ClinVar Genomic variation as it relates to human health
NM_000038.6(APC):c.647G>A (p.Arg216Gln)
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.
Uncertain significance(8); Likely benign(3)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000038.6(APC):c.647G>A (p.Arg216Gln)
Variation ID: 188275 Accession: VCV000188275.30
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 5q22.2 5: 112792447 (GRCh38) [ NCBI UCSC ] 5: 112128144 (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 Dec 6, 2016 May 1, 2024 Feb 29, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000038.6:c.647G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000029.2:p.Arg216Gln missense NM_001127510.3:c.647G>A NP_001120982.1:p.Arg216Gln missense NM_001127511.3:c.676-8832G>A intron variant NM_001354895.2:c.647G>A NP_001341824.1:p.Arg216Gln missense NM_001354896.2:c.647G>A NP_001341825.1:p.Arg216Gln missense NM_001354897.2:c.677G>A NP_001341826.1:p.Arg226Gln missense NM_001354898.2:c.572G>A NP_001341827.1:p.Arg191Gln missense NM_001354899.2:c.646-8832G>A intron variant NM_001354900.2:c.470G>A NP_001341829.1:p.Arg157Gln missense NM_001354901.2:c.470G>A NP_001341830.1:p.Arg157Gln missense NM_001354902.2:c.677G>A NP_001341831.1:p.Arg226Gln missense NM_001354903.2:c.647G>A NP_001341832.1:p.Arg216Gln missense NM_001354904.2:c.572G>A NP_001341833.1:p.Arg191Gln missense NM_001354905.2:c.470G>A NP_001341834.1:p.Arg157Gln missense NM_001354906.2:c.-389G>A 5 prime UTR NC_000005.10:g.112792447G>A NC_000005.9:g.112128144G>A NG_008481.4:g.104927G>A LRG_130:g.104927G>A - Protein change
- R216Q, R157Q, R191Q, R226Q
- Other names
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- Canonical SPDI
- NC_000005.10:112792446: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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0.00060 (A)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00008
1000 Genomes Project 0.00060
1000 Genomes Project 30x 0.00062
The Genome Aggregation Database (gnomAD) 0.00003
The Genome Aggregation Database (gnomAD), exomes 0.00004
Exome Aggregation Consortium (ExAC) 0.00007
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
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. |
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APC | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
14583 | 14717 |
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
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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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Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
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Oct 16, 2023 | RCV000168256.22 | |
Likely benign (1) |
criteria provided, single submitter
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Mar 6, 2018 | RCV000364207.12 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Nov 22, 2022 | RCV000480784.12 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Feb 29, 2024 | RCV000563625.15 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jan 24, 2024 | RCV003534462.1 | |
Likely benign (1) |
criteria provided, single submitter
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Jan 23, 2024 | RCV003491922.1 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jan 2, 2024 | RCV003987392.1 |
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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Uncertain significance
(Jun 06, 2017)
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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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Counsyl
Accession: SCV000785219.2
First in ClinVar: Jul 14, 2018 Last updated: Jul 14, 2018 |
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Likely benign
(Mar 06, 2018)
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criteria provided, single submitter
Method: clinical testing
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APC-Associated Polyposis Disorders
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000451984.3
First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020 |
Comment:
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more)
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. (less)
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Uncertain significance
(Nov 22, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000568267.7
First in ClinVar: Apr 29, 2017 Last updated: Dec 11, 2022 |
Comment:
In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with colorectal cancer or adenomas (Azzopardi et al., 2008; … (more)
In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with colorectal cancer or adenomas (Azzopardi et al., 2008; Minde et al., 2011; Yurgelun et al., 2017); This variant is associated with the following publications: (PMID: 21859464, 28748566, 28873162, 27329244, 18199528, 26332594, 28135145) (less)
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Uncertain significance
(Oct 16, 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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Baylor Genetics
Accession: SCV004196422.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Likely benign
(Jan 23, 2024)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer
Affected status: unknown
Allele origin:
unknown
