ClinVar Genomic variation as it relates to human health
NM_001048174.2(MUTYH):c.954G>A (p.Ser318=)
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.
Likely pathogenic(6); Uncertain significance(5)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001048174.2(MUTYH):c.954G>A (p.Ser318=)
Variation ID: 186251 Accession: VCV000186251.62
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1p34.1 1: 45797481 (GRCh37) [ NCBI UCSC ] 1: 45331809 (GRCh38) [ 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 Oct 9, 2016 Oct 8, 2024 Jun 10, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001048174.2:c.954G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001041639.1:p.Ser318= synonymous NM_001128425.2:c.1038G>A MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001121897.1:p.Ser346= synonymous NM_001048171.2:c.954G>A NP_001041636.2:p.Ser318= synonymous NM_001048172.2:c.957G>A NP_001041637.1:p.Ser319= synonymous NM_001048173.2:c.954G>A NP_001041638.1:p.Ser318= synonymous NM_001293190.2:c.999G>A NP_001280119.1:p.Ser333= synonymous NM_001293191.2:c.987G>A NP_001280120.1:p.Ser329= synonymous NM_001293192.2:c.678G>A NP_001280121.1:p.Ser226= synonymous NM_001293195.2:c.954G>A NP_001280124.1:p.Ser318= synonymous NM_001293196.2:c.678G>A NP_001280125.1:p.Ser226= synonymous NM_001350650.2:c.609G>A NP_001337579.1:p.Ser203= synonymous NM_001350651.2:c.609G>A NP_001337580.1:p.Ser203= synonymous NM_012222.3:c.1029G>A NP_036354.1:p.Ser343= synonymous NR_146882.2:n.1182G>A non-coding transcript variant NR_146883.2:n.1031G>A non-coding transcript variant NC_000001.11:g.45331809C>T NC_000001.10:g.45797481C>T NG_008189.1:g.13662G>A LRG_220:g.13662G>A LRG_220t1:c.1038G>A LRG_220p1:p.Ser346= - Protein change
- Other names
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- Canonical SPDI
- NC_000001.11:45331808:C:T
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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.
Trans-Omics for Precision Medicine (TOPMed) 0.00003
The Genome Aggregation Database (gnomAD) 0.00004
Exome Aggregation Consortium (ExAC) 0.00007
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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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
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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 |
2686 | 2842 |
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
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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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Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Feb 9, 2024 | RCV000165812.15 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Aug 15, 2023 | RCV000255834.6 | |
Conflicting interpretations of pathogenicity (4) |
criteria provided, conflicting classifications
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Jun 10, 2024 | RCV000459930.16 | |
Conflicting interpretations of pathogenicity (4) |
criteria provided, conflicting classifications
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Jan 19, 2024 | RCV000584863.36 |
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
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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
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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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Uncertain significance
(Mar 29, 2016)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000539817.1
First in ClinVar: Oct 09, 2016 Last updated: Oct 09, 2016 |
Comment:
Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or … (more)
Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Silent, 1 paper in HGMD (less)
Method: Genome/Exome Filtration
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Likely pathogenic
(Feb 09, 2024)
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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: SCV000216559.8
First in ClinVar: Mar 24, 2015 Last updated: May 01, 2024 |
Comment:
The c.1038G>A variant (also known as p.S346S), located in coding exon 12 of the MUTYH gene, results from a G to A substitution at nucleotide … (more)
The c.1038G>A variant (also known as p.S346S), located in coding exon 12 of the MUTYH gene, results from a G to A substitution at nucleotide position 1038. This nucleotide substitution does not change the serine amino acid at codon 346. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). This variant has been reported in the compound heterozygous state with different pathogenic MUTYH mutations in individuals with multiple adenomatous polyps (Olschwang S et al. Genet Test, 2007;11:315-20; Kairupan CF et al. Int. J. Cancer, 2005 Aug;116:73-7; Thibodeau ML et al. Cold Spring Harb Mol Case Stud, 2019 04;5; Ambry internal data). This variant was observed in an individual with early onset-breast cancer amongst a cohort of 1781 non-Ashkenazi Jewish individuals undergoing BRCA1/2 gene testing based on a personal history of breast cancer (Tung N et al. Cancer, 2015 Jan;121:25-33). Of note, this alteration is also designated as c.996G>A (p.S332S) in the literature. This nucleotide position is poorly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration may weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. Based on the majority of available evidence to date, this variant is likely to be pathogenic. (less)
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Uncertain significance
(Feb 07, 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:
unknown
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Baylor Genetics
Accession: SCV004198797.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
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Likely pathogenic
(Feb 01, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001480054.1
First in ClinVar: Feb 20, 2021 Last updated: Feb 20, 2021 |
Clinical Features:
Colon cancer (present) , Colorectal polyposis (present)
Sex: male
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Uncertain significance
(Nov 25, 2022)
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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: SCV000889517.4
First in ClinVar: Mar 03, 2018 Last updated: Jan 06, 2024 |
Comment:
The frequency of this variant in the general population, 0.0001 (11/108924 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the … (more)
The frequency of this variant in the general population, 0.0001 (11/108924 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in compound heterozygous individuals with colorectal adenomas and colorectal cancer (PMIDs: 17949294 (2007), 15761860 (2005)), pancreatic cancer (PMID: 30833417 (2019)), and in a heterozygous individual with breast cancer (PMID: 25186627 (2015)). The variant was shown to cause aberrant splicing in tumor RNA (PMID: 30833417 (2019)), however additional studies are needed to corroborate this finding in a germline context. Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on MUTYH mRNA splicing yielded predictions that this variant may result in the gain of a cryptic splice site without affecting the natural splice sites . Based on the available information, we are unable to determine the clinical significance of this variant. (less)
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Uncertain significance
(Mar 28, 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: SCV000685535.5
First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024 |
Comment:
This variant is a synonymous variant located in exon 12 of the MUTYH gene. This variant is also known as c.996G>A (p.Ser332=) in the literature … (more)
This variant is a synonymous variant located in exon 12 of the MUTYH gene. This variant is also known as c.996G>A (p.Ser332=) in the literature based on a different NM_001048171 transcript. Splice site prediction tools suggest that this variant may impact RNA splicing by the creation of a de novo splice acceptor site. Variant g.T is a reference nucleotide in most mammalian species including 4 primate species (https://genome.ucsc.edu/), suggesting that the variant is likely to be tolerated for MUTYH gene function. A RNA study has shown that this variant causes an in-frame deletion of the first 42 bps of exon 12 (r.998_1039del, p.Ala333_Ser346del; https://databases.lovd.nl/shared/variants/0000418407#00023838). The impacted region does not contain a known functional domain and does not show a high evolutionary conservation. To our knowledge, protein functional studies have not been reported for this variant. This variant has been identified in four individuals affected with adenomatous polyposis together with a known pathogenic mutation in the same gene (PMID: 15761860, 17949294, 30833417). Three of these probands were reported to be compound heterozygotes (PMID: 17949294, 30833417). This variant has also been identified in 11/242534 chromosomes (11/108924 Non-Finnish European 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)
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Likely pathogenic
(Jan 19, 2024)
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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: SCV000321910.13
First in ClinVar: Oct 09, 2016 Last updated: Sep 16, 2024 |
Comment:
Splice variant demonstrated to result in the creation of novel splice acceptor site which may result in the deletion of 14 amino acids of exon … (more)
Splