The p.G216E variant (also known as c.647G>A), located in coding exon 8 of the MUTYH gene, results from a G to A substitution at nucleotide position 647. The glycine at codon 216 is replaced by glutamic acid, an amino acid with similar properties. This variant has been confirmed in trans with a MUTYH founder mutation in a patient diagnosed with three separate primary colorectal cancers at age 38 (Morak M et al. Clin Genet, 2010 Oct;78:353-63). This variant has also been detected in conjunction with a MUTYH founder mutation in an individual with multiple colorectal adenomas (Dallosso AR et al. Gut 2008 Sep; 57(9):1252-5; Vogt S et al. Gastroenterology. 2009 Dec;137(6):1976-85.e1-10) and in 1/257 patients with MUTYH-associated polyposis (Nielsen M et al. Gastroenterology, 2009 Feb;136:471-6). Additionally, this variant has been identified in at least one patient with a personal or family history of breast and/or ovarian cancer (Maxwell KN et al. Am J Hum Genet. 2016 May 5;98(5):801-17). Based on internal structural analysis using published crystal structures, p.G216E is structurally deleterious (Ambry internal data). Of note, this alteration is also designated as p.G213E in published literature. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
ClinVar Genomic variation as it relates to human health
NM_001048174.2(MUTYH):c.563G>A (p.Gly188Glu)
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.
(7)
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.
Conflicting classifications of pathogenicity
Likely pathogenic(4); Uncertain significance(3)
Likely pathogenic(4); Uncertain significance(3)
7
criteria provided, conflicting classifications
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_001048174.2(MUTYH):c.563G>A (p.Gly188Glu)
Variation ID: 231491 Accession: VCV000231491.21
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 1p34.1 1: 45798289 (GRCh37) [ NCBI UCSC ] 1: 45332617 (GRCh38) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Feb 8, 2018 Aug 11, 2024 Jun 17, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001048174.2:c.563G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001041639.1:p.Gly188Glu missense NM_001128425.2:c.647G>A MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001121897.1:p.Gly216Glu missense NM_001048171.2:c.563G>A NP_001041636.2:p.Gly188Glu missense NM_001048172.2:c.566G>A NP_001041637.1:p.Gly189Glu missense NM_001048173.2:c.563G>A NP_001041638.1:p.Gly188Glu missense NM_001293190.2:c.608G>A NP_001280119.1:p.Gly203Glu missense NM_001293191.2:c.596G>A NP_001280120.1:p.Gly199Glu missense NM_001293192.2:c.287G>A NP_001280121.1:p.Gly96Glu missense NM_001293195.2:c.563G>A NP_001280124.1:p.Gly188Glu missense NM_001293196.2:c.287G>A NP_001280125.1:p.Gly96Glu missense NM_001350650.2:c.218G>A NP_001337579.1:p.Gly73Glu missense NM_001350651.2:c.218G>A NP_001337580.1:p.Gly73Glu missense NM_012222.3:c.638G>A NP_036354.1:p.Gly213Glu missense NR_146882.2:n.791G>A non-coding transcript variant NR_146883.2:n.640G>A non-coding transcript variant NC_000001.11:g.45332617C>T NC_000001.10:g.45798289C>T NG_008189.1:g.12854G>A LRG_220:g.12854G>A LRG_220t1:c.647G>A LRG_220p1:p.Gly216Glu - Protein change
- G216E, G189E, G203E, G73E, G188E, G199E, G213E, G96E
- Other names
- -
- Canonical SPDI
- NC_000001.11:45332616:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00001
- 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. |
|||
| MUTYH | - | - |
GRCh38 GRCh37 |
2688 | 2844 | |
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. |
|---|---|---|---|---|
| Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
|
Jun 17, 2024 | RCV000216464.7 | |
| Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
|
Feb 2, 2024 | RCV000542510.14 | |
| Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
|
Aug 4, 2023 | RCV001576133.7 |
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. |
|
|---|---|---|---|---|---|
|
Likely pathogenic
(Jun 17, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000275359.8
First in ClinVar: May 29, 2016 Last updated: Aug 11, 2024 |
Comment:
The p.G216E variant (also known as c.647G>A), located in coding exon 8 of the MUTYH gene, results from a G to A substitution at nucleotide … (more)
