ClinVar Genomic variation as it relates to human health
NM_001048174.2(MUTYH):c.1400G>A (p.Arg467His)
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(10); Likely benign(2)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001048174.2(MUTYH):c.1400G>A (p.Arg467His)
Variation ID: 142440 Accession: VCV000142440.38
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1p34.1 1: 45330550 (GRCh38) [ NCBI UCSC ] 1: 45796222 (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 Jul 1, 2016 Jun 17, 2024 Feb 5, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001048174.2:c.1400G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001041639.1:p.Arg467His missense NM_001128425.2:c.1484G>A MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001121897.1:p.Arg495His missense NM_001048171.2:c.1400G>A NP_001041636.2:p.Arg467His missense NM_001048172.2:c.1403G>A NP_001041637.1:p.Arg468His missense NM_001048173.2:c.1400G>A NP_001041638.1:p.Arg467His missense NM_001293190.2:c.1445G>A NP_001280119.1:p.Arg482His missense NM_001293191.2:c.1433G>A NP_001280120.1:p.Arg478His missense NM_001293192.2:c.1124G>A NP_001280121.1:p.Arg375His missense NM_001293195.2:c.1400G>A NP_001280124.1:p.Arg467His missense NM_001293196.2:c.1124G>A NP_001280125.1:p.Arg375His missense NM_001350650.2:c.1055G>A NP_001337579.1:p.Arg352His missense NM_001350651.2:c.1055G>A NP_001337580.1:p.Arg352His missense NM_012222.3:c.1475G>A NP_036354.1:p.Arg492His missense NR_146882.2:n.1628G>A non-coding transcript variant NR_146883.2:n.1477G>A non-coding transcript variant NC_000001.11:g.45330550C>T NC_000001.10:g.45796222C>T NG_008189.1:g.14921G>A LRG_220:g.14921G>A LRG_220t1:c.1484G>A LRG_220p1:p.Arg495His - Protein change
- R495H, R481H, R375H, R492H, R467H, R468H, R478H, R482H, R352H
- Other names
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- Canonical SPDI
- NC_000001.11:45330549:C:T
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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.
The Genome Aggregation Database (gnomAD), exomes 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00006
Exome Aggregation Consortium (ExAC) 0.00007
The Genome Aggregation Database (gnomAD) 0.00008
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00015
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 | ||
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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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MUTYH | - | - |
GRCh38 GRCh37 |
2654 | 2807 |
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. |
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Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Dec 15, 2022 | RCV000131561.17 | |
Uncertain significance (5) |
criteria provided, multiple submitters, no conflicts
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Feb 5, 2024 | RCV000231615.19 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Nov 27, 2019 | RCV000236240.10 | |
Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Oct 1, 2023 | RCV000656913.15 | |
Uncertain significance (1) |
no assertion criteria provided
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- | RCV001353893.2 |
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. |
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Uncertain significance
(Nov 17, 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: SCV000292631.12
First in ClinVar: Jul 24, 2016 Last updated: Mar 11, 2023 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in … (more)
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with endometrial cancer (Ring et al., 2016); This variant is associated with the following publications: (PMID: 25188385, 26694661, 28577310, 27443514, 23108399) (less)
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Uncertain significance
(Aug 21, 2023)
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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: SCV000889523.3
First in ClinVar: Jul 09, 2018 Last updated: Jan 06, 2024 |
Comment:
In the published literature, this variant has been reported in individuals with endometrial cancer (PMID: 27443514 (2016)), melanoma (PMID: 29684080 (2018)), and breast cancer (PMID: … (more)
In the published literature, this variant has been reported in individuals with endometrial cancer (PMID: 27443514 (2016)), melanoma (PMID: 29684080 (2018)), and breast cancer (PMID: 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/MUTYH)). This variant was also reported in unaffected individuals (PMID: 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/MUTYH)). The frequency of this variant in the general population, 0.000032 (4/123842 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 benign. Based on the available information, we are unable to determine the clinical significance of this variant. (less)
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Uncertain significance
(Dec 15, 2022)
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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: SCV000685589.6
First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces arginine with histidine at codon 495 of the MUTYH protein. Computational prediction suggests that this variant may not impact protein structure … (more)
This missense variant replaces arginine with histidine at codon 495 of the MUTYH protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with melanoma (PMID: 29684080) and at least one individual affected with endometrial cancer (PMID: 26832770, 27443514). This variant has been identified in 8/272492 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)
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Uncertain significance
(Jan 30, 2024)
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criteria provided, single submitter
Method: clinical testing
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Familial adenomatous polyposis 2
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000285933.11
