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.
ClinVar Genomic variation as it relates to human health
NM_000038.6(APC):c.1312+5G>A
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(6)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic
6
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000038.6(APC):c.1312+5G>A
Variation ID: 411416 Accession: VCV000411416.20
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 5q22.2 5: 112819349 (GRCh38) [ NCBI UCSC ] 5: 112155046 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Oct 10, 2018 May 1, 2024 Dec 29, 2022 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000038.6:c.1312+5G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
intron variant NM_001127510.3:c.1312+5G>A intron variant NM_001127511.3:c.1258+5G>A intron variant NM_001354895.2:c.1312+5G>A intron variant NM_001354896.2:c.1312+5G>A intron variant NM_001354897.2:c.1342+5G>A intron variant NM_001354898.2:c.1237+5G>A intron variant NM_001354899.2:c.1228+5G>A intron variant NM_001354900.2:c.1135+5G>A intron variant NM_001354901.2:c.1135+5G>A intron variant NM_001354902.2:c.1039+5G>A intron variant NM_001354903.2:c.1009+5G>A intron variant NM_001354904.2:c.934+5G>A intron variant NM_001354905.2:c.832+5G>A intron variant NM_001354906.2:c.463+5G>A intron variant NC_000005.10:g.112819349G>A NC_000005.9:g.112155046G>A NG_008481.4:g.131829G>A LRG_130:g.131829G>A - Protein change
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- Other names
- -
- Canonical SPDI
- NC_000005.10:112819348:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
- -
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
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- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| APC | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
14965 | 15103 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Dec 29, 2022 | RCV000490993.15 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Nov 19, 2018 | RCV000985284.10 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jul 10, 2019 | RCV001192946.9 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Nov 25, 2021 | RCV003476101.3 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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|---|---|---|---|---|---|
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Pathogenic
(Jul 10, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Familial adenomatous polyposis
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001361420.1
First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020 |
Comment:
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 … (more)
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. (less)
|
|
|
Pathogenic
(Nov 19, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV001133298.3
First in ClinVar: Jan 05, 2020 Last updated: Jan 01, 2022 |
Comment:
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. … (more)
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. (less)
|
|
|
Pathogenic
(Jun 14, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV002053495.1
First in ClinVar: Jan 08, 2022 Last updated: Jan 08, 2022 |
Comment:
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 … (more)
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. (less)
|
|
|
Pathogenic
(Nov 25, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Familial adenomatous polyposis 1
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000552563.10
First in ClinVar: Apr 17, 2017 Last updated: Feb 28, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing … (more)
For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 411416). 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. This variant is not present in population databases (gnomAD no frequency). 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. (less)
|
|
|
Pathogenic
(Dec 29, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000579784.7
First in ClinVar: Jun 25, 2017 Last updated: May 01, 2024 |
Comment:
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 … (more)
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. (less)
|
|
|
Pathogenic
(Sep 16, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Familial adenomatous polyposis 1
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004200385.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
|
Comment:
Comment:
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.
Comment:
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.
Comment:
For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 411416). 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. This variant is not present in population databases (gnomAD no frequency). 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.
Comment:
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.
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
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.
Comment:
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.
Comment:
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.
Comment:
For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 411416). 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. This variant is not present in population databases (gnomAD no frequency). 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.
Comment:
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.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Spectrum of APC and MUTYH germ-line mutations in Russian patients with colorectal malignancies. | Yanus GA | Clinical genetics | 2018 | PMID: 29406563 |
| Molecular profiling of colorectal pulmonary metastases and primary tumours: implications for targeted treatment. | Moorcraft SY | Oncotarget | 2017 | PMID: 29029407 |
| Identification of novel point mutations in splicing sites integrating whole-exome and RNA-seq data in myeloproliferative diseases. | Spinelli R | Molecular genetics & genomic medicine | 2013 | PMID: 24498620 |
| Novel mutations of the APC gene and genetic consequences of splicing mutations in the Czech FAP families. | Schwarzová L | Familial cancer | 2013 | PMID: 22987206 |
| Analysis of rare APC variants at the mRNA level: six pathogenic mutations and literature review. | Kaufmann A | The Journal of molecular diagnostics : JMD | 2009 | PMID: 19196998 |
| Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization. | Buratti E | Nucleic acids research | 2007 | PMID: 17576681 |
| Familial adenomatous polyposis: experience from a study of 1164 unrelated german polyposis patients. | Friedl W | Hereditary cancer in clinical practice | 2005 | PMID: 20223039 |
| Rare mutations predisposing to familial adenomatous polyposis in Greek FAP patients. | Mihalatos M | BMC cancer | 2005 | PMID: 15833136 |
| Familial adenomatous polyposis: aberrant splicing due to missense or silent mutations in the APC gene. | Aretz S | Human mutation | 2004 | PMID: 15459959 |
| Statistical features of human exons and their flanking regions. | Zhang MQ | Human molecular genetics | 1998 | PMID: 9536098 |
Text-mined citations for rs886039507 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Nov 03, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.