This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 506 of the MUTYH protein (p.Met506Ile). This variant also falls at the last nucleotide of exon 15, which is part of the consensus splice site for this exon. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MUTYH-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.
ClinVar Genomic variation as it relates to human health
NM_001048174.2(MUTYH):c.1434G>A (p.Met478Ile)
Germline
Classification
Help
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.
(2)
Help
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.
Uncertain significance
2
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_001048174.2(MUTYH):c.1434G>A (p.Met478Ile)
Variation ID: 1983746 Accession: VCV001983746.3
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 1p34.1 1: 45330516 (GRCh38) [ NCBI UCSC ] 1: 45796188 (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 Feb 8, 2023 May 1, 2024 Jan 31, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001048174.2:c.1434G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001041639.1:p.Met478Ile missense NM_001128425.2:c.1518G>A MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001121897.1:p.Met506Ile missense NM_001048171.2:c.1434G>A NP_001041636.2:p.Met478Ile missense NM_001048172.2:c.1437G>A NP_001041637.1:p.Met479Ile missense NM_001048173.2:c.1434G>A NP_001041638.1:p.Met478Ile missense NM_001293190.2:c.1479G>A NP_001280119.1:p.Met493Ile missense NM_001293191.2:c.1467G>A NP_001280120.1:p.Met489Ile missense NM_001293192.2:c.1158G>A NP_001280121.1:p.Met386Ile missense NM_001293195.2:c.1434G>A NP_001280124.1:p.Met478Ile missense NM_001293196.2:c.1158G>A NP_001280125.1:p.Met386Ile missense NM_001350650.2:c.1089G>A NP_001337579.1:p.Met363Ile missense NM_001350651.2:c.1089G>A NP_001337580.1:p.Met363Ile missense NM_001407069.1:c.1467G>A NP_001393998.1:p.Met489Ile missense NM_001407070.1:c.1434G>A NP_001393999.1:p.Met478Ile missense NM_001407071.1:c.1437G>A NP_001394000.1:p.Met479Ile missense NM_001407072.1:c.1434G>A NP_001394001.1:p.Met478Ile missense NM_001407073.1:c.1434G>A NP_001394002.1:p.Met478Ile missense NM_001407075.1:c.1350G>A NP_001394004.1:p.Met450Ile missense NM_001407077.1:c.1467G>A NP_001394006.1:p.Met489Ile missense NM_001407078.1:c.1437G>A NP_001394007.1:p.Met479Ile missense NM_001407079.1:c.1395G>A NP_001394008.1:p.Met465Ile missense NM_001407080.1:c.1392G>A NP_001394009.1:p.Met464Ile missense NM_001407081.1:c.1434G>A NP_001394010.1:p.Met478Ile missense NM_001407082.1:c.1089G>A NP_001394011.1:p.Met363Ile missense NM_001407083.1:c.1476G>A NP_001394012.1:p.Met492Ile missense NM_001407085.1:c.1476G>A NP_001394014.1:p.Met492Ile missense NM_001407086.1:c.1437G>A NP_001394015.1:p.Met479Ile missense NM_001407087.1:c.1455G>A NP_001394016.1:p.Met485Ile missense NM_001407088.1:c.1434G>A NP_001394017.1:p.Met478Ile missense NM_001407089.1:c.1434G>A NP_001394018.1:p.Met478Ile missense NM_001407091.1:c.1158G>A NP_001394020.1:p.Met386Ile missense NM_012222.3:c.1509G>A NP_036354.1:p.Met503Ile missense NR_146882.2:n.1662G>A non-coding transcript variant NR_146883.2:n.1511G>A non-coding transcript variant NR_176269.1:n.1658G>A NR_176270.1:n.1598G>A NR_176271.1:n.1521G>A NR_176272.1:n.1585G>A NR_176273.1:n.1543G>A NR_176274.1:n.1598G>A NC_000001.11:g.45330516C>T NC_000001.10:g.45796188C>T NG_008189.1:g.14955G>A LRG_220:g.14955G>A LRG_220t1:c.1518G>A LRG_220p1:p.Met506Ile - Protein change
- M386I, M465I, M503I, M478I, M479I, M506I, M363I, M489I, M450I, M464I, M485I, M492I, M493I
- Other names
- -
- Canonical SPDI
- NC_000001.11:45330515:C:T
-
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.
- -
- 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 | ||
|---|---|---|---|---|---|---|
| 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 |
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
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. |
|---|---|---|---|---|
| Uncertain significance (1) |
criteria provided, single submitter
|
Apr 12, 2022 | RCV002800091.3 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Jan 31, 2024 | RCV004064674.1 |
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. |
|
|---|---|---|---|---|---|
|
Uncertain significance
(Apr 12, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Familial adenomatous polyposis 2
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV003021905.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 506 of the MUTYH protein (p.Met506Ile). … (more)
This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 506 of the MUTYH protein (p.Met506Ile). This variant also falls at the last nucleotide of exon 15, which is part of the consensus splice site for this exon. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MUTYH-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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)
|
|
|
Uncertain significance
(Jan 31, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV005038207.1
First in ClinVar: May 01, 2024 Last updated: May 01, 2024 |
Comment:
The c.1518G>A variant (also known as p.M506I), located in coding exon 15 of the MUTYH gene, results from a G to A substitution at nucleotide … (more)
The c.1518G>A variant (also known as p.M506I), located in coding exon 15 of the MUTYH gene, results from a G to A substitution at nucleotide position 1518. The amino acid change results in methionine to isoleucine at codon 506, an amino acid with highly similar properties. However, this change occurs in the last base pair of coding exon 15, which makes it likely to have some effect on normal mRNA splicing. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration may weaken the native splice donor site; however, direct evidence is insufficient at this time (Ambry internal data). Based on the available evidence, the clinical significance of this alteration remains unclear. (less)
|
Comment:
Comment:
The c.1518G>A variant (also known as p.M506I), located in coding exon 15 of the MUTYH gene, results from a G to A substitution at nucleotide position 1518. The amino acid change results in methionine to isoleucine at codon 506, an amino acid with highly similar properties. However, this change occurs in the last base pair of coding exon 15, which makes it likely to have some effect on normal mRNA splicing. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration may weaken the native splice donor site; however, direct evidence is insufficient at this time (Ambry internal data). Based on the available evidence, the clinical significance of this alteration remains unclear.
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. |
Comment:
This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 506 of the MUTYH protein (p.Met506Ile). This variant also falls at the last nucleotide of exon 15, which is part of the consensus splice site for this exon. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MUTYH-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.
Comment:
The c.1518G>A variant (also known as p.M506I), located in coding exon 15 of the MUTYH gene, results from a G to A substitution at nucleotide position 1518. The amino acid change results in methionine to isoleucine at codon 506, an amino acid with highly similar properties. However, this change occurs in the last base pair of coding exon 15, which makes it likely to have some effect on normal mRNA splicing. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration may weaken the native splice donor site; however, direct evidence is insufficient at this time (Ambry internal data). Based on the available evidence, the clinical significance of this alteration remains unclear.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization. | Buratti E | Nucleic acids research | 2007 | PMID: 17576681 |
| Statistical features of human exons and their flanking regions. | Zhang MQ | Human molecular genetics | 1998 | PMID: 9536098 |
Text-mined citations for this variant ...
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.