(APC):c.3920T>A (p.Ile1307Lys)

Allele ID
15861
Variant type
single nucleotide variant
Variant length
1 bp
Cytogenetic location
5q22.2
Genomic location
5: 112839514 (GRCh38) GRCh38 UCSC
5: 112175211 (GRCh37) GRCh37 UCSC
HGVS
Nucleotide Protein Molecular
consequence
NC_000005.9:g.112175211T>A
NC_000005.10:g.112839514T>A
NM_000038.6:c.3920T>A NP_000029.2:p.Ile1307Lys missense
... more HGVS
Protein change
I1307K
Other names
p.I1307K:ATA>AAA
CCDS4107.1:c.3920T>A
3920T>A
Functional consequence
-
Global minor allele frequency (GMAF)
-

Allele frequency
Exome Aggregation Consortium (ExAC) 0.00169
The Genome Aggregation Database (gnomAD) 0.00064
Trans-Omics for Precision Medicine (TOPMed) 0.00130
The Genome Aggregation Database (gnomAD), exomes 0.00201
Links
ClinGen: CA008761
UniProtKB: P25054#VAR_005049
OMIM: 611731.0029
dbSNP: rs1801155
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Aggregate interpretations per condition

Interpreted condition Interpretation Number of submissions Review status Last evaluated Variation/condition record
Pathogenic/Likely pathogenic, risk factor 4 criteria provided, multiple submitters, no conflicts Aug 1, 2018 RCV000115087.12
Uncertain significance 4 criteria provided, multiple submitters, no conflicts Aug 27, 2019 RCV000120049.4
risk factor 1 criteria provided, single submitter Nov 20, 2015 RCV000210085.1
Uncertain significance 1 criteria provided, single submitter Nov 24, 2015 RCV000238802.1
Uncertain significance 1 criteria provided, single submitter Jun 1, 2018 RCV000680453.1
risk factor 1 criteria provided, single submitter Jan 1, 2017 RCV000722046.1
Conflicting interpretations of pathogenicity, risk factor 6 criteria provided, conflicting interpretations Jan 14, 2019 RCV000020088.11
Conflicting interpretations of pathogenicity, risk factor 5 criteria provided, conflicting interpretations Jun 20, 2018 RCV000034388.7
Adenomatous polyposis coli, susceptibility to
risk factor 1 no assertion criteria provided Apr 1, 2019 RCV000000864.3
risk factor 1 no assertion criteria provided Dec 1, 2003 RCV000000865.4
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Gene OMIM ClinGen Gene Dosage Sensitivity Curation Variation viewer Related variants
HI score Help TS score Help Within gene All
APC Sufficient evidence for dosage pathogenicity No evidence available GRCh38
GRCh37
5942 5973

Submitted interpretations and evidence

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Interpretation
(Last evaluated)
Review status
(Assertion criteria)
Condition
(Inheritance)
Submitter Supporting information
Uncertain significance
(Nov 24, 2015)
criteria provided, single submitter
Method: clinical testing
Adenomatous polyposis coli
Allele origin: unknown
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia
Accession: SCV000297021.2
Submitted: (Jan 06, 2016)
Evidence details
risk factor
(May 08, 2015)
criteria provided, single submitter
Method: clinical testing
Not Provided
Allele origin: germline
GeneDx
Accession: SCV000148996.4
Submitted: (Sep 07, 2018)
Evidence details
Comment:
This variant is denoted APC c.3920T>A at the DNA level and p.Ile1307Lys (I1307K) at the protein level, replacing an Isoleucine with a Lysine. APC Ile1307Lys ... (more)
Uncertain significance
(Jan 06, 2016)
criteria provided, single submitter
Method: clinical testing
not provided
Allele origin: germline
PreventionGenetics,PreventionGenetics
Accession: SCV000805404.1
Submitted: (Jan 29, 2018)
Evidence details
Uncertain significance
(Jun 01, 2018)
criteria provided, single submitter
Method: clinical testing
Familial adenomatous polyposis
Allele origin: germline
Center for Human Genetics, Inc
Accession: SCV000807826.1
Submitted: (Jul 17, 2018)
Evidence details
Pathogenic
(Feb 28, 2018)
criteria provided, single submitter
Method: clinical testing
Hereditary cancer-predisposing syndrome
Allele origin: germline
Ambry Genetics
Accession: SCV000183892.7
Submitted: (Jul 30, 2018)
Evidence details
Publications
PubMed (15)
Comment:
Lines of evidence used in support of classification: Significant disease association in appropriately sized case-control study(ies),Detected in individual satisfying established diagnostic critera for classic disease ... (more)
Likely benign
(Jun 20, 2018)
criteria provided, single submitter
Method: clinical testing
Not Provided
Allele origin: germline
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000602533.2
Submitted: (Oct 10, 2018)
Evidence details
Comment:
The APC c.3920T>A; p.Ile1307Lys variant has been reported extensively in the literature. One recent meta-analysis of 30 published population studies, all of which examined the ... (more)
risk factor
