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 likely benign not provided 2021-06-25 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 22703879, 25479140, 23159591, 27443514, 28135145, 28873162, 27600092)
Invitae RCV000987559 SCV000219011 likely benign Familial adenomatous polyposis 1 2020-12-07 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).
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000034405 SCV000600048 likely benign not provided 2020-02-24 criteria provided, single submitter clinical testing
Color Health, Inc RCV000131638 SCV000681479 likely benign Hereditary cancer-predisposing syndrome 2020-01-14 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353623 SCV000591082 uncertain significance Carcinoma of colon no assertion criteria provided clinical testing The APC p.Ile544Thr variant was identified in 1 of 3082 proband chromosomes (frequency: 0.000) from an individual with FAP (Kerr 2013). The variant was also identified in dbSNP (ID: rs144056494) “With other allele”, Clinvar database (with conflicting interpretations of pathogenicity, classified as benign by Ambry Genetics and uncertain significance by GeneDx, Invitae and Biesecker Laboratory-ClinSeq Project), Clinvitae database. This variant was also identified in the 1000 Genomes Project in 2 of 5000 chromosomes (frequency: 0.0004), HAPMAP-EUR in 2 of 1006 chromosomes (frequency: 0.002), NHLBI GO Exome Sequencing Project (ESP) in 2 of 5000 European American alleles, and the Exome Aggregation Consortium (ExAC) database (released Jan 13, 2015) in 17 of 66250 chromosomes (frequency:0.0003) in the European (Non-Finnish) population. The p.Ile544 residue is conserved across mammals and other organisms and 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 occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, 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 RCV000131638 SCV000787830 uncertain significance Hereditary cancer-predisposing syndrome 2017-12-01 no assertion criteria provided clinical testing

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