Submissions for variant NM_000038.6(APC):c.136-2A>G

dbSNP: rs886039625

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000254746	SCV000322549	pathogenic	not provided	2018-04-12	criteria provided, single submitter	clinical testing	This variant is denoted APC c.136-2A>G or IVS2-2A>G and consists of an A>G nucleotide substitution at the -2 position of intron 2 of the APC gene. This variant destroys a canonical splice acceptor site and is predicted to cause abnormal gene splicing, leading to an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. This variant has not, to our knowledge, been published in the literature. Based on the current evidence, we consider this variant to be pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002518766	SCV001229485	pathogenic	Familial adenomatous polyposis 1	2025-01-15	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 2 of the APC gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or altered protein product. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with APC-related conditions. ClinVar contains an entry for this variant (Variation ID: 265561). Studies have shown that disruption of this splice site results in skipping of exon 3, and produces a non-functional protein and/or introduces a premature termination codon (internal data). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV004943828	SCV005460470	likely pathogenic	Hereditary cancer-predisposing syndrome	2024-12-09	criteria provided, single submitter	clinical testing	The c.136-2A>G intronic variant results from an A to G substitution two nucleotides upstream from coding exon 2 in the APC gene. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and may result in the creation or strengthening of a novel splice acceptor site. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic. However, variants at this splice site are associated with an attenuated phenotype and may have reduced penetrance compared to classic familial adenomatous polyposis syndrome. Clinical correlation is advised.