ClinVar Genomic variation as it relates to human health
NM_001048174.2(MUTYH):c.1393G>T (p.Val465Phe)
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.1393G>T (p.Val465Phe)
Variation ID: 219953 Accession: VCV000219953.26
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1p34.1 1: 45330557 (GRCh38) [ NCBI UCSC ] 1: 45796229 (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 Jul 1, 2016 Feb 14, 2024 Jan 10, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001048174.2:c.1393G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001041639.1:p.Val465Phe missense NM_001128425.2:c.1477G>T MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001121897.1:p.Val493Phe missense NM_001048171.2:c.1393G>T NP_001041636.2:p.Val465Phe missense NM_001048172.2:c.1396G>T NP_001041637.1:p.Val466Phe missense NM_001048173.2:c.1393G>T NP_001041638.1:p.Val465Phe missense NM_001293190.2:c.1438G>T NP_001280119.1:p.Val480Phe missense NM_001293191.2:c.1426G>T NP_001280120.1:p.Val476Phe missense NM_001293192.2:c.1117G>T NP_001280121.1:p.Val373Phe missense NM_001293195.2:c.1393G>T NP_001280124.1:p.Val465Phe missense NM_001293196.2:c.1117G>T NP_001280125.1:p.Val373Phe missense NM_001350650.2:c.1048G>T NP_001337579.1:p.Val350Phe missense NM_001350651.2:c.1048G>T NP_001337580.1:p.Val350Phe missense NM_012222.3:c.1468G>T NP_036354.1:p.Val490Phe missense NR_146882.2:n.1621G>T non-coding transcript variant NR_146883.2:n.1470G>T non-coding transcript variant NC_000001.11:g.45330557C>A NC_000001.10:g.45796229C>A NG_008189.1:g.14914G>T LRG_220:g.14914G>T LRG_220t1:c.1477G>T LRG_220p1:p.Val493Phe - Protein change
- V493F, V479F, V373F, V465F, V466F, V350F, V480F, V476F, V490F
- Other names
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- Canonical SPDI
- NC_000001.11:45330556:C: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.
Exome Aggregation Consortium (ExAC) 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00002
The Genome Aggregation Database (gnomAD) 0.00003
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 |
2565 | 2715 |
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. |
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Pathogenic/Likely pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Jan 10, 2024 | RCV000204688.18 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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May 15, 2023 | RCV000215469.14 | |
Likely pathogenic (1) |
criteria provided, single submitter
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May 6, 2021 | RCV000479402.4 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jul 21, 2021 | RCV002503805.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Jul 17, 2023 | RCV003407724.4 |
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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Likely pathogenic
(Oct 16, 2015)
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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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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000697680.1
First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018 |
Comment:
Variant summary: c.1477G>T affects a conserved nucleotide located at the first position of exon 15, resulting in amino acid change from Val to Phe. 3/4 … (more)
Variant summary: c.1477G>T affects a conserved nucleotide located at the first position of exon 15, resulting in amino acid change from Val to Phe. 3/4 in-silico tools predict this variant to be damaging (SNPs&GO not captured due to low reliability index). 5/5 programs in Alamut predict that this variant does not significantly affect normal splicing. ESE finder predicts that this variant may affect ESE site of SC35. Grandval_2015 predicted that this variant leads to major loss of exon 5 and an inframe deletion (p.Val479_Met492del) based on RT-PCR product sequencing (data not shown). This variant has been reported in homozygous and compound heterozygous state in patients with atypical polyposis, colorectal adenomas, MUTYH associated polyposis. Heterozygous variant was found in 3/87104 control chromosomes at a frequency of 0.0000344 and one patient with sporadic colorectal cancer. One functional study in E.coli showed that protein with this variant partially lost the normal function in suppressing spontaneous mutations (Komine_2015). However, its function in human cells is still not clear. Taken together, this variant was classified as likely pathogenic. (less)
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Likely pathogenic
(May 06, 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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GeneDx
Accession: SCV000565264.6
First in ClinVar: Apr 27, 2017 Last updated: Jul 24, 2021 |