The p.G216E variant (also known as c.647G>A), located in coding exon 8 of the MUTYH gene, results from a G to A substitution at nucleotide position 647. The glycine at codon 216 is replaced by glutamic acid, an amino acid with similar properties. This variant has been confirmed in trans with a MUTYH founder mutation in a patient diagnosed with three separate primary colorectal cancers at age 38 (Morak M et al. Clin Genet, 2010 Oct;78:353-63). This variant has also been detected in conjunction with a MUTYH founder mutation in an individual with multiple colorectal adenomas (Dallosso AR et al. Gut 2008 Sep; 57(9):1252-5; Vogt S et al. Gastroenterology. 2009 Dec;137(6):1976-85.e1-10) and in 1/257 patients with MUTYH-associated polyposis (Nielsen M et al. Gastroenterology, 2009 Feb;136:471-6). Additionally, this variant has been identified in at least one patient with a personal or family history of breast and/or ovarian cancer (Maxwell KN et al. Am J Hum Genet. 2016 May 5;98(5):801-17). Based on internal structural analysis using published crystal structures, p.G216E is structurally deleterious (Ambry internal data). Of note, this alteration is also designated as p.G213E in published literature. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. (less)
|
|
|
Uncertain significance
(Sep 07, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: no
Allele origin:
germline
|
GeneID Lab - Advanced Molecular Diagnostics
Accession: SCV000680454.1
First in ClinVar: Feb 08, 2018 Last updated: Feb 08, 2018 |
Number of individuals with the variant: 1
Age: 40-49 years
Sex: male
Ethnicity/Population group: Latino
Geographic origin: United States
|
|
|
Likely pathogenic
(Aug 30, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV001803257.3
First in ClinVar: Aug 21, 2021 Last updated: Mar 04, 2023 |
Comment:
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); … (more)
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 19032956, 19732775, 20618354, 27153395, 19394335, 18515411) (less)
|
|
|
Uncertain significance
(Aug 04, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV004222097.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
In the published literature, this variant has been reported in individuals with MUTYH associated polyposis (MAP) (PMID: 18515411 (2008), 19032956 (2009)) and attenuated familial polyposis … (more)
In the published literature, this variant has been reported in individuals with MUTYH associated polyposis (MAP) (PMID: 18515411 (2008), 19032956 (2009)) and attenuated familial polyposis (PMID: 20618354 (2010)). The frequency of this variant in the general population, 0.000058 (2/34584 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant. (less)
|
|
|
Uncertain significance
(Dec 29, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Familial adenomatous polyposis 2
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000639350.8
First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 216 of the MUTYH protein … (more)
This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 216 of the MUTYH protein (p.Gly216Glu). This variant is present in population databases (rs768553551, gnomAD 0.006%). This missense change has been observed in individual(s) with MUTYH-related conditions (PMID: 18515411, 19732775, 20618354; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 231491). 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 disruptive. 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)
|
|
|
Likely Pathogenic
(Mar 04, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Familial adenomatous polyposis 2
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
|
All of Us Research Program, National Institutes of Health
Accession: SCV004814570.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024
Comment:
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more)
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)
|
Number of individuals with the variant: 1
|
|
|
Likely pathogenic
(Feb 02, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Familial adenomatous polyposis 2
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004198926.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
|
Comment:
Comment:
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 19032956, 19732775, 20618354, 27153395, 19394335, 18515411)
Comment:
In the published literature, this variant has been reported in individuals with MUTYH associated polyposis (MAP) (PMID: 18515411 (2008), 19032956 (2009)) and attenuated familial polyposis (PMID: 20618354 (2010)). The frequency of this variant in the general population, 0.000058 (2/34584 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 216 of the MUTYH protein (p.Gly216Glu). This variant is present in population databases (rs768553551, gnomAD 0.006%). This missense change has been observed in individual(s) with MUTYH-related conditions (PMID: 18515411, 19732775, 20618354; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 231491). 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 disruptive. 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.
