ClinVar Genomic variation as it relates to human health
NM_001048174.2(MUTYH):c.763A>G (p.Met255Val)
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.763A>G (p.Met255Val)
Variation ID: 232291 Accession: VCV000232291.19
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1p34.1 1: 45332252 (GRCh38) [ NCBI UCSC ] 1: 45797924 (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 Apr 27, 2017 Jun 17, 2024 Feb 16, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001048174.2:c.763A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001041639.1:p.Met255Val missense NM_001128425.2:c.847A>G MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001121897.1:p.Met283Val missense NM_001048171.2:c.763A>G NP_001041636.2:p.Met255Val missense NM_001048172.2:c.766A>G NP_001041637.1:p.Met256Val missense NM_001048173.2:c.763A>G NP_001041638.1:p.Met255Val missense NM_001293190.2:c.808A>G NP_001280119.1:p.Met270Val missense NM_001293191.2:c.796A>G NP_001280120.1:p.Met266Val missense NM_001293192.2:c.487A>G NP_001280121.1:p.Met163Val missense NM_001293195.2:c.763A>G NP_001280124.1:p.Met255Val missense NM_001293196.2:c.487A>G NP_001280125.1:p.Met163Val missense NM_001350650.2:c.418A>G NP_001337579.1:p.Met140Val missense NM_001350651.2:c.418A>G NP_001337580.1:p.Met140Val missense NM_012222.3:c.838A>G NP_036354.1:p.Met280Val missense NR_146882.2:n.991A>G non-coding transcript variant NR_146883.2:n.840A>G non-coding transcript variant NC_000001.11:g.45332252T>C NC_000001.10:g.45797924T>C NG_008189.1:g.13219A>G LRG_220:g.13219A>G LRG_220t1:c.847A>G LRG_220p1:p.Met283Val - Protein change
- M283V, M140V, M163V, M256V, M255V, M266V, M270V, M280V
- Other names
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- Canonical SPDI
- NC_000001.11:45332251:T:C
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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
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00000
Trans-Omics for Precision Medicine (TOPMed) 0.00001
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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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 |
2685 | 2841 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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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Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jan 11, 2024 | RCV000216419.9 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 13, 2023 | RCV000479475.2 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Feb 16, 2024 | RCV000536194.10 | |
Pathogenic (1) |
no assertion criteria provided
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- | RCV001355443.2 |
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
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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
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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
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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
(Jan 03, 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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Color Diagnostics, LLC DBA Color Health
Accession: SCV000911616.3
First in ClinVar: May 20, 2019 Last updated: Jan 12, 2022 |
Comment:
This missense variant replaces methionine with valine at codon 283 of the MUTYH protein. Computational prediction suggests that this variant may have deleterious impact on … (more)
This missense variant replaces methionine with valine at codon 283 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. Functional studies have reported the variant protein to be defective in the suppression of oxidative mutagenesis when expressed in human cell lines (PMID: 23322991) and in adenine DNA glycosylase assay in vitro (PMID: 20848659). This variant has been reported with a pathogenic MUTYH co-variant in two families affected with cancer of the cecum and colorectal polyposis (PMID: 18172263, 16941501). This variant has been identified in 1/250754 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
(Feb 13, 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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GeneDx
Accession: SCV000567803.5
First in ClinVar: Apr 27, 2017 Last updated: May 06, 2023 |
Comment:
Published functional studies demonstrate a damaging effect: reduced glycosylase activity and ability to suppress 8OHG-induced damage (Goto et al., 2010; Shinmura et al., 2012); In … (more)
Published functional studies demonstrate a damaging effect: reduced glycosylase activity and ability to suppress 8OHG-induced damage (Goto et al., 2010; Shinmura et al., 2012); 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); Also known as c.763A>G (p.M255V); c.805A>G p.(M269V); This variant is associated with the following publications: (PMID: 20848659, 23605219, 30787465, 18172263, 16941501, 23322991, 25820570, 11092888, 11160897) (less)
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Likely pathogenic
(Nov 11, 2023)
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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: SCV000639358.7
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 283 of the MUTYH protein (p.Met283Val). … (more)
