ClinVar Genomic variation as it relates to human health
NM_001048174.2(MUTYH):c.1217C>T (p.Thr406Met)
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.1217C>T (p.Thr406Met)
Variation ID: 127837 Accession: VCV000127837.35
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1p34.1 1: 45331442 (GRCh38) [ NCBI UCSC ] 1: 45797114 (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 Jan 6, 2017 Sep 16, 2024 Jul 1, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001048174.2:c.1217C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001041639.1:p.Thr406Met missense NM_001128425.2:c.1301C>T MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001121897.1:p.Thr434Met missense NM_001048171.2:c.1217C>T NP_001041636.2:p.Thr406Met missense NM_001048172.2:c.1220C>T NP_001041637.1:p.Thr407Met missense NM_001048173.2:c.1217C>T NP_001041638.1:p.Thr406Met missense NM_001293190.2:c.1262C>T NP_001280119.1:p.Thr421Met missense NM_001293191.2:c.1250C>T NP_001280120.1:p.Thr417Met missense NM_001293192.2:c.941C>T NP_001280121.1:p.Thr314Met missense NM_001293195.2:c.1217C>T NP_001280124.1:p.Thr406Met missense NM_001293196.2:c.941C>T NP_001280125.1:p.Thr314Met missense NM_001350650.2:c.872C>T NP_001337579.1:p.Thr291Met missense NM_001350651.2:c.872C>T NP_001337580.1:p.Thr291Met missense NM_012222.3:c.1292C>T NP_036354.1:p.Thr431Met missense NR_146882.2:n.1445C>T non-coding transcript variant NR_146883.2:n.1294C>T non-coding transcript variant NC_000001.11:g.45331442G>A NC_000001.10:g.45797114G>A NG_008189.1:g.14029C>T LRG_220:g.14029C>T LRG_220t1:c.1301C>T LRG_220p1:p.Thr434Met - Protein change
- T434M, T420M, T291M, T314M, T406M, T407M, T417M, T421M, T431M
- Other names
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p.T434M:ACG>ATG
- Canonical SPDI
- NC_000001.11:45331441: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
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The frequency of the allele represented by this VCV record.
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The Genome Aggregation Database (gnomAD) 0.00001
Exome Aggregation Consortium (ExAC) 0.00003
Trans-Omics for Precision Medicine (TOPMed) 0.00003
- 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 | ||
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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
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. |
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MUTYH | - | - |
GRCh38 GRCh37 |
2688 | 2844 |
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
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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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Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Jun 21, 2023 | RCV000115757.17 | |
Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
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Jun 4, 2023 | RCV000235188.12 | |
Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
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Jan 26, 2024 | RCV000411291.16 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Jul 1, 2024 | RCV001818275.7 |
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. |
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Uncertain significance
(Jul 30, 2020)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: no
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV002070313.1
First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022 |
Comment:
DNA sequence analysis of the MUTYH gene demonstrated a sequence change, c.1301C>T, in exon 13 that results in an amino acid change, p.Thr434Met. This sequence … (more)
DNA sequence analysis of the MUTYH gene demonstrated a sequence change, c.1301C>T, in exon 13 that results in an amino acid change, p.Thr434Met. This sequence change has been described in the gnomAD database with a low overall population frequency of 0.004% (dbSNP rs587780084). Also known as c.1259C>T in the literature, this sequence change has been reported in an individual with colorectal cancer (PMID:28135145) and an individual with suspected Lynch syndrome (PMID: 25980754). The p.Thr434Met change affects a poorly conserved amino acid residue located in a domain of the MUTYH protein that is known to be functional. The p.Thr434Met substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Thr434Met change remains unknown at this time. (less)
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Uncertain significance
(Dec 07, 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: SCV000690516.5
First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces threonine with methionine at codon 434 of the MUTYH protein. This variant is also known as c.1259C>T (p.Thr420Met) based on the … (more)
This missense variant replaces threonine with methionine at codon 434 of the MUTYH protein. This variant is also known as c.1259C>T (p.Thr420Met) based on the NM_001048171.1 transcript. 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. This variant has been reported in an individual suspected of having Lynch syndrome (PMID: 25980754) and in an individual affected with colorectal cancer (PMID: 28135145). This variant has also been identified in 11/282736 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)
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Uncertain significance
(Jun 04, 2023)
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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: SCV000149666.17
First in ClinVar: May 17, 2014 Last updated: Jun 10, 2023 |
Comment:
In silico analysis supports that this missense variant does not alter protein structure/function; Also known as c.1259C>T, p.(Thr420Met); This variant is associated with the following … (more)
In silico analysis supports that this missense variant does not alter protein structure/function; Also known as c.1259C>T, p.(Thr420Met); This variant is associated with the following publications: (PMID: 25980754, 28135145, 24728327, 23108399) (less)
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Uncertain significance
(Jul 01, 2024)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002598690.3
First in ClinVar: Nov 05, 2022 Last updated: Sep 16, 2024 |
Comment:
Variant summary: MUTYH c.1301C>T (p.Thr434Met) results in a non-conservative amino acid change located in the NUDIX hydrolase domain (IPR000086) of the encoded protein sequence. Four … (more)