(Jan 14, 2019)
criteria provided, single submitter
Method: clinical testing
Familial adenomatous polyposis 1
Allele origin: germline
Invitae
Accession: SCV000153895.9
Submitted: (Mar 28, 2019)
Evidence details
Publications
PubMed (4)
Comment:
This sequence change replaces isoleucine with lysine at codon 1307 of the APC protein (p.Ile1307Lys). The isoleucine residue is weakly conserved and there is a ... (more)
risk factor
(Nov 20, 2015)
criteria provided, single submitter
Method: clinical testing
Colorectal cancer, susceptibility to
Allele origin: germline
University of Washington Department of Laboratory Medicine,University of Washington
Accession: SCV000266006.1
Submitted: (Mar 03, 2016)
Evidence details
Comment:
Low penetrance mutation that is associated with a small increase in risk of colon cancer and with an increased risk of colon polyps (Boursi 2013)
Uncertain significance
(Aug 15, 2016)
criteria provided, single submitter
Method: clinical testing
not specified
Allele origin: germline
Department of Pathology and Laboratory Medicine,Sinai Health System
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV000591159.1
Submitted: (Apr 19, 2017)
Evidence details
Publications
PubMed (8)
Uncertain significance
(Feb 08, 2017)
criteria provided, single submitter
Method: clinical testing
not specified
Allele origin: germline
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000600091.1
Submitted: (Aug 01, 2017)
Evidence details
Publications
PubMed (17)
Uncertain significance
(Jul 27, 2017)
criteria provided, single submitter
Method: clinical testing
not provided
Allele origin: germline
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics
Accession: SCV000610138.1
Submitted: (Oct 05, 2017)
Evidence details
Likely pathogenic
(Sep 27, 2016)
criteria provided, single submitter
Method: clinical testing
Familial adenomatous polyposis 1
Allele origin: unknown
Counsyl
Accession: SCV000677724.1
Submitted: (Jun 22, 2017)
Evidence details
Publications
PubMed (13)
Comment:
I1307K is associated with a 10-20% lifetime risk of developing colon cancer in individuals of Ashkenazi Jewish ancestry and is not known to cause classic ... (more)
risk factor
(Aug 01, 2018)
criteria provided, single submitter
Method: clinical testing
Hereditary cancer-predisposing syndrome
Allele origin: germline
GeneKor MSA
Accession: SCV000821694.1
Submitted: (Aug 08, 2018)
Evidence details
risk factor
(Jun 02, 2017)
criteria provided, single submitter
Method: clinical testing
Familial adenomatous polyposis 1
Allele origin: germline
Human Genome Sequencing Center Clinical Lab,Baylor College of Medicine
Accession: SCV000839876.1
Submitted: (Jun 14, 2018)
Evidence details
Comment:
The c.3920T>A (p.Ile1307Lys) variant in the APC gene has been reported as a common risk allele associated with familial colorectal cancer in the Ashkenazi Jewish ... (more)
risk factor
(Jan 01, 2017)
criteria provided, single submitter
Method: research
Carcinoma of colon
Allele origin: germline
Snyder Lab, Genetics Department,Stanford University
Accession: SCV000853088.1
Submitted: (Oct 29, 2018)
Evidence details
Publications
PubMed (5)
Uncertain significance
(Nov 21, 2018)
criteria provided, single submitter
Method: clinical testing
Familial adenomatous polyposis 1
Allele origin: unknown
Equipe Genetique des Anomalies du Developpement,Université de Bourgogne
Accession: SCV000883121.1
Submitted: (Nov 26, 2018)
Evidence details
Likely pathogenic
(Jul 02, 2018)
criteria provided, single submitter
Method: clinical testing
Familial adenomatous polyposis 1
Allele origin: unknown
Mendelics
Accession: SCV000838110.2
Submitted: (Nov 11, 2018)
Evidence details
Likely pathogenic
(May 21, 2018)
criteria provided, single submitter
Method: clinical testing
Hereditary cancer-predisposing syndrome
Allele origin: germline
Color
Accession: SCV000686956.2
Submitted: (Nov 06, 2018)
Evidence details
Uncertain significance
(Aug 27, 2019)
criteria provided, single submitter
Method: clinical testing
not specified
Allele origin: germline
Integrated Genetics/Laboratory Corporation of America
Accession: SCV000694042.2
Submitted: (Sep 24, 2019)
Evidence details
Publications
PubMed (24)
Comment:
Variant summary: APC c.3920T>A (p.Ile1307Lys) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign ... (more)
variant of unknown significance
(Jul 13, 2012)
no assertion criteria provided
Method: research
not provided
Allele origin: germline
Biesecker Lab/Clinical Genomics Section,National Institutes of Health
Study: ClinSeq
Accession: SCV000043125.1
Submitted: (Jul 15, 2012)
Evidence details
Publications
PubMed (1)
Comment:
Converted during submission to Uncertain significance.