This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 283 of the MUTYH protein (p.Met283Val). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individual(s) with clinical features of MUTYH-related conditions (PMID: 16941501, 18172263). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 232291). 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: 20848659, 23322991). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. (less)
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Likely pathogenic
(Jan 11, 2024)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000276384.7
First in ClinVar: May 29, 2016 Last updated: May 01, 2024 |
Comment:
The p.M283V variant (also known as c.847A>G), located in coding exon 10 of the MUTYH gene, results from an A to G substitution at nucleotide … (more)
The p.M283V variant (also known as c.847A>G), located in coding exon 10 of the MUTYH gene, results from an A to G substitution at nucleotide position 847. The methionine at codon 283 is replaced by valine, an amino acid with highly similar properties. This variant has been reported in conjunction with a MUTYH pathogenic mutation in patients with multiple adenomas and/or colorectal cancer (Lejeune S et al, Hum. Mutat. 2006 Oct; 27(10):1064; van Puijenbroek M et al. Clin Cancer Res. 2008 Jan 1;14(1):139-42). In addition, functional studies have shown this alteration causes severe impairment in DNA glycosylase activity compared to the wild-type protein (Goto M et al. Hum. Mutat. 2010 Nov; 31(11):E1861-74); as well as suppression of oxidative mutagenesis, thought to severely impair function in human cells (Shinmura K et al. World J. Gastroenterol. 2012 Dec; 18(47):6935-42). Of note, this alteration is also designated as p.M269V (c.805A>G) in 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 majority of available evidence to date, this variant is likely to be pathogenic. (less)
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Pathogenic
(Feb 16, 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:
unknown
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Baylor Genetics
Accession: SCV005056047.1
First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024 |
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Pathogenic
(-)
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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: SCV001550329.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
The MUTYH p.Met283Val variant was identified in 2 of 460 proband chromosomes (frequency: 0.004) from individuals or families with colorectal cancer or cecum carcinoma (Lejeune … (more)
The MUTYH p.Met283Val variant was identified in 2 of 460 proband chromosomes (frequency: 0.004) from individuals or families with colorectal cancer or cecum carcinoma (Lejeune 2006, Puijenbroek 2008). The variant was also identified in dbSNP (ID: rs876659676) as "With Pathogenic allele", ClinVar (classified as likely pathogenic by Ambry Genetics and Invitae; as pathogenic by GeneDx), Clinvitae, and in UMD-LSDB (10x as unclassified variant). In UMD the variant was identified with co-occurring pathogenic MUTYH variants (c.1059dup (p.Arg354GlnfsX164) and c.1105delC (p.Ala371ProfsX23)). The variant was not identified in the COGR, Cosmic, or MutDB databases. The variant was identified in control databases in 1 of 245722 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the European (Non-Finnish) in 1 of 111308 chromosomes (freq: 0.00001); it was not observed in the African, Ashkenazi Jewish, East Asian, Finnish, Latino, Other, and South Asian populations. Several In vitro studies show that this variant severely reduces gycosylase activity. The variant protein exhibited only 4.5% of the glycosylase activity of the wild-type protein, which is more than 20-fold lower than that of the wildtype protein (Goto 2010, Shinmura 2012). The p.Met283 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic. (less)
Number of individuals with the variant: 1
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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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Functional Complementation Assay for 47 MUTYH Variants in a MutY-Disrupted Escherichia coli Strain. | Komine K | Human mutation | 2015 | PMID: 25820570 |
Impaired suppressive activities of human MUTYH variant proteins against oxidative mutagenesis. | Shinmura K | World journal of gastroenterology | 2012 | PMID: 23322991 |
Adenine DNA glycosylase activity of 14 human MutY homolog (MUTYH) variant proteins found in patients with colorectal polyposis and cancer. | Goto M | Human mutation | 2010 | PMID: 20848659 |
Identification of patients with (atypical) MUTYH-associated polyposis by KRAS2 c.34G > T prescreening followed by MUTYH hotspot analysis in formalin-fixed paraffin-embedded tissue. | van Puijenbroek M | Clinical cancer research : an official journal of the American Association for Cancer Research | 2008 | PMID: 18172263 |
Low frequency of AXIN2 mutations and high frequency of MUTYH mutations in patients with multiple polyposis. | Lejeune S | Human mutation | 2006 | PMID: 16941501 |
Text-mined citations for rs876659676 ...
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.