ClinVar Miner

Submissions for variant NM_000038.6(APC):c.1312+5G>C (rs886039507)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000254697 SCV000322200 likely pathogenic not provided 2016-05-12 criteria provided, single submitter clinical testing This variant is denoted APC c.1312+5G>C or IVS10+5G>C and consists of a G>C nucleotide substitution at the +5 position of intron 10 of the APC gene. Multiple in silico models predict this variant to destroy the nearby natural donor site and to possibly cause abnormal gene splicing; however, in the absence of RNA or functional studies, the actual effect of this variant is unknown. Importantly, two other variants impacting the same nucleotide, APC c.1312+5G>A and c.1312+5G>T, have both been shown in RNA based assays to result in skipping of exon 10, also published as exon 9, resulting in a frameshift and a subsequent premature stop codon (Mihalatos 2005, Varesco 1994). This variant, APC c.1312+5G>C, has been observed in one individual undergoing APC testing at a clinical laboratory (Kerr 2013). APC c.1312+5G>C was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. The guanine (G) nucleotide that is altered is conserved across species. Based on the currently available information, we consider APC c.1312+5G>C to be a likely pathogenic variant.
Invitae RCV001065091 SCV001230030 likely pathogenic Familial adenomatous polyposis 1 2019-03-05 criteria provided, single submitter clinical testing This sequence change falls in intron 10 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 observed in an individual undergoing testing for familial adenomatous polyposis (PMID: 23159591). ClinVar contains an entry for this variant (Variation ID: 265372). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. A different variant affecting this nucleotide (c.1312+5G>A) has been determined to be pathogenic (PMID: 15459959, 22987206, 20223039). This suggests that this nucleotide is important for normal RNA splicing, and that other variants at this position may also be pathogenic. 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.

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