ClinVar Miner

Submissions for variant NM_000038.6(APC):c.3920T>A (p.Ile1307Lys) (rs1801155)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 27
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000034388 SCV000148996 risk factor not provided 2015-05-08 criteria provided, single submitter clinical testing 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 is a common variant, observed at an allele frequency of 3.7% (371/10,138) in individuals of Ashkenazi Jewish ancestry in large population cohorts (Lek 2016) and in up to 11% of individuals in Ashkenazi Jewish cohorts in the literature (Liang 2013, Boursi 2013). A meta-analysis of epidemiologic studies of APC polymorphisms suggests that individuals of Ashkenazi Jewish ancestry who carry this variant have a 2-fold increased risk of colorectal cancer (Liang 2013). However, studies of this variant in other populations did not report an increased risk of colorectal cancer (Liang 2013); therefore, the clinical significance in individuals without Jewish ancestry is not clear at this time. In sum, we consider APC Ile1307Lys to be a risk allele. The National Comprehensive Cancer Network has management guidelines for individuals carrying the APC Ile1307Lys risk allele (NCCN).
Invitae RCV000020088 SCV000153895 risk factor Familial adenomatous polyposis 1 2020-01-08 criteria provided, single submitter clinical testing 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 moderate physicochemical difference between isoleucine and lysine. This variant is present in population databases (rs1801155, ExAC 0.3%). This variant is found in ~10% of Ashkenazi Jewish individuals and ~3% of Sephardic Jewish individuals (PMID: 23896379). Other studies have reported a 6-7% frequency in Ashkenazi individuals (PMID: 9288102). This variant is found in ~28% of Ashkenazi Jewish individuals with familial colorectal cancer (PMID: 9288102). ClinVar contains an entry for this variant (Variation ID: 822). In a large meta-analysis involving ~10,000 cases and controls (PMID: 23576677), Ashkenazi Jewish individuals who carried the I1307K change had a significantly increased risk of colorectal cancer (OR=2.17, 95% CI=1.65-2.86). By contrast, the I1307K change did not appear to confer any additional risk of colorectal cancer in non-Ashkenazi Jewish individuals (OR=1.36, 95% CI=0.59-3.13). This DNA substitution converts an AAATAAAA sequence element into an extended tract of eight adenosine nucleotides (A8). The A8 mononucleotide tract created by this change has been shown to confer an increased propensity for somatic truncating mutations on this allele (PMID: 9751605). In summary, this is a frequently observed variant that is associated with a 2-fold increased risk of colorectal cancer in the Ashkenazi Jewish population. An increased risk of colorectal cancer in individuals who are not of Ashkenazi Jewish ancestry has not been established.
Ambry Genetics RCV000115087 SCV000183892 pathogenic Hereditary cancer-predisposing syndrome 2019-02-28 criteria provided, single submitter clinical testing Significant disease association in appropriately sized case-control study(ies);Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Other strong data supporting pathogenic classification
University of Washington Department of Laboratory Medicine, University of Washington RCV000210085 SCV000266006 risk factor Colorectal cancer, susceptibility to 2015-11-20 criteria provided, single submitter clinical testing 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)
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000238802 SCV000297021 uncertain significance Familial multiple polyposis syndrome 2015-11-24 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000120049 SCV000591159 uncertain significance not specified 2016-08-15 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000034388 SCV000600091 uncertain significance not provided 2019-08-04 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000034388 SCV000602533 likely benign not provided 2018-06-20 criteria provided, single submitter clinical testing 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 association between p.Ile1307Lys and colorectal neoplasia, colorectal adenoma, and/or colorectal cancer, concluded that this variant confers a two-fold increased risk of developing a colorectal neoplasia to persons of Ashkenazi Jewish ancestry (Liang 2013 and references therein). However, the c.3920T>A;p.Ile1307Lys variant is observed in the general population at an overall frequency of 0.18% (506/276756 alleles, 6 homozygotes) in the Genome Aggregation Database. Due to the high frequency in the general population, this variant is considered likely benign. REFERENCES Liang et al. APC polymorphisms and the risk of colorectal neoplasia: a HuGE review and meta-analysis. Am J Epidemiol. 2013;177(11):1169-1179.
