ClinVar Genomic variation as it relates to human health
NM_001048174.2(MUTYH):c.928C>T (p.Gln310Ter)
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.928C>T (p.Gln310Ter)
Variation ID: 127835 Accession: VCV000127835.49
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1p34.1 1: 45331835 (GRCh38) [ NCBI UCSC ] 1: 45797507 (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 Oct 9, 2016 Oct 8, 2024 Dec 29, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001048174.2:c.928C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001041639.1:p.Gln310Ter nonsense NM_001128425.2:c.1012C>T MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001121897.1:p.Gln338Ter nonsense NM_001048171.2:c.928C>T NP_001041636.2:p.Gln310Ter nonsense NM_001048172.2:c.931C>T NP_001041637.1:p.Gln311Ter nonsense NM_001048173.2:c.928C>T NP_001041638.1:p.Gln310Ter nonsense NM_001293190.2:c.973C>T NP_001280119.1:p.Gln325Ter nonsense NM_001293191.2:c.961C>T NP_001280120.1:p.Gln321Ter nonsense NM_001293192.2:c.652C>T NP_001280121.1:p.Gln218Ter nonsense NM_001293195.2:c.928C>T NP_001280124.1:p.Gln310Ter nonsense NM_001293196.2:c.652C>T NP_001280125.1:p.Gln218Ter nonsense NM_001350650.2:c.583C>T NP_001337579.1:p.Gln195Ter nonsense NM_001350651.2:c.583C>T NP_001337580.1:p.Gln195Ter nonsense NM_012222.3:c.1003C>T NP_036354.1:p.Gln335Ter nonsense NR_146882.2:n.1156C>T non-coding transcript variant NR_146883.2:n.1005C>T non-coding transcript variant NC_000001.11:g.45331835G>A NC_000001.10:g.45797507G>A NG_008189.1:g.13636C>T LRG_220:g.13636C>T LRG_220t1:c.1012C>T LRG_220p1:p.Gln338Ter - Protein change
- Q338*, Q310*, Q324*, Q311*, Q325*, Q195*, Q321*, Q218*, Q335*
- Other names
- p.Q338*:CAG>TAG
- Canonical SPDI
- NC_000001.11:45331834:G:A
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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.
Trans-Omics for Precision Medicine (TOPMed) 0.00002
The Genome Aggregation Database (gnomAD) 0.00004
The Genome Aggregation Database (gnomAD), exomes 0.00008
Exome Aggregation Consortium (ExAC) 0.00012
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 |
2686 | 2842 |
Conditions - Germline
Condition
Help
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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Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Dec 14, 2022 | RCV000115753.17 | |
Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Oct 27, 2022 | RCV000212713.32 | |
Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Dec 29, 2023 | RCV000465024.19 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 18, 2021 | RCV002498495.3 |
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
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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
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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Pathogenic
(Oct 01, 2016)
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criteria provided, single submitter
Method: research
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MUTYH associated polyposis
Affected status: yes
Allele origin:
germline
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CSER _CC_NCGL, University of Washington
Study: CSER - NEXT Medicine variant annotation
Accession: SCV000700131.1 First in ClinVar: Mar 23, 2018 Last updated: Mar 23, 2018 |
Comment:
Found in patient having exome sequencing due to suspicion for hereditary colon cancer and/or polyps. Patient is a 53 year old male diagnosed with colon … (more)
Found in patient having exome sequencing due to suspicion for hereditary colon cancer and/or polyps. Patient is a 53 year old male diagnosed with colon cancer at age 47. Patient is compound heterozygous for a second pathogenic variant in MUTYH. This interpretation considers GERP score and allele frequency data, in addition to published reports of the variant in the literature, available at the time of review. (less)
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Pathogenic
(Dec 29, 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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000545804.9
First in ClinVar: Apr 17, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Gln338*) in the MUTYH gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Gln338*) in the MUTYH gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MUTYH are known to be pathogenic (PMID: 18534194, 20663686). This variant is present in population databases (rs587780082, gnomAD 0.04%). This premature translational stop signal has been observed in individual(s) with MUTYH-associated polyposis (MAP) (PMID: 2084865, 12853198, 16557584, 19732775, 24470512). This variant is also known as Q310X and Q324X. ClinVar contains an entry for this variant (Variation ID: 127835). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Dec 31, 2021)
