Submissions for variant NM_000038.6(APC):c.1312+3_1312+4del (rs730881228)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000159517	SCV000209473	pathogenic	not provided	2014-08-14	criteria provided, single submitter	clinical testing	This pathogenic variant is denoted APC c.1312+(3_4)delAT or IVS10+(3_4)delAT and consists of a deletion of two nucleotides at the +3 to +4 positions in intron 10 of the APC gene. The normal sequence, with the bases that are deleted in brackets, is AAgt[delat]gttc. Multiple in silico models predict this mutation to destroy the nearby natural splice donor site therefore causing abnormal gene splicing. The first adenine (A) nucleotide which is altered is conserved across species and the thymine (T) nucleotide is moderately conserved across species. APC c.1312+(3_4)delAT 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. Although this variant has not been previously reported to our knowledge, multiple other mutations altering the same splice donor site including APC c.1312+3A>C, APC c.1312+3A>G, and APC c.1312+(3_6)delATGT, lead to aberrant splicing, have been reported in association with a Familial Adenomatous Polyposis (FAP)-associated syndrome, and are considered pathogenic (Nielsen 2007, Olschwang 1993, Aretz 2004, Kerr 2013, Wu 2001). The available information about APC c.1312+(3_4)delAT leads us to classify this mutation as pathogenic.
Invitae	RCV000198238	SCV000255243	pathogenic	Familial adenomatous polyposis 1	2015-05-12	criteria provided, single submitter	clinical testing	This sequence change affects a highly conserved nucleotide within the donor consensus splice site. This variant has not been published in the literature and is not present in population databases. ClinVar contains an entry for this variant (RCV000159517). While this particular variant has not been published in the literature, multiple substitutions involving the c.1312+3A have been reported to cause exon skipping and are considered pathogenic (PMID: 24599579, 8381580, 23159591, 17489848). Algorithms developed to predict the effect of nucleotide changes on mRNA splicing indicate that this deletion abrogates the donor splice site for exon 10 of the APC gene. This is expected to disrupt splicing of the APC mRNA. For these reasons, this variant has been classified as Pathogenic.