rs1801155
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Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2
The NM_000038.6(APC):c.3920T>A(p.Ile1307Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00124 in 1,614,038 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity,association,risk factor (no stars).
Frequency
Genomes: 𝑓 0.0013 ( 1 hom., cov: 32)
Exomes 𝑓: 0.0012 ( 28 hom. )
Consequence
APC
NM_000038.6 missense
NM_000038.6 missense
Scores
3
16
Clinical Significance
Conservation
PhyloP100: 0.887
Genes affected
APC (HGNC:583): (APC regulator of WNT signaling pathway) This gene encodes a tumor suppressor protein that acts as an antagonist of the Wnt signaling pathway. It is also involved in other processes including cell migration and adhesion, transcriptional activation, and apoptosis. Defects in this gene cause familial adenomatous polyposis (FAP), an autosomal dominant pre-malignant disease that usually progresses to malignancy. Mutations in the APC gene have been found to occur in most colorectal cancers, where disease-associated mutations tend to be clustered in a small region designated the mutation cluster region (MCR) and result in a truncated protein product. [provided by RefSeq, Jun 2022]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -9 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.007214457).
BS1
Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00124 (1809/1461874) while in subpopulation MID AF= 0.022 (127/5768). AF 95% confidence interval is 0.0189. There are 28 homozygotes in gnomad4_exome. There are 954 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
BS2
High AC in GnomAd4 at 191 AD gene.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| APC | NM_000038.6 | c.3920T>A | p.Ile1307Lys | missense_variant | 16/16 | ENST00000257430.9 | NP_000029.2 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| APC | ENST00000257430.9 | c.3920T>A | p.Ile1307Lys | missense_variant | 16/16 | 5 | NM_000038.6 | ENSP00000257430 | P1 |
Frequencies
GnomAD3 genomes 0.00128 AC: 194AN: 152046Hom.: 1 Cov.: 32
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GnomAD3 exomes AF: 0.00201 AC: 504AN: 251040Hom.: 7 AF XY: 0.00194 AC XY: 263AN XY: 135676
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GnomAD4 exome AF: 0.00124 AC: 1809AN: 1461874Hom.: 28 Cov.: 33 AF XY: 0.00131 AC XY: 954AN XY: 727238
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GnomAD4 genome 0.00126 AC: 191AN: 152164Hom.: 1 Cov.: 32 AF XY: 0.00112 AC XY: 83AN XY: 74402
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ClinVar
Significance: Conflicting classifications of pathogenicity; association; risk factor
Submissions summary: Pathogenic:17Uncertain:19Other:15
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Pathogenic:5Uncertain:8Other:2
| risk factor, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jun 17, 2021 | - - |
| Uncertain significance, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Nov 03, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jan 06, 2020 | In the published literature, 6%-7% of Ashkenazi Jewish individuals are reported to carry this variant, with a much higher frequency found in cohorts of Ashkenazi Jewish individuals with a history of colorectal cancer and/or polyps (PMIDs: 11159880 (2001), 10938175 (2000), 9288102 (1997)). This variant is reported as a risk factor for colorectal neoplasia (PMIDs: 30152102 (2019), 29506128 (2018), 26421687 (2016), 26314409 (2016), 23896379 (2013)). The risk of colorectal cancer for Ashkenazi Jewish carriers of the p.Ile1307Lys APC variant is reported to be approximately twice that of the general population (PMID: 23576677 (2013)). While this variant has been associated with a moderately increased risk of colorectal cancer, it is important to note that the p.Ile1307Lys variant does not cause classic Familial Adenomatous Polyposis (FAP). The risk for cancers other than colorectal cancer, and the risk of colorectal cancer for groups other than the Ashkenazi Jewish population, have not been well established. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Jul 27, 2017 | - - |
| risk factor, criteria provided, single submitter | clinical testing | GeneDx | May 08, 2015 | 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). - |
| Uncertain significance, no assertion criteria provided | research | Biesecker Lab/Clinical Genomics Section, National Institutes of Health | Jul 13, 2012 | - - |
