ClinVar Miner

Submissions for variant NM_000038.6(APC):c.6354TGC[5] (p.Ala2122dup) (rs587780602)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001080265 SCV000166048 likely benign Familial adenomatous polyposis 1 2020-12-07 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 RCV000237032 SCV000292463 uncertain significance not specified 2017-03-29 criteria provided, single submitter clinical testing This duplication of three nucleotides in APC is denoted c.6363_6365dupTGC at the cDNA level and p.Ala2122dup at the protein level. The normal sequence, with the bases that are duplicated in brackets, is CTGC[dupTGC]ATGT. This in-frame duplication of a single Alanine residue is not located in a known functional domain (Azzopardi 2008, UniProt). This variant was reported in an individual undergoing multigene cancer panel testing due to a history of a Lynch syndrome-related cancer and/or polyps (Yurgelun 2015). APC Ala2122dup was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since in-frame duplications may or may not inhibit proper protein functioning, the clinical significance of this finding remains unclear at this time and we consider APC Ala2122dup to be a variant of uncertain significance.
Color Health, Inc 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].
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.

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