Submissions for variant NM_000038.6(APC):c.645+1G>A

dbSNP: rs863225370

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel	RCV002517337	SCV003836624	likely pathogenic	Familial adenomatous polyposis 1	2023-02-18	reviewed by expert panel	curation	The c.645+1G>A variant in APC occurs within the canonical splice donor site +1 of intron 6. It is predicted to result in an inframe skipping of exon 6 (PVS1_Moderate). The results from more than 2 in silico splicing predictors (SpliceAI, MaxEntScan, VarSeak) indicate that this variant may affect splicing by disrupting the donor splice site of intron 6 (PP3 supplanted by PVS1_Moderate). RT-PCR of patient blood demonstrated that the variant impacts splicing by removing exon 6 from the transcript, resulting in an NMD-escaping in-frame event with uncertain impact (PMID: 22987206, PS3 supplanted by PVS1_Moderate). This variant has been reported in 9 families with FAP with a total phenotype score of 6 points (PS4; Ambry, Invitae, GeneDX, Barcelona, Edinburgh and Leiden internal data; PMID 22987206; PMID 17411426; PMID 20685668; PMID 8381580). This variant is absent from gnomAD v2.1.1 (PM2_supporting). In summary, this variant meets the criteria to be classified as Likely Pathogenic for FAP based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel: PVS1_Moderate, PS4, and PM2_Supporting; (VCEP specifications version 1; date of approval: 12/12/2022).
Invitae	RCV003335222	SCV000282796	pathogenic	Familial adenomatous polyposis 1	2023-11-27	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 6 of the APC gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site 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 is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with familial adenomatous polyposis (PMID: 8381580, 17411426, 20685668, 22987206). ClinVar contains an entry for this variant (Variation ID: 218000). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000202059	SCV000322199	likely pathogenic	not provided	2017-04-27	criteria provided, single submitter	clinical testing	This variant is denoted APC c.645+1G>A or IVS6+1G>A and consists of a G>A nucleotide substitution at the +1 position of intron 6 of the APC gene. This variant destroys a canonical splice donor site and is predicted to cause abnormal gene splicing, leading to either an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. This variant has been reported in individuals with a history of familial adenomatous polyposis (Olschwang 1993, Lagarde 2010). Based on the currently available information, we consider APC c.645+1G>A to be a likely pathogenic variant.
Ambry Genetics	RCV001025281	SCV001187442	pathogenic	Hereditary cancer-predisposing syndrome	2019-03-18	criteria provided, single submitter	clinical testing	The c.645+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 5 of the APC gene. This alteration was identified in 1/934 French patients with familial adenomatous polyposis (FAP) (Lagarde A et al. J. Med. Genet., 2010 Oct;47:721-2), and in a cohort of 160 unrelated patients with FAP (Olschwang S et al. Am. J. Hum. Genet., 1993 Feb;52:273-9). In addition to the clinical data presented in the literature, 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 a disease-causing mutation.
Myriad Genetics, Inc.	RCV003335222	SCV004044713	likely pathogenic	Familial adenomatous polyposis 1	2023-04-27	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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000202059	SCV000257024	pathogenic	not provided		no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000202059	SCV001551106	uncertain significance	not provided		no assertion criteria provided	clinical testing