| Established risk allele, criteria provided, single submitter | curation | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Dec 19, 2023 | The APC c.3920T>A; p.Ile1307Lys variant (rs1801155) has been reported extensively in the literature, and is listed in ClinVar (Variation ID: 822). 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 risk in other populations is unclear. Additionally, this variant is observed in the general population at an overall frequency of 0.19% (524/282418 alleles, including 7 homozygotes) in the Genome Aggregation Database. Due to the high frequency in the general population, this variant is considered likely benign for most populations, but confers an increased risk of cancer in individuals of Ashkenazi Jewish ancestry. 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. PMID: 23576677. - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | AiLife Diagnostics, AiLife Diagnostics | Jan 09, 2022 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center | Aug 28, 2020 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Aug 01, 2024 | APC: PS3, PM1, PS4:Moderate, BP1, BP4 - |
| Uncertain significance, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
| Uncertain significance, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
| Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
| Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Familial adenomatous polyposis 1 Pathogenic:6Uncertain:4Other:3
| Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Sep 27, 2016 | 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. - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jul 27, 2021 | This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. - |
| association, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 31, 2024 | This sequence change replaces isoleucine, which is neutral and non-polar, with lysine, which is basic and polar, at codon 1307 of the APC protein (p.Ile1307Lys). This variant is present in population databases (rs1801155, gnomAD 4%), including at least one homozygous and/or hemizygous individual. 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). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt APC protein function with a negative predictive value of 95%. 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. - |
| Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The APC c.3920T>A (p.Ile1307Lys) variant was identified in 6 of 812 proband chromosomes (frequency: 0.007) from individuals or families with colorectal cancer and was present in 16 of 286 control chromosomes (frequency: 0.056) from healthy individuals (Fraying 1998, Nielsen 2005, Yantiss 2009). The p.Ile1307Lys variant was also identified in dbSNP (ID: rs1801155) as “With Pathogenic allele”; in NHLBI Exome Sequencing Project (Exome Variant Server), the variant was identified in 14 of 8600 European American alleles and was not found in 4404 African American alleles. In the Exome Aggregation Consortium database, the variant was identified 205 of 121054 chromosomes (frequency: 0.002), including 177 of 66620 alleles of European (Non-Finnish), 15 of 16502 of South Asian, 10 of 11546 of Latinos and 3 of 906 of Other alleles. The variant was not found in African, East Asian and Finnish populations. In the ClinVar database, the variant was identified by 8 submitters with conflicting classifications: classified as pathogenic by GeneReviews and by Ambry Genetics, (who used as assertion method the Ambry Genetics Dominant and X-linked criteria); GeneDx, Invitae, OMIM (2X) classified the variant as Risk Factor; Biesecker Laboratory ClinSeq Project-NHGRI classified the variant as Uncertain significance and ITMI did not provide a classification. The variant was identified in the UMD Colon cancer database and was classified as Neutral; in COSMIC it was identified in an adenocarcinoma tumour of the large intestine. In the InSIGHT database, the variant was identified 10X and classified as a low penetrance risk allele. The p.Ile1307 residue is not conserved in mammals and mouse has a valine at the 1307 position and fish and fruit fly carry the variant 1307Lys amino acid at this position, increasing the likelihood that this variant is benign. Computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant protein remains perfectly functional, yet the genetic alteration results in a small hypermutable region of DNA that may be prone to somatic mutations (Laken 1997). Several studies suggest that this variant increases risk of colon cancer. Woodage (1998) genotyped 5,081 Ashkenazi volunteers in a community survey, identifying 376 heterozygotes and 2 homozygotes (6.1%) and concluded that APC I1307K carriers have a modestly elevated risk of developing cancer (less than 2-fold). Woodage also emphasized that the large majority of I1307K carriers would not develop cancer of the colon. In