ClinVar Genomic variation as it relates to human health
NM_000038.6(APC):c.646-2A>G
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000038.6(APC):c.646-2A>G
Variation ID: 495370 Accession: VCV000495370.11
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 5q22.2 5: 112792444 (GRCh38) [ NCBI UCSC ] 5: 112128141 (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 Mar 17, 2018 May 1, 2024 Apr 27, 2023 - HGVS
- ... more HGVS ... less HGVS
- Protein change
- Other names
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- Canonical SPDI
- NC_000005.10:112792443:A:G
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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
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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. |
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APC | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
14934 | 15072 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Likely pathogenic (1) |
criteria provided, single submitter
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Aug 8, 2016 | RCV000588727.8 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 30, 2017 | RCV002367986.9 | |
Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Apr 27, 2023 | RCV002530879.12 |
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
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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
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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
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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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Likely pathogenic
(Aug 08, 2016)
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criteria provided, single submitter
Method: clinical testing
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Familial multiple polyposis syndrome
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000694093.1
First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018 |
Comment:
Variant summary: The APC c.646-2A>G variant involves the alteration of a conserved splice site nucleotide. One in silico tool predicts a damaging outcome for this … (more)
Variant summary: The APC c.646-2A>G variant involves the alteration of a conserved splice site nucleotide. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict that this variant abolishes a normal splice site. This variant has been reported in at least one FAP patient and one hepatocellular carcinoma sample, and is absent in 112706 control chromosomes. Taken together, this variant is classified as likely pathogenic. (less)
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Likely pathogenic
(Sep 07, 2021)
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criteria provided, single submitter
Method: clinical testing
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Familial adenomatous polyposis 1
Affected status: yes
Allele origin:
germline
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MGZ Medical Genetics Center
Accession: SCV002580163.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Comment:
ACMG criteria applied: PVS1, PM2_SUP
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Number of individuals with the variant: 1
Sex: female
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Likely pathogenic
(Apr 27, 2023)
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criteria provided, single submitter
Method: clinical testing
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Familial adenomatous polyposis 1
Affected status: unknown
Allele origin:
unknown
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Myriad Genetics, Inc.
Accession: SCV004044023.2
First in ClinVar: Oct 21, 2023 Last updated: Oct 28, 2023 |
Comment:
This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either … (more)
This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function. (less)
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Likely pathogenic
(Feb 06, 2021)
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criteria provided, single submitter
Method: clinical testing
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Familial adenomatous polyposis 1
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV002317306.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
Disruption of this splice site has been observed in individual(s) with clinical features of familial adenomatous polyposis (PMID: 20685668, 12702169). ClinVar contains an entry for … (more)
Disruption of this splice site has been observed in individual(s) with clinical features of familial adenomatous polyposis (PMID: 20685668, 12702169). ClinVar contains an entry for this variant (Variation ID: 495370). This variant is not present in population databases (ExAC no frequency). This sequence change affects an acceptor splice site in intron 6 of the APC gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in APC are known to be pathogenic (PMID: 17963004, 20685668). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. (less)
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Pathogenic
(Jan 30, 2017)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV002659674.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The c.646-2A>G intronic pathogenic mutation results from an A to G substitution two nucleotides upstream from coding exon 6 in the APC gene. This alteration … (more)
The c.646-2A>G intronic pathogenic mutation results from an A to G substitution two nucleotides upstream from coding exon 6 in the APC gene. This alteration was previously identified in a French cohort of patients with FAP (Lagarde A et al. J. Med. Genet. 2010 Oct;47:721-2). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation. (less)
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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RNA splicing. The human splicing code reveals new insights into the genetic determinants of disease. | Xiong HY | Science (New York, N.Y.) | 2015 | PMID: 25525159 |
Diverse modes of genomic alteration in hepatocellular carcinoma. | Jhunjhunwala S | Genome biology | 2014 | PMID: 25159915 |
Germline APC mutation spectrum derived from 863 genomic variations identified through a 15-year medical genetics service to French patients with FAP. | Lagarde A | Journal of medical genetics | 2010 | PMID: 20685668 |
Mutational screening of the APC gene in Chilean families with familial adenomatous polyposis: nine novel truncating mutations. | De la Fuente MK | Diseases of the colon and rectum | 2007 | PMID: 17963004 |
Splicing in action: assessing disease causing sequence changes. | Baralle D | Journal of medical genetics | 2005 | PMID: 16199547 |
Detection of five new mutations in the APC gene using denaturing high-performance liquid chromatography. | Heinritz W | Clinical genetics | 2003 | PMID: 12702169 |
Text-mined citations for rs777848503 ...
HelpRecord last updated Sep 01, 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.