ClinVar Genomic variation as it relates to human health
NM_001048174.2(MUTYH):c.307T>A (p.Trp103Arg)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001048174.2(MUTYH):c.307T>A (p.Trp103Arg)
Variation ID: 182688 Accession: VCV000182688.22
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1p34.1 1: 45333168 (GRCh38) [ NCBI UCSC ] 1: 45798840 (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 Jun 3, 2016 Feb 28, 2024 Jan 19, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001048174.2:c.307T>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001041639.1:p.Trp103Arg missense NM_001128425.2:c.391T>A MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001121897.1:p.Trp131Arg missense NM_001048171.2:c.307T>A NP_001041636.2:p.Trp103Arg missense NM_001048172.2:c.310T>A NP_001041637.1:p.Trp104Arg missense NM_001048173.2:c.307T>A NP_001041638.1:p.Trp103Arg missense NM_001293190.2:c.352T>A NP_001280119.1:p.Trp118Arg missense NM_001293191.2:c.340T>A NP_001280120.1:p.Trp114Arg missense NM_001293192.2:c.31T>A NP_001280121.1:p.Trp11Arg missense NM_001293195.2:c.307T>A NP_001280124.1:p.Trp103Arg missense NM_001293196.2:c.31T>A NP_001280125.1:p.Trp11Arg missense NM_001350650.2:c.33+117T>A intron variant NM_001350651.2:c.33+117T>A intron variant NM_012222.3:c.382T>A NP_036354.1:p.Trp128Arg missense NR_146882.2:n.535T>A non-coding transcript variant NC_000001.11:g.45333168A>T NC_000001.10:g.45798840A>T NG_008189.1:g.12303T>A LRG_220:g.12303T>A LRG_220t1:c.391T>A LRG_220p1:p.Trp131Arg - Protein change
- W131R, W104R, W114R, W118R, W128R, W103R, W11R
- Other names
- p.W131R:TGG>AGG
- Canonical SPDI
- NC_000001.11:45333167:A: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 0.00000
Exome Aggregation Consortium (ExAC) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
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
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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 |
2565 | 2715 |
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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Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Aug 9, 2023 | RCV000160751.10 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Aug 18, 2021 | RCV000212700.4 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jan 19, 2024 | RCV000701601.10 |
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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Likely pathogenic
(Aug 18, 2021)
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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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AiLife Diagnostics, AiLife Diagnostics
Accession: SCV002501902.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
Number of individuals with the variant: 1
Secondary finding: no
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Pathogenic
(Dec 29, 2020)
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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: SCV000216757.6
First in ClinVar: Mar 24, 2015 Last updated: Nov 29, 2022 |
Comment:
The p.W131R pathogenic mutation (also known as c.391T>A) is located in coding exon 5 of the MUTYH gene. This alteration results from a T to … (more)
The p.W131R pathogenic mutation (also known as c.391T>A) is located in coding exon 5 of the MUTYH gene. This alteration results from a T to A substitution at nucleotide position 391. The tryptophan at codon 131 is replaced by arginine, an amino acid with dissimilar properties. This alteration has been detected in conjunction with the MUTYH p.Y179C pathogenic mutation in an individual with 152 colorectal polyps diagnosed at age 30 (Sampson JR et al. Lancet 2003 Jul; 362(9377):39-41; Vogt S et al. Gastroenterology 2009 Dec; 137(6):1976-85.e1-10). It was also detected in a patient diagnosed with colon cancer and colon polyps who underwent multi-gene panel testing (Susswein LR et al. Genet Med. 2016 Aug;18(8):823-32). Functional and structural assays demonstrated that this alteration is functionally defective and predicted to disrupt DNA-binding ability (David SS et al. Nature 2007 Jun;447(7147):941-50; Komine K et al. Hum Mutat. 2015 Jul;36(7):704-11). This alteration is also known as p.W117R in the published literature. 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 supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
Number of individuals with the variant: 1
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Pathogenic
(Oct 16, 2019)
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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: SCV000211401.13
First in ClinVar: Feb 24, 2015 Last updated: Mar 04, 2023 |
Comment:
Published functional studies demonstrate a damaging effect based on results of a complementation assay in E. coli (Komine 2015); In silico analysis supports that this … (more)
Published functional studies demonstrate a damaging effect based on results of a complementation assay in E. coli (Komine 2015); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at a significant frequency in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 25525159, 19822006, 25820570, 26681312, 19732775, 12853198, 19032956, 19394335, 19725997, 17581577, 30604180) (less)
