ClinVar Genomic variation as it relates to human health
NM_001048174.2(MUTYH):c.1103-2A>G
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.1103-2A>G
Variation ID: 141282 Accession: VCV000141282.38
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1p34.1 1: 45331558 (GRCh38) [ NCBI UCSC ] 1: 45797230 (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 Jun 8, 2015 Apr 20, 2024 Jan 30, 2024 - HGVS
- ... more HGVS ... less HGVS
- Protein change
- Other names
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- Canonical SPDI
- NC_000001.11:45331557:T:C
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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.
The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00002
Exome Aggregation Consortium (ExAC) 0.00002
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
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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 |
2599 | 2751 |
Conditions - Germline
Condition
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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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Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Apr 18, 2023 | RCV000129730.19 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 30, 2014 | RCV000172819.9 | |
Pathogenic/Likely pathogenic (7) |
criteria provided, multiple submitters, no conflicts
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Jan 30, 2024 | RCV000338621.33 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Nov 22, 2022 | RCV000480885.16 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 6, 2022 | RCV002478389.8 |
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
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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Pathogenic
(Oct 30, 2014)
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criteria provided, single submitter
Method: clinical testing
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Carcinoma of colon
Affected status: yes
Allele origin:
germline
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Pathway Genomics
Accession: SCV000223785.1
First in ClinVar: Jun 08, 2015 Last updated: Jun 08, 2015 |
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Pathogenic
(Jan 31, 2019)
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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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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000711779.2
First in ClinVar: Apr 09, 2018 Last updated: Jul 03, 2020 |
Comment:
The c.1187-2A>G variant has been reported in 2 individuals with colorectal cancer and/or polyps, one whom was compound heterozygous for this variant and a second … (more)
The c.1187-2A>G variant has been reported in 2 individuals with colorectal cancer and/or polyps, one whom was compound heterozygous for this variant and a second pathogenic variant in MUTYH (Wang 2004, Eliason 2005). This variant has also been identified in 1/19908 East Asian chromosomes by the Genome Aggregation Database (GnomAD, http://gnomad.broadinstitute.org; dbSNP rs587781628). However, this frequency is low enough to be consistent with the frequency of MUTYH-related attenuated familial adenomatous polyposis in the general population. This variant occurs in the invariant region (+/- 1,2) of the splice consensus sequence and is predicted to cause altered splicing leading to an abnormal or absent protein. In summary, this variant meets criteria to be classified as pathogenic for MUTYH-related attenuated familial adenomatous polyposis in an autosomal recessive manner based upon its predict impact to the protein. ACMG/AMP criteria applied: PVS1, PM3, PS4_P. (less)
Number of individuals with the variant: 1
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Pathogenic
(May 03, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV002049429.1
First in ClinVar: Jan 08, 2022 Last updated: Jan 08, 2022 |
Comment:
The MUTYH c.1187-2A>G variant (rs587781628), also known as IVS12-2A>G and 9639A>G, is reported in the literature in both the heterozygous and compound heterozygous states in … (more)
The MUTYH c.1187-2A>G variant (rs587781628), also known as IVS12-2A>G and 9639A>G, is reported in the literature in both the heterozygous and compound heterozygous states in individuals with MYH-associated polyposis (Church 2016, Eliason 2005, Farrington 2005, Wang 2004). This variant is also reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 141282). It is found in the general population with an overall allele frequency of 0.002% (7/281032 alleles) in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant disrupts the canonical splice acceptor site of intron 12, and RNA analysis demonstrated transcripts with this splicing variant were absent, indicating this variant causes a null allele (Farrington 2005). Based on available information, this variant is considered to be pathogenic. REFERENCES Church J et al. The "Studded" Rectum: Phenotypic Evidence of MYH-Associated Polyposis. Dis Colon Rectum. 2016 Jun;59(6):565-9. PMID: 27145315. Eliason K et al. The potential for increased clinical sensitivity in genetic testing for polyposis colorectal cancer through the analysis of MYH mutations in North American patients. J Med Genet. 2005 Jan;42(1):95-6. PMID: 15635083. Farrington SM et al. Germline susceptibility to colorectal cancer due to base-excision repair gene defects. Am J Hum Genet. 2005 Jul;77(1):112-9. PMID: 15931596. Wang L et al. MYH mutations in patients with attenuated and classic polyposis and with young-onset colorectal cancer without polyps. Gastroenterology. 2004 Jul;127(1):9-16. PMID: 15236166. (less)
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Pathogenic