addition, Gryfe (1999) identified the APC I1307K allele in 48 (10.1%) of 476 Ashkenazi Jewish subjects with adenomatous polyps and/or colorectal cancer. Compared with the frequency of 2 separate population control groups, the APC I1307K allele was associated with an estimated relative risk of 1.5 to 1.7 for colorectal neoplasia (P = 0.01). Compared with non-carriers, APC I1307K carriers had increased numbers of adenomas and colorectal cancers per patient, as well as a younger age at diagnosis. Fraying (1998), identified this variant in 3 individuals with multiple colonic adenomas, but also identified this variant in 8% of Ashkenazi controls from North London. In the most recent study (Boursi 2013), the variant was analyzed in 3305 Israelis undergoing colonoscopy; clinical data regarding potential risk factors were collected to determine if the p.Ile1307Lys variant was a risk factor in CRC in Ashkenazi Jews. This analysis included the prospective evaluation of 3305 consecutive Israeli subjects. Analysis consisted of high risk and average risk subjects. High risk (n=560) were diagnosed less than 60 years with family or personal history of CRC; Average risk (n=1779) were asymptomatic. It focused on a unique subpopulation of Ashkenazi Jews at average risk for CRC in order to assess the need to modify colonoscopy surveillanc - |
| not provided, no classification provided | literature only | GeneReviews | - | - - |
| Established risk allele, criteria provided, single submitter | clinical testing | New York Genome Center | May 26, 2023 | The c.3920T>A p.(Ile1307Lys) variant identified in APC is a common variant with ~3.5% minor allele frequency in individuals of Ashkenazi Jewish ancestry (gnomAD v2.1 and v3.1.2). The variant affects a conserved residue located in beta-catening binding domain and changes the (A)3(T)(A)4 sequence element into an extended tract of adenosine nucleotides (A8) which might predispose to slippage of polymerase during DNA replication and confer increased propensity for somatic truncating mutations on the allele [PMID: 37076288]. It has been reported that individuals of Ashkenazi Jewish ancestry who carry the p.(Ile1307Lys) variant are 1.7-2.17 times more likely to develop colorectal neoplasia compared to non-carrier individuals [PMID: 23896379, 23576677, 12173321], hence this variant is classified as a risk allele for colorectal neoplasia in the Ashkenazi Jewish population. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Johns Hopkins Genomics, Johns Hopkins University | Nov 03, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Department of Molecular Diagnostics, Institute of Oncology Ljubljana | Apr 02, 2020 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | KCCC/NGS Laboratory, Kuwait Cancer Control Center | Jul 07, 2023 | 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). 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 and is present in ClinVar (ID: 822). Several large studies have showed increased risk for developing colorectal cancer in Ashkenazi Jewish population. However, the cancer risk remains unknown in individuals of non-Jewish descent. In summary, this variant is an established risk factor for colorectal cancer in Ashkenazi Jewish populations and variant of uncertain significance in other populations. - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 28, 2024 | - - |
| risk factor, criteria provided, single submitter | clinical testing | Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine | Jun 02, 2017 | 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. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Equipe Genetique des Anomalies du Developpement, Université de Bourgogne | Nov 21, 2018 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Mendelics | Jul 02, 2018 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:5Uncertain:1Other:2
| Uncertain significance, no assertion criteria provided | clinical testing | Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. | Mar 22, 2022 | - - |
