5-112819347-A-G
Position:
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong
The NM_000038.6(APC):c.1312+3A>G variant causes a splice region, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 32)
Consequence
APC
NM_000038.6 splice_region, intron
NM_000038.6 splice_region, intron
Scores
2
Splicing: ADA: 0.9993
2
Clinical Significance
Conservation
PhyloP100: 5.88
Genes affected
APC (HGNC:583): (APC regulator of WNT signaling pathway) This gene encodes a tumor suppressor protein that acts as an antagonist of the Wnt signaling pathway. It is also involved in other processes including cell migration and adhesion, transcriptional activation, and apoptosis. Defects in this gene cause familial adenomatous polyposis (FAP), an autosomal dominant pre-malignant disease that usually progresses to malignancy. Mutations in the APC gene have been found to occur in most colorectal cancers, where disease-associated mutations tend to be clustered in a small region designated the mutation cluster region (MCR) and result in a truncated protein product. [provided by RefSeq, Jun 2022]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 10 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 5-112819347-A-G is Pathogenic according to our data. Variant chr5-112819347-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 217924.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112819347-A-G is described in Lovd as [Pathogenic]. Variant chr5-112819347-A-G is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| APC | NM_000038.6 | c.1312+3A>G | splice_region_variant, intron_variant | ENST00000257430.9 | NP_000029.2 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| APC | ENST00000257430.9 | c.1312+3A>G | splice_region_variant, intron_variant | 5 | NM_000038.6 | ENSP00000257430.4 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 33
GnomAD4 exome
Cov.:
33
GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:15
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:5
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Feb 26, 2019 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Sep 01, 2015 | - - |
| Pathogenic, no assertion criteria provided | research | Mayo Clinic Laboratories, Mayo Clinic | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Mar 13, 2023 | 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 15, 2017 | 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. - |
Familial adenomatous polyposis 1 Pathogenic:4
| Likely pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Feb 16, 2023 | 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). - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Feb 16, 2017 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 16, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 30, 2023 | 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. - |
Familial multiple polyposis syndrome Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 22, 2024 | 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. - |
Neoplasm of stomach;C0699790:Carcinoma of colon;C1851124:Desmoid disease, hereditary;C2239176:Hepatocellular carcinoma;C2713442:Familial adenomatous polyposis 1 Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Carcinoma of colon Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | 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. - |
Classic or attenuated familial adenomatous polyposis Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Feb 05, 2024 | 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. - |
APC-related disorder Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Feb 21, 2023 | 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. - |
Hereditary cancer-predisposing syndrome Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 09, 2022 | 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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
Position offset: -3
Find out detailed SpliceAI scores and Pangolin per-transcript scores at