ClinVar Genomic variation as it relates to human health
NM_001048174.2(MUTYH):c.469C>T (p.Arg157Trp)
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(2); Uncertain significance(5)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_001048174.2(MUTYH):c.469C>T (p.Arg157Trp)
Variation ID: 419386 Accession: VCV000419386.50
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 1p34.1 1: 45332786 (GRCh38) [ NCBI UCSC ] 1: 45798458 (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 27, 2017 Oct 8, 2024 Mar 26, 2024 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_001048174.2:c.469C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001041639.1:p.Arg157Trp missense NM_001128425.2:c.553C>T MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001121897.1:p.Arg185Trp missense NM_001048171.2:c.469C>T NP_001041636.2:p.Arg157Trp missense NM_001048172.2:c.472C>T NP_001041637.1:p.Arg158Trp missense NM_001048173.2:c.469C>T NP_001041638.1:p.Arg157Trp missense NM_001293190.2:c.514C>T NP_001280119.1:p.Arg172Trp missense NM_001293191.2:c.502C>T NP_001280120.1:p.Arg168Trp missense NM_001293192.2:c.193C>T NP_001280121.1:p.Arg65Trp missense NM_001293195.2:c.469C>T NP_001280124.1:p.Arg157Trp missense NM_001293196.2:c.193C>T NP_001280125.1:p.Arg65Trp missense NM_001350650.2:c.124C>T NP_001337579.1:p.Arg42Trp missense NM_001350651.2:c.124C>T NP_001337580.1:p.Arg42Trp missense NM_012222.3:c.544C>T NP_036354.1:p.Arg182Trp missense NR_146882.2:n.697C>T non-coding transcript variant NR_146883.2:n.546C>T non-coding transcript variant NC_000001.11:g.45332786G>A NC_000001.10:g.45798458G>A NG_008189.1:g.12685C>T LRG_220:g.12685C>T LRG_220t1:c.553C>T LRG_220p1:p.Arg185Trp - Protein change
- R185W, R65W, R158W, R168W, R172W, R157W, R182W, R42W
- Other names
- -
- Canonical SPDI
- NC_000001.11:45332785:G:A
-
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.
-
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD), exomes 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 | ||
---|---|---|---|---|---|---|
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 |
2686 | 2842 |
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. |
---|---|---|---|---|
Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Nov 12, 2019 | RCV000478161.25 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
|
Oct 11, 2023 | RCV000562580.11 | |
Uncertain significance (1) |
no assertion criteria provided
|
Jul 15, 2020 | RCV001004834.6 | |
Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
|
Mar 26, 2024 | RCV000803247.12 | |
Pathogenic (1) |
no assertion criteria provided
|
Sep 10, 2021 | RCV001643192.3 |
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
(Jun 26, 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: SCV004837345.1
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 arginine with tryptophan at codon 185 of the MUTYH protein. Computational prediction is inconclusive regarding the impact of this variant on … (more)
This missense variant replaces arginine with tryptophan at codon 185 of the MUTYH protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have shown that this variant has no detectable glycosylase activity and reduced substrate binding (PMID: 19953527, 20418187). This variant has been reported in individuals affected with colorectal cancer and polyposis (PMID: 18091433) or breast cancer (PMID: 32658311). This variant has been identified in 2/251446 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: 4
|
|
Likely pathogenic
(Aug 01, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV000891830.27
First in ClinVar: Mar 31, 2019 Last updated: Oct 08, 2024 |
Number of individuals with the variant: 1
|
|
Uncertain significance
(Aug 10, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Familial adenomatous polyposis 2
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000943109.5
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 185 of the MUTYH protein … (more)
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 185 of the MUTYH protein (p.Arg185Trp). 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. Experimental studies have shown that this missense change affects MUTYH function (PMID: 19953527, 20418187, 22252118). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Not Available". The tryptophan amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 419386). This missense change has been observed in individual(s) with polyposis, colorectal cancer, and/or breast cancer (PMID: 18091433, 32658311). This variant is present in population databases (rs750592289, gnomAD 0.004%). (less)
|
|
Uncertain significance
(Mar 22, 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: SCV000913518.3
First in ClinVar: May 20, 2019 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces arginine with tryptophan at codon 185 of the MUTYH protein. Computational prediction is inconclusive regarding the impact of this variant on … (more)
This missense variant replaces arginine with tryptophan at codon 185 of the MUTYH protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have shown that this variant has no detectable glycosylase activity and reduced substrate binding (PMID: 19953527, 20418187). This variant has been reported in individuals affected with colorectal cancer and polyposis (PMID: 18091433) or breast cancer (PMID: 32658311). This variant has been identified in 2/251446 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)
