chr5-112819347-A-G
Variant summary
Our verdict is Pathogenic. The variant received 9 ACMG points: 9P and 0B. PS3_ModeratePM2_SupportingPS4PS2_Moderate
This summary comes from the ClinGen Evidence Repository: The NM_000038.6(APC):c.1312+3A>G variant in APC is an intronic variant which is located at the 3rd nucleotide in intron 10. This variant has been reported in more than 16 cases meeting phenotypic criteria resulting in a total phenotype score of 16 points (internal data Labcorp Genetics [formerly Invitae], Peter MacCallum Cancer Centre, Victoria, Australia, GeneDx, Ambry; PMID:8381580, 15459959, 20223039, 17489848, 19793053, 20685668) (PS4_Very Strong). This variant has been identified as a de novo occurrence with confirmed parental relationships in one individual with FAP, resulting in a total de novo score of 1 (PS2_Moderate, Ambry internal data). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). RNA studies demonstrated that the variant impacts splicing by causing exon 10 skipping (PMID:15459959, Ambry internal data) (PS3_Moderate). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal-dominant inherited FAP based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP: criteria PS4_Very Strong, PS2_Moderate, PM2_Supporting, PS3_Moderate applied (VCEP specifications version v2.1.0; date of approval 11/24/2023). LINK:https://erepo.genome.network/evrepo/ui/classification/CA279764/MONDO:0021056/089
Frequency
Consequence
NM_000038.6 splice_region, intron
Scores
Clinical Significance
Conservation
Publications
- classic or attenuated familial adenomatous polyposisInheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
- desmoid tumorInheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp
- familial adenomatous polyposis 1Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
- gastric adenocarcinoma and proximal polyposis of the stomachInheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, Orphanet
- sarcomaInheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
- APC-related attenuated familial adenomatous polyposisInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- Turcot syndrome with polyposisInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- Cenani-Lenz syndactyly syndromeInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Our verdict: Pathogenic. The variant received 9 ACMG points.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_000038.6. You can select a different transcript below to see updated ACMG assignments.
RefSeq Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| APC | NM_000038.6 | MANE Select | c.1312+3A>G | splice_region intron | N/A | NP_000029.2 | |||
| APC | NM_001407446.1 | c.1342+3A>G | splice_region intron | N/A | NP_001394375.1 | ||||
| APC | NM_001354896.2 | c.1312+3A>G | splice_region intron | N/A | NP_001341825.1 |
Ensembl Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| APC | ENST00000257430.9 | TSL:5 MANE Select | c.1312+3A>G | splice_region intron | N/A | ENSP00000257430.4 | |||
| APC | ENST00000508376.6 | TSL:1 | c.1312+3A>G | splice_region intron | N/A | ENSP00000427089.2 | |||
| APC | ENST00000502371.3 | TSL:1 | n.1312+3A>G | splice_region intron | N/A | ENSP00000484935.2 |
Frequencies
GnomAD3 genomes
GnomAD4 exome Cov.: 33
GnomAD4 genome
ClinVar
Submissions by phenotype
Familial adenomatous polyposis 1 Pathogenic:6
This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.
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 altered 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; internal data). 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 produces a non-functional protein and/or introduces a premature termination codon (PMID: 15459959; internal data). For these reasons, this variant has been classified as Pathogenic.
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).
The NM_000038.6(APC):c.1312+3A>G variant in APC is an intronic variant which is located at the 3rd nucleotide in intron 10. This variant has been reported in more than 16 cases meeting phenotypic criteria resulting in a total phenotype score of 16 points (internal data Labcorp Genetics [formerly Invitae], Peter MacCallum Cancer Centre, Victoria, Australia, GeneDx, Ambry; PMID: 8381580, 15459959, 20223039, 17489848, 19793053, 20685668) (PS4_Very Strong). This variant has been identified as a de novo occurrence with confirmed parental relationships in one individual with FAP, resulting in a total de novo score of 1 (PS2_Moderate, Ambry internal data). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). RNA studies demonstrated that the variant impacts splicing by causing exon 10 skipping (PMID: 15459959, Ambry internal data) (PS3_Moderate). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal-dominant inherited FAP based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP: criteria PS4_Very Strong, PS2_Moderate, PM2_Supporting, PS3_Moderate applied (VCEP specifications version v2.1.0; date of approval 11/24/2023).
Absent from controls (or at extremely low frequency if recessive) in Genome Aggregation Database, Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium.;Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.;The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
not provided Pathogenic:5
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.
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 multiple polyposis syndrome Pathogenic:1
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.
Carcinoma of colon Pathogenic:1
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.
Neoplasm of stomach;C0699790:Carcinoma of colon;C1851124:Desmoid disease, hereditary;C2239176:Hepatocellular carcinoma;C2713442:Familial adenomatous polyposis 1 Pathogenic:1
Classic or attenuated familial adenomatous polyposis Pathogenic:1
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
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
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 variant is interpreted as a disease-causing mutation.
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at