Submissions for variant NM_000038.6(APC):c.1744-2A>G

dbSNP: rs587783035

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV003650400	SCV000552754	pathogenic	Familial adenomatous polyposis 1	2023-05-09	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site results in skipping of exon 15 and introduces a new termination codon (PMID: 9298819, 15459959). However the mRNA is not expected to undergo nonsense-mediated decay. ClinVar contains an entry for this variant (Variation ID: 156482). Disruption of this splice site has been observed in individuals with familial adenomatous polyposis (FAP) (PMID: 8990002, 9298819, 11247896, 15459959, 20223039, 20564245). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 14 of the APC gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely disrupts the C-terminus of the protein.
Ambry Genetics	RCV001012984	SCV001173514	pathogenic	Hereditary cancer-predisposing syndrome	2019-12-03	criteria provided, single submitter	clinical testing	The c.1744-2A>G intronic pathogenic mutation results from an A to G substitution two nucleotides upstream from coding exon 14 in the APC gene. This alteration has been seen in multiple unrelated families with personal and/or family history consistent with familial adenomatous polyposis and has been demonstrated to result in an RNA transcript that skips coding exon 14 (Ambry internal data; van der Luijt RB et al. Hum. Mutat. 1997;9:7-16; Bala S et al. Hum. Mutat., 1997;10:201-6; Aretz S et al. Hum. Mutat. 2004 Nov;24:370-80; Friedl W et al. Hered Cancer Clin Pract, 2005 Sep;3:95-114; Miclea RL et al. J. Bone Miner. Res., 2010 Dec;25:2624-32; Kerr SE et al. J Mol Diagn, 2013 Jan;15:31-43). In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site. As such, this alteration is classified as a disease-causing mutation.
Color Diagnostics, LLC DBA Color Health	RCV001012984	SCV001343079	pathogenic	Hereditary cancer-predisposing syndrome	2019-08-07	criteria provided, single submitter	clinical testing	This variant causes an A>G nucleotide substitution at the -2 position of intron 14 of the APC gene. Functional RNA studies have shown that this variant causes skipping of exon 15 (also reported as exon 14 in the literature) and this mutant transcript is expected to create a frameshift and a premature translation stop signal and be expressed as a truncated protein (PMID: 9298819, 15459959). Analysis of lymphoblastoid B cells from individuals carrying this variant has demonstrated the expression of the low-molecular-weight APC protein encoded by this mutant transcript (PMID: 9298819). This variant has been reported in more than 10 individuals affected with familial adenomatous polyposis (PMID: 8990002, 9298819, 10713886, 11247896, 15459959, 20223039, 20564245, 23159591). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of APC function is a known mechanism of disease. Based on available evidence, this variant is classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002281962	SCV002572256	pathogenic	Familial multiple polyposis syndrome	2022-08-23	criteria provided, single submitter	clinical testing	Variant summary: APC c.1744-2A>G is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a canonical 3' splice acceptor site. At least one publication reports experimental evidence that this variant affects mRNA splicing resulting in skipping of exon 14 (example, Bala_1997). The variant was absent in 251084 control chromosomes. c.1744-2A>G has been reported in the literature in multiple individuals affected with Familial Adenomatous Polyposis (example, Aretz_2004, Cao_2000, Lima_2011, Miclea_2010, Kim_2019). These data indicate that the variant is very likely to be associated with disease. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV003321518	SCV004026363	pathogenic	not provided	2023-05-02	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000144573	SCV004044846	pathogenic	Familial adenomatous polyposis 1	2023-05-03	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function. mRNA analysis has demonstrated abnormal mRNA splicing occurs [PMID: 15459959]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 10713886].
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003321518	SCV004221733	pathogenic	not provided	2023-05-26	criteria provided, single submitter	clinical testing	The APC c.1744-2A>G variant disrupts a canonical splice-acceptor site and interferes with normal APC mRNA splicing. This variant has been reported in the published literature in individuals and families with familial adenomatous polyposis (FAP) (PMIDs: 23159591 (2013), 21315632 (2011), 20564245 (2010), 20223039 (2005), 15459959 (2004), 11247896 (2001), 10713886 (2000), 8990002 (1997), 9298819 (1997)). An experimental study reports the skipping of exon 14 due to improper splicing is damaging to APC protein function (PMID: 9298819 (1997)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic.
Pathway Genomics	RCV000144573	SCV000189872	pathogenic	Familial adenomatous polyposis 1	2014-07-24	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000500538	SCV000591088	pathogenic	Carcinoma of colon		no assertion criteria provided	clinical testing	The APC c.1744-2A>G variant was identified in 2 of 2542 proband chromosomes (frequency: 0.001) from individuals or families with FAP (van der Luijt 1997, Friedl 2005, Friedl 2001, Aretz 2004). RNA based analysis showed that the variant caused exon 14 skipping by abolishing the consensus splice site, correlating with in silico prediction models (Aretz 2004). The variant was identified in the HGMD, InSiGHT Colon Cancer Gene Variant Database (3X), and the ClinVar database (classified as a Pathogenic variant by Pathway Genomics). The c.1744-2A>G variant is predicted to cause abnormal splicing because the nucleotide substitution occurs in the invariant region of the splice consensus sequence. In addition, 5 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, this variant meets our laboratory’s criteria to be classified as pathogenic.