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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: SCV000216400.9
First in ClinVar: Mar 24, 2015 Last updated: May 01, 2024 |
Comment:
The p.Q338* pathogenic mutation (also known as c.1012C>T), located in coding exon 12 of the MUTYH gene, results from a C to T substitution at … (more)
The p.Q338* pathogenic mutation (also known as c.1012C>T), located in coding exon 12 of the MUTYH gene, results from a C to T substitution at nucleotide position 1012. This changes the amino acid from a glutamine to a stop codon within coding exon 12. This alteration has been described in several individuals with attenuated polyposis and/or colon cancer (Sampson JR et al. Lancet. 2003 Jul;362:39-41; Aretz S et al. Int. J. Cancer. 2006 Aug;119:807-14; Olschwang S et al. Genet. Test. 2007;11:315-20; Bouguen G et al. Dis. Colon Rectum. 2007 Oct;50:1612-7; Nielsen M et al. Gastroenterology. 2009 Feb;136:471-6; Jones N et al. Gastroenterology. 2009 Aug;137:489-94, 494.e1; Vogt S et al. Gastroenterology. 2009 Dec;137:1976-85.e1-10; Guarinos C et al. Clin. Cancer Res. 2014 Mar;20:1158-68). The glycosylation function of the p.Q338* mutant MUTYH was classified as extremely impaired in one study measuring DNA glycosylase activity on adenine mispaired with 8-hydroxyguanine (Goto M et al. Hum. Mutat. 2010 Nov;31:E1861-74). Of note, p.Q338* has also been referred to as p.Q324X and p.Q310* in the literature. In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. (less)
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Pathogenic
(Jan 01, 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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001500819.22
First in ClinVar: Mar 14, 2021 Last updated: Oct 08, 2024 |
Number of individuals with the variant: 1
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Pathogenic
(Dec 30, 2016)
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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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PreventionGenetics, part of Exact Sciences
Accession: SCV000806334.1
First in ClinVar: Oct 09, 2016 Last updated: Oct 09, 2016 |
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Pathogenic
(Jul 10, 2019)
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criteria provided, single submitter
Method: clinical testing
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MUTYH-associated polyposis
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001361132.1
First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020 |
Comment:
Variant summary: MUTYH c.1012C>T (p.Gln338X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: MUTYH c.1012C>T (p.Gln338X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 8.2e-05 in 232530 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in MUTYH causing MUTYH-associated Polyposis (8.2e-05 vs 0.0046), allowing no conclusion about variant significance. c.1012C>T has been reported in the literature in multiple individuals affected with MUTYH-associated Polyposis (Sampson_2003, Vogt_2009, Ricci_2017). These data indicate that the variant is very likely to be associated with disease. A functional study, GOTO_2010 reports the variant severely impairs adenine DNA glycosylase activity. Six ClinVar submissions (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Oct 27, 2022)
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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: SCV000149662.15
First in ClinVar: May 17, 2014 Last updated: Mar 04, 2023 |
Comment:
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Observed … (more)
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Observed with a pathogenic variant on the opposite allele (in trans) in individuals with colorectal cancer and/or polyps the published literature (Sampson et al., 2003; Aretz et al., 2006; Bouguen et al., 2007; Cattaneo et al., 2008; Vogt et al., 2009; Ricci et al., 2017); Published functional studies demonstrate a damaging effect: severely defective DNA glycosylase activity (Goto et al., 2010); Also known as c.970C>T p.(Gln324Ter) and c.928C>T p.(Gln310Ter); This variant is associated with the following publications: (PMID: 12853198, 25525159, 19032956, 31589614, 16557584, 17674103, 18091433, 19732775, 27829682, 26556299, 31203172, 20848659) (less)
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Pathogenic
(Nov 18, 2021)
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criteria provided, single submitter
Method: clinical testing
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Familial adenomatous polyposis 2
Gastric cancer