| Established risk allele, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 25, 2024 | The p.I1307K alteration (also known as c.3920T>A) is located in coding exon 15 of the APC gene. This alteration is present in 6-10% of the Ashkenazi Jewish population and has been reported at even higher frequencies in Ashkenazi Jewish colorectal cancer (CRC) cohorts (Boursi B et al. Eur. J. Cancer. 2013 Nov;49:3680-5; Gryfe R et al. Am J. Hum. Genet. 1999 Feb;64:378-84; Syngal S et al. JAMA. 2000 Aug;284:857-60; Stern HS et al. Gasteroenterol. 2001 Feb;120:392-400). The magnitude of CRC risk associated with p.I1307K has been debated in the literature; however, a meta-analysis of data from numerous independent studies found that p.I1307K confers an increased lifetime risk for CRC in the Ashkenazi Jewish population (OR=2.17, 95% CI=1.64-2.86; Liang J et al. Am. J. Epidemiol. 2013 Jun;177:1169-79). Associations between p.I1307K and risk of CRC and other malignancies is not well defined risk in non-Ashkenazi Jewish populations (Liang J et al. Am. J. Epidemiol. 2013 Jun;177:1169-79; Leshno A et al. Int. J. Cancer. 2016 Mar;138:1361-7; Abdel-Malak C et al. Fam. Cancer. 2016 Jan;15:49-56). This alteration is considered a risk allele for colorectal cancer and is not known to be associated with polyposis. Although controversial, increased colonoscopic surveillance is an option for carriers of this mutation (Rennert G et al. Dis. Colon Rectum. 2005 Dec;48:2317-21). Clinical correlation is advised. - |
| Pathogenic, criteria provided, single submitter | curation | Sema4, Sema4 | Dec 25, 2021 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Knight Diagnostic Laboratories, Oregon Health and Sciences University | Aug 05, 2019 | - - |
| risk factor, no assertion criteria provided | clinical testing | True Health Diagnostics | Nov 10, 2017 | - - |
| risk factor, criteria provided, single submitter | clinical testing | GeneKor MSA | Jan 01, 2020 | 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). - |
| Established risk allele, no assertion criteria provided | clinical testing | Laboratory of Medical Genetics Unit, Bambino Gesù Children's Hospital | - | The c.3920T>A (p.Ile1307Lys) variant in the APC gene has been associated with a moderate increased risk of colorectal cancer (CRC), particularly in individuals of Ashkenazi Jewish population [PMID 18770064, 24416237]. 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]. There is not enough evidence to support an increased risk of cancer in other populations/subpopulations. - |
| Established risk allele, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Apr 05, 2023 | This missense variant replaces isoleucine with lysine at codon 1307 of the APC protein. This variant is common in the population and has been identified in 524/282418 chromosomes (0.19%) in the general population by the Genome Aggregation Database (gnomAD). In particular, this variant has been identified in 375/10358 Ashkenazi Jewish chromosomes (3.62%), including 7 homozygous individuals, by the Genome Aggregation Database (gnomAD). Several large case-control studies and meta-analyses have reported a slightly increased risk of colorectal cancer in Ashkenazi Jewish individuals who carried this p.Ile1307Lys variant: OR=1.51 [95% CI 1.16-1.98] (PMID: 23896379); OR=2.17 [95% CI 1.64-2.86] (PMID: 23576677); OR=2.53 [95% CI 2.11-3.04] (PMID: 26421687). However, the cancer risk remains unclear in individuals of non-Ashkenazi Jewish descent. One study has shown that this variant did not show significant association with colorectal cancer in non-Ashkenazi Jewish individuals (OR=1.36, 95% CI=0.59-3.13) (PMID: 23576677). - |
Colorectal cancer Pathogenic:1Uncertain:1Other:1
| risk factor, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 04, 2020 | 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. - |
| Established risk allele, no assertion criteria provided | research | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The APC c.3920T>A (p.Ile1307Lys) variant was identified in 6 of 812 proband chromosomes (frequency: 0.007) from individuals or families with colorectal cancer and was present in 16 of 286 control chromosomes (frequency: 0.056) from healthy individuals (Fraying 1998, Nielsen 2005, Yantiss 2009). The p.Ile1307Lys variant was also identified in dbSNP (ID: rs1801155) as “With Pathogenic allele”; in NHLBI Exome Sequencing Project (Exome Variant Server), the variant was identified in 14 of 8600 European American alleles and was not found in 4404 African American alleles. In the Exome Aggregation Consortium database, the variant was identified 205 of 121054 chromosomes (frequency: 0.002), including 177 of 66620 alleles of European (Non-Finnish), 15 of 16502 of South Asian, 10 of 11546 of Latinos and 3 of 906 of Other alleles. The variant was not found in African, East Asian and Finnish populations. In the ClinVar database, the variant was identified by 8 submitters with conflicting classifications: classified as pathogenic by GeneReviews and by Ambry Genetics, (who used as assertion method the Ambry Genetics Dominant and X-linked criteria); GeneDx, Invitae, OMIM (2X) classified the variant as Risk Factor; Biesecker Laboratory ClinSeq Project-NHGRI classified the variant as Uncertain significance and