(Feb 21, 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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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001361391.2
First in ClinVar: Jun 22, 2020 Last updated: Mar 12, 2022 |
Comment:
Variant summary: MUTYH c.1187-2A>G is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to … (more)
Variant summary: MUTYH c.1187-2A>G is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 3 prime acceptor site. Four predict the variant creates/strengthens an exonic cryptic 3 prime acceptor site. One study reports experimental evidence in support of a deleterious effect of the variant, specifically demonstrating no expression of the variant allele following cDNA analysis in one patient (Farrington_2005). The variant allele was found at a frequency of 2.4e-05 in 249628 control chromosomes (gnomAD). c.1187-2A>G has been reported in the literature in individuals affected with MUTYH-associated Polyposis (e.g. Church_2016, Eliason_2005, Farrington_2005, Wang_2004). These data indicate that the variant is likely to be associated with disease. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all laboratories classified the variant as pathogenic (n=8) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Sep 03, 2021)
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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: SCV000184535.8
First in ClinVar: Aug 06, 2014 Last updated: Nov 29, 2022 |
Comment:
The c.1187-2A>G intronic pathogenic mutation results from an A to G substitution 2 nucleotides before coding exon 13 in the MUTYH gene. This alteration was … (more)
The c.1187-2A>G intronic pathogenic mutation results from an A to G substitution 2 nucleotides before coding exon 13 in the MUTYH gene. This alteration was reported in an individual who was diagnosed with colon cancer at age 38 and had 20-50 colon polyps, who also carried the well described MUTYH founder mutation p.G396D (also known as p.G382D) (Wang et al. Gastroenterology. 2004 Jul;127(1):9-16). In another study, this variant was reported in heterozygous form in a colon polyposis patient who previously tested negative for FAP and HNPCC (Eliason et al. J Med Genet. 2005 Jan;42(1):95-6). This variant has also been identified in the homozygous state and as compound heterozygous with MUTYH founder mutations in individuals with adenomatous polyposis (Ambry internal data). RNA studies have demonstrated this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Note, this mutation is also referred to as c.1145-2A>G and IVS12-2A>G in published literature. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
Number of individuals with the variant: 1
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Pathogenic
(Nov 22, 2022)
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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: SCV000568579.6
First in ClinVar: Apr 27, 2017 Last updated: Dec 03, 2022 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); Canonical splice site variant predicted to result in a null allele in a gene for … (more)
Not observed at significant frequency in large population cohorts (gnomAD); Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 21171015, 26202870, 25525159, 19725997, 19245865, 27194394, 24444654, 27096365, 15635083, 15236166, 27799157, 29490034, 31277343, 30787465, 18534194, 27145315, 15931596) (less)
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Pathogenic
(Oct 20, 2017)
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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: SCV002774364.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
Comment:
This variant is located in a canonical splice-acceptor site and interferes with normal MUTYH mRNA splicing. In addition, this variant has been reported in individuals … (more)
This variant is located in a canonical splice-acceptor site and interferes with normal MUTYH mRNA splicing. In addition, this variant has been reported in individuals with colorectal cancer in the published literature (PMIDs: 15931596 (2005), 15635083 (2005), and 15236166 (2004)). A published RNA transcript analysis from a patient sample confirmed this variant causes loss of the wild-type transcript (PMID: 15931596 (2005)). Based on the available information, this variant is classified as pathogenic. (less)
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Pathogenic
(Mar 06, 2022)
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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: SCV000894023.2
First in ClinVar: Mar 31, 2019 Last updated: Dec 31, 2022 |
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Pathogenic
(Oct 16, 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: SCV004198826.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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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: SCV000685552.4
First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024 |
Comment:
This variant causes an A to G nucleotide substitution at the -2 position of intron 12 of the MUTYH gene. This variant is also known … (more)
This variant causes an A to G nucleotide substitution at the -2 position of intron 12 of the MUTYH gene. This variant is also known as IVS12-2A>G and 9639A>G in the literature. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. An RNA study has reported this variant to result in a null allele (PMID: 15931596). This variant has been reported in three individuals affected with colorectal cancer and/or polyposis, including two individuals who were compound heterozygous with a known pathogenic variant (PMID: 15236166, 15931596, 27145315). This variant has been identified in 7/281032 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of MUTYH function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. (less)