risk factor
(Apr 01, 2019)
no assertion criteria provided
Method: literature only
FAMILIAL ADENOMATOUS POLYPOSIS 1, SUSCEPTIBILITY TO
Allele origin: unknown
OMIM
Accession: SCV000021014.3
Submitted: (Feb 19, 2014)
Evidence details
Publications
PubMed (17)
risk factor
(Dec 01, 2003)
no assertion criteria provided
Method: literature only
BREAST CANCER, SUSCEPTIBILITY TO
Allele origin: unknown
OMIM
Accession: SCV000021015.3
Submitted: (Dec 30, 2010)
Evidence details
Publications
PubMed (17)
pathologic
(Oct 27, 2011)
no assertion criteria provided
Method: curation
APC-Associated Polyposis Conditions
Allele origin: not provided
GeneReviews
Accession: SCV000040392.1
Submitted: (Jan 08, 2013)
Evidence details
Comment:
Converted during submission to Pathogenic.
risk factor
(Nov 10, 2017)
no assertion criteria provided
Method: clinical testing
Hereditary cancer-predisposing syndrome
Allele origin: germline
True Health Diagnostics
Accession: SCV000693480.1
Submitted: (Nov 15, 2017)
Evidence details
not provided
(Sep 19, 2013)
no assertion provided
Method: reference population
AllHighlyPenetrant
Allele origin: germline
ITMI
Accession: SCV000084184.1
Submitted: (May 29, 2014)
Comment:
Please see associated publication for description of ethnicities
Evidence details
Publications
PubMed (1)

Citations for this variant

Title Author Journal Year Link
The identification of pathogenic variants in BRCA1/2 negative, high risk, hereditary breast and/or ovarian cancer patients: High frequency of FANCM pathogenic variants. Schubert S International journal of cancer 2019 PMID: 30426508
Germline cancer susceptibility gene variants, somatic second hits, and survival outcomes in patients with resected pancreatic cancer. Yurgelun MB Genetics in medicine : official journal of the American College of Medical Genetics 2019 PMID: 29961768
Hereditary cancer screening: Case reports and review of literature on ten Ashkenazi Jewish founder mutations. Cox DM Molecular genetics & genomic medicine 2018 PMID: 30152102
Racial/ethnic differences in multiple-gene sequencing results for hereditary cancer risk. Caswell-Jin JL Genetics in medicine : official journal of the American College of Medical Genetics 2018 PMID: 28749474
Cancer Susceptibility Gene Mutations in Individuals With Colorectal Cancer. Yurgelun MB Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2017 PMID: 28135145
Clinical Genetics Testing Laboratories Have a Remarkably Low Rate of Clinically Significant Discordance When Interpreting Variants in Hereditary Cancer Syndrome Genes. Nussbaum RL Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2017 PMID: 28135136
Assigning clinical meaning to somatic and germ-line whole-exome sequencing data in a prospective cancer precision medicine study. Ghazani AA Genetics in medicine : official journal of the American College of Medical Genetics 2017 PMID: 28125075
Benchmarking of Whole Exome Sequencing and Ad Hoc Designed Panels for Genetic Testing of Hereditary Cancer. Feliubadaló L Scientific reports 2017 PMID: 28050010
Prevalence and Spectrum of Germline Cancer Susceptibility Gene Mutations Among Patients With Early-Onset Colorectal Cancer. Pearlman R JAMA oncology 2017 PMID: 27978560
<i>APC</i>-Associated Polyposis Conditions Jasperson KW - 2017 PMID: 20301519
Evaluation of ACMG-Guideline-Based Variant Classification of Cancer Susceptibility and Non-Cancer-Associated Genes in Families Affected by Breast Cancer. Maxwell KN American journal of human genetics 2016 PMID: 27153395
Germline variants in Hamartomatous Polyposis Syndrome-associated genes from patients with one or few hamartomatous polyps. Jelsig AM Scandinavian journal of gastroenterology 2016 PMID: 27146957