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000034388 SCV000610138 uncertain significance not provided 2017-07-27 criteria provided, single submitter clinical testing
Counsyl RCV000020088 SCV000677724 likely pathogenic Familial adenomatous polyposis 1 2016-09-27 criteria provided, single submitter clinical testing 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 or attenuated FAP.
Color RCV000115087 SCV000686956 likely pathogenic Hereditary cancer-predisposing syndrome 2019-11-26 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000120049 SCV000694042 uncertain significance not specified 2019-08-27 criteria provided, single submitter clinical testing 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 effect of the variant on protein function. The variant allele was found at a frequency of 0.002 in 251040 control chromosomes in the gnomAD database (exomes dataset), predominantly found within the Ashkenazi Jewish subpopulation at a frequency of 0.036, including 7 homozygotes. The observed variant frequency within Ashkenazi Jewish control individuals in the gnomAD database is approximately 500 fold of the estimated maximal expected allele frequency for a pathogenic variant in APC causing Familial Adenomatous Polyposis (FAP) phenotype (7.1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Ashkenazi Jewish origin. The variant, c.3920T>A, has been reported in the literature in multiple individuals affected with colorectal cancer (CRC) and other tumor phenotypes, however in some of these cases it was also reported to co-occur with other pathogenic variants (Yurgelun_2017 and Simbolo_2015). Multiple case-control studies (Abdel-Malak_2016, Drucker_2000, Fidder_2005, Gryfe_1998, Laken_1997, Leshno_2016, and Shtoyerman-Chen_2001), demonstrated that this variant is associated with a moderately increased risk for CRC in Ashkenazi Jewish population. A large meta-analysis concluded that the variant increases the risk about two-fold for CRC in individuals of Ashkenazi Jewish ancestry (OR=2.17, 95% CI=1.65-2.86), however it does not appear to confer an additional risk for CRC in non-Ashkenazi cases (Liang_2013). A recent case-control study involving a large Israeli cohort indicated that this variant might be also associated with a significantly higher risk for non-CRC cancers, with the APC I1307K variant being proposed as a reliable marker for overall cancer risk (OR=2.53) (Leshno_2016). The A8 mononucleotide tract created by this germline change has been shown to confer an increased propensity for generating somatic frameshift mutations on this allele, leading to a loss of function of APC that constitutes an important somatic event in tumor initiation (Gryfe_1998; Laken_1997). 19 other submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments, with 7 reporting it as a risk factor. Taken together, this polymorphic variant is associated with a modestly increased risk for CRC in the Ashkenazi Jewish population, but is not associated with FAP or AFAP. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
PreventionGenetics,PreventionGenetics RCV000034388 SCV000805404 uncertain significance not provided 2016-01-06 criteria provided, single submitter clinical testing
Center for Human Genetics, Inc,Center for Human Genetics, Inc RCV000680453 SCV000807826 uncertain significance Familial adenomatous polyposis 2018-06-01 criteria provided, single submitter clinical testing
GeneKor MSA RCV000115087 SCV000821694 risk factor Hereditary cancer-predisposing syndrome 2020-01-01 criteria provided, single submitter clinical testing This sequence change replaces Isoleucine with Lysine at codon 1307 of the APC protein. The isoleucine residue is mildly conserved among species and is located in a known functional domain of the protein. There is a big physiochemical difference between isoleucine and lysine (Grantham Score 102). This variant is listed in population databases (rs1801155, ExAC 0.3) and is a common finding in individuals of Ashkenazi (~6-10%) and Sephardic Jewish decent (~3%; PMID: 9288102 ,23896379 ).Multiple studies have associated this variant with a moderate increase in the risk of colorectal cancer in individuals of Ashkenazi Jewish ancestry, in whom this variant is identified in 28% of cases with familial colorectal cancer (PMID: 9288102 ). In a recent meta-analysis the risk of colorectal cancer development was estimated to be increased 2-fold in Ashkenazi Jewish individuals carrying this variant, while this increase was not evident in other populations (PMID: 23576677). The mutation database ClinVar contains multiple entries for this variant (Variation ID:822).