Comment:
Not observed at a significant frequency in large population cohorts (Lek 2016); Reported in the homozygous or compound heterozygous state in at least 3 individuals … (more)
Not observed at a significant frequency in large population cohorts (Lek 2016); Reported in the homozygous or compound heterozygous state in at least 3 individuals with multiple colorectal adenomas, with or without colorectal cancer (Aretz 2006, Buecher 2008, Reggoug 2009); Published functional studies demonstrate a damaging effect: partially defective base excision repair activity in a yeast-based complementation assay (Komine 2015); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as c.1435G>T, p.Val479Phe; This variant is associated with the following publications: (PMID: 18787472, 29684080, 22493355, 22538434, 27631816, 21279954, 25368107, 26689913, 25820570, 20618354, 19806110, 16557584, 17931073, 17949294) (less)
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Pathogenic
(May 04, 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: SCV000487353.2
First in ClinVar: Jul 01, 2016 Last updated: Dec 24, 2022 |
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Likely pathogenic
(Jul 21, 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: SCV002807691.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(May 15, 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: SCV000274772.9
First in ClinVar: May 29, 2016 Last updated: Jul 08, 2023 |
Comment:
The c.1477G>T pathogenic mutation (also known as p.V493F) is located in coding exon 15 of the MUTYH gene. The valine at codon 493 is replaced … (more)
The c.1477G>T pathogenic mutation (also known as p.V493F) is located in coding exon 15 of the MUTYH gene. The valine at codon 493 is replaced by phenylalanine, an amino acid with highly similar properties. This change occurs in the first base pair of coding exon 15 and this nucleotide position is highly conserved in available vertebrate species. This alteration has been identified both in conjunction with a pathogenic MUTYH mutation and in the homozygous state in polyposis patients (Aretz S et al. Int. J. Cancer. 2006 Aug 15;119:807-14; Olschwang S et al. Genet. Test. 2007;11:315-20; Ambry internal data). In addition, this alteration was classified by a functional complementation assay as partially defective (Komine K et al. Hum. Mutat. 2015 Jul;36:704-11). Of note, this alteration is also designated as p.V479F (c.1435G>T) in published literature. In silico splice site analysis predicts that this alteration may weaken the native splice acceptor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). As such, this alteration is classified as a disease-causing mutation. (less)
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Pathogenic
(Jul 17, 2023)
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criteria provided, single submitter
Method: clinical testing
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MUTYH-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004113352.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The MUTYH c.1477G>T variant is predicted to result in the amino acid substitution p.Val493Phe. This variant was reported in multiple individuals with MUTYH-associated polyposis, colorectal … (more)
The MUTYH c.1477G>T variant is predicted to result in the amino acid substitution p.Val493Phe. This variant was reported in multiple individuals with MUTYH-associated polyposis, colorectal cancer, or small cell lung cancer (see for example Aretz et al 2006. PubMed ID: 16557584; Küry et al 2007. PubMed ID: 17931073; Olschwang et al 2007. PubMed ID: 17949294; Reggoug et al 2009. PubMed ID: 19806110; Morak et al 2010. PubMed ID: 20618354; Tlemsani et al 2021. PubMed ID: 33504652). A published functional study demonstrated the damaging effect of this variant (Komine K et al 2015. PubMed ID: 25820570). This variant is also known as c.1435G>T (p.Val479Phe). This variant is reported in 0.0033% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-45796229-C-A). This variant is interpreted as pathogenic. (less)
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Likely pathogenic
(Aug 21, 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: SCV004198888.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Likely pathogenic
(Jan 06, 2022)
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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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Revvity Omics, Revvity
Accession: SCV003828432.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
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Pathogenic
(Jan 10, 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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Invitae
