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

dbSNP: rs863225311

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000204247	SCV000261158	pathogenic	Familial adenomatous polyposis 1	2023-10-30	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. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with familial adenomatous polyposis (FAP) (PMID: 8381580, 15459959, 20685668, 23159591, 24599579; Invitae). ClinVar contains an entry for this variant (Variation ID: 217924). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 10 (also known as exon 9) 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.
Eurofins Ntd Llc (ga)	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	2022-08-09	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
Revvity Omics, Revvity	RCV000202161	SCV002017596	pathogenic	not provided	2019-02-26	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000204247	SCV004019979	likely pathogenic	Familial adenomatous polyposis 1	2023-02-16	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. mRNA analysis has demonstrated abnormal mRNA splicing occurs [PMID: 15459959, 20685668]. This mutation has been shown to segregate with cancer in multiple families (Myriad internal data).
PreventionGenetics, part of Exact Sciences	RCV003422107	SCV004118399	pathogenic	APC-related disorder	2023-02-21	criteria provided, single submitter	clinical testing	The APC c.1312+3A>G variant is predicted to interfere with splicing. This variant was reported in multiple individuals with adenomatous polyposis (reported as codon 438 in Table 3, Olschwang et al 1993. PubMed ID: 8381580; Table S1, Grandval et al 2014. PubMed ID: 24599579; Table 2, Filipe et al 2009. PubMed ID: 19793053; Table 1, Lagarde et al. 2010. PubMed ID: 20685668; Lee et al 2022. PubMed ID: 35189564 ), stomach cancer (Supplemental File 2, Cavaillé. 2020. PubMed ID: 33047316). RNA studies suggest that this variant led to abnormal RNA splicing (Grandval. 2014. PubMed ID: 24599579). In ClinVar, this variant is reported as likely pathogenic/pathogenic (https://preview.ncbi.nlm.nih.gov/clinvar/variation/217924/). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic.
Baylor Genetics	RCV000204247	SCV004207172	pathogenic	Familial adenomatous polyposis 1	2023-02-16	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000202161	SCV004219507	pathogenic	not provided	2023-03-13	criteria provided, single submitter	clinical testing	This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in individuals with familial adenomatous polyposis (FAP) (PMIDs: 8381580 (1993), 15459959 (2004), 20223039 (2005), 17489848 (2007), 19793053 (2009), 20685668 (2010), 25590978 (2015)). Published RNA analysis studies show that this variant causes exon 9 skipping (PMID: 15459959 (2004)). Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on splicing yielded predictions that this variant may affect proper APC mRNA splicing . Based on the available information, this variant is classified as pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003987449	SCV004803932	pathogenic	Familial multiple polyposis syndrome	2024-01-22	criteria provided, single submitter	clinical testing	Variant summary: APC c.1312+3A>G alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a canonical 5' splicing donor site. Two predict the variant weakens a canonical 5' donor site. At least one publication reports experimental evidence that this variant leads to skipping of exon 9 (Aretz_2004). The variant was absent in 250694 control chromosomes (gnomAD). c.1312+3A>G has been reported in the literature in multiple individuals affected with Familial Adenomatous Polyposis (examples: Aretz_2004, Filipe_2009, Lee_2022). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 15459959, 35189564, 19793053). ClinVar contains an entry for this variant (Variation ID: 217924). Based on the evidence outlined above, the variant was classified as pathogenic.
All of Us Research Program, National Institutes of Health	RCV003997041	SCV004822011	pathogenic	Classic or attenuated familial adenomatous polyposis	2024-02-05	criteria provided, single submitter	clinical testing	This variant causes an A to G nucleotide substitution at the +3 position of intron 10 of the APC gene. Functional RNA studies have shown that this variant causes a partial out-of-frame skipping of exon 9, creating a frameshift and premature translation stop signal and expected to result in an absent or non-functional protein product (PMID: 15459959, 20223039, 22431159). This variant has been reported in at least ten individuals affected with familial adenomatous polyposis or attenuated form of familial adenomatous polyposis (PMID: 8381580, 15459959, 20223039, 17489848, 19793053, 20685668, 22431159, 23159591, 28051113; ClinVar: SCV000579815.5, SCV000261158.10, SCV004019979.1) and was shown to segregate with the disease in multiple families (ClinVar: SCV004019979.1). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of APC function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
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.