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:
The p.G216E variant (also known as c.647G>A), located in coding exon 8 of the MUTYH gene, results from a G to A substitution at nucleotide position 647. The glycine at codon 216 is replaced by glutamic acid, an amino acid with similar properties. This variant has been confirmed in trans with a MUTYH founder mutation in a patient diagnosed with three separate primary colorectal cancers at age 38 (Morak M et al. Clin Genet, 2010 Oct;78:353-63). This variant has also been detected in conjunction with a MUTYH founder mutation in an individual with multiple colorectal adenomas (Dallosso AR et al. Gut 2008 Sep; 57(9):1252-5; Vogt S et al. Gastroenterology. 2009 Dec;137(6):1976-85.e1-10) and in 1/257 patients with MUTYH-associated polyposis (Nielsen M et al. Gastroenterology, 2009 Feb;136:471-6). Additionally, this variant has been identified in at least one patient with a personal or family history of breast and/or ovarian cancer (Maxwell KN et al. Am J Hum Genet. 2016 May 5;98(5):801-17). Based on internal structural analysis using published crystal structures, p.G216E is structurally deleterious (Ambry internal data). Of note, this alteration is also designated as p.G213E in published literature. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Comment:
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 19032956, 19732775, 20618354, 27153395, 19394335, 18515411)
Comment:
In the published literature, this variant has been reported in individuals with MUTYH associated polyposis (MAP) (PMID: 18515411 (2008), 19032956 (2009)) and attenuated familial polyposis (PMID: 20618354 (2010)). The frequency of this variant in the general population, 0.000058 (2/34584 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 216 of the MUTYH protein (p.Gly216Glu). This variant is present in population databases (rs768553551, gnomAD 0.006%). This missense change has been observed in individual(s) with MUTYH-related conditions (PMID: 18515411, 19732775, 20618354; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 231491). 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 disruptive. 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.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Monoallelic MUTYH pathogenic variants ascertained via multi-gene hereditary cancer panels are not associated with colorectal, endometrial, or breast cancer. | Thompson AB | Familial cancer | 2022 | PMID: 34981295 |
| Rare loss of function variants in candidate genes and risk of colorectal cancer. | Rosenthal EA | Human genetics | 2018 | PMID: 30267214 |
| Identification of Medically Actionable Secondary Findings in the 1000 Genomes. | Olfson E | PloS one | 2015 | PMID: 26332594 |
| Achieving high-sensitivity for clinical applications using augmented exome sequencing. | Patwardhan A | Genome medicine | 2015 | PMID: 26269718 |
| MUTYH-associated polyposis - variability of the clinical phenotype in patients with biallelic and monoallelic MUTYH mutations and report on novel mutations. | Morak M | Clinical genetics | 2010 | PMID: 20618354 |
| Expanded extracolonic tumor spectrum in MUTYH-associated polyposis. | Vogt S | Gastroenterology | 2009 | PMID: 19732775 |
| MUTYH-associated polyposis. | Sampson JR | Best practice & research. Clinical gastroenterology | 2009 | PMID: 19414147 |
| Increased colorectal cancer incidence in obligate carriers of heterozygous mutations in MUTYH. | Jones N | Gastroenterology | 2009 | PMID: 19394335 |
| Analysis of MUTYH genotypes and colorectal phenotypes in patients With MUTYH-associated polyposis. | Nielsen M | Gastroenterology | 2009 | PMID: 19032956 |
| Inherited predisposition to colorectal adenomas caused by multiple rare alleles of MUTYH but not OGG1, NUDT1, NTH1 or NEIL 1, 2 or 3. | Dallosso AR | Gut | 2008 | PMID: 18515411 |
Text-mined citations for rs768553551 ...
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 Sep 29, 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.