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Pathogenic
(Dec 13, 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: SCV004821945.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
This variant causes an A to G nucleotide substitution at the -2 position of intron 12 of the MUTYH gene. This variant is also known … (more)
This variant causes an A to G nucleotide substitution at the -2 position of intron 12 of the MUTYH gene. This variant is also known as IVS12-2A>G and 9639A>G in the literature. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. An RNA study has reported this variant to result in a null allele (PMID: 15931596). This variant has been reported in three individuals affected with colorectal cancer and/or polyposis, including two individuals who were compound heterozygous with a known pathogenic variant (PMID: 15236166, 15931596, 27145315). This variant has been identified in 7/281032 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of MUTYH function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. (less)
Number of individuals with the variant: 4
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Likely pathogenic
(Jun 14, 2016)
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criteria provided, single submitter
Method: clinical testing
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MYH-Associated Polyposis
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000357894.2
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
Comment:
The c.1187-2A>G variant, also referred to as c.1145-2A>G and IVS12-2A>G, occurs in a canonical splice site (acceptor) and is therefore predicted to disrupt or distort … (more)
The c.1187-2A>G variant, also referred to as c.1145-2A>G and IVS12-2A>G, occurs in a canonical splice site (acceptor) and is therefore predicted to disrupt or distort the normal gene product. Across three studies, this variant was reported in three colorectal cancer patients, including two patients who carried the variant in a compound heterozygous state with a second known pathogenic variant and in one patient who was heterozygous for the c.1187-2A>G variant (Wang et al. 2004; Eliason et al. 2005; Farrington et al. 2005). The variant was absent from 1845 control individuals but is reported at a frequency of 0.00003 in the European (Non-Finnish) population of the Exome Aggregation Consortium. This frequency is based on only two alleles so it is presumed to be rare. RNA transcript analysis of RNA from one of the compound heterozygous patients revealed only the missense variant transcript and no wild type transcript, indicating that the splice acceptor variant is a null allele (Farrington et al. 2005). Based on the evidence and due to the potential impact of splice acceptor variants, the c.1187-2A>G variant is classified as likely pathogenic for MYH-associated polyposis. (less)
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Pathogenic
(Jan 29, 2019)
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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: SCV002017634.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Jan 30, 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: SCV000545702.10
First in ClinVar: Dec 06, 2016 Last updated: Feb 20, 2024 |
Comment:
This sequence change affects an acceptor splice site in intron 12 of the MUTYH gene. RNA analysis indicates that disruption of this splice site induces … (more)
This sequence change affects an acceptor splice site in intron 12 of the MUTYH gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in the loss of 4 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. This variant is present in population databases (rs587781628, gnomAD 0.005%). Disruption of this splice site has been observed in individual(s) with polyposis and/or colon/rectum cancer (PMID: 15236166, 15931596). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as 9639A>G and IVS12-2A>G. ClinVar contains an entry for this variant (Variation ID: 141282). Studies have shown that disruption of this splice site results in the activation of a cryptic splice site in exon 13 (Invitae). This variant disrupts a region of the MUTYH protein in which other variant(s) (p.Gly396Asp) have been determined to be pathogenic (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as 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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The "Studded" Rectum: Phenotypic Evidence of MYH-Associated Polyposis. | Church J | Diseases of the colon and rectum | 2016 | PMID: 27145315 |
Risk of colorectal cancer for people with a mutation in both a MUTYH and a DNA mismatch repair gene. | Win AK | Familial cancer | 2015 | PMID: 26202870 |
Cancer risks for monoallelic MUTYH mutation carriers with a family history of colorectal cancer. | Win AK | International journal of cancer | 2011 | PMID: 21171015 |
Germline susceptibility to colorectal cancer due to base-excision repair gene defects. | Farrington SM | American journal of human genetics | 2005 | PMID: 15931596 |
The potential for increased clinical sensitivity in genetic testing for polyposis colorectal cancer through the analysis of MYH mutations in North American patients. | Eliason K | Journal of medical genetics | 2005 | PMID: 15635083 |
MYH mutations in patients with attenuated and classic polyposis and with young-onset colorectal cancer without polyps. | Wang L | Gastroenterology | 2004 | PMID: 15236166 |
http://chromium.lovd.nl/LOVD2/colon_cancer/variants.php?action=search_unique&select_db=MUTYH | - | - | - | - |
Text-mined citations for rs587781628 ...
HelpRecord last updated Apr 20, 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.