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Pathogenic
(Jul 14, 2021)
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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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Baylor Genetics
Accession: SCV004199441.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Likely pathogenic
(Aug 09, 2023)
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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: SCV001343955.2
First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces tryptophan with arginine at codon 131 of the MUTYH protein. Computational prediction suggests that this variant may have deleterious impact on … (more)
This missense variant replaces tryptophan with arginine at codon 131 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). A functional study has shown that the variant protein is severely defective in a complementation assay conducted in E. coli (PMID: 25820570). This variant has been reported in two individuals with biallelic mutations in MUTYH and affected with MUTYH-associated polyposis, with one individual carrying the pathogenic co-variant c.536A>G (PMID: 12853198, 19032956, 19394335, 19732775, 30604180). This variant has also been reported in an individual affected with colon cancer and polyps (PMID 26681312). This variant has been identified in 1/251412 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. (less)
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Pathogenic
(Jan 19, 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: SCV000830411.7
First in ClinVar: Oct 10, 2018 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 131 of the MUTYH protein … (more)
This sequence change replaces tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 131 of the MUTYH protein (p.Trp131Arg). This variant is present in population databases (rs730881832, gnomAD 0.0009%). This missense change has been observed in individual(s) with colon cancer and MUTYH-associated polyposis (PMID: 12853198, 19032956, 19394335, 19732775, 25820570, 26681312; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as Trp117Arg. ClinVar contains an entry for this variant (Variation ID: 182688). 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. Experimental studies have shown that this missense change affects MUTYH function (PMID: 25820570). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Jun 26, 2021)
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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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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000917811.2
First in ClinVar: Jun 02, 2019 Last updated: Jul 10, 2021 |
Comment:
Variant summary: MUTYH c.391T>A (p.Trp131Arg) results in a non-conservative amino acid change located in the HhH-GPD domain of the encoded protein sequence. Five of five … (more)
Variant summary: MUTYH c.391T>A (p.Trp131Arg) results in a non-conservative amino acid change located in the HhH-GPD domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. 3/4 computational 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-06 in 251412 control chromosomes (gnomAD). c.391T>A has been reported in the literature in individuals affected with MUTYH-Associated Polyposis (e.g. Sampson_2003, Jones_2009, Susswein_2016, Sutcliffe_2019). These data indicate that the variant is likely to be associated with disease. A functional study, Komine_2015, found the variant to be defective in base excision repair in a MUTY-deficient E. coli complementation assay. Four ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Dec 08, 2020)
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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: SCV002532285.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 |
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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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Multi-gene panel testing confirms phenotypic variability in MUTYH-Associated Polyposis. | Sutcliffe EG | Familial cancer | 2019 | PMID: 30604180 |
Pathogenic and likely pathogenic variant prevalence among the first 10,000 patients referred for next-generation cancer panel testing. | Susswein LR | Genetics in medicine : official journal of the American College of Medical Genetics | 2016 | PMID: 26681312 |
Functional Complementation Assay for 47 MUTYH Variants in a MutY-Disrupted Escherichia coli Strain. | Komine K | Human mutation | 2015 | PMID: 25820570 |
RNA splicing. The human splicing code reveals new insights into the genetic determinants of disease. | Xiong HY | Science (New York, N.Y.) | 2015 | PMID: 25525159 |
Expanded extracolonic tumor spectrum in MUTYH-associated polyposis. | Vogt S | Gastroenterology | 2009 | PMID: 19732775 |
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 |
Base-excision repair of oxidative DNA damage. | David SS | Nature | 2007 | PMID: 17581577 |
Autosomal recessive colorectal adenomatous polyposis due to inherited mutations of MYH. | Sampson JR | Lancet (London, England) | 2003 | PMID: 12853198 |
Text-mined citations for rs730881832 ...
HelpRecord last updated Mar 05, 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.