Variant summary: MUTYH c.1301C>T (p.Thr434Met) results in a non-conservative amino acid change located in the NUDIX hydrolase domain (IPR000086) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.3e-05 in 326508 control chromosomes (gnomAD and Okawa_2023). This frequency is not significantly higher than estimated for a pathogenic variant in MUTYH causing MUTYH-Associated Polyposis (4.3e-05 vs 0.0046), allowing no conclusion about variant significance. c.1301C>T (aka c.1259C>T (p.Thr420Met)) has been reported in the literature in the heterozygous state in an individual affected with suspected Lynch syndrome and/or polyps (Yurgelun_2015), and in a patient with colorectal cancer (Yurgelun_2017). The variant was also reported in a large study evaluating breast cancer cases and controls in the Breast Cancer Association Consortium (BCAC), in 9/60466 cases, and in 5/53461 controls (Dorling_2021 through LOVD). These reports do not provide unequivocal conclusions about association of the variant with MUTYH-Associated Polyposis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 33471991, 36243179, 25980754, 28135145). ClinVar contains an entry for this variant (Variation ID: 127837). Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
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Uncertain significance
(Mar 03, 2016)
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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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Counsyl
Accession: SCV000487339.2
First in ClinVar: Jan 06, 2017 Last updated: Dec 24, 2022 |
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Uncertain significance
(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: SCV002011065.3
First in ClinVar: Nov 06, 2021 Last updated: Jul 16, 2023 |
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Uncertain significance
(Dec 27, 2022)
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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: SCV000888306.3
First in ClinVar: Dec 19, 2017 Last updated: Jan 06, 2024 |
Comment:
The frequency of this variant in the general population, 0.000046 (6/129092 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, 0.000046 (6/129092 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 colorectal cancer (PMID: 28135145 (2017)) and an individual with a Lynch syndrome associated cancer (PMID: 25980754 (2015)). In a large-scale breast cancer association study, the variant was observed in individuals with breast cancer as well as in unaffected individuals (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)
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Uncertain significance
(Jan 26, 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: SCV000639269.9
First in ClinVar: Dec 26, 2017 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 434 of the MUTYH protein (p.Thr434Met). … (more)
This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 434 of the MUTYH protein (p.Thr434Met). This variant is present in population databases (rs587780084, gnomAD 0.008%). This missense change has been observed in individual(s) with clinical features of Lynch syndrome and/or colorectal cancer (PMID: 25980754, 28135145). This variant is also known as c.1259C>T (p.Thr420Met). ClinVar contains an entry for this variant (Variation ID: 127837). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The methionine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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)
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Uncertain Significance
(Nov 28, 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: SCV004841115.1
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 missense variant replaces threonine with methionine at codon 434 of the MUTYH protein. This variant is also known as c.1259C>T (p.Thr420Met) based on the … (more)
This missense variant replaces threonine with methionine at codon 434 of the MUTYH protein. This variant is also known as c.1259C>T (p.Thr420Met) based on the NM_001048171.1 transcript. 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. This variant has been reported in an individual suspected of having Lynch syndrome (PMID: 25980754) and in an individual affected with colorectal cancer (PMID: 28135145). This variant has also been identified in 11/282736 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: 7
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Uncertain significance
(Jun 21, 2023)
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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: SCV000184172.9
First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024 |
Comment:
The p.T434M variant (also known as c.1301C>T), located in coding exon 13 of the MUTYH gene, results from a C to T substitution at nucleotide … (more)
The p.T434M variant (also known as c.1301C>T), located in coding exon 13 of the MUTYH gene, results from a C to T substitution at nucleotide position 1301. The threonine at codon 434 is replaced by methionine, an amino acid with similar properties. This alteration was identified in a cohort of 1,260 individuals undergoing panel testing for Lynch syndrome due to having a diagnosis of a Lynch-associated cancer and/or polyps (Yurgelun MB et al. Gastroenterology 2015 Sep;149(3):604-613.e20). This alteration was also reported in 9/60,466 breast cancer cases as well as 5/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). Additionally, this alteration was identified in an individual diagnosed with colorectal cancer (DeRycke MS et al. Mol Genet Genomic Med, 2017 Sep;5:553-569). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (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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Hereditary cancer variants and homologous recombination deficiency in biliary tract cancer. | Okawa Y | Journal of hepatology | 2023 | PMID: 36243179 |
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 |
Targeted sequencing of 36 known or putative colorectal cancer susceptibility genes. | DeRycke MS | Molecular genetics & genomic medicine | 2017 | PMID: 28944238 |
Cancer Susceptibility Gene Mutations in Individuals With Colorectal Cancer. | Yurgelun MB | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2017 | PMID: 28135145 |
Identification of a Variety of Mutations in Cancer Predisposition Genes in Patients With Suspected Lynch Syndrome. | Yurgelun MB | Gastroenterology | 2015 | PMID: 25980754 |
Germline variation in cancer-susceptibility genes in a healthy, ancestrally diverse cohort: implications for individual genome sequencing. | Bodian DL | PloS one | 2014 | PMID: 24728327 |
Text-mined citations for rs587780084 ...
HelpRecord 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.