ClinVar Genomic variation as it relates to human health
NM_001048174.2(MUTYH):c.461G>C (p.Arg154Pro)
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.
Likely pathogenic(1); Uncertain significance(3)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001048174.2(MUTYH):c.461G>C (p.Arg154Pro)
Variation ID: 651962 Accession: VCV000651962.20
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1p34.1 1: 45332794 (GRCh38) [ NCBI UCSC ] 1: 45798466 (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 Aug 14, 2019 May 1, 2024 Jan 24, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001048174.2:c.461G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001041639.1:p.Arg154Pro missense NM_001128425.2:c.545G>C MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001121897.1:p.Arg182Pro missense NM_001048171.2:c.461G>C NP_001041636.2:p.Arg154Pro missense NM_001048172.2:c.464G>C NP_001041637.1:p.Arg155Pro missense NM_001048173.2:c.461G>C NP_001041638.1:p.Arg154Pro missense NM_001293190.2:c.506G>C NP_001280119.1:p.Arg169Pro missense NM_001293191.2:c.494G>C NP_001280120.1:p.Arg165Pro missense NM_001293192.2:c.185G>C NP_001280121.1:p.Arg62Pro missense NM_001293195.2:c.461G>C NP_001280124.1:p.Arg154Pro missense NM_001293196.2:c.185G>C NP_001280125.1:p.Arg62Pro missense NM_001350650.2:c.116G>C NP_001337579.1:p.Arg39Pro missense NM_001350651.2:c.116G>C NP_001337580.1:p.Arg39Pro missense NM_012222.3:c.536G>C NP_036354.1:p.Arg179Pro missense NR_146882.2:n.689G>C non-coding transcript variant NR_146883.2:n.538G>C non-coding transcript variant NC_000001.11:g.45332794C>G NC_000001.10:g.45798466C>G NG_008189.1:g.12677G>C LRG_220:g.12677G>C LRG_220t1:c.545G>C LRG_220p1:p.Arg182Pro - Protein change
- R39P, R155P, R154P, R169P, R182P, R62P, R165P, R179P
- Other names
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- Canonical SPDI
- NC_000001.11:45332793:C:G
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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.
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- Links
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 |
2654 | 2807 |
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
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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Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Jan 24, 2024 | RCV000807417.16 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jun 14, 2023 | RCV001024139.12 | |
Uncertain significance (1) |
criteria provided, single submitter
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Aug 28, 2019 | RCV001811496.13 |
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
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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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Uncertain significance
(Aug 28, 2019)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV001472176.1
First in ClinVar: Jan 26, 2021 Last updated: Jan 26, 2021 |
Comment:
The MUTYH c.545G>C; p.Arg182Pro variant, to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 651962). This variant … (more)
The MUTYH c.545G>C; p.Arg182Pro variant, to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 651962). This variant is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. The arginine at codon 182 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Additionally, other variants at this codon (His, Cys, Gly) have been reported in individuals with MUTYH-associated polyposis, and the p.Arg182His variant, also known as R154H (NM_001048174) and R168H (NM_001048171), is considered pathogenic (Aretz 2006, Isidro 2004, Morak 2010, Tricarico 2011). However, given the lack of clinical and functional data, the significance of the p.Arg182Pro variant is uncertain at this time. References: Aretz S et al. MUTYH-associated polyposis: 70 of 71 patients with biallelic mutations present with an attenuated or atypical phenotype. Int J Cancer. 2006 Aug 15;119(4):807-14. Isidro G et al. Germline MUTYH (MYH) mutations in Portuguese individuals with multiple colorectal adenomas. Hum Mutat. 2004 Oct;24(4):353-4. Morak M et al. MUTYH-associated polyposis - variability of the clinical phenotype in patients with biallelic and monoallelic MUTYH mutations and report on novel mutations. Clin Genet. 2010 Oct;78(4):353-63. Tricarico R et al. High resolution melting analysis for a rapid identification of heterozygous and homozygous sequence changes in the MUTYH gene. BMC Cancer. 2011 Jul 21;11:305. (less)
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Uncertain significance
(Jan 24, 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: SCV000947466.4
