ClinVar Genomic variation as it relates to human health
NM_001048174.2(MUTYH):c.1017dup (p.Arg340fs)
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
-
NM_001048174.2(MUTYH):c.1017dup (p.Arg340fs)
Variation ID: 185770 Accession: VCV000185770.18
- Type and length
-
Duplication, 1 bp
- Location
-
Cytogenetic: 1p34.1 1: 45331745-45331746 (GRCh38) [ NCBI UCSC ] 1: 45797417-45797418 (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 Sep 24, 2016 Feb 14, 2024 Oct 26, 2023 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_001048174.2:c.1017dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001041639.1:p.Arg340fs frameshift NM_001128425.2:c.1101dup MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001121897.1:p.Arg368fs frameshift NM_001048171.2:c.1017dup NP_001041636.2:p.Arg340fs frameshift NM_001048172.2:c.1020dup NP_001041637.1:p.Arg341fs frameshift NM_001048173.2:c.1017dup NP_001041638.1:p.Arg340fs frameshift NM_001128425.1:c.1101dupC NM_001293190.2:c.1062dup NP_001280119.1:p.Arg355fs frameshift NM_001293191.2:c.1050dup NP_001280120.1:p.Arg351fs frameshift NM_001293192.2:c.741dup NP_001280121.1:p.Arg248fs frameshift NM_001293195.2:c.1017dup NP_001280124.1:p.Arg340fs frameshift NM_001293196.2:c.741dup NP_001280125.1:p.Arg248fs frameshift NM_001350650.2:c.672dup NP_001337579.1:p.Arg225fs frameshift NM_001350651.2:c.672dup NP_001337580.1:p.Arg225fs frameshift NM_012222.3:c.1092dup NP_036354.1:p.Arg365fs frameshift NR_146882.2:n.1245dup non-coding transcript variant NR_146883.2:n.1094dup non-coding transcript variant NC_000001.11:g.45331751dup NC_000001.10:g.45797423dup NG_008189.1:g.13725dup LRG_220:g.13725dup - Protein change
- R351fs, R225fs, R248fs, R340fs, R341fs, R355fs, R365fs, R368fs
- Other names
- -
- Canonical SPDI
- NC_000001.11:45331745:GGGGGG:GGGGGGG
-
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.
-
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 |
2566 | 2714 |
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. |
---|---|---|---|---|
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Oct 26, 2023 | RCV000165254.8 | |
Likely pathogenic (1) |
criteria provided, single submitter
|
Jan 4, 2017 | RCV000485059.1 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Sep 26, 2023 | RCV000688652.9 |
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. |
|
---|---|---|---|---|---|
Likely pathogenic
(Jan 04, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000568580.3
First in ClinVar: Apr 27, 2017 Last updated: Apr 27, 2017 |
Comment:
This duplication of one nucleotide in MUTYH is denoted c.1101dupC at the cDNA level and p.Arg368GlnfsX164 (R368QfsX164) at the protein level. The normal sequence, with … (more)
This duplication of one nucleotide in MUTYH is denoted c.1101dupC at the cDNA level and p.Arg368GlnfsX164 (R368QfsX164) at the protein level. The normal sequence, with the base that is duplicated in brackets, is GCCCCC[dupC]AGGG. The duplication causes a frameshift which changes an Arginine to a Glutamine at codon 368, and creates a premature stop codon at position 164 of the new reading frame. Even though nonsense-mediated decay is not expected to occur due to the position of the variant, it is significant since the last 182 amino acids are no longer translated correctly and are replaced by 163 incorrect ones. This variant is predicted to cause loss of normal protein function through protein truncation. MUTYH Arg368GlnfsX164 has been reported in the compound heterozygous state with a pathogenic MUTYH variant in an individual with colorectal and breast cancer (Castillejo 2014). Based on the currently available information, we consider this duplication to be a likely pathogenic variant. (less)
|
|
Pathogenic
(Jun 03, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000215970.6
First in ClinVar: Mar 24, 2015 Last updated: Nov 29, 2022 |
Comment:
The c.1101dupC pathogenic mutation, located in coding exon 12 of the MUTYH gene, results from a duplication of C at nucleotide position 1101, causing a … (more)
The c.1101dupC pathogenic mutation, located in coding exon 12 of the MUTYH gene, results from a duplication of C at nucleotide position 1101, causing a translational frameshift with a predicted alternate stop codon (p.R368Qfs*164). This alteration has been detected in conjunction with another MUTYH mutation in patients diagnosed with colorectal cancer and/or polyps (Lejeune S. et al. Hum Mutat. 2006 Oct;27(10):1064; Castillejo A et al. Eur J Cancer. 2014 Sep;50(13):2241-50). This alteration as also been detected as monoallelic in patients diagnosed with breast or ovarian cancer (Bonache S et al. J Cancer Res Clin Oncol. 2018 Oct 10). This variant is designated as 1059dupC in published 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)
Number of individuals with the variant: 1
|
|
Pathogenic
(Oct 15, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Familial adenomatous polyposis 2
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002014923.1
First in ClinVar: Nov 20, 2021 Last updated: Nov 20, 2021 |
