Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Co-occurred with MUTYH p.Gly396Asp in an individual with MMR-deficient colorectal cancer and multiple adenomas (Pearlman 2017); This variant is associated with the following publications: (PMID: 27978560)
ClinVar Genomic variation as it relates to human health
NM_001048174.2(MUTYH):c.614G>A (p.Gly205Asp)
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
Pathogenic(1); Uncertain significance(6)
Pathogenic(1); Uncertain significance(6)
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.614G>A (p.Gly205Asp)
Variation ID: 406839 Accession: VCV000406839.21
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 1p34.1 1: 45332481 (GRCh38) [ NCBI UCSC ] 1: 45798153 (GRCh37) [ 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 Apr 29, 2017 Jun 17, 2024 Mar 9, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001048174.2:c.614G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001041639.1:p.Gly205Asp missense NM_001128425.2:c.698G>A MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001121897.1:p.Gly233Asp missense NM_001048171.2:c.614G>A NP_001041636.2:p.Gly205Asp missense NM_001048172.2:c.617G>A NP_001041637.1:p.Gly206Asp missense NM_001048173.2:c.614G>A NP_001041638.1:p.Gly205Asp missense NM_001293190.2:c.659G>A NP_001280119.1:p.Gly220Asp missense NM_001293191.2:c.647G>A NP_001280120.1:p.Gly216Asp missense NM_001293192.2:c.338G>A NP_001280121.1:p.Gly113Asp missense NM_001293195.2:c.614G>A NP_001280124.1:p.Gly205Asp missense NM_001293196.2:c.338G>A NP_001280125.1:p.Gly113Asp missense NM_001350650.2:c.269G>A NP_001337579.1:p.Gly90Asp missense NM_001350651.2:c.269G>A NP_001337580.1:p.Gly90Asp missense NM_012222.3:c.689G>A NP_036354.1:p.Gly230Asp missense NR_146882.2:n.842G>A non-coding transcript variant NR_146883.2:n.691G>A non-coding transcript variant NC_000001.11:g.45332481C>T NC_000001.10:g.45798153C>T NG_008189.1:g.12990G>A LRG_220:g.12990G>A LRG_220t1:c.698G>A LRG_220p1:p.Gly233Asp - Protein change
- G233D, G113D, G90D, G205D, G206D, G216D, G220D, G230D
- Other names
- -
- Canonical SPDI
- NC_000001.11:45332480: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.
-
0.00020 (A)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 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. |
|---|---|---|---|---|
| Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
|
Mar 9, 2024 | RCV000460021.14 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Aug 6, 2019 | RCV000480983.3 | |
| Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
|
Feb 9, 2023 | RCV000567412.10 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Mar 15, 2022 | RCV002480377.2 |
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. |
|
|---|---|---|---|---|---|
|
Uncertain significance
(Aug 06, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000571095.4
First in ClinVar: Apr 29, 2017 Last updated: Apr 29, 2017 |
Comment:
Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious … (more)
Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Co-occurred with MUTYH p.Gly396Asp in an individual with MMR-deficient colorectal cancer and multiple adenomas (Pearlman 2017); This variant is associated with the following publications: (PMID: 27978560) (less)
|
|
|
Uncertain significance
(Mar 15, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Familial adenomatous polyposis 2
Gastric cancer
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002785410.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
|
Uncertain significance
(Feb 09, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV000907357.3
First in ClinVar: May 20, 2019 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces glycine with aspartic acid at codon 233 of the MUTYH protein. Computational prediction suggests that this variant may have deleterious impact … (more)
This missense variant replaces glycine with aspartic acid at codon 233 of the MUTYH protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported with a pathogenic co-variant in an individual affected with early-onset colorectal cancer (PMID: 27978560). This variant has been identified in 2/250678 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
|
|
|
Uncertain significance
(Jan 29, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Familial adenomatous polyposis 2
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000545746.9
First in ClinVar: Apr 17, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 233 of the MUTYH protein … (more)
This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 233 of the MUTYH protein (p.Gly233Asp). This variant is present in population databases (rs147487160, gnomAD 0.007%). This missense change has been observed in individual(s) with colorectal cancer (PMID: 27978560; Invitae). This missense change has been observed to co-occur in individuals with a different variant in MUTYH that has been determined to be pathogenic (PMID: 27978560; Invitae), but the significance of this finding is unclear. ClinVar contains an entry for this variant (Variation ID: 406839). 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)
|
|
|
Uncertain Significance
(Dec 13, 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: SCV004841448.1
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)
|
Comment:
This missense variant replaces glycine with aspartic acid at codon 233 of the MUTYH protein. Computational prediction suggests that this variant may have deleterious impact … (more)
This missense variant replaces glycine with aspartic acid at codon 233 of the MUTYH protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported with a pathogenic co-variant in an individual affected with early-onset colorectal cancer (PMID: 27978560). This variant has been identified in 2/250678 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
Number of individuals with the variant: 5
|
|
|
Pathogenic
(Oct 28, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000670162.5
First in ClinVar: Jan 01, 2018 Last updated: May 01, 2024 |
Comment:
The p.G233D variant (also known as c.698G>A), located in coding exon 9 of the MUTYH gene, results from a G to A substitution at nucleotide … (more)
The p.G233D variant (also known as c.698G>A), located in coding exon 9 of the MUTYH gene, results from a G to A substitution at nucleotide position 698. The glycine at codon 233 is replaced by aspartic acid, an amino acid with similar properties. This alteration has been reported in a patient with multiple polyps and colorectal cancer diagnosed at age 39; this individual was also found to carry the MUTYH p.G396D founder mutation (Pearlman R et al. JAMA Oncol, 2017 Apr;3:464-471). Based on internal structural analysis, G233D is strongly disruptive to the active site of MUTYH, a region enriched with pathogenic variants (Guan Y et al. Nat Struct Biol, 1998 Dec;5:1058-64; Luncsford PJ et al. J Mol Biol, 2010 Oct;403:351-70; Manuel RC et al. J Biol Chem, 2004 Nov;279:46930-9). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
|
|
|
Uncertain significance
(Mar 09, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Familial adenomatous polyposis 2
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV005056037.1
First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024 |
|
Comment:
Comment:
This missense variant replaces glycine with aspartic acid at codon 233 of the MUTYH protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported with a pathogenic co-variant in an individual affected with early-onset colorectal cancer (PMID: 27978560). This variant has been identified in 2/250678 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 233 of the MUTYH protein (p.Gly233Asp). This variant is present in population databases (rs147487160, gnomAD 0.007%). This missense change has been observed in individual(s) with colorectal cancer (PMID: 27978560; Invitae). This missense change has been observed to co-occur in individuals with a different variant in MUTYH that has been determined to be pathogenic (PMID: 27978560; Invitae), but the significance of this finding is unclear. ClinVar contains an entry for this variant (Variation ID: 406839). 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.
