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. 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. ClinVar contains an entry for this variant (Variation ID: 230572). This variant has not been reported in the literature in individuals affected with MUTYH-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.003%). This sequence change affects codon 168 of the MUTYH mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the MUTYH protein. This variant also falls at the last nucleotide of exon 6, which is part of the consensus splice site for this exon.
ClinVar Genomic variation as it relates to human health
NM_001048174.2(MUTYH):c.420G>A (p.Glu140=)
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.
(5)
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.
Conflicting classifications of pathogenicity
Likely pathogenic(1); Uncertain significance(4)
Likely pathogenic(1); Uncertain significance(4)
5
criteria provided, conflicting classifications
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_001048174.2(MUTYH):c.420G>A (p.Glu140=)
Variation ID: 230572 Accession: VCV000230572.18
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 1p34.1 1: 45332918 (GRCh38) [ NCBI UCSC ] 1: 45798590 (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 Apr 17, 2017 May 1, 2024 Dec 18, 2023 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001048174.2:c.420G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001041639.1:p.Glu140= synonymous NM_001128425.2:c.504G>A MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001121897.1:p.Glu168= synonymous NM_001048171.2:c.420G>A NP_001041636.2:p.Glu140= synonymous NM_001048172.2:c.423G>A NP_001041637.1:p.Glu141= synonymous NM_001048173.2:c.420G>A NP_001041638.1:p.Glu140= synonymous NM_001293190.2:c.465G>A NP_001280119.1:p.Glu155= synonymous NM_001293191.2:c.453G>A NP_001280120.1:p.Glu151= synonymous NM_001293192.2:c.144G>A NP_001280121.1:p.Glu48= synonymous NM_001293195.2:c.420G>A NP_001280124.1:p.Glu140= synonymous NM_001293196.2:c.144G>A NP_001280125.1:p.Glu48= synonymous NM_001350650.2:c.75G>A NP_001337579.1:p.Glu25= synonymous NM_001350651.2:c.75G>A NP_001337580.1:p.Glu25= synonymous NM_012222.3:c.495G>A NP_036354.1:p.Glu165= synonymous NR_146882.2:n.648G>A non-coding transcript variant NR_146883.2:n.497G>A non-coding transcript variant NC_000001.11:g.45332918C>T NC_000001.10:g.45798590C>T NG_008189.1:g.12553G>A LRG_220:g.12553G>A LRG_220t1:c.504G>A LRG_220p1:p.Glu168= - Protein change
- -
- Other names
- -
- Canonical SPDI
- NC_000001.11:45332917: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.
-
The Genome Aggregation Database (gnomAD), exomes 0.00000
- 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. |
|---|---|---|---|---|
| Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
|
Aug 22, 2023 | RCV000222177.11 | |
| Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
|
Dec 18, 2023 | RCV000471395.9 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Oct 9, 2020 | RCV001264555.1 |
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
(Jun 27, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Familial adenomatous polyposis 2
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000545710.7
First in ClinVar: Apr 17, 2017 Last updated: Feb 20, 2024 |
Comment:
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 … (more)
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. 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. ClinVar contains an entry for this variant (Variation ID: 230572). This variant has not been reported in the literature in individuals affected with MUTYH-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.003%). This sequence change affects codon 168 of the MUTYH mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the MUTYH protein. This variant also falls at the last nucleotide of exon 6, which is part of the consensus splice site for this exon. (less)
|
|
|
Likely pathogenic
(Aug 22, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000274164.8
First in ClinVar: May 29, 2016 Last updated: May 01, 2024 |
Comment:
The c.504G>A variant (also known as p.E168E), located in coding exon 6 of the MUTYH gene, results from a G to A substitution at nucleotide … (more)
The c.504G>A variant (also known as p.E168E), located in coding exon 6 of the MUTYH gene, results from a G to A substitution at nucleotide position 504. This nucleotide substitution does not change the glutamic acid at codon 168. However, this change occurs in the last base pair of coding exon 6, which makes it likely to have some effect on normal mRNA splicing. This variant has been detected in conjunction with a MUTYH pathogenic variant in an individual with clinical features of MUTYH-associated polyposis (MAP); however, the phase of the two variants is unknown (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). The resulting transcript preserves the reading frame and is not expected to trigger nonsense-mediated mRNA decay; however, the impacted region is critical for protein function and a significant portion of the protein is affected (Ambry internal data). Based on the majority of available evidence to date, this variant is likely to be pathogenic. (less)
|
|
|
Uncertain significance
(Oct 09, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001442764.1
First in ClinVar: Nov 12, 2020 Last updated: Nov 12, 2020 |
Comment:
Variant summary: MUTYH c.504G>A (p.Glu168Glu) alters a conserved nucleotide located at the last position of exon 6 adjacent to the canonical donor splice site and … (more)
Variant summary: MUTYH c.504G>A (p.Glu168Glu) alters a conserved nucleotide located at the last position of exon 6 adjacent to the canonical donor splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Four predict the variant weakens the canonical 5' donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 250620 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.504G>A in individuals affected with MUTYH-Associated Polyposis and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
|
|
|
Uncertain significance
(Feb 09, 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: SCV000685636.5
First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024 |
Comment:
This variant causes a G>A nucleotide substitution in the last nucleotide of exon 6 in the MUTYH gene. Splice site prediction tools suggest that this … (more)
This variant causes a G>A nucleotide substitution in the last nucleotide of exon 6 in the MUTYH gene. Splice site prediction tools suggest that this variant may impact RNA splicing, potentially disrupting the consensus donor splice site for this exon. This variant has been reported to impact RNA splicing by an external laboratory, however, detailed data are not available for review (ClinVar SCV000274164.6). This variant has been reported in an individual affected with early-onset colorectal cancer (PMID: 33359728). This variant has been identified in 1/250620 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)
|
|
|
Uncertain Significance
(Dec 18, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Familial adenomatous polyposis 2
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
|
All of Us Research Program, National Institutes of Health
Accession: SCV004839705.1