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 182 of the MUTYH protein (p.Arg182Pro). … (more)
This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 182 of the MUTYH protein (p.Arg182Pro). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MUTYH-related conditions. ClinVar contains an entry for this variant (Variation ID: 651962). 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. This variant disrupts the p.Arg182 amino acid residue in MUTYH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15366000, 16557584, 19032956, 19394335, 20618354). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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
(Dec 18, 2023)
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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: SCV004837401.1
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 proline at codon 182 of the MUTYH protein. This variant is also known as c.503G>C (p.Arg168Pro) based on an … (more)
This missense variant replaces arginine with proline at codon 182 of the MUTYH protein. This variant is also known as c.503G>C (p.Arg168Pro) based on an alternative transcript, NM_001048171. 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. However, two other missense variants at this codon have been reported as loss-of-function in mutation suppressive activity and in vitro glycosylase activity assays (PMID: 20848659, 23322991). This variant has not been reported in individuals affected with hereditary cancer in the literature. Two different missense variants at the same codon, p.Arg182Cys and p.Arg182His, are reported as disease-causing in ClinVar (variation ID: 182689, 187280). These two other missense variants have been reported in heterozygosity with a second pathogenic MUTYH variant in individuals affected with MUTYH-associated polyposis and/or colorectal cancer (PMID: 15366000, 16207212, 16557584, 16890597, 19394335, 20618354). This variant has been identified in 1/251468 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: 1
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Likely pathogenic
(Jun 14, 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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Ambry Genetics
Accession: SCV001186106.5
First in ClinVar: Mar 16, 2020 Last updated: May 01, 2024 |
Comment:
The p.R182P variant (also known as c.545G>C), located in coding exon 7 of the MUTYH gene, results from a G to C substitution at nucleotide … (more)
The p.R182P variant (also known as c.545G>C), located in coding exon 7 of the MUTYH gene, results from a G to C substitution at nucleotide position 545. The arginine at codon 182 is replaced by proline, an amino acid with dissimilar properties. Based on internal structural analysis, this variant is more disruptive than known pathogenic variants (Ambry internal data). A different alteration at this position, p.R182H, has been identified in trans in several individuals with MAP phenotypes and has been determined to be functionally deficient (Isidro et al. Hum Mutat 2004 Oct; 24(4):353-4; Di Gregorio et al. Gastroenterology 2006 Aug; 131(2):439-44; Aretz et al. Int J Cancer 2006 Aug 15;119(4): 807-14; Jones N et al. Gastroenterology. 2009 Aug;137(2):489-94, 494.e1; Morak M et al. Clin Genet. 2010 Oct;78(4):353-63; Goto et al. Hum Mutat 2010 Nov; 31(11):E1861-74; Komine K et al. Hum. Mutat., 2015 Jul;36:704-11). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. (less)
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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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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 |
MUTYH-associated polyposis - variability of the clinical phenotype in patients with biallelic and monoallelic MUTYH mutations and report on novel mutations. | Morak M | Clinical genetics | 2010 | PMID: 20618354 |
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 |
Immunohistochemical expression of MYH protein can be used to identify patients with MYH-associated polyposis. | Di Gregorio C | Gastroenterology | 2006 | PMID: 16890597 |
MUTYH-associated polyposis: 70 of 71 patients with biallelic mutations present with an attenuated or atypical phenotype. | Aretz S | International journal of cancer | 2006 | PMID: 16557584 |
Attenuated familial adenomatous polyposis and Muir-Torre syndrome linked to compound biallelic constitutional MYH gene mutations. | Ponti G | Clinical genetics | 2005 | PMID: 16207212 |
Germline MUTYH (MYH) mutations in Portuguese individuals with multiple colorectal adenomas. | Isidro G | Human mutation | 2004 | PMID: 15366000 |
Text-mined citations for rs143353451 ...
HelpRecord last updated Jul 07, 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.