ClinVar Miner

Submissions for variant NM_000038.6(APC):c.1312+3A>G (rs863225311)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000204247 SCV000261158 pathogenic Familial adenomatous polyposis 1 2020-09-01 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 reported in many individuals affected with familial adenomatous polyposis (FAP), and has been found to segregate with disease in at least one family (PMID: 8381580, 20685668, 15459959, 23159591, 24599579, Invitae). ClinVar contains an entry for this variant (Variation ID: 217924). Nucleotide substitutions within the consensus splice site are relatively common causes of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this variant leads to partial skipping of exon 9 (PMID: 15459959). For these reasons, this variant has been classified as Pathogenic.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000202161 SCV000333807 likely pathogenic not provided 2015-09-01 criteria provided, single submitter clinical testing
GeneDx RCV000202161 SCV000565782 pathogenic not provided 2017-05-15 criteria provided, single submitter clinical testing This variant is denoted APC c.1312+3A>G or IVS10+3A>G and consists of an A>G nucleotide substitution at the +3 position of intron 10 of the APC gene. This variant, also reported as APC IVS9+3A>G using alternate nomenclature, has been observed in multiple individuals with a personal and/or family history of polyposis (Olschwang 1993, Aretz 2004, Friedl 2005, Nielsen 2007, Filipe 2009, Kaufmann 2009, Lagarde 2010, Kerr 2013). Multiple in silico models predict this variant to damage the nearby natural splice donor site. In addition, mRNA analysis has identified that this variant results in partial skipping of exon 9 (Aretz 2004). Based on the current evidence, we consider this variant to be pathogenic.
Ambry Genetics RCV000490831 SCV000579815 pathogenic Hereditary cancer-predisposing syndrome 2019-06-05 criteria provided, single submitter clinical testing The c.1312+3A>G intronic pathogenic mutation results from an A to G substitution 3 nucleotides after coding exon 9 in the APC gene. This alteration has been reported in numerous French, Dutch and Portuguese familial adenomatous polyposis (FAP) families (Aretz S, et al. Hum. Mutat. 2004 Nov; 24(5):370-80; Lagarde A, et al. J. Med. Genet. 2010 Oct; 47(10):721-2; Nielsen M, et al. Clin. Genet. 2007 May; 71(5):427-33; Filipe B, et al. Clin. Genet. 2009 Sep; 76(3):242-55; Ambry internal data). It was also detected as the result of a de novo mutation in an affected proband whose parents were unaffected (Ambry internal data). RNA analysis has shown that this alteration leads to exon 9 skipping (Ambry internal data; Aretz S et al. Hum Mutat. 2004 Nov;24(5):370-80). This nucleotide position is well 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 RCV000204247 SCV000677777 likely pathogenic Familial adenomatous polyposis 1 2017-02-16 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000763540 SCV000894353 likely pathogenic Desmoid disease, hereditary; Carcinoma of colon; Familial adenomatous polyposis 1; Neoplasm of stomach; Hepatocellular carcinoma 2018-10-31 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000202161 SCV000256916 pathogenic not provided no assertion criteria provided research
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000500343 SCV000591068 pathogenic Carcinoma of colon no assertion criteria provided clinical testing The APC c.1312+3A>G variant was identified in 11 of 5628 proband chromosomes (frequency 0.002) from individuals or families with familial adenomatous polyposis (FAP) (Aretz 2004, Friedl 2005, Kerr 2013, Nielsen 2007). The variant was also identified in HGMD, the “InSiGHT Colon Cancer Database”, and the UMD (25X as a causal variant). The c.1312+3A>G variant is located in the 5' splice region but does not affect the invariant +1 and +2 positions. However, positions +3 to +6 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. Four out of five in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. In addition, two studies demonstrated a partial loss of exon 9 in patient RNA transcripts; these patients all presented with an attenuated FAP phenotype (Aretz 2004, Friedl 2005). In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.

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