ClinVar Miner

Submissions for variant NM_000038.6(APC):c.4420G>A (p.Ala1474Thr) (rs139387758)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000759431 SCV000167009 benign not provided 2018-12-04 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 18199528, 24728327, 24055113, 24861525, 25637381, 21859464, 26332594)
Ambry Genetics RCV000129100 SCV000183811 benign Hereditary cancer-predisposing syndrome 2015-01-04 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
Invitae RCV000987573 SCV000252587 benign Familial adenomatous polyposis 1 2020-12-06 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000321870 SCV000452012 likely benign APC-Associated Polyposis Disorders 2018-11-29 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000120040 SCV000602521 likely benign not specified 2016-10-27 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000120040 SCV000805409 benign not specified 2017-04-25 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000759431 SCV000888745 benign not provided 2018-06-05 criteria provided, single submitter clinical testing
Color Health, Inc RCV000129100 SCV000902635 benign Hereditary cancer-predisposing syndrome 2016-03-23 criteria provided, single submitter clinical testing
Mendelics RCV000987573 SCV001136913 benign Familial adenomatous polyposis 1 2019-05-28 criteria provided, single submitter clinical testing
ITMI RCV000120040 SCV000084173 not provided not specified 2013-09-19 no assertion provided reference population
CSER _CC_NCGL, University of Washington RCV000148366 SCV000190058 uncertain significance Colorectal adenoma 2014-06-01 no assertion criteria provided research
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001358624 SCV001554414 likely benign Carcinoma of colon no assertion criteria provided clinical testing The APC p.Ala1474Thr variant was identified in 1 of 1382 proband chromosomes (frequency: 0.0007) from individuals or families with colorectal polyps (Azzopardi, 2008). The variant was also identified in dbSNP (ID: rs139387758 as With Uncertain significance allele), ClinVar (3x as benign, 2x as likely benign, 1x as a variant of uncertain significance), Cosmic (2x), LOVD 3.0 (1x as not classified), and UMD-LSDB (1x). The variant was not identified in MutDB or the Zhejiang Colon Cancer Database. The variant was identified in control databases in 290 of 276830 chromosomes (2 homozygous) at a frequency of 0.001, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 270 of 24026 chromosomes (freq: 0.01), Other in 2 of 6456 chromosomes (freq: 0.0003), Latino in 13 of 34404 chromosomes (freq: 0.0004), European Non-Finnish in 4 of 126384 chromosomes (freq: 0.00003), and SouthAsian in 1 of 30774 chromosomes (freq: 0.00003), while the variant was not observed in the Ashkenazi Jewish, East Asian, or Finnish, populations. The p.Ala1474 residue is moderately conserved in mammals, although 5 of 5 computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 5 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, the clinical significance of this variant cannot be determined with certainty at this time although the available information is suggestive of a benign role. This variant is classified as likely benign.

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