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002810552.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Dec 14, 2022)
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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: SCV000685534.4
First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024 |
Comment:
This variant changes 1 nucleotide in exon 12 of the MUTYH gene, creating a premature translation stop signal. This variant is expected to result in … (more)
This variant changes 1 nucleotide in exon 12 of the MUTYH gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. A functional study reported that this variant was severely defective for DNA glycosylase activity (PMID: 20848659). This variant has been reported in individuals affected with MUTYH-associated polyposis (PMID: 12853198, 16557584, 17674103, 17949294, 19032956, 19394335, 19732775, 24470512, 26556299, 27829682, 34704405). This variant has been identified in 20/263922 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of MUTYH function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. (less)
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Pathogenic
(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: SCV004835137.1
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 variant changes 1 nucleotide in exon 12 of the MUTYH gene, creating a premature translation stop signal. This variant is expected to result in … (more)
This variant changes 1 nucleotide in exon 12 of the MUTYH gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. A functional study reported that this variant was severely defective for DNA glycosylase activity (PMID: 20848659). To our knowledge, this variant has been reported in individuals affected with MUTYH-associated polyposis (PMID: 12853198, 16557584, 17674103, 17949294, 19032956, 19394335, 19732775, 24470512, 26556299, 27829682). This variant has been identified in 20/263922 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of MUTYH function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. (less)
Number of individuals with the variant: 10
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Pathogenic
(Dec 28, 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:
unknown
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Baylor Genetics
Accession: SCV004198822.2
First in ClinVar: Dec 30, 2023 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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not provided
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: SCV000592706.2 First in ClinVar: Aug 27, 2017 Last updated: Apr 13, 2021 |
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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Filling the gap: A thorough investigation for the genetic diagnosis of unsolved polyposis patients with monoallelic MUTYH pathogenic variants. | Dell'Elice A | Molecular genetics & genomic medicine | 2021 | PMID: 34704405 |
Type and frequency of MUTYH variants in Italian patients with suspected MAP: a retrospective multicenter study. | Ricci MT | Journal of human genetics | 2017 | PMID: 27829682 |
Germline Variants in Targeted Tumor Sequencing Using Matched Normal DNA. | Schrader KA | JAMA oncology | 2016 | PMID: 26556299 |
Prevalence and characteristics of MUTYH-associated polyposis in patients with multiple adenomatous and serrated polyps. | Guarinos C | Clinical cancer research : an official journal of the American Association for Cancer Research | 2014 | PMID: 24470512 |
MUTYH-associated polyposis (MAP). | Nielsen M | Critical reviews in oncology/hematology | 2011 | PMID: 20663686 |
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 |
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 |
Characterization of mutant MUTYH proteins associated with familial colorectal cancer. | Ali M | Gastroenterology | 2008 | PMID: 18534194 |
Similar colorectal cancer risk in patients with monoallelic and biallelic mutations in the MYH gene identified in a population with adenomatous polyposis. | Olschwang S | Genetic testing | 2007 | PMID: 17949294 |
Colorectal adenomatous polyposis Associated with MYH mutations: genotype and phenotype characteristics. | Bouguen G | Diseases of the colon and rectum | 2007 | PMID: 17674103 |
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 |
Autosomal recessive colorectal adenomatous polyposis due to inherited mutations of MYH. | Sampson JR | Lancet (London, England) | 2003 | PMID: 12853198 |
[Two cases of allergic granulomatosis and angiitis (AGA); Churg-Strauss syndrome]. | Ohkubo M | Ryumachi. [Rheumatism] | 1990 | PMID: 2084865 |
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Text-mined citations for rs587780082 ...
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.