Accession: SCV000260144.12
First in ClinVar: Feb 02, 2016 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces valine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 493 of the MUTYH protein (p.Val493Phe). … (more)
This sequence change replaces valine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 493 of the MUTYH protein (p.Val493Phe). RNA analysis indicates that this missense change induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs587782228, gnomAD 0.002%). This missense change has been observed in individuals with polyposis or colorectal cancer and/or small cell lung cancer (PMID: 16557584, 17931073, 17949294, 19806110, 20618354, 23729658, 33504652). This variant is also known as c.1435G>T (p.Val479Phe). ClinVar contains an entry for this variant (Variation ID: 219953). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects MUTYH function (PMID: 25820570). Studies have shown that this missense change results in skipping of exon 15 skipping, but is expected to preserve the integrity of the reading-frame (Invitae). For these reasons, this variant has been classified as Pathogenic. (less)
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Likely pathogenic
(Apr 18, 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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Color Diagnostics, LLC DBA Color Health
Accession: SCV000690532.5
First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces valine with phenylalanine at codon 493 in the nudix hydrolase domain of the MUTYH protein. Computational prediction is inconclusive regarding the … (more)
This missense variant replaces valine with phenylalanine at codon 493 in the nudix hydrolase domain of the MUTYH protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). A functional study has shown the mutant protein to be partially defective in a complementation assay in a MutY-deficient E.coli strain (PMID: 25820570). This variant has been reported in the homozygous or compound heterozygous state in individuals affected with multiple colorectal adenomas (PMID: 16557584, 17949294). It has also been reported in a heterozygous individual affected with colorectal cancer (PMID: 17931073). This variant has been identified in 4/271092 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. (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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Whole-exome sequencing reveals germline-mutated small cell lung cancer subtype with favorable response to DNA repair-targeted therapies. | Tlemsani C | Science translational medicine | 2021 | PMID: 33504652 |
Patterns and functional implications of rare germline variants across 12 cancer types. | Lu C | Nature communications | 2015 | PMID: 26689913 |
Functional Complementation Assay for 47 MUTYH Variants in a MutY-Disrupted Escherichia coli Strain. | Komine K | Human mutation | 2015 | PMID: 25820570 |
Genomic variations integrated database for MUTYH-associated adenomatous polyposis. | Grandval P | Journal of medical genetics | 2015 | PMID: 25368107 |
UMD-MLH1/MSH2/MSH6 databases: description and analysis of genetic variations in French Lynch syndrome families. | Grandval P | Database : the journal of biological databases and curation | 2013 | PMID: 23729658 |
French experts report on MUTYH-associated polyposis (MAP). | Buecher B | Familial cancer | 2012 | PMID: 22538434 |
Leiden Open Variation Database of the MUTYH gene. | Out AA | Human mutation | 2010 | PMID: 20725929 |
MUTYH-associated polyposis - variability of the clinical phenotype in patients with biallelic and monoallelic MUTYH mutations and report on novel mutations. | Morak M | Clinical genetics | 2010 | PMID: 20618354 |
Idiopathic gastric acid hypersecretion in a patient with MUTYH-associated polyposis. | Reggoug S | The American journal of gastroenterology | 2009 | PMID: 19806110 |
Low-penetrance alleles predisposing to sporadic colorectal cancers: a French case-controlled genetic association study. | Küry S | BMC cancer | 2008 | PMID: 18992148 |
Base excision repair and the role of MUTYH. | Kairupan C | Hereditary cancer in clinical practice | 2007 | PMID: 19725997 |
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 |
The thorough screening of the MUTYH gene in a large French cohort of sporadic colorectal cancers. | Küry S | Genetic testing | 2007 | PMID: 17931073 |
MUTYH-associated polyposis--from defect in base excision repair to clinical genetic testing. | Cheadle JP | DNA repair | 2007 | PMID: 17161978 |
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 |
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Text-mined citations for rs587782228 ...
HelpRecord last updated Mar 17, 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.