ClinVar Miner

Submissions for variant NM_000038.6(APC):c.531+1G>C

dbSNP: rs876659973
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000217536 SCV000276971 pathogenic Hereditary cancer-predisposing syndrome 2022-04-26 criteria provided, single submitter clinical testing The c.531+1G>C intronic pathogenic mutation results from a G to C substitution one nucleotide after coding exon 4 of the APC gene. This alteration has been observed in multiple individuals with a personal and/or family history that is consistent with APC-related disease (Ambry internal data). RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). 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 donor site. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Counsyl RCV000411683 SCV000488635 likely pathogenic Familial adenomatous polyposis 1 2016-05-18 criteria provided, single submitter clinical testing
GeneDx RCV000482581 SCV000573019 pathogenic not provided 2017-02-01 criteria provided, single submitter clinical testing This variant is denoted APC c.531+1G>C or IVS5+1G>C and consists of a G>C nucleotide substitution at the +1 position of intron 5 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 not, to our knowledge, been published in the literature. Based on the current evidence, we consider this variant to be pathogenic.
Invitae RCV000411683 SCV001229176 pathogenic Familial adenomatous polyposis 1 2023-10-22 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 5 of the APC gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with clinical features of familial adenomatous polyposis (PMID: 12010888, 15459959, 17411426, 20924072, 20977806, 22987206, 31113927). ClinVar contains an entry for this variant (Variation ID: 232758). Studies have shown that disruption of this splice site results in skipping of exon 5 (also known as exon 4 in the literature) and introduces a premature termination codon (PMID: 15459959; Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Mayo Clinic Laboratories, Mayo Clinic RCV000482581 SCV001714741 pathogenic not provided 2019-12-26 criteria provided, single submitter clinical testing PVS1, PM2, PP4
Myriad Genetics, Inc. RCV000411683 SCV004019957 pathogenic Familial adenomatous polyposis 1 2023-02-16 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. Functional studies indicate this variant impacts protein function [PMID:12010888].
Baylor Genetics RCV000411683 SCV004209749 likely pathogenic Familial adenomatous polyposis 1 2022-07-31 criteria provided, single submitter clinical testing

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