Mendelics RCV000020088 SCV000838110 likely pathogenic Familial adenomatous polyposis 1 2018-07-02 criteria provided, single submitter clinical testing
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV000020088 SCV000839876 risk factor Familial adenomatous polyposis 1 2017-06-02 criteria provided, single submitter clinical testing 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 population [PMID 18770064, 24416237]. The c.3920T>A variant has been reported to result in an adenine replacing a thymine and creating an oligo-adenine (A8) tract that appears to be inherently prone to further somatic mis-pairing and slippage during DNA replication, thereby creating a frameshift change [PMID 9288102, 18770064 and 244162370]. However, this variant has also been reported at a high frequency, present in 6% of Ashkenazi Jews and about 28% of Ashkenazim with a family history of colorectal cancer [PMID: 9288102]. Isoleucine at amino acid position 1307 of the APC protein is weakly conserved during evolution. While not validated for clinical use, the SIFT and PolyPhen-2 algorithms predict this variant to be benign. Ashkenazi Jews who carry the p.Ile1307Lys variant are at increased risk for colorectal neoplasia: the risk for colorectal neoplasia in heterozygous Ashkenazi Jewish individuals was estimated to be between 1.7 to 2.17 compared to non carrier individuals [PMID 12173321, 23576677, 23896379]. This variant is classified as as a risk allele with an increased risk for colorectal neoplasia in the Ashkenazi Jewish population. However the risk in non Jewish populations has not been determined.
Snyder Lab, Genetics Department,Stanford University RCV000722046 SCV000853088 risk factor Carcinoma of colon 2017-01-01 criteria provided, single submitter research
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne RCV000020088 SCV000883121 uncertain significance Familial adenomatous polyposis 1 2018-11-21 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000034388 SCV001154466 uncertain significance not provided 2019-05-01 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV001195214 SCV001365521 risk factor Colorectal cancer 2020-03-04 criteria provided, single submitter clinical testing APC c.3920T>A (p.Ile1307Lys, also known as I1307K) has been associated with colorectal cancer. This variant has been observed in multiple ethnic backgrounds with highest frequencies in individuals of Ashkenazi Jewish ancestry (3.6% Genome Aggregation Database (gnomAD); rs1801155) and is present in ClinVar (ID: 822). Several large studies and meta-analyses have reported odds ratios 1.51-2.53 for developing colorectal cancer in Ashkenazi Jewish population (OR=1.51 [95% CI 1.16-1.98] Boursi 2013, OR=2.17 [95% CI 1.64-2.86] Liang 2013, OR=2.53 [95% CI 2.11-3.04] Leshno 2016). However, the cancer risk remains unknown in individuals of non-Jewish descent. This variant introduces a polyA(8) region that is subject to slippage during DNA replication, which increases the susceptibility for somatic changes (Laken 1997, Gryfe 1998). In summary, this variant is an established risk factor for colorectal cancer.
OMIM RCV000000864 SCV000021014 risk factor Adenomatous polyposis coli, susceptibility to 2019-04-01 no assertion criteria provided literature only
OMIM RCV000000865 SCV000021015 risk factor Breast cancer, susceptibility to 2003-12-01 no assertion criteria provided literature only
GeneReviews RCV000020088 SCV000040392 pathologic Familial adenomatous polyposis 1 2011-10-27 no assertion criteria provided curation Converted during submission to Pathogenic.
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000034388 SCV000043125 variant of unknown significance not provided 2012-07-13 no assertion criteria provided research Converted during submission to Uncertain significance.
ITMI RCV000120049 SCV000084184 not provided not specified 2013-09-19 no assertion provided reference population
True Health Diagnostics RCV000115087 SCV000693480 risk factor Hereditary cancer-predisposing syndrome 2017-11-10 no assertion criteria provided clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.