Comment:
This missense variant replaces glycine with aspartic acid at codon 233 of the MUTYH protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported with a pathogenic co-variant in an individual affected with early-onset colorectal cancer (PMID: 27978560). This variant has been identified in 2/250678 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Comment:
The p.G233D variant (also known as c.698G>A), located in coding exon 9 of the MUTYH gene, results from a G to A substitution at nucleotide position 698. The glycine at codon 233 is replaced by aspartic acid, an amino acid with similar properties. This alteration has been reported in a patient with multiple polyps and colorectal cancer diagnosed at age 39; this individual was also found to carry the MUTYH p.G396D founder mutation (Pearlman R et al. JAMA Oncol, 2017 Apr;3:464-471). Based on internal structural analysis, G233D is strongly disruptive to the active site of MUTYH, a region enriched with pathogenic variants (Guan Y et al. Nat Struct Biol, 1998 Dec;5:1058-64; Luncsford PJ et al. J Mol Biol, 2010 Oct;403:351-70; Manuel RC et al. J Biol Chem, 2004 Nov;279:46930-9). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. 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:
Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Co-occurred with MUTYH p.Gly396Asp in an individual with MMR-deficient colorectal cancer and multiple adenomas (Pearlman 2017); This variant is associated with the following publications: (PMID: 27978560)
Comment:
This missense variant replaces glycine with aspartic acid at codon 233 of the MUTYH protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported with a pathogenic co-variant in an individual affected with early-onset colorectal cancer (PMID: 27978560). This variant has been identified in 2/250678 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 233 of the MUTYH protein (p.Gly233Asp). This variant is present in population databases (rs147487160, gnomAD 0.007%). This missense change has been observed in individual(s) with colorectal cancer (PMID: 27978560; Invitae). This missense change has been observed to co-occur in individuals with a different variant in MUTYH that has been determined to be pathogenic (PMID: 27978560; Invitae), but the significance of this finding is unclear. ClinVar contains an entry for this variant (Variation ID: 406839). 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.
Comment:
This missense variant replaces glycine with aspartic acid at codon 233 of the MUTYH protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported with a pathogenic co-variant in an individual affected with early-onset colorectal cancer (PMID: 27978560). This variant has been identified in 2/250678 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Comment:
The p.G233D variant (also known as c.698G>A), located in coding exon 9 of the MUTYH gene, results from a G to A substitution at nucleotide position 698. The glycine at codon 233 is replaced by aspartic acid, an amino acid with similar properties. This alteration has been reported in a patient with multiple polyps and colorectal cancer diagnosed at age 39; this individual was also found to carry the MUTYH p.G396D founder mutation (Pearlman R et al. JAMA Oncol, 2017 Apr;3:464-471). Based on internal structural analysis, G233D is strongly disruptive to the active site of MUTYH, a region enriched with pathogenic variants (Guan Y et al. Nat Struct Biol, 1998 Dec;5:1058-64; Luncsford PJ et al. J Mol Biol, 2010 Oct;403:351-70; Manuel RC et al. J Biol Chem, 2004 Nov;279:46930-9). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. 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 |
|---|---|---|---|---|
| Prevalence and Spectrum of Germline Cancer Susceptibility Gene Mutations Among Patients With Early-Onset Colorectal Cancer. | Pearlman R | JAMA oncology | 2017 | PMID: 27978560 |
| A structural hinge in eukaryotic MutY homologues mediates catalytic activity and Rad9-Rad1-Hus1 checkpoint complex interactions. | Luncsford PJ | Journal of molecular biology | 2010 | PMID: 20816984 |
| Reaction intermediates in the catalytic mechanism of Escherichia coli MutY DNA glycosylase. | Manuel RC | The Journal of biological chemistry | 2004 | PMID: 15326180 |
| MutY catalytic core, mutant and bound adenine structures define specificity for DNA repair enzyme superfamily. | Guan Y | Nature structural biology | 1998 | PMID: 9846876 |
Text-mined citations for rs147487160 ...
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.