First in ClinVar: Jul 01, 2016 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 495 of the MUTYH protein (p.Arg495His). … (more)
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 495 of the MUTYH protein (p.Arg495His). This variant is present in population databases (rs144111588, gnomAD 0.007%). This missense change has been observed in individual(s) with endometrial cancer (PMID: 27443514). ClinVar contains an entry for this variant (Variation ID: 142440). 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
(Nov 24, 2017)
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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: SCV000917799.1
First in ClinVar: Jun 02, 2019 Last updated: Jun 02, 2019 |
Comment:
Variant summary: The MUTYH c.1484G>A (p.Arg495His) variant involves the alteration of a non-conserved nucleotide. 2/4 in silico tools predict a benign outcome for this variant … (more)
Variant summary: The MUTYH c.1484G>A (p.Arg495His) variant involves the alteration of a non-conserved nucleotide. 2/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 9/267106 control chromosomes at a frequency of 0.0000337, which does not exceed the estimated maximal expected allele frequency of a pathogenic MUTYH variant (0.0055902). The variant has been reported in Lynch Syndrome patients in the literature, one in the tumor of a patient who carried a likely pathogenic MSH2 germline variant, as well as in the germline of a patient carrying a pathogenic MSH6 variant (Vargas-Parra_2017, Ring_2016). However, due to the predominantly recessive mode of inheritance attributed to variants in MUTYH, the possibility of incidental carrier status for a pathogenic variant cannot be excluded. The DNA glycosylase activity and ability to suppress mutations caused by 8-hydroxyguanine, an oxidized form of guanine, were examined for the nine variants of type 2 MUTYH, a nuclear form of the enzyme, by DNA cleavage activity assay and supF forward mutation assay, respectively. The variant was similar to WT in DNA glycosylase activity and mutation frequency of the supF gene. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as VUS. (less)
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Uncertain significance
(Nov 27, 2019)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: no
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV002067820.1
First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022 |
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Uncertain significance
(Apr 21, 2021)
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criteria provided, single submitter
Method: curation
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Sema4, Sema4
Accession: SCV002532246.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Comment:
The MUTYH c.1484G>A (p.R495H) variant has been reported in heterozygosity in at least one individual with endometrial cancer; however, this individual also carried a potentially … (more)
The MUTYH c.1484G>A (p.R495H) variant has been reported in heterozygosity in at least one individual with endometrial cancer; however, this individual also carried a potentially pathogenic variant in the MSH6 gene (PMID: 27443514). It was observed in 8/272492 chromosomes in the large and broad cohorts of the Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654). The variant has been reported in ClinVar (Variation ID: 142440). In silico tools suggest the impact of the variant on protein function is inconclusive, while an in vitro functional assay suggested normal function of the protein (PMID: 26694661). The evidence is insufficient to meet ACMG/AMP criteria for classifying the variant as benign or pathogenic. Thus, the clinical significance of this variant is currently uncertain. (less)
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Uncertain significance
(Mar 17, 2022)
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criteria provided, single submitter
Method: clinical testing
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Familial adenomatous polyposis 2
Affected status: unknown
Allele origin:
germline
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St. Jude Molecular Pathology, St. Jude Children's Research Hospital
Accession: SCV002526090.2
First in ClinVar: Jun 16, 2022 Last updated: Dec 24, 2022 |
Comment:
The MUTYH c.1484G>A (p.Arg495His) missense change has a maximum subpopulation frequency of 0.0069% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/1-45796222-C-T?dataset=gnomad_r2_1). In silico tools are not in agreement about … (more)
The MUTYH c.1484G>A (p.Arg495His) missense change has a maximum subpopulation frequency of 0.0069% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/1-45796222-C-T?dataset=gnomad_r2_1). In silico tools are not in agreement about the effect of this variant on protein function. Functional studies have examined the DNA glycosylase activity and ability to suppress mutations caused by 8-hydroxyguanine, an oxidized form of guanine, for this variant by a DNA cleavage activity assay and supF forward mutation assay, respectively. Both assays demonstrated that this variant behaves similar to the wild-type (BS3_supporting; PMID: 26694661). This variant has been reported as heterozygous in an individual with endometrial cancer (PMID: 27443514) and a pediatric precursor B-ALL patient (PMID: 33332384). It has also been identified in an individual with breast cancer and several family members with various cancer types (PMID: 30374176); other germline variants, including a likely pathogenic variant in PMS2, were also identified in the family. In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: BS3_supporting. (less)
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Uncertain significance
(Jun 04, 2016)
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criteria provided, single submitter
Method: clinical testing