Improving performance of multigene panels for genomic analysis of cancer predisposition. Shirts BH Genetics in medicine : official journal of the American College of Medical Genetics 2016 PMID: 26845104
The APC I1307K allele conveys a significant increased risk for cancer. Leshno A International journal of cancer 2016 PMID: 26421687
Association of APC I1307K and E1317Q polymorphisms with colorectal cancer among Egyptian subjects. Abdel-Malak C Familial cancer 2016 PMID: 26314409
CD24 and APC Genetic Polymorphisms in Pancreatic Cancers as Potential Biomarkers for Clinical Outcome. Shamai S PloS one 2015 PMID: 26394139
Next-generation sequencing for genetic testing of familial colorectal cancer syndromes. Simbolo M Hereditary cancer in clinical practice 2015 PMID: 26300997
Association of CD24 and the adenomatous polyposis coli gene polymorphisms with oral lichen planus. Kaplan I Oral surgery, oral medicine, oral pathology and oral radiology 2015 PMID: 26187149
High-resolution melting (HRM) re-analysis of a polyposis patients cohort reveals previously undetected heterozygous and mosaic APC gene mutations. Out AA Familial cancer 2015 PMID: 25604157
Germline variation in cancer-susceptibility genes in a healthy, ancestrally diverse cohort: implications for individual genome sequencing. Bodian DL PloS one 2014 PMID: 24728327
The UMD-APC database, a model of nation-wide knowledge base: update with data from 3,581 variations. Grandval P Human mutation 2014 PMID: 24599579
Colorectal tumors from APC*I1307K carriers principally harbor somatic APC mutations outside the A8 tract. Zauber P PloS one 2014 PMID: 24416237
ACMG technical standards and guidelines for genetic testing for inherited colorectal cancer (Lynch syndrome, familial adenomatous polyposis, and MYH-associated polyposis). Hegde M Genetics in medicine : official journal of the American College of Medical Genetics 2014 PMID: 24310308
The APC p.I1307K polymorphism is a significant risk factor for CRC in average risk Ashkenazi Jews. Boursi B European journal of cancer (Oxford, England : 1990) 2013 PMID: 23896379
APC polymorphisms and the risk of colorectal neoplasia: a HuGE review and meta-analysis. Liang J American journal of epidemiology 2013 PMID: 23576677
Secondary variants in individuals undergoing exome sequencing: screening of 572 individuals identifies high-penetrance mutations in cancer-susceptibility genes. Johnston JJ American journal of human genetics 2012 PMID: 22703879
Clinical, pathologic, and molecular features of early-onset colorectal carcinoma. Yantiss RK The American journal of surgical pathology 2009 PMID: 19047896
No evidence of the APC D1822V missense variant's pathogenicity in Tunisian patients with sporadic colorectal cancer. Bougatef K Pathologie-biologie 2009 PMID: 18343606
How the I1307K adenomatous polyposis coli gene variant contributes in the assessment of risk of colorectal cancer, but not stomach cancer, in a Turkish population. Dundar M Cancer genetics and cytogenetics 2007 PMID: 17854661
The I1307K APC polymorphism in Ashkenazi Jews with colorectal cancer: clinical and pathologic features. Locker GY Cancer genetics and cytogenetics 2006 PMID: 16875934
Colorectal polyps in carriers of the APC I1307K polymorphism. Rennert G Diseases of the colon and rectum 2005 PMID: 16228836
Multiplicity in polyp count and extracolonic manifestations in 40 Dutch patients with MYH associated polyposis coli (MAP). Nielsen M Journal of medical genetics 2005 PMID: 16140997
Genetic analyses in consecutive israeli jewish colorectal cancer patients. Fidder HH The American journal of gastroenterology 2005 PMID: 15929773
