The p.Ala287ProfsX32 variant in MUTYH has been reported in the heterozygous stat e in one individuals with familial adenomatouspolyposis (Aretz 20016). It has al so been identified in 1/30782 of South Asian chromosomes by gnomAD (http://gnoma d.broadinstitute.org). This variant is predicted to cause a frameshift, which al ters the protein?s amino acid sequence beginning at position 287 and leads to a premature termination codon 32 amino acids downstream. This alteration is then p redicted to lead to a truncated or absent protein. In summary, although addition al studies are required to fully establish its clinical significance, the p.Ala2 87ProfsX32 variant is likely pathogenic. ACMG/AMP Criteria applied: PVS1, PM2.
ClinVar Genomic variation as it relates to human health
NM_001048174.2(MUTYH):c.775del (p.Ala259fs)
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.
(10)
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.
Pathogenic/Likely pathogenic
10
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.775del (p.Ala259fs)
Variation ID: 433934 Accession: VCV000433934.49
- Type and length
-
Deletion, 1 bp
- Location
-
Cytogenetic: 1p34.1 1: 45332240 (GRCh38) [ NCBI UCSC ] 1: 45797912 (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 Aug 28, 2017 Oct 20, 2024 Nov 25, 2023 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001048174.2:c.775del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001041639.1:p.Ala259fs frameshift NM_001128425.2:c.859del MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001121897.1:p.Ala287fs frameshift NM_001048171.2:c.775del NP_001041636.2:p.Ala259fs frameshift NM_001048172.2:c.778del NP_001041637.1:p.Ala260fs frameshift NM_001048173.2:c.775del NP_001041638.1:p.Ala259fs frameshift NM_001128425.1:c.859delG NM_001293190.2:c.820del NP_001280119.1:p.Ala274fs frameshift NM_001293191.2:c.808del NP_001280120.1:p.Ala270fs frameshift NM_001293192.2:c.499del NP_001280121.1:p.Ala167fs frameshift NM_001293195.2:c.775del NP_001280124.1:p.Ala259fs frameshift NM_001293196.2:c.499del NP_001280125.1:p.Ala167fs frameshift NM_001350650.2:c.430del NP_001337579.1:p.Ala144fs frameshift NM_001350651.2:c.430del NP_001337580.1:p.Ala144fs frameshift NM_012222.3:c.850del NP_036354.1:p.Ala284fs frameshift NR_146882.2:n.1003del non-coding transcript variant NR_146883.2:n.852del non-coding transcript variant NC_000001.11:g.45332243del NC_000001.10:g.45797915del NG_008189.1:g.13231del LRG_220:g.13231del LRG_220t1:c.859del LRG_220p1:p.Ala287fs - Protein change
- A274fs, A270fs, A144fs, A260fs, A287fs, A167fs, A259fs, A284fs
- Other names
- -
- Canonical SPDI
- NC_000001.11:45332239:CCCC:CCC
-
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. |
|---|---|---|---|---|
| Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Jun 15, 2023 | RCV000499908.17 | |
| Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Feb 2, 2023 | RCV000777643.11 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Nov 25, 2023 | RCV001310852.23 | |
| Pathogenic (1) |
no assertion criteria provided
|
- | RCV001353713.3 |
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. |
|
|---|---|---|---|---|---|
|
Likely pathogenic
(Sep 06, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Familial adenomatous polyposis 2
Affected status: not provided
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000967776.1
First in ClinVar: Aug 26, 2019 Last updated: Aug 26, 2019 |
Comment:
The p.Ala287ProfsX32 variant in MUTYH has been reported in the heterozygous stat e in one individuals with familial adenomatouspolyposis (Aretz 20016). It has al so … (more)
The p.Ala287ProfsX32 variant in MUTYH has been reported in the heterozygous stat e in one individuals with familial adenomatouspolyposis (Aretz 20016). It has al so been identified in 1/30782 of South Asian chromosomes by gnomAD (http://gnoma d.broadinstitute.org). This variant is predicted to cause a frameshift, which al ters the protein?s amino acid sequence beginning at position 287 and leads to a premature termination codon 32 amino acids downstream. This alteration is then p redicted to lead to a truncated or absent protein. In summary, although addition al studies are required to fully establish its clinical significance, the p.Ala2 87ProfsX32 variant is likely pathogenic. ACMG/AMP Criteria applied: PVS1, PM2. (less)
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Apr 15, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV000913514.3
First in ClinVar: May 20, 2019 Last updated: Jan 12, 2022 |
Comment:
This variant deletes 1 nucleotide in exon 10 of the MUTYH gene, creating a frameshift and premature translation stop signal. This variant is expected to … (more)
This variant deletes 1 nucleotide in exon 10 of the MUTYH gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant (also known as c.817del in the literature) has been reported in an individual affected with MUTYH-associated polyposis (PMID: 16557584). This variant has also been identified in 1/250896 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)
|
|
|
Likely pathogenic
(Feb 10, 2022)
|
criteria provided, single submitter
Method: curation
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Sema4, Sema4
Accession: SCV002532336.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Comment:
The MUTYH c.859delG (p.A287PfsX32) variant has been reported as heterozygous in at least one individual with polyposis (PMID: 16557584). It is also known as c.817delG … (more)
The MUTYH c.859delG (p.A287PfsX32) variant has been reported as heterozygous in at least one individual with polyposis (PMID: 16557584). It is also known as c.817delG in the literature. This variant causes a frameshift at amino acid 287 that results in premature termination 32 amino acids downstream. At this location, this is predicted to cause nonsense-mediated decay and result in an absent protein (loss of function). Loss-of-function variants in MUTYH are known to be pathogenic (PMID: 18534194, 20663686). This variant was observed in 1/30616 chromosomes in the South Asian population, according to the Genome Aggregation Database (PMID: 27535533). This variant has been reported in ClinVar (Variation ID:433934). Based on the current evidence available, this variant is interpreted as likely pathogenic. (less)
|
|
|
|
Pathogenic
(Jun 15, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Familial adenomatous polyposis 2
Affected status: yes
Allele origin:
germline
|
Human Genetics Bochum, Ruhr University Bochum
Accession: SCV004042788.1
First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023 |
Comment:
ACMG criteria used to clasify this variant:PVS1, PS4_SUP, PM2_SUP
|
|
|
Pathogenic
(Oct 14, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Familial adenomatous polyposis 2
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004199417.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
|
|
|
Pathogenic
(Jan 16, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Familial adenomatous polyposis 2
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001399526.5
First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 433934). This variant is also known … (more)
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 433934). This variant is also known as c.817delG, p.A273PfsX32. This premature translational stop signal has been observed in individual(s) with polyposis (PMID: 16557584). This variant is present in population databases (rs761468459, gnomAD 0.003%). This sequence change creates a premature translational stop signal (p.Ala287Profs*32) in the MUTYH gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MUTYH are known to be pathogenic (PMID: 18534194, 20663686). (less)
|
|
|
Pathogenic
(Feb 02, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV001179223.5
First in ClinVar: Mar 16, 2020 Last updated: May 01, 2024 |
Comment:
The c.859delG variant, located in coding exon 10 of the MUTYH gene, results from a deletion of one nucleotide at nucleotide position 859, causing a … (more)
The c.859delG variant, located in coding exon 10 of the MUTYH gene, results from a deletion of one nucleotide at nucleotide position 859, causing a translational frameshift with a predicted alternate stop codon (p.A287Pfs*32). This variant (designated as MUTYH c.817delG p.A273PfsX32) has been reported in the heterozygous state in one individual with a clinical diagnosis of familial adenomatous polyposis (Aretz S et al. Int. J. Cancer. 2006 Aug;119:807-14). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. (less)
|
|
|
Pathogenic
(Nov 25, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV005202010.1
First in ClinVar: Sep 16, 2024 Last updated: Sep 16, 2024 |
Comment:
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of … (more)
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Observed in the heterozygous state in an individual with a history of polyposis (PMID: 16557584); Also known as 817delG; This variant is associated with the following publications: (PMID: 16557584) (less)
|
|
|
Pathogenic
(Aug 01, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001500820.23
First in ClinVar: Mar 14, 2021 Last updated: Oct 20, 2024 |
Number of individuals with the variant: 1
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
Carcinoma of colon
Affected status: yes
Allele origin:
unknown
|
Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV000592699.2 First in ClinVar: Aug 28, 2017 Last updated: Apr 13, 2021 |
Comment:
The MUTYH p.Ala287ProfsX32 variant was identified in 1 of 658 proband chromosomes (frequency: 0.002) from individuals or families with MUTYH associated polyposis, and was not … (more)
The MUTYH p.Ala287ProfsX32 variant was identified in 1 of 658 proband chromosomes (frequency: 0.002) from individuals or families with MUTYH associated polyposis, and was not identified in 116 control chromosomes from healthy individuals (Aretz 2006). The p.Ala287ProfsX32 variant was also identified in HGMD and the “InSiGHT Colon Cancer Database”. The p.Ala287ProfsX32 variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 287 and leads to a premature stop codon 32 codons downstream. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants in the MUTYH gene are an established mechanism of disease in MUTYH-associated polyposis. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic. (less)
Number of individuals with the variant: 1
|
Comment:
Comment:
This variant deletes 1 nucleotide in exon 10 of the MUTYH gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant (also known as c.817del in the literature) has been reported in an individual affected with MUTYH-associated polyposis (PMID: 16557584). This variant has also been identified in 1/250896 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.
