ClinVar Miner

Submissions for variant NM_000038.6(APC):c.531+5G>C (rs587779798)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000491896 SCV000579766 likely pathogenic Hereditary cancer-predisposing syndrome 2016-04-07 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Deficient protein function in appropriate functional assay(s),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
GeneDx RCV000322468 SCV000329071 pathogenic not provided 2016-05-13 criteria provided, single submitter clinical testing This variant is denoted APC c.531+5 G>C or IVS5+5 G>C and consists of a G>C nucleotide substitution at the +5 position of intron 5 of the APC gene. This variant has been observed in at least two individuals presenting with a phenotype suggestive of Attenuated Familial Adenomatous Polyposis (Moisio 2002, Kaufmann 2009). Importantly, Kaufmann et al. (2009) found via mRNA analysis that APC c.531+5 G>C results in the heterozygous deletion of exon 5 (published as exon 4 due to the use of alternate nomenclature). APC c.531+5 G>C was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations and the guanine (G) nucleotide that is altered is well conserved across species. Based on the current evidence, we consider APC c.531+5 G>C to be pathogenic.
Invitae RCV000542745 SCV000647574 likely pathogenic Familial adenomatous polyposis 1 2017-04-21 criteria provided, single submitter clinical testing This sequence change falls in intron 5 of the APC gene. It does not directly change the encoded amino acid sequence of the APC protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the literature in two individuals from a single family affected with attenuated familial adenomatous polyposis (PMID: 12010888) and in an individual affected with familial adenomatous polyposis (PMID: 19196998). Intron 5 is also known as intron 4 in the literature due to alternative exon numbering. ClinVar contains an entry for this variant (Variation ID: 279681). Experimental studies in patient-derived leukocytes using RT-PCR of mRNA followed by cDNA sequencing showed that this variant results in out-of-frame skipping of exon 5 (PMID: 19196998, 12010888). In summary, this variant is a rare intronic change that has been shown to affect mRNA splicing and is absent from the population and reported in affected individuals. This evidence indicates that the variant is pathogenic, but additional data is needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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