The frequency of this variant in the general population, 0.000033 (1/30014 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in an individual with breast cancer (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/MUTYH)). 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.
ClinVar Genomic variation as it relates to human health
NM_001048174.2(MUTYH):c.1409A>G (p.Gln470Arg)
Germline
Classification
Help
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.
(10)
Help
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
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_001048174.2(MUTYH):c.1409A>G (p.Gln470Arg)
Variation ID: 127840 Accession: VCV000127840.28
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 1p34.1 1: 45330541 (GRCh38) [ NCBI UCSC ] 1: 45796213 (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 Jul 24, 2016 Sep 16, 2024 Jun 11, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001048174.2:c.1409A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001041639.1:p.Gln470Arg missense NM_001128425.2:c.1493A>G MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001121897.1:p.Gln498Arg missense NM_001048171.2:c.1409A>G NP_001041636.2:p.Gln470Arg missense NM_001048172.2:c.1412A>G NP_001041637.1:p.Gln471Arg missense NM_001048173.2:c.1409A>G NP_001041638.1:p.Gln470Arg missense NM_001293190.2:c.1454A>G NP_001280119.1:p.Gln485Arg missense NM_001293191.2:c.1442A>G NP_001280120.1:p.Gln481Arg missense NM_001293192.2:c.1133A>G NP_001280121.1:p.Gln378Arg missense NM_001293195.2:c.1409A>G NP_001280124.1:p.Gln470Arg missense NM_001293196.2:c.1133A>G NP_001280125.1:p.Gln378Arg missense NM_001350650.2:c.1064A>G NP_001337579.1:p.Gln355Arg missense NM_001350651.2:c.1064A>G NP_001337580.1:p.Gln355Arg missense NM_012222.3:c.1484A>G NP_036354.1:p.Gln495Arg missense NR_146882.2:n.1637A>G non-coding transcript variant NR_146883.2:n.1486A>G non-coding transcript variant NC_000001.11:g.45330541T>C NC_000001.10:g.45796213T>C NG_008189.1:g.14930A>G LRG_220:g.14930A>G LRG_220t1:c.1493A>G LRG_220p1:p.Gln498Arg - Protein change
- Q498R, Q355R, Q470R, Q481R, Q378R, Q471R, Q485R, Q495R
- Other names
-
p.Q498R:CAG>CGG
- Canonical SPDI
- NC_000001.11:45330540:T:C
-
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.
-
The Genome Aggregation Database (gnomAD), exomes 0.00000
The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
- Links
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 |
2689 | 2845 | |
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. |
|---|---|---|---|---|
| Uncertain significance (4) |
criteria provided, multiple submitters, no conflicts
|
Jun 11, 2024 | RCV000115760.18 | |
| Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
|
Feb 14, 2023 | RCV000212721.8 | |
| Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
|
Dec 18, 2023 | RCV000640383.13 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Oct 31, 2018 | RCV000765173.2 |
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. |
|
|---|---|---|---|---|---|
|
Uncertain significance
(Feb 14, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000889524.3
First in ClinVar: Jul 24, 2016 Last updated: Jan 06, 2024 |
Comment:
The frequency of this variant in the general population, 0.000033 (1/30014 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the … (more)
The frequency of this variant in the general population, 0.000033 (1/30014 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in an individual with breast cancer (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/MUTYH)). 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)
|
|
|
Uncertain significance
(Jun 11, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.
