ClinVar Miner

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

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Total submissions: 38
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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 association Familial adenomatous polyposis 1 2020-11-02 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 The p.I1307K moderate risk mutation (also known as c.3920T>A) is located in coding exon 15 of the APC gene. This alteration is present in 6-7% of the Ashkenazi Jewish population and has been reported at even higher frequencies in Ashkenazi Jewish colorectal cancer (CRC) and adenomatous polyp cohorts (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). One recent study of over 2200 Ashkenazi Jewish individuals reported an even higher prevalence (10.1%) of this mutation in the general Ashkenazi Jewish population (Boursi B et al. Eur. J. Cancer. 2013 Nov;49:3680-5). 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 a moderate increase (OR=2.17, 95% CI=1.64-2.86) in lifetime CRC risk in the Ashkenazi Jewish population (Liang J et al. Am. J. Epidemiol. 2013 Jun;177:1169-79). Associations between p.I1307K and CRC risk in non-Ashkenazi Jewish populations and the risk of other malignancies for p.I1307K carriers have not been well defined, but one study found a statistically significant association between this allele and extra-colonic malignancies (95% CI 2.11-3.04 p<0.0001); and another case-control study in an Egyptian population found a similar association with colorectal cancer as reported in the Ashkenazi Jewish population (OR=2.588, 95% CI=1.90-6.09) (Leshno A et al. Int. J. Cancer. 2016 Mar;138:1361-7; Abdel-Malak C et al. Fam. Cancer. 2016 Jan;15:49-56). 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.
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)
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics,Children's Hospital of Philadelphia RCV000238802 SCV000297021 uncertain significance Familial multiple polyposis syndrome 2015-11-24 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000034388 SCV000600091 pathogenic not provided 2020-01-06 criteria provided, single submitter clinical testing Frequency is not informative. This variant is statistically more frequent in affected individuals than in the general population and/or healthy controls. Predicted to have a tolerated effect on the protein. Assessment of experimental evidence regarding the effect of this variant on protein function is inconclusive. Very strong co-segregation with disease in affected individuals from multiple families.
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 Health, Inc RCV000115087 SCV000686956 likely pathogenic Hereditary cancer-predisposing syndrome 2020-11-23 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000120049 SCV000694042 uncertain significance not specified 2021-03-02 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 0.0024 in 254250 control chromosomes in the gnomAD database, predominantly at a frequency of 0.036 within the Ashkenazi Jewish subpopulation, 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 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. 24 other ClinVar submitters have reported clinical assessments for this variant (evaluation after 2014). 7 cite the variant as pathogenic/likely pathogenic, 9 cite it as a risk factor/associated, and 8 cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as a VUS-possibly pathogenic risk factor for colorectal cancer.
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 RCV000238802 SCV000807826 uncertain significance Familial multiple polyposis syndrome 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 likely pathogenic not provided 2021-02-01 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.
Johns Hopkins Genomics, Johns Hopkins University RCV000020088 SCV001441544 uncertain significance Familial adenomatous polyposis 1 2020-11-03 criteria provided, single submitter clinical testing
Knight Diagnostic Laboratories, Oregon Health and Sciences University RCV000115087 SCV001448808 likely pathogenic Hereditary cancer-predisposing syndrome 2019-08-05 criteria provided, single submitter clinical testing
Greenwood Genetic Center Diagnostic Laboratories,Greenwood Genetic Center RCV000034388 SCV001468082 likely pathogenic not provided 2020-08-28 criteria provided, single submitter clinical testing
Department of Molecular Diagnostics, Institute of Oncology Ljubljana RCV000020088 SCV001499607 pathogenic Familial adenomatous polyposis 1 2020-04-02 criteria provided, single submitter clinical testing
New York Genome Center RCV000020088 SCV001761068 risk factor Familial adenomatous polyposis 1 2020-05-29 criteria provided, single submitter clinical testing The heterozygous APC variant (c.3920T>A, p.Ile1307Lys) is a common variant, and observed at an allele frequency of 3.7% (382/10,358) in individuals of Ashkenazi Jewish ancestry in the gnomAD database. Individuals of Ashkenazi Jewish ancestry 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: 23896379; PMID: 23576677; PMID: 12173321]. This variant is classified 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.
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
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000020088 SCV000591159 uncertain significance Familial adenomatous polyposis 1 no assertion criteria provided clinical testing The APC 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 surveillance among p.I1307K carriers. Overall, the odds ratio for CRC among carriers was 1.51. Among average risk AJ patients the OR was 1.75 (adjusted for other risk factors). A recent meta-analysis of APC polymorphism and colorectal cancer from published data using pooled odds ratios and 95% confidence intervals were calculated by using Comprehensive Meta-Analysis software with a 2-tailed a-value of 0.05. Compared with those who carried the wild-type I1307K, Ashkenazi Jews who carried the I1307K variant were at a significantly increased risk for colorectal neoplasia, with a pooled odds ratio of 2.17 (95% confidence interval: 1.64-2.86)(Liang 2013). The authors suggest that the APC p.I1307K variant is an important risk factor for colorectal neoplasia in Ashkenazi Jews and carriers in this group should be considered for screening colonoscopy at the age of 40, to be repeated every 5 years, similar to recommendations in individuals with family history of colorectal cancer. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time, although this variant may be a low-penetrance allele that mildly increases the risk of developing colorectal cancer, it is not directly linked to a “polyposis” phenotype. Based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
True Health Diagnostics RCV000115087 SCV000693480 risk factor Hereditary cancer-predisposing syndrome 2017-11-10 no assertion criteria provided clinical testing
GenomeConnect - Invitae Patient Insights Network RCV001535784 SCV001749942 not provided APC-Associated Polyposis Disorders no assertion provided phenotyping only 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.
Medical Genetics Laboratory, Umraniye Training and Research Hospital,University of Health Sciences RCV001554302 SCV001774787 uncertain significance Breast carcinoma 2021-08-09 no assertion criteria provided clinical testing Diagnosis: Breast Cancer Pathology: Invasive breast carcinoma(NST) IHC: ER:+ , PR:+ , HER2:+ , KI67:%20
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) RCV000034388 SCV001798309 uncertain significance not provided no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000034388 SCV001808307 uncertain significance not provided no assertion criteria provided clinical testing
Clinical Genetics,Academic Medical Center RCV000034388 SCV001924111 uncertain significance not provided no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000034388 SCV001952767 uncertain significance not provided no assertion criteria provided clinical testing

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