Comment:
ACMG criteria used to clasify this variant:PVS1, PS4_SUP, PM2_SUP
Comment:
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 433934). This variant is also known as c.817delG, p.A273PfsX32. This premature translational stop signal has been observed in individual(s) with polyposis (PMID: 16557584). This variant is present in population databases (rs761468459, gnomAD 0.003%). This sequence change creates a premature translational stop signal (p.Ala287Profs*32) in the MUTYH gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MUTYH are known to be pathogenic (PMID: 18534194, 20663686).
Comment:
The c.859delG variant, located in coding exon 10 of the MUTYH gene, results from a deletion of one nucleotide at nucleotide position 859, causing a translational frameshift with a predicted alternate stop codon (p.A287Pfs*32). This variant (designated as MUTYH c.817delG p.A273PfsX32) has been reported in the heterozygous state in one individual with a clinical diagnosis of familial adenomatous polyposis (Aretz S et al. Int. J. Cancer. 2006 Aug;119:807-14). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Comment:
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Observed in the heterozygous state in an individual with a history of polyposis (PMID: 16557584); Also known as 817delG; This variant is associated with the following publications: (PMID: 16557584)
Comment:
The MUTYH p.Ala287ProfsX32 variant was identified in 1 of 658 proband chromosomes (frequency: 0.002) from individuals or families with MUTYH associated polyposis, and was not identified in 116 control chromosomes from healthy individuals (Aretz 2006). The p.Ala287ProfsX32 variant was also identified in HGMD and the “InSiGHT Colon Cancer Database”. The p.Ala287ProfsX32 variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 287 and leads to a premature stop codon 32 codons downstream. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants in the MUTYH gene are an established mechanism of disease in MUTYH-associated polyposis. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.
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:
The p.Ala287ProfsX32 variant in MUTYH has been reported in the heterozygous stat e in one individuals with familial adenomatouspolyposis (Aretz 20016). It has al so been identified in 1/30782 of South Asian chromosomes by gnomAD (http://gnoma d.broadinstitute.org). This variant is predicted to cause a frameshift, which al ters the protein?s amino acid sequence beginning at position 287 and leads to a premature termination codon 32 amino acids downstream. This alteration is then p redicted to lead to a truncated or absent protein. In summary, although addition al studies are required to fully establish its clinical significance, the p.Ala2 87ProfsX32 variant is likely pathogenic. ACMG/AMP Criteria applied: PVS1, PM2.
Comment:
This variant deletes 1 nucleotide in exon 10 of the MUTYH gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant (also known as c.817del in the literature) has been reported in an individual affected with MUTYH-associated polyposis (PMID: 16557584). This variant has also been identified in 1/250896 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.
Comment:
ACMG criteria used to clasify this variant:PVS1, PS4_SUP, PM2_SUP
Comment:
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 433934). This variant is also known as c.817delG, p.A273PfsX32. This premature translational stop signal has been observed in individual(s) with polyposis (PMID: 16557584). This variant is present in population databases (rs761468459, gnomAD 0.003%). This sequence change creates a premature translational stop signal (p.Ala287Profs*32) in the MUTYH gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MUTYH are known to be pathogenic (PMID: 18534194, 20663686).
Comment:
The c.859delG variant, located in coding exon 10 of the MUTYH gene, results from a deletion of one nucleotide at nucleotide position 859, causing a translational frameshift with a predicted alternate stop codon (p.A287Pfs*32). This variant (designated as MUTYH c.817delG p.A273PfsX32) has been reported in the heterozygous state in one individual with a clinical diagnosis of familial adenomatous polyposis (Aretz S et al. Int. J. Cancer. 2006 Aug;119:807-14). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Comment:
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Observed in the heterozygous state in an individual with a history of polyposis (PMID: 16557584); Also known as 817delG; This variant is associated with the following publications: (PMID: 16557584)
Comment:
The MUTYH p.Ala287ProfsX32 variant was identified in 1 of 658 proband chromosomes (frequency: 0.002) from individuals or families with MUTYH associated polyposis, and was not identified in 116 control chromosomes from healthy individuals (Aretz 2006). The p.Ala287ProfsX32 variant was also identified in HGMD and the “InSiGHT Colon Cancer Database”. The p.Ala287ProfsX32 variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 287 and leads to a premature stop codon 32 codons downstream. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants in the MUTYH gene are an established mechanism of disease in MUTYH-associated polyposis. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| MUTYH-associated polyposis (MAP). | Nielsen M | Critical reviews in oncology/hematology | 2011 | PMID: 20663686 |
| Characterization of mutant MUTYH proteins associated with familial colorectal cancer. | Ali M | Gastroenterology | 2008 | PMID: 18534194 |
| 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 |
Text-mined citations for rs761468459 ...
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 Oct 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.