Comment:
Variant summary: MUTYH c.1101dupC (p.Arg368GlnfsX164) 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.1101dupC (p.Arg368GlnfsX164) 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. The variant allele was found at a frequency of 4e-06 in 250124 control chromosomes (gnomAD). c.1101dupC has been reported in the literature in compound heterozygous individuals affected with MUTYH-Associated Polyposis or colorectal cancer (e.g. Lejeune_2006, Castillejo_2014, Thomas_2021). In addition, the variant has been reported in heterozygous individuals affected with breast and ovarian cancer (e.g. Bonache_2018, Feliubadalo_2019, Ramirez-Calvo_2019). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
Pathogenic
(Sep 26, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Familial adenomatous polyposis 2
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV000816274.6
First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg368Glnfs*164) in the MUTYH gene. While this is not anticipated to result in nonsense mediated decay, … (more)
This sequence change creates a premature translational stop signal (p.Arg368Glnfs*164) in the MUTYH gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 182 amino acid(s) of the MUTYH protein. 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 premature translational stop signal has been observed in individual(s) with attenuated familial adenomatous polyposis and colon and breast cancer (PMID: 16941501, 24953332). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.1059dupC (Arg354Glnfs*164). ClinVar contains an entry for this variant (Variation ID: 185770). This variant disrupts the conserved PCNA binding motif of the MUTYH protein, which has been shown to be critical for MUTYH-PCNA binding and repair efficiency (PMID: 11092888, 26377631, 11433026, 11864576). While functional studies have not been performed to directly test the effect of this variant on MUTYH protein function, this suggests that disruption of this region of the protein is causative of disease. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
Pathogenic
(Oct 26, 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: SCV000905857.4
First in ClinVar: May 20, 2019 Last updated: Feb 14, 2024 |
Comment:
This variant inserts 1 nucleotide in exon 12 of the MUTYH gene, creating a frameshift and premature translation stop signal. This variant is expected to … (more)
This variant inserts 1 nucleotide in exon 12 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 is also known as c.1059dupC (Arg354Glnfs*164). This variant has been observed in biallelic individuals affected with colorectal cancer and/or polyposis (PMID: 16941501, 24953332, 33130102). This variant has been identified in 1/250124 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)
|
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 |
---|---|---|---|---|
Duodenal Adenomas and Cancer in MUTYH-associated Polyposis: An International Cohort Study. | Collaborative Group on Duodenal Polyposis in MAP | Gastroenterology | 2021 | PMID: 33130102 |
Opportunistic testing of BRCA1, BRCA2 and mismatch repair genes improves the yield of phenotype driven hereditary cancer gene panels. | Feliubadaló L | International journal of cancer | 2019 | PMID: 30927264 |
Implementation of massive sequencing in the genetic diagnosis of hereditary cancer syndromes: diagnostic performance in the Hereditary Cancer Programme of the Valencia Community (FamCan-NGS). | Ramírez-Calvo M | Hereditary cancer in clinical practice | 2019 | PMID: 30675318 |
Multigene panel testing beyond BRCA1/2 in breast/ovarian cancer Spanish families and clinical actionability of findings. | Bonache S | Journal of cancer research and clinical oncology | 2018 | PMID: 30306255 |
Distinct functional consequences of MUTYH variants associated with colorectal cancer: Damaged DNA affinity, glycosylase activity and interaction with PCNA and Hus1. | Brinkmeyer MK | DNA repair | 2015 | PMID: 26377631 |
Prevalence of germline MUTYH mutations among Lynch-like syndrome patients. | Castillejo A | European journal of cancer (Oxford, England : 1990) | 2014 | PMID: 24953332 |
Low frequency of AXIN2 mutations and high frequency of MUTYH mutations in patients with multiple polyposis. | Lejeune S | Human mutation | 2006 | PMID: 16941501 |
Replication-associated repair of adenine:8-oxoguanine mispairs by MYH. | Hayashi H | Current biology : CB | 2002 | PMID: 11864576 |
hMYH cell cycle-dependent expression, subcellular localization and association with replication foci: evidence suggesting replication-coupled repair of adenine:8-oxoguanine mispairs. | Boldogh I | Nucleic acids research | 2001 | PMID: 11433026 |
Human homolog of the MutY repair protein (hMYH) physically interacts with proteins involved in long patch DNA base excision repair. | Parker A | The Journal of biological chemistry | 2001 | PMID: 11092888 |
Text-mined citations for rs768130289 ...
HelpRecord last updated Feb 20, 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.