Colonic adenomas do not cosegregate with the I1307K APC missense mutation in an Israeli non-Ashkenazi family. Fidder HH Digestive diseases and sciences 2005 PMID: 15712637
Reconstructed beta-catenin/TCF4 signaling in yeast applicable to functional evaluation of APC mutations. Yamada H The American journal of pathology 2003 PMID: 14633595
Genetic anthropology of the colorectal cancer-susceptibility allele APC I1307K: evidence of genetic drift within the Ashkenazim. Niell BL American journal of human genetics 2003 PMID: 14624392
Hereditary colorectal cancer. Lynch HT The New England journal of medicine 2003 PMID: 12621137
Colorectal tumourigenesis in carriers of the APC I1307K variant: lone gunman or conspiracy? Sieber O The Journal of pathology 2003 PMID: 12533824
Clinical and screening implications of the I1307K adenomatous polyposis coli gene variant in Israeli Ashkenazi Jews with familial colorectal neoplasia. Evidence for a founder effect. Rozen P Cancer 2002 PMID: 12173321
Carrier rate of APC I1307K is not increased in inflammatory bowel disease patients of Ashkenazi Jewish origin. Silverberg MS Human genetics 2001 PMID: 11354631
The frequency of the predominant Jewish mutations in BRCA1 and BRCA2 in unselected Ashkenazi colorectal cancer patients. Chen-Shtoyerman R British journal of cancer 2001 PMID: 11207040
APC I1307K increases risk of transition from polyp to colorectal carcinoma in Ashkenazi Jews. Stern HS Gastroenterology 2001 PMID: 11159880
Germline APC variants in patients with multiple colorectal adenomas, with evidence for the particular importance of E1317Q. Lamlum H Human molecular genetics 2000 PMID: 11001924
Phenotypic characteristics associated with the APC gene I1307K mutation in Ashkenazi Jewish patients with colorectal polyps. Syngal S JAMA 2000 PMID: 10938175
Adenomatous polyposis coli I1307K mutation in Jewish patients with different ethnicity: prevalence and phenotype. Drucker L Cancer 2000 PMID: 10679643
Common origin of the I1307K APC polymorphism in Ashkenazi and non-Ashkenazi Jews. Patael Y European journal of human genetics : EJHG 1999 PMID: 10439961
Inherited colorectal polyposis and cancer risk of the APC I1307K polymorphism. Gryfe R American journal of human genetics 1999 PMID: 9973276
Cancer, crash sites, and the new genetics of neoplasia. Gruber SB Gastroenterology 1999 PMID: 9869620
The I1307K polymorphism of the APC gene in colorectal cancer. Prior TW Gastroenterology 1999 PMID: 9869603
Prevalence of the I1307K APC gene variant in Israeli Jews of differing ethnic origin and risk for colorectal cancer. Rozen P Gastroenterology 1999 PMID: 9869602
I1307K APC and hMLH1 mutations in a non-Jewish family with hereditary non-polyposis colorectal cancer. Yuan ZQ Clinical genetics 1998 PMID: 9831355
Somatic instability of the APC I1307K allele in colorectal neoplasia. Gryfe R Cancer research 1998 PMID: 9751605
The APCI1307K allele and cancer risk in a community-based study of Ashkenazi Jews. Woodage T Nature genetics 1998 PMID: 9731533
The APCI1307K allele and breast cancer risk. Redston M Nature genetics 1998 PMID: 9731522
The APC variants I1307K and E1317Q are associated with colorectal tumors, but not always with a family history. Frayling IM Proceedings of the National Academy of Sciences of the United States of America 1998 PMID: 9724771
Missense mutations in disease genes: a Bayesian approach to evaluate causality. Petersen GM American journal of human genetics 1998 PMID: 9585599
Familial colorectal cancer in Ashkenazim due to a hypermutable tract in APC. Laken SJ Nature genetics 1997 PMID: 9288102
Desmoid tumors: genotype-phenotype differences in familial adenomatous polyposis--a nosological dilemma. Lynch HT American journal of human genetics 1996 PMID: 8940262

Record last updated Nov 07, 2019