ClinVar Miner

Submissions for variant NM_000038.6(APC):c.6354TGC[5] (p.Ala2122dup)

dbSNP: rs587780602
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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV002228473 SCV000166048 likely benign Familial adenomatous polyposis 1 2021-12-16 criteria provided, single submitter clinical testing
Ambry Genetics RCV000129306 SCV000184068 likely benign Hereditary cancer-predisposing syndrome 2018-08-13 criteria provided, single submitter clinical testing Co-occurence with a mutation in another gene that clearly explains a proband's phenotype;Other data supporting benign classification
GeneDx RCV000588527 SCV000292463 likely benign not provided 2021-11-12 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 25980754, 27060149, 27443514, 27978560, 25186627, 25604157, 30671715)
Color Diagnostics, LLC DBA Color Health RCV000129306 SCV000681795 likely benign Hereditary cancer-predisposing syndrome 2020-02-05 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000588527 SCV000694090 benign not provided 2016-09-30 criteria provided, single submitter clinical testing Variant summary: The APC c.6363_6365dupTGC (p.Ala2121dup) variant involves the insertion of three nucleotides in a 5 alanine repeat region, resulting in an in-frame duplication of single Alanine. One in silico tool predicts a benign outcome for this variant. This variant was found in 36/121200 control chromosomes, predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.0004797 (32/66714). This frequency is about 7 times the estimated maximal expected allele frequency of a pathogenic APC variant (0.0000714), suggesting this is likely a benign polymorphism found primarily in the populations of European (Non-Finnish) origin. This variant has been reported in affected individuals without strong evidence of causality. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance/likely benign, all without evidence to independently evaluate. Taken together, this variant is classified as benign.
PreventionGenetics,PreventionGenetics RCV000588527 SCV000805452 uncertain significance not provided 2017-08-24 criteria provided, single submitter clinical testing
Baylor Genetics RCV001080265 SCV001482688 uncertain significance Familial adenomatous polyposis 1 2019-04-30 criteria provided, single submitter clinical testing This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden RCV001762289 SCV002011086 uncertain significance Colorectal cancer 2021-11-03 criteria provided, single submitter clinical testing
Genetic Services Laboratory,University of Chicago RCV001818301 SCV002065870 uncertain significance not specified 2021-09-16 criteria provided, single submitter clinical testing DNA sequence analysis of the APC gene demonstrated a three base pair duplication in exon 16, c.6363_6365dup. This in-frame duplication is predicted to result in the duplication of a alaine residue, p.Ala2122dup, located in an alanine-rich region. This sequence change has been described in the gnomAD database with a frequency of 0.053% in the non-Finnish European subpopulation (dbSNP rs587780602). This duplication has been reported in an individual with colorectal cancer and was considered a variant of uncertain significance (PMID: 27978560). The functional significance of this sequence change is not known at present and its contribution to this individual's disease phenotype cannot definitively be determined.
Sema4,Sema4 RCV000129306 SCV002528652 benign Hereditary cancer-predisposing syndrome 2020-10-04 criteria provided, single submitter curation
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001080265 SCV000591198 uncertain significance Familial adenomatous polyposis 1 no assertion criteria provided clinical testing The p.Ala2122dup variant was identified in 1 of 342 proband chromosomes (frequency: 0.003) from individuals or families with FAP, but was classified as a VUS by the authors (Out 2015). The variant was also identified in the Clinvitae database (1X with “uncertain significance”), COSMIC (1X found in a lung adenocarcinoma), ClinVar database (1X with uncertain significance, classified by Ambry Genetics), and UMD (1X with an “unclassified variant” classification). The variant was not identified in the general population cohort databases; 1000 Genomes Project, Exome Variant Server project or the Exome Aggregation Consortium (ExAC) database. This variant is an in-frame duplication resulting in the duplication of an Alanine (Ala) residue at codon 2122; the impact of this alteration on APC protein function is not known. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. 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 unknown significance.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV001818301 SCV002550640 uncertain significance not specified 2022-01-07 no assertion criteria provided clinical testing

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