chr5-112819349-G-A
Position:
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PP3PP5_Very_Strong
The NM_000038.6(APC):c.1312+5G>A variant causes a splice region, intron change involving the alteration of a conserved nucleotide. 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 Pathogenic (★★).
Frequency
Genomes: not found (cov: 32)
Consequence
APC
NM_000038.6 splice_region, intron
NM_000038.6 splice_region, intron
Scores
1
1
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 9.60
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 11 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
Multiple lines of computational evidence support a deleterious effect 4: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai, phyloP100way_vertebrate [when BayesDel_noAF, Cadd was below the threshold]
PP5
Variant 5-112819349-G-A is Pathogenic according to our data. Variant chr5-112819349-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 411416.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112819349-G-A is described in Lovd as [Likely_pathogenic]. Variant chr5-112819349-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 33
GnomAD4 exome
Cov.:
33
GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Familial adenomatous polyposis 1 Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 16, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 25, 2021 | 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 (PMID: 15459959, 20223039, 22987206). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 411416). 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 referred to as exon 9) and introduces a premature termination codon (PMID: 15459959, 22987206). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. - |
Hereditary cancer-predisposing syndrome Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 29, 2022 | The c.1312+5G>A intronic pathogenic mutation results from a G to A substitution 5 nucleotides after coding exon 9 in the APC gene. This mutation has been detected in individuals with clinical diagnoses of familial adenomatous polyposis (FAP) and attenuated FAP (Ambry internal data; Aretz et al. Hum Mutat. 2004 Nov;24(5):370-80; Mihalatos M et al. BMC Cancer 2005 Apr;5:40; Schwarzova et al. Fam Cancer. 2013 Mar;12(1):35-42). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). RNA analysis reveals that this mutation leads to substantially increased exon 9 skipping relative to control RNA samples (Ambry internal data; Aretz et al. Hum Mutat. 2004 Nov;24(5):370-80; Mihalatos M et al. BMC Cancer 2005 Apr;5:40; Schwarzova et al. Fam Cancer. 2013 Mar;12(1):35-42). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jun 14, 2021 | This variant causes a G to A nucleotide substitution at the +5 position of intron 10 of the APC gene. RNA studies show that this variants resulted in exon 10 skipping (PMID: 8125478, 15459959, 15833136, 19196998, 22987206). This variant has been reported in individuals affected with familial adenomatous polyposis or colonic polyposis (PMID: 8125478, 15459959, 15833136, 22987206, 29029407, 29406563). It has been shown that this variant segregates with disease (PMID: 8125478). 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. - |
Familial multiple polyposis syndrome Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 10, 2019 | Variant summary: APC c.1312+5G>A 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: Three predict the variant abolishes a 5' splicing donor site. Two predict the variant weakens a 5' donor site. Several publications report experimental evidence that this variant affects mRNA splicing, resulting in skipping of exon 9 and truncation of the protein (Aretz_2004, Mihalatos_2005, Schwarzova_2013). The variant was absent in 250464 control chromosomes. c.1312+5G>A has been reported in the literature in individuals affected with Familial Adenomatous Polyposis(FAP) or Attenuated Familial Adenomatous Polyposis(AFAP) (Aretz_2004, Mihalatos_2005, Schwarzova_2013, Yanus_2018). These data indicate that the variant is likely to be associated with disease. Two clinical diagnostic laboratories have submitted clinical-significance assessments of pathogenic for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. - |
not provided Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Nov 19, 2018 | A splicing study showed that this variant produced a shift of frame, and is therefore predicted to result in the loss of a functional protein. Not found in the gnomAD dataset, and the data is high quality (0/34534 chr). Statistically enriched in patients compared to ethnically matched controls. Found in at least one symptomatic patient. Predicted to negatively affect a known splice site. Nucleotide conservation is uninformative. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
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: -5
Find out detailed SpliceAI scores and Pangolin per-transcript scores at