ClinVar Miner

Submissions for variant NM_000038.6(APC):c.1958+1_1958+2dup (rs1561569606)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000780852 SCV000918463 likely pathogenic Familial multiple polyposis syndrome 2017-12-15 criteria provided, single submitter clinical testing Variant summary: The c.1958+1_1958+2dupGTvariant in APC gene is an intronic change that results in dinucleotide duplication immediately after canonical +2 position. 5/5 in silico tools via Alamut tools predicted to severely decrease canonical donor site, however no functional studies confirming these predictions have been published at the time of evaluation. The variant is absent from the large control population dataset of gnomAD (~240190 chrs tested). The c.1958+1_1958+2dupGT has been reported in at least three affected with histologically documented and genetically confirmed diagnosis of FAP (Out_2015; Miclea_2010). Taking together, the variant was classified as Likely Pathogenic.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001354694 SCV001549371 uncertain significance not provided no assertion criteria provided clinical testing The APC c.1958+1_1958+2dupGT variant was identified in 1 of 342 proband chromosomes (frequency: 0.003) from an individual with familial adenomatous polyposis (FAP) (Out 2015); however, control chromosomes were not evaluated in these studies, thus the prevalence of this variant in the general population could not be determined. The variant was also identified in the LOVD 3.0 database (1x, splicing affected). The variant was not identified in dbSNP, ClinVar, Clinvitae, Cosmic, MutDB, UMD-LSDB, or the Zhejiang Colon Cancer Database. The variant was also not identified in the following control databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). In a study by Out 2015, in silico analysis predicted an in-frame skipping of exon 14, which was confirmed by reverse transcriptase PCR. The c.1958+1_1958+2dupGT variant is located in the 5' splice region but does not affect the invariant +1 and +2 positions. However, positions +3 to +6 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. In addition, 4 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% 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 uncertain significance.

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