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Mendelics
Accession: SCV000838066.3
First in ClinVar: Oct 10, 2018 Last updated: Feb 04, 2024 |
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Uncertain significance
(Feb 29, 2024)
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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: SCV000672497.6
First in ClinVar: Jan 01, 2018 Last updated: May 01, 2024 |
Comment:
The p.R216Q variant (also known as c.647G>A), located in coding exon 6 of the APC gene, results from a G to A substitution at nucleotide … (more)
The p.R216Q variant (also known as c.647G>A), located in coding exon 6 of the APC gene, results from a G to A substitution at nucleotide position 647. The arginine at codon 216 is replaced by glutamine, an amino acid with highly similar properties. This alteration was reported in a cohort of 691 North Americans, in one individual with 11-99 colorectal adenomas (Azzopardi D et al. Cancer Res. 2008 Jan;68:358-63), and has also been reported in a cohort of individuals with unselected colorectal cancer (Yurgelun MB et al. J. Clin. Oncol. 2017 Apr;35:1086-1095). This amino acid position is not well conserved in available vertebrate species. In addition, in silico predictors for this gene do not accurately predict pathogenicity. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
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Likely benign
(Jun 05, 2016)
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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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Color Diagnostics, LLC DBA Color Health
Accession: SCV000911013.1
First in ClinVar: May 20, 2019 Last updated: May 20, 2019 |
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Uncertain significance
(Aug 24, 2019)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV001133356.3
First in ClinVar: Jan 05, 2020 Last updated: Jan 05, 2020 |
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Uncertain significance
(Feb 15, 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: SCV004018933.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
Comment:
This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
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Uncertain significance
(Jan 24, 2024)
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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: SCV000218927.13
First in ClinVar: Mar 29, 2015 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 216 of the APC protein (p.Arg216Gln). … (more)
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 216 of the APC protein (p.Arg216Gln). This variant is present in population databases (rs76685252, gnomAD 0.02%). This missense change has been observed in individual(s) with colorectal cancer, breast cancer (PMID: 18199528, 28135145, 35264596). ClinVar contains an entry for this variant (Variation ID: 188275). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
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Uncertain significance
(Jan 02, 2024)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004804237.1
First in ClinVar: Mar 30, 2024 Last updated: Mar 30, 2024 |
Comment:
Variant summary: APC c.647G>A (p.Arg216Gln) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign … (more)
Variant summary: APC c.647G>A (p.Arg216Gln) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-05 in 250290 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in APC causing Familial Adenomatous Polyposis (4e-05 vs 7.1e-05), allowing no conclusion about variant significance. c.647G>A has been reported in the literature in individuals affected with colorectal cancer and breast cancer (examples:Azzopardi_2008, Yurgelun_2017, Guindalini_2022). These report(s) do not provide unequivocal conclusions about association of the variant with Familial Adenomatous Polyposis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 18199528, 35264596, 21859464, 36243179, 26332594, 28135145). Nine submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments (VUS n=7, likely benign n=2). Based on the evidence outlined above, the variant was classified as uncertain significance. (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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Hereditary cancer variants and homologous recombination deficiency in biliary tract cancer. | Okawa Y | Journal of hepatology | 2023 | PMID: 36243179 |
Detection of germline variants in Brazilian breast cancer patients using multigene panel testing. | Guindalini RSC | Scientific reports | 2022 | PMID: 35264596 |
Cancer Susceptibility Gene Mutations in Individuals With Colorectal Cancer. | Yurgelun MB | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2017 | PMID: 28135145 |
Identification of Medically Actionable Secondary Findings in the 1000 Genomes. | Olfson E | PloS one | 2015 | PMID: 26332594 |
Messing up disorder: how do missense mutations in the tumor suppressor protein APC lead to cancer? | Minde DP | Molecular cancer | 2011 | PMID: 21859464 |
Multiple rare nonsynonymous variants in the adenomatous polyposis coli gene predispose to colorectal adenomas. | Azzopardi D | Cancer research | 2008 | PMID: 18199528 |
Text-mined citations for rs76685252 ...
HelpRecord last updated May 12, 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.