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Familial adenomatous polyposis 2
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000487360.2
First in ClinVar: Jul 01, 2016 Last updated: Dec 24, 2022 |
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Uncertain Significance
(Feb 05, 2024)
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criteria provided, single submitter
Method: clinical testing
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Familial adenomatous polyposis 2
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
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All of Us Research Program, National Institutes of Health
Accession: SCV004832834.1
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)
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Comment:
This missense variant replaces arginine with histidine at codon 495 of the MUTYH protein. Computational prediction suggests that this variant may not impact protein structure … (more)
This missense variant replaces arginine with histidine at codon 495 of the MUTYH protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with melanoma (PMID: 29684080), at least one individual affected with endometrial cancer (PMID: 26832770, 27443514), and reported to occur in 0.12% of the Japanese population (PMID: 26694661). This variant has been identified in 8/272492 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: 15
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Likely benign
(Mar 01, 2022)
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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: SCV000186565.8
First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024 |
Comment:
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more)
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
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Likely benign
(Oct 01, 2023)
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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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV004123768.6
First in ClinVar: Nov 20, 2023 Last updated: Jun 17, 2024 |
Comment:
MUTYH: BP4, BS3:Supporting
Number of individuals with the variant: 1
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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Carcinoma of colon
Affected status: yes
Allele origin:
unknown
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Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV000592720.2 First in ClinVar: Aug 27, 2017 Last updated: Apr 13, 2021 |
Comment:
The p.Arg495His variant was not identified in the literature. This residue is conserved in mammals but not lower organisms such as chicken or zebrafish where … (more)
The p.Arg495His variant was not identified in the literature. This residue is conserved in mammals but not lower organisms such as chicken or zebrafish where a Lysine (Lys) is present at this position. In addition, computational analyses (PolyPhen, SIFT, AlignGVGD) provide inconsistent predictions regarding the impact to the protein, but this information is not very predictive of pathogenicity. This variant was identified in the dbSNP database (ID: rs144111588) but was not validated and in the exome variant server in a European cohort with a frequency of 0.00023 increasing the likelihood that this may be a low frequency rare variant in this population of origin. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of unknown significance. (less)
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not provided
(-)
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no classification provided
Method: phenotyping only
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Familial adenomatous polyposis 2
Affected status: unknown
Allele origin:
unknown
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GenomeConnect - Invitae Patient Insights Network
Accession: SCV001749558.1
First in ClinVar: Jul 18, 2021 Last updated: Jul 18, 2021 |
Comment:
Variant interpreted as Uncertain significance and reported on 06-04-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided … (more)
Variant interpreted as Uncertain significance and reported on 06-04-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. (less)
Clinical Features:
Breast carcinoma (present) , Family history of cancer (present)
Indication for testing: Diagnostic
Age: 50-59 years
Sex: female
Ethnicity/Population group: Caucasians MedGen:C0043157
Testing laboratory: Invitae
Date variant was reported to submitter: 2020-06-04
Testing laboratory interpretation: Uncertain significance
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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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Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women. | Breast Cancer Association Consortium | The New England journal of medicine | 2021 | PMID: 33471991 |
Unexpected cancer-predisposition gene variants in Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome patients without underlying germline PTEN mutations. | Yehia L | PLoS genetics | 2018 | PMID: 29684080 |
Elucidating the molecular basis of MSH2-deficient tumors by combined germline and somatic analysis. | Vargas-Parra GM | International journal of cancer | 2017 | PMID: 28577310 |
Germline multi-gene hereditary cancer panel testing in an unselected endometrial cancer cohort. | Ring KL | Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc | 2016 | PMID: 27443514 |
Massively Parallel Sequencing-Based Clonality Analysis of Synchronous Endometrioid Endometrial and Ovarian Carcinomas. | Schultheis AM | Journal of the National Cancer Institute | 2016 | PMID: 26832770 |
Functional Evaluation of Nine Missense-Type Variants of the Human DNA Glycosylase Enzyme MUTYH in the Japanese Population. | Shinmura K | Human mutation | 2016 | PMID: 26694661 |
Text-mined citations for rs144111588 ...
HelpRecord last updated Jun 23, 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.