ClinVar Genomic variation as it relates to human health
NM_001048174.2(MUTYH):c.1363dup (p.Thr455fs)
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.1363dup (p.Thr455fs)
Variation ID: 418345 Accession: VCV000418345.5
- Type and length
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Duplication, 1 bp
- Location
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Cytogenetic: 1p34.1 1: 45331210-45331211 (GRCh38) [ NCBI UCSC ] 1: 45796882-45796883 (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 Apr 27, 2017 Feb 28, 2024 Jun 30, 2021 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001048174.2:c.1363dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001041639.1:p.Thr455fs frameshift NM_001128425.2:c.1447dup MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001121897.1:p.Thr483fs frameshift NM_001048171.2:c.1363dup NP_001041636.2:p.Thr455fs frameshift NM_001048172.2:c.1366dup NP_001041637.1:p.Thr456fs frameshift NM_001048173.2:c.1363dup NP_001041638.1:p.Thr455fs frameshift NM_001128425.1:c.1447dupA NM_001293190.2:c.1408dup NP_001280119.1:p.Thr470fs frameshift NM_001293191.2:c.1396dup NP_001280120.1:p.Thr466fs frameshift NM_001293192.2:c.1087dup NP_001280121.1:p.Thr363fs frameshift NM_001293195.2:c.1363dup NP_001280124.1:p.Thr455fs frameshift NM_001293196.2:c.1087dup NP_001280125.1:p.Thr363fs frameshift NM_001350650.2:c.1018dup NP_001337579.1:p.Thr340fs frameshift NM_001350651.2:c.1018dup NP_001337580.1:p.Thr340fs frameshift NM_012222.3:c.1438dup NP_036354.1:p.Thr480fs frameshift NR_146882.2:n.1591dup non-coding transcript variant NR_146883.2:n.1440dup non-coding transcript variant NC_000001.11:g.45331211dup NC_000001.10:g.45796883dup NG_008189.1:g.14260dup LRG_220:g.14260dup - Protein change
- T340fs, T456fs, T483fs, T363fs, T455fs, T466fs, T470fs, T480fs
- Other names
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- Canonical SPDI
- NC_000001.11:45331210:T:TT
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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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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 |
2566 | 2714 |
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 (1) |
criteria provided, single submitter
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Oct 17, 2014 | RCV000486471.1 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jun 30, 2021 | RCV001851135.3 |
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
(Oct 17, 2014)
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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: SCV000565263.3
First in ClinVar: Apr 27, 2017 Last updated: Apr 27, 2017 |
Comment:
This duplication of one nucleotide in MUTYH is denoted c.1447dupA at the cDNA level and p.Thr483AsnfsX49 (T483NfsX49) at the protein level. The normal sequence, with … (more)
This duplication of one nucleotide in MUTYH is denoted c.1447dupA at the cDNA level and p.Thr483AsnfsX49 (T483NfsX49) at the protein level. The normal sequence, with the bases that are duplicated in brackets, is TCAC[A]CCGC. The duplication causes a frameshift, which changes a Threonine to an Asparagine at codon 483, and creates a premature stop codon at position 49 of the new reading frame. Although this variant has not, to our knowledge, been reported in the literature, it is predicted to cause loss of normal protein function through protein truncation. we consider this variant to be pathogenic. Although this variant is considered pathogenic, a second mutation, as expected for an autosomal recessive disorder such as MAP, was not detected in this individual. The possibility that this patient harbors a second disease-causing MUTYH mutation that is undetectable by this test cannot be excluded. While a single variant in the MUTYH gene has been reported in association with a slightly increased risk for colon cancer, endometrial cancer, and breast cancer, particularly among those with a family history of colorectal cancer (Jenkins 2006, Win 2011, Rennert 2012), there are conflicting data regarding these associations (Santonocito 2011, Out 2012). MUTYH-associated polyposis (MAP) is an autosomal recessive condition caused by two mutations (one affecting each allele) in the MUTYH gene which results in an increased risk for the development of colon cancer and colon polyps. If a MUTYH mutation carrier'spartner is also heterozygous for a MUTYH mutation, the risk to have a child with MAP is 25% with each pregnancy. One study from the UK estimated the overall carrier frequency for any MUTYH mutation to be about 2% (Aretz 2010). (less)
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Likely pathogenic
(Jun 30, 2021)
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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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Invitae
Accession: SCV002279512.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 28, 2024 |
Comment:
ClinVar contains an entry for this variant (Variation ID: 418345). This variant disrupts the conserved PCNA binding motif of MUTYH (Gln526-Phe533, also known as Gln512-Phe519 … (more)
ClinVar contains an entry for this variant (Variation ID: 418345). This variant disrupts the conserved PCNA binding motif of MUTYH (Gln526-Phe533, also known as Gln512-Phe519 in the literature because of transcript nomenclature differences), which has been shown to be critical for MUTYH-PCNA binding (PMID: 11092888, 26377631). Experimental studies have shown that MUTYH and PCNA co-localize at sites of DNA replication, and that MUTYH-PCNA complexes possess adenine glycosylase activity (PMID: 11433026). In MUTYH-deficient murine cells, a mutated MUTYH protein in which the conserved PCNA binding motif was disrupted did not increase repair efficiency as compared to wild-type MUTYH (PMID: 11864576). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This sequence change creates a premature translational stop signal (p.Thr483Asnfs*49) in the MUTYH gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 67 amino acid(s) of the MUTYH protein. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with MUTYH-related conditions. (less)
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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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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 |
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 rs1553124893 ...
HelpRecord last updated Feb 28, 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.