Accession: SCV005205749.1
First in ClinVar: Sep 16, 2024 Last updated: Sep 16, 2024 |
|
|
|
Uncertain significance
(Dec 01, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000149669.16
First in ClinVar: May 17, 2014 Last updated: Mar 04, 2023 |
Comment:
Not observed at significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Has … (more)
Not observed at significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 16645203, 10612827, 23108399) (less)
|
|
|
Uncertain significance
(Oct 15, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Familial adenomatous polyposis 2
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004198829.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
|
|
|
Uncertain significance
(Mar 01, 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: SCV000903808.4
First in ClinVar: May 20, 2019 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces glutamine with arginine at codon 498 of the MUTYH protein. Computational prediction suggests that this variant may not impact protein structure … (more)
This missense variant replaces glutamine with arginine at codon 498 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. In a large international case-control study, this variant was reported in 1/60466 breast cancer cases and absent in 53461 controls (PMID: 33471991). This variant has been identified in 1/242852 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)
|
|
|
Uncertain significance
(Oct 31, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Pilomatrixoma
Familial adenomatous polyposis 2 Gastric cancer
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV000896406.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
|
|
|
Uncertain significance
(Sep 20, 2021)
|
criteria provided, single submitter
Method: curation
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Sema4, Sema4
Accession: SCV002532247.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Comment:
The MUTYH c.1493A>G (p.Q498R) variant has been reported in heterozygosity in one individual with breast cancer in a large case-control study (PMID: 33471991). It was … (more)
The MUTYH c.1493A>G (p.Q498R) variant has been reported in heterozygosity in one individual with breast cancer in a large case-control study (PMID: 33471991). It was observed in 1/109394 chromosomes of the Non-Finnish European subpopulation 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: 127840). Functional studies have not been performed, and in silico predictions of the variant's effect on protein function are inconclusive. 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)
|
|
|
|
Uncertain significance
(Dec 18, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Familial adenomatous polyposis 2
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000761974.8
First in ClinVar: May 28, 2018 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 498 of the MUTYH protein (p.Gln498Arg). … (more)
This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 498 of the MUTYH protein (p.Gln498Arg). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with clinical features of MUTYH-related conditions (PMID: 10612827). This variant is also known as c.1451A>G (p.Gln484Arg). ClinVar contains an entry for this variant (Variation ID: 127840). 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)
|
|
|
Uncertain Significance
(Oct 27, 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: SCV004832723.1
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 glutamine with arginine at codon 498 of the MUTYH protein. Computational prediction suggests that this variant may not impact protein structure … (more)
This missense variant replaces glutamine with arginine at codon 498 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. In a large international case-control study, this variant was reported in 1/60466 breast cancer cases and absent in 53461 controls (PMID: 33471991). This variant has been identified in 1/242852 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: 5
|
|
|
Uncertain significance
(May 29, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000184342.9
First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024 |
Comment:
The p.Q498R variant (also known as c.1493A>G), located in coding exon 15 of the MUTYH gene, results from an A to G substitution at nucleotide … (more)
The p.Q498R variant (also known as c.1493A>G), located in coding exon 15 of the MUTYH gene, results from an A to G substitution at nucleotide position 1493. The glutamine at codon 498 is replaced by arginine, an amino acid with highly similar properties. This amino acid position is poorly 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)
|
Comment:
Comment:
Not observed at significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 16645203, 10612827, 23108399)
Comment:
This missense variant replaces glutamine with arginine at codon 498 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. In a large international case-control study, this variant was reported in 1/60466 breast cancer cases and absent in 53461 controls (PMID: 33471991). This variant has been identified in 1/242852 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.
Comment:
This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 498 of the MUTYH protein (p.Gln498Arg). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with clinical features of MUTYH-related conditions (PMID: 10612827). This variant is also known as c.1451A>G (p.Gln484Arg). ClinVar contains an entry for this variant (Variation ID: 127840). 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.
Comment:
This missense variant replaces glutamine with arginine at codon 498 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. In a large international case-control study, this variant was reported in 1/60466 breast cancer cases and absent in 53461 controls (PMID: 33471991). This variant has been identified in 1/242852 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.
Comment:
The p.Q498R variant (also known as c.1493A>G), located in coding exon 15 of the MUTYH gene, results from an A to G substitution at nucleotide position 1493. The glutamine at codon 498 is replaced by arginine, an amino acid with highly similar properties. This amino acid position is poorly 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.
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. |
Comment:
The frequency of this variant in the general population, 0.000033 (1/30014 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in an individual with breast cancer (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/MUTYH)). 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.
Comment:
Not observed at significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 16645203, 10612827, 23108399)
Comment:
This missense variant replaces glutamine with arginine at codon 498 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. In a large international case-control study, this variant was reported in 1/60466 breast cancer cases and absent in 53461 controls (PMID: 33471991). This variant has been identified in 1/242852 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.
Comment:
This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 498 of the MUTYH protein (p.Gln498Arg). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with clinical features of MUTYH-related conditions (PMID: 10612827). This variant is also known as c.1451A>G (p.Gln484Arg). ClinVar contains an entry for this variant (Variation ID: 127840). 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.
Comment:
This missense variant replaces glutamine with arginine at codon 498 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. In a large international case-control study, this variant was reported in 1/60466 breast cancer cases and absent in 53461 controls (PMID: 33471991). This variant has been identified in 1/242852 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.
Comment:
The p.Q498R variant (also known as c.1493A>G), located in coding exon 15 of the MUTYH gene, results from an A to G substitution at nucleotide position 1493. The glutamine at codon 498 is replaced by arginine, an amino acid with highly similar properties. This amino acid position is poorly 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.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| 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 |
| Microsatellite stable colorectal cancers in clinically suspected hereditary nonpolyposis colorectal cancer patients without vertical transmission of disease are unlikely to be caused by biallelic germline mutations in MYH. | Görgens H | The Journal of molecular diagnostics : JMD | 2006 | PMID: 16645203 |
| UMD (Universal mutation database): a generic software to build and analyze locus-specific databases. | Béroud C | Human mutation | 2000 | PMID: 10612827 |
Text-mined citations for rs587780085 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Sep 29, 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.