ClinVar Miner

Submissions for variant NM_000038.6(APC):c.1631T>C (p.Ile544Thr) (rs144056494)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131638 SCV000186662 benign Hereditary cancer-predisposing syndrome 2014-11-28 criteria provided, single submitter clinical testing General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance
GeneDx RCV000034405 SCV000209496 uncertain significance not provided 2017-07-03 criteria provided, single submitter clinical testing This variant is denoted APC c.1631T>C at the cDNA level, p.Ile544Thr (I544T) at the protein level, and results in the change of an Isoleucine to a Threonine (ATT>ACT). APC Ile544Thr was observed in one of 1592 individuals being evaluated for Familial Adenomatous Polyposis (Kerr 2013). This variant was also observed to co-occur with APC Gln2291His in individuals with endometrial or colorectal cancer (Ring 2016, Yurgelun 2017), as well as in 1/568 individuals with atherosclerosis, with no specific information about cancer history (Johnston 2012). APC Ile544Thr was observed at an allele frequency of 0.03% (17/66250) in individuals of European (Non-Finnish) ancestry in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Isoleucine and Threonine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. APC Ile544Thr occurs at a position that is conserved across species and is located in the Armadillo region (Azzopardi 2008). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether APC Ile544Thr is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000987559 SCV000219011 likely benign Familial adenomatous polyposis 1 2019-12-31 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000211900 SCV000538296 uncertain significance not specified 2017-01-24 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant has been seen in one individual evaluated for FAP (Kerr 2013). It is classified in ClinVar with 1 star as Benign by Ambry and as VUS by Invitae, GeneDx, and Biesecker lab. It is present in gnomAD with a Max MAF of 0.03% (42 alleles - frequency too high for disease).
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000211900 SCV000591082 uncertain significance not specified 2016-09-23 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000211900 SCV000600048 uncertain significance not specified 2017-03-10 criteria provided, single submitter clinical testing
Color RCV000131638 SCV000681479 likely benign Hereditary cancer-predisposing syndrome 2020-01-14 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000211900 SCV000694003 likely benign not specified 2020-08-23 criteria provided, single submitter clinical testing Variant summary: APC c.1631T>C (p.Ile544Thr) results in a non-conservative amino acid change located in the Armadillo repeat region (IPR000225) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00016 in 251106 control chromosomes, predominantly at a frequency of 0.00033 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 4.6- fold the estimated maximal expected allele frequency for a pathogenic variant in APC causing Familial Adenomatous Polyposis phenotype (7.1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.1631T>C has been reported in the literature in an individual affected with Familial Adenomatous Polyposis without strong evidence for causality (e.g. Kerr_2012). The variant has also been reported in patients with Li_Fraumeni-like syndrome (e.g. Henn_2019) and other cancer phenotypes (e.g. Grant_2015, Ring_2016, Yurgelun_2017). These reports do not provide unequivocal conclusions about association of the variant with Familial Adenomatous Polyposis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Ten other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign, n=3; uncertain significance, n=7). Based on the evidence outlined above, the variant was classified as likely benign.
Mendelics RCV000987559 SCV001136886 uncertain significance Familial adenomatous polyposis 1 2019-05-28 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000034405 SCV001154455 uncertain significance not provided 2019-07-01 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001154528 SCV001315901 likely benign APC-Associated Polyposis Disorders 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000034405 SCV000043112 variant of unknown significance not provided 2012-07-13 no assertion criteria provided research Converted during submission to Uncertain significance.
True Health Diagnostics RCV000131638 SCV000787830 uncertain significance Hereditary cancer-predisposing syndrome 2017-12-01 no assertion criteria provided clinical testing

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