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)
|
Comment:
This variant causes a G>A nucleotide substitution in the last nucleotide of exon 6 in the MUTYH gene. Splice site prediction tools suggest that this … (more)
This variant causes a G>A nucleotide substitution in the last nucleotide of exon 6 in the MUTYH gene. Splice site prediction tools suggest that this variant may impact RNA splicing, potentially disrupting the consensus donor splice site for this exon. This variant has been reported to impact RNA splicing by an external laboratory, however, detailed data are not available for review (ClinVar SCV000274164.6). This variant has been reported in an individual affected with early-onset colorectal cancer (PMID: 33359728). This variant has been identified in 1/250620 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: 2
|
Comment:
Comment:
The c.504G>A variant (also known as p.E168E), located in coding exon 6 of the MUTYH gene, results from a G to A substitution at nucleotide position 504. This nucleotide substitution does not change the glutamic acid at codon 168. However, this change occurs in the last base pair of coding exon 6, which makes it likely to have some effect on normal mRNA splicing. This variant has been detected in conjunction with a MUTYH pathogenic variant in an individual with clinical features of MUTYH-associated polyposis (MAP); however, the phase of the two variants is unknown (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). The resulting transcript preserves the reading frame and is not expected to trigger nonsense-mediated mRNA decay; however, the impacted region is critical for protein function and a significant portion of the protein is affected (Ambry internal data). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Comment:
Variant summary: MUTYH c.504G>A (p.Glu168Glu) alters a conserved nucleotide located at the last position of exon 6 adjacent to the canonical donor splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Four predict the variant weakens the canonical 5' donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 250620 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.504G>A in individuals affected with MUTYH-Associated Polyposis and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Comment:
This variant causes a G>A nucleotide substitution in the last nucleotide of exon 6 in the MUTYH gene. Splice site prediction tools suggest that this variant may impact RNA splicing, potentially disrupting the consensus donor splice site for this exon. This variant has been reported to impact RNA splicing by an external laboratory, however, detailed data are not available for review (ClinVar SCV000274164.6). This variant has been reported in an individual affected with early-onset colorectal cancer (PMID: 33359728). This variant has been identified in 1/250620 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.
Comment:
This variant causes a G>A nucleotide substitution in the last nucleotide of exon 6 in the MUTYH gene. Splice site prediction tools suggest that this variant may impact RNA splicing, potentially disrupting the consensus donor splice site for this exon. This variant has been reported to impact RNA splicing by an external laboratory, however, detailed data are not available for review (ClinVar SCV000274164.6). This variant has been reported in an individual affected with early-onset colorectal cancer (PMID: 33359728). This variant has been identified in 1/250620 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.
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:
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. 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. ClinVar contains an entry for this variant (Variation ID: 230572). This variant has not been reported in the literature in individuals affected with MUTYH-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.003%). This sequence change affects codon 168 of the MUTYH mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the MUTYH protein. This variant also falls at the last nucleotide of exon 6, which is part of the consensus splice site for this exon.
Comment:
The c.504G>A variant (also known as p.E168E), located in coding exon 6 of the MUTYH gene, results from a G to A substitution at nucleotide position 504. This nucleotide substitution does not change the glutamic acid at codon 168. However, this change occurs in the last base pair of coding exon 6, which makes it likely to have some effect on normal mRNA splicing. This variant has been detected in conjunction with a MUTYH pathogenic variant in an individual with clinical features of MUTYH-associated polyposis (MAP); however, the phase of the two variants is unknown (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). The resulting transcript preserves the reading frame and is not expected to trigger nonsense-mediated mRNA decay; however, the impacted region is critical for protein function and a significant portion of the protein is affected (Ambry internal data). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Comment:
Variant summary: MUTYH c.504G>A (p.Glu168Glu) alters a conserved nucleotide located at the last position of exon 6 adjacent to the canonical donor splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Four predict the variant weakens the canonical 5' donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 250620 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.504G>A in individuals affected with MUTYH-Associated Polyposis and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Comment:
This variant causes a G>A nucleotide substitution in the last nucleotide of exon 6 in the MUTYH gene. Splice site prediction tools suggest that this variant may impact RNA splicing, potentially disrupting the consensus donor splice site for this exon. This variant has been reported to impact RNA splicing by an external laboratory, however, detailed data are not available for review (ClinVar SCV000274164.6). This variant has been reported in an individual affected with early-onset colorectal cancer (PMID: 33359728). This variant has been identified in 1/250620 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.
Comment:
This variant causes a G>A nucleotide substitution in the last nucleotide of exon 6 in the MUTYH gene. Splice site prediction tools suggest that this variant may impact RNA splicing, potentially disrupting the consensus donor splice site for this exon. This variant has been reported to impact RNA splicing by an external laboratory, however, detailed data are not available for review (ClinVar SCV000274164.6). This variant has been reported in an individual affected with early-onset colorectal cancer (PMID: 33359728). This variant has been identified in 1/250620 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.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Racial and Ethnic Disparities in Germline Genetic Testing of Patients With Young-Onset Colorectal Cancer. | Dharwadkar P | Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association | 2022 | PMID: 33359728 |
| 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 rs876658641 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record 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.