ClinVar Genomic variation as it relates to human health
NM_001048174.2(MUTYH):c.1272del (p.Tyr425fs)
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.1272del (p.Tyr425fs)
Variation ID: 464690 Accession: VCV000464690.23
- Type and length
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Deletion, 1 bp
- Location
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Cytogenetic: 1p34.1 1: 45331302 (GRCh38) [ NCBI UCSC ] 1: 45796974 (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 Dec 26, 2017 Jan 13, 2025 Aug 1, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001048174.2:c.1272del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001041639.1:p.Tyr425fs frameshift NM_001128425.2:c.1356del MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001121897.1:p.Tyr453fs frameshift NM_001048171.2:c.1272del NP_001041636.2:p.Tyr425fs frameshift NM_001048172.2:c.1275del NP_001041637.1:p.Tyr426fs frameshift NM_001048173.2:c.1272del NP_001041638.1:p.Tyr425fs frameshift NM_001128425.1:c.1356delA NM_001293190.2:c.1317del NP_001280119.1:p.Tyr440fs frameshift NM_001293191.2:c.1305del NP_001280120.1:p.Tyr436fs frameshift NM_001293192.2:c.996del NP_001280121.1:p.Tyr333fs frameshift NM_001293195.2:c.1272del NP_001280124.1:p.Tyr425fs frameshift NM_001293196.2:c.996del NP_001280125.1:p.Tyr333fs frameshift NM_001350650.2:c.927del NP_001337579.1:p.Tyr310fs frameshift NM_001350651.2:c.927del NP_001337580.1:p.Tyr310fs frameshift NM_012222.3:c.1347del NP_036354.1:p.Tyr450fs frameshift NR_146882.2:n.1500del non-coding transcript variant NR_146883.2:n.1349del non-coding transcript variant NC_000001.11:g.45331302del NC_000001.10:g.45796974del NG_008189.1:g.14169del LRG_220:g.14169del - Protein change
- Y436fs, Y310fs, Y425fs, Y440fs, Y333fs, Y426fs, Y450fs
- Other names
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- Canonical SPDI
- NC_000001.11:45331301:T:
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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
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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 |
2739 | 2896 |
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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Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Jun 9, 2024 | RCV000550116.13 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Aug 1, 2024 | RCV000570640.9 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Nov 3, 2021 | RCV001800753.3 |
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
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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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Pathogenic
(Jan 03, 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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000639276.7
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Tyr453Ilefs*14) 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.Tyr453Ilefs*14) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with colorectal adenoma (PMID: 17219385). This variant is also known as c.1314delA (p.Val452X). ClinVar contains an entry for this variant (Variation ID: 464690). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Aug 01, 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: SCV000666456.6
First in ClinVar: Jan 01, 2018 Last updated: Jan 13, 2025 |
Comment:
The c.1356delA pathogenic mutation, located in coding exon 14 of the MUTYH gene, results from a deletion of one nucleotide at nucleotide position 1356, causing … (more)
The c.1356delA pathogenic mutation, located in coding exon 14 of the MUTYH gene, results from a deletion of one nucleotide at nucleotide position 1356, causing a translational frameshift with a predicted alternate stop codon (p.Y453Ifs*14). This truncating mutation was detected in conjunction with a second pathogenic MUTYH mutation in an individual with MUTYH-associated polyposis (MAP) (Croitoru ME et al J. Surg. Oncol. 2007 May; 95(6):499-506). This mutation has also been detected in a patient with advanced cancer (Mandelker D et al. JAMA. 2017 Sep 5;318(9):825-835). 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
(Apr 08, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV002046871.1
First in ClinVar: Jan 03, 2022 Last updated: Jan 03, 2022 |
Comment:
This frameshift variant causes the premature termination of MUTYH protein synthesis. It has been reported along with another pathogenic MUTYH variant in an individual with … (more)
This frameshift variant causes the premature termination of MUTYH protein synthesis. It has been reported along with another pathogenic MUTYH variant in an individual with familial colorectal cancer in the published literature (PMID: 17219385 (2007)). Therefore, the variant is classified as pathogenic. (less)
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Pathogenic
(Jan 15, 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: SCV000904314.3
First in ClinVar: May 19, 2019 Last updated: Jan 12, 2022 |
Comment:
This variant deletes 1 nucleotide in exon 14 of the MUTYH gene, creating a frameshift and premature translation stop signal. This variant is expected to … (more)
This variant deletes 1 nucleotide in exon 14 of the MUTYH gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has not been identified 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
(Nov 03, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: not provided
Allele origin:
germline
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Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden
Accession: SCV002011064.3
First in ClinVar: Nov 06, 2021 Last updated: Jul 16, 2023 |
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Pathogenic
(Feb 22, 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: SCV004199403.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Mar 26, 2021)
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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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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV004848034.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
The p.Tyr453IlefsX14 variant in MUTYH has been reported in the compound heterozygous state in 1 individual with polyposis and colorectal cancer (Croitoru 2007 PMID: 17219385). … (more)
The p.Tyr453IlefsX14 variant in MUTYH has been reported in the compound heterozygous state in 1 individual with polyposis and colorectal cancer (Croitoru 2007 PMID: 17219385). It has also been identified in heterozygous state in individuals with endometrial and pancreatic cancers (Ring 2016 PMID: 27443514, Lowery 2018 PMID: 29506128). It was absent from large population studies and has been reported as Pathogenic by multiple laboratories in ClinVar (Variation ID 464690). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 453 and leads to a premature termination codon 14 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the MUTYH gene is an established disease mechanism in autosomal recessive MUTYH-associated polyposis. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive MUTYH-associated polyposis. ACMG/AMP Criteria applied: PVS1, PM3_Supporting, PM2_Supporting. (less)
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Pathogenic
(Jun 09, 2024)
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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: SCV004832243.2
First in ClinVar: Apr 20, 2024 Last updated: Dec 14, 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 deletes 1 nucleotide in exon 14/16 of the MUTYH gene, creating a frameshift and premature translation stop signal. This variant is expected to … (more)
This variant deletes 1 nucleotide in exon 14/16 of the MUTYH gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant, described as c.1314delA (p.Val452X), has been reported in an individual affected with colorectal cancer carrying a second variant in trans (PMID: 17219385). This variant has also been reported in an individual affected with advanced cancer (PMID: 28873162) and exocrine pancreatic neoplasms (PMID: 29506128). This variant has not been identified 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: 3
Zygosity: Single Heterozygote
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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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Prospective Evaluation of Germline Alterations in Patients With Exocrine Pancreatic Neoplasms. | Lowery MA | Journal of the National Cancer Institute | 2018 | PMID: 29506128 |
Mutation Detection in Patients With Advanced Cancer by Universal Sequencing of Cancer-Related Genes in Tumor and Normal DNA vs Guideline-Based Germline Testing. | Mandelker D | JAMA | 2017 | PMID: 28873162 |
Germline multi-gene hereditary cancer panel testing in an unselected endometrial cancer cohort. | Ring KL | Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc | 2016 | PMID: 27443514 |
MUTYH-associated polyposis (MAP). | Nielsen M | Critical reviews in oncology/hematology | 2011 | PMID: 20663686 |
Characterization of mutant MUTYH proteins associated with familial colorectal cancer. | Ali M | Gastroenterology | 2008 | PMID: 18534194 |
Germline MYH mutations in a clinic-based series of Canadian multiple colorectal adenoma patients. | Croitoru ME | Journal of surgical oncology | 2007 | PMID: 17219385 |
Text-mined citations for rs1553125243 ...
HelpRecord last updated Jan 13, 2025
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.