|
|
Likely pathogenic
(Nov 12, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000567147.4
First in ClinVar: Apr 27, 2017 Last updated: Mar 31, 2019 |
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; Also known as c.511C>T, p.Arg171Trp; This variant is associated with the following publications: (PMID: 19953527, 25820570, 18091433, 20418187, 25638157, 32658311) (less)
|
|
Uncertain significance
(Oct 11, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000670141.5
First in ClinVar: Jan 01, 2018 Last updated: May 01, 2024 |
Comment:
The p.R185W variant (also known as c.553C>T), located in coding exon 7 of the MUTYH gene, results from a C to T substitution at nucleotide … (more)
The p.R185W variant (also known as c.553C>T), located in coding exon 7 of the MUTYH gene, results from a C to T substitution at nucleotide position 553. The arginine at codon 185 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration was first reported in a male patient with colon cancer at age 49 and 90-100 polyps (Cattaneo F et al Genet. Med. 2007 Dec; 9(12):836-41). One functional analysis of this alteration using human proteins from a bacterial system suggests this alteration results in severe reduction in binding affinity as well as reduced adenine removal activity compared to the wild-type protein (D'Agostino VG et al DNA Repair (Amst.). 2010 Jun; 9(6):700-7). An additional study in which this alteration was expressed in Mutyh-/- mouse defective cells showed dysfunctional Base Excision Repair and goes on to suggest that the mutant protein produced by this alteration revealed a more pronounced phenotype than the simple loss of the Mutyh protein, suggesting a sort of dominant-negative effect (Molatore S et al Hum. Mutat. 2010 Feb; 31(2):159-66). Of note, this alteration is also designated as p.R171W (c.511C>T) in some published literature. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
|
|
Uncertain significance
(Mar 26, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Familial adenomatous polyposis 2
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004198825.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
|
|
Uncertain significance
(Jul 15, 2020)
|
no assertion criteria provided
Method: research
|
Familial cancer of breast
Affected status: yes
Allele origin:
germline
|
Center of Medical Genetics and Primary Health Care
Accession: SCV000987256.3
First in ClinVar: Mar 01, 2020 Last updated: Dec 10, 2020 |
Comment:
ACMG Guidelines 2015 criteria The MUTYH gene variant p.Arg185Trp is in exon 7 and in the HhH-GPD domain (V118-249W aa) with a function in base-excision … (more)
ACMG Guidelines 2015 criteria The MUTYH gene variant p.Arg185Trp is in exon 7 and in the HhH-GPD domain (V118-249W aa) with a function in base-excision repair (PMID: 10706276). Experimental studies showed this missense change abolishes the glycosylase activity of the MUTYH protein (PMID: 20418187, 19953527) (PS3 Pathogenic Strong). It is in a mutation hotspot of 7 pathogenic, including missense pathogenic variants (PM1 Pathogenic Moderate). The allele frequency in GnomAD exomes is 0.00000795 which is less the threshold 0.0001 for recessive gene MUTYH, and the variant is not found in GnomAD genomes (PM2 Pathogenic Moderate). Meantime, majority of missense variants detected in MUTYH are pathogenic and known cause of disease (PP2 Pathogenic Supporting). In our study this variant was found in a 54-year-old female patient with unilateral breast cancer and a family history of cancer. Based on the evidence above we classified this variant as a Variant of Unknown Significance. (less)
Age: 50-59 years
Sex: female
|
|
Pathogenic
(Sep 10, 2021)
|
no assertion criteria provided
Method: clinical testing
|
Breast carcinoma
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences
Accession: SCV001852740.1
First in ClinVar: Sep 19, 2021 Last updated: Sep 19, 2021 |
Sex: female
|
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 |
---|---|---|---|---|
Germline pathogenic variant spectrum in 25 cancer susceptibility genes in Turkish breast and colorectal cancer patients and elderly controls. | Akcay IM | International journal of cancer | 2021 | PMID: 32658311 |
Functional Complementation Assay for 47 MUTYH Variants in a MutY-Disrupted Escherichia coli Strain. | Komine K | Human mutation | 2015 | PMID: 25820570 |
Base excision repair and cancer. | Wallace SS | Cancer letters | 2012 | PMID: 22252118 |
Functional analysis of MUTYH mutated proteins associated with familial adenomatous polyposis. | D'Agostino VG | DNA repair | 2010 | PMID: 20418187 |
MUTYH mutations associated with familial adenomatous polyposis: functional characterization by a mammalian cell-based assay. | Molatore S | Human mutation | 2010 | PMID: 19953527 |
Heterogeneous molecular mechanisms underlie attenuated familial adenomatous polyposis. | Cattaneo F | Genetics in medicine : official journal of the American College of Medical Genetics | 2007 | PMID: 18091433 |
Prevalence of MYH germline mutations in Swiss APC mutation-negative polyposis patients. | Russell AM | International journal of cancer | 2006 | PMID: 16287072 |
Text-mined citations for rs750592289 ...
HelpRecord last updated Oct 08, 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.