Submissions for variant NM_000038.6(APC):c.933+1G>A

dbSNP: rs876660765

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000217532	SCV000278445	pathogenic	Hereditary cancer-predisposing syndrome	2015-09-18	criteria provided, single submitter	clinical testing	The c.933+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 8 of the APC gene. This mutation has been identified in an FAP kindred (Wells D et al, Hum. Mutat. 1996 ; 8(2):193-5). This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6502 samples (13004 alleles) with coverage at this position. This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice donor site; however, direct evidence is unavailable. In addition to the clinical data presented in the literature, since alterations that disrupt the canonical splice donor site are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294).
Labcorp Genetics (formerly Invitae), Labcorp	RCV004563220	SCV000768026	likely pathogenic	Familial adenomatous polyposis 1	2020-06-03	criteria provided, single submitter	clinical testing	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in APC are known to be pathogenic (PMID: 17963004, 20685668). This variant has been reported in individuals affected with familial adenomatous polyposis (PMID: 8844222, 20685668). ClinVar contains an entry for this variant (Variation ID: 233970). This variant is not present in population databases (ExAC no frequency). This sequence change affects a donor splice site in intron 9 of the APC gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product.
Fulgent Genetics, Fulgent Genetics	RCV000763539	SCV000894352	pathogenic	Desmoid disease, hereditary; Carcinoma of colon; Familial adenomatous polyposis 1; Neoplasm of stomach; Hepatocellular carcinoma	2018-10-31	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV004563220	SCV004045648	likely pathogenic	Familial adenomatous polyposis 1	2023-04-28	criteria provided, single submitter	clinical testing	This variant is considered likely 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.