ITMI did not provide a classification. The variant was identified in the UMD Colon cancer database and was classified as Neutral; in COSMIC it was identified in an adenocarcinoma tumour of the large intestine. In the InSIGHT database, the variant was identified 10X and classified as a low penetrance risk allele. The p.Ile1307 residue is not conserved in mammals and mouse has a valine at the 1307 position and fish and fruit fly carry the variant 1307Lys amino acid at this position, increasing the likelihood that this variant is benign. Computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant protein remains perfectly functional, yet the genetic alteration results in a small hypermutable region of DNA that may be prone to somatic mutations (Laken 1997). Several studies suggest that this variant increases risk of colon cancer. Woodage (1998) genotyped 5,081 Ashkenazi volunteers in a community survey, identifying 376 heterozygotes and 2 homozygotes (6.1%) and concluded that APC p.Ile1307Lys carriers have a modestly elevated risk of developing cancer (less than 2-fold). Woodage also emphasized that the large majority of p.Ile1307Lys carriers would not develop cancer of the colon. In addition, Gryfe (1999) identified the APC p.Ile1307Lys allele in 48 (10.1%) of 476 Ashkenazi Jewish subjects with adenomatous polyps and/or colorectal cancer. Compared with the frequency of 2 separate population control groups, the APC p.Ile1307Lys allele was associated with an estimated relative risk of 1.5 to 1.7 for colorectal neoplasia (P = 0.01). Compared with non-carriers, APC p.Ile1307Lys carriers had increased numbers of adenomas and colorectal cancers per patient, as well as a younger age at diagnosis. Fraying (1998), identified this variant in 3 individuals with multiple colonic adenomas, but also identified this variant in 8% of Ashkenazi controls from North London. In the most recent study (Boursi 2013), the variant was analyzed in 3305 Israelis undergoing colonoscopy; clinical data regarding potential risk factors were collected to determine if the p.Ile1307Lys variant was a risk factor in CRC in Ashkenazi Jews. This analysis included the prospective evaluation of 3305 consecutive Israeli subjects. Analysis consisted of high risk and average risk subjects. High risk (n=560) were diagnosed less than 60 years with family or personal history of CRC; Average risk (n=1779) were asymptomatic. It focused on a unique subpopulation of Ashkenazi Jews at average risk for CRC in order to assess the need to - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | May 20, 2023 | The observed missense variant c.3920T>A (p.Ile1307Lys) in APC gene has been reported previously in heterozygous state in multiple individuals affected with Colorectal cancer (Breen KE et al. 2022; Long JM et al. 2022). The p.Ile1307Lys variant has allele frequency 0.2% in gnomAD Exomes. This variant has been submitted to the ClinVar database as Likely Benign / Uncertain Significance / Risk factor / Established risk allele / Likely pathogenic / Pathogenic (multiple submiters). Multiple lines of computational evidence (Polyphen - Benign, SIFT -Tolerated and Mutation Taster - Disease causing) predicts conflicting evidence on protein structure and function for this variant. The amino acid change p.Ile1307Lys in APC is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Ile at position 1307 is changed to a Lys changing protein sequence and it might alter its composition and physico-chemical properties. Functional studies related to this variant is unclear, the variant is enriched in patients with colorectal cancer in Ashkenazi Jewish population (Boursi B et al. 2013). For these reasons, this variant has been classified as a Pathogenic variant which acts as a risk factor for the development of colorectal cancer. - |
not specified Uncertain:2Other:1
| not provided, no classification provided | reference population | ITMI | Sep 19, 2013 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 29, 2024 | 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 0.0024 in 254250 control chromosomes in the gnomAD database, including 7 homozygotes. The observed variant frequency within the Ashkenazi Jewish subpopulation is nearly 33-fold the estimated maximal expected allele frequency for a pathogenic variant in APC causing the Colorectal Cancer Risk phenotype (0.0011), suggesting that the variant is a benign polymorphism found primarily in populations of Ashkenazi-Jewish origin. However, multiple case-control studies have reported this variant with increased risk for colorectal cancer within the Ashkenazi Jewish population (e.g. Laken_1997, Gryfe_1999, Drucker_2000, Shtoyerman-Chen_2001, Fidder_2005, Boursi_2013). c.3920T>A has also been reported in the literature in individuals affected with non-colorectal cancer phenotypes (e.g. Maxwell_2016, Feliubadalo_2017, Schubert_2019, Fanale_2020, Akcay_2020), however these reports do not provide unequivocal conclusions about association of the variant with Colorectal Cancer Risk. A large meta-analysis concluded that the variant increases the risk of colorectal cancer by approximately 2-fold in individuals of Ashkenazi Jewish ancestry (OR=2.17, 95% CI=1.65-2.86), however the variant was not associated with additional risk in Non-Ashkenazi Jewish individuals in this study (Liang_2013). Another large case-control study identified the variant as a risk factor for non-colorectal cancers in an Israeli population (Leshno_2016). Co-occurrences with other pathogenic variants have been reported [BRCA1 c.68_69del, p.E23VfsX17 (Yurgelun_2017); RAD51C c.630T>G, p.Tyr210X (internal sample); MSH6 c.3743_3744insT, p.Tyr1249LeufsTer26 (Zhang_2020)], providing some supporting evidence for a benign role, however most case-control studies in the Ashkenazi-Jewish population support classification of the variant as a risk-factor for colorectal cancer. While there is insufficient evidence to determine risk in individuals without Ashkenazi-Jewish heritage, in-vivo and in-vitro studies have indicated that this germline variant may result in a much more highly mutable allele by creating an (A)8 mononucloetide tract that has a higher propensity for somatic frameshift mutations (e.g. Laken_1997, Gryfe_1998). Current NCCN guidelines recommend colorectal cancer surveillance measures for carriers of this variant due to association with a higher colorectal cancer risk. The following publications have been ascertained in the context of this evaluation (PMID: 32658311, 30980208, 18343606, 23896379, 28749474, 11207040, 30152102, 10679643, 32854451, 28050010, 15929773, 9973276, 9751605, 26187149, 9288102, 26421687, 23576677, 27153395, 25604157, 27978560, 30814645, 30426508, 26394139, 26845104, 11551102, 26300997, 14633595, 29961768, 28135145, 24416237, 31444830). ClinVar contains an entry for this variant (Variation ID: 822). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Jul 31, 2024 | - - |
Familial multiple polyposis syndrome Uncertain:2
| Uncertain significance, criteria provided, single submitter | clinical testing | Center for Human Genetics, Inc, Center for Human Genetics, Inc | Jun 01, 2018 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia | Nov 24, 2015 | - - |
Breast carcinoma Uncertain:1
| Uncertain significance, no assertion criteria provided | clinical testing | Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences | Aug 09, 2021 | Diagnosis: Breast Cancer Pathology: Invasive breast carcinoma(NST) IHC: ER:+ , PR:+ , HER2:+ , KI67:%20 - |
APC-Associated Polyposis Disorders Other:1
| not provided, no classification provided | phenotyping only | GenomeConnect - Invitae Patient Insights Network | - | Variant reported in multiple Invitae PIN participants. Variant interpreted as an increased risk allele and reported most recently on 11/13/2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. - |
Familial colorectal cancer Other:1
| not provided, no classification provided | phenotyping only | GenomeConnect, ClinGen | - | Variant interpreted as Pathogenic "Moderate Risk Allele" and reported on 07-15-2020 by Lab or GTR ID 61756. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. - |
FAMILIAL ADENOMATOUS POLYPOSIS 1, SUSCEPTIBILITY TO Other:1
| risk factor, no assertion criteria provided | literature only | OMIM | Apr 01, 2019 | - - |
Carcinoma of colon Other:1
| risk factor, criteria provided, single submitter | research | Snyder Lab, Genetics Department, Stanford University | Jan 01, 2017 | - - |
Breast cancer, susceptibility to Other:1
| risk factor, no assertion criteria provided | literature only | OMIM | Dec 01, 2003 | - - |
Colorectal cancer, susceptibility to Other:1
| risk factor, criteria provided, single submitter | clinical testing | University of Washington Department of Laboratory Medicine, University of Washington | Nov 20, 2015 | 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) - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
DEOGEN2
Uncertain
T;T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
.;T
M_CAP
Uncertain
D
MetaRNN
Benign
T;T
MetaSVM
Benign
T
MutationAssessor
Benign
L;L
MutationTaster
Benign
D;D;D
PrimateAI
Benign
T
PROVEAN
Benign
N;N
REVEL
Benign
Sift
Benign
T;T
Sift4G
Benign
T;T
Polyphen
B;B
Vest4
MVP
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at