ClinVar Miner

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

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Total submissions: 12
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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 Lines of evidence used in support of classification: 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 RCV000034405 SCV000219011 likely benign not provided 2019-03-05 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 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-21 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000211900 SCV000694003 likely benign not specified 2019-03-28 criteria provided, single submitter clinical testing Variant summary: APC c.1631T>C (p.Ile544Thr) results in a non-conservative amino acid change 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 0.00015 in 276928 control chromosomes, predominantly within the Non-Finnish European subpopulation at a frequency of 0.00032 in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 4.5 fold of 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 evaluated for familial adenomatous polyposis (Kerr 2012) and in an individual with Li-Fraumeni-like syndrome, together with other variants (Henn 2019). The variant was also found in co-occurrence with the variant APC c. 6873 A>T (p.Gln2291His) in an individual with endometrial- (Ring 2016) and in another individual with colorectal cancer (Yurgelun 2017). As well as, these two variants were listed to be found in one individual in a cohort of individuals affected with atherosclerosis, with no information about cancer history (Johnston 2012), and in a cohort of patients with pancreatic cancer (Grant 2015); unclear if these two variants were found in the same individual in these cohorts. These report(s) 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. Seven other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, all classifying the variant as VUS. 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 2017-03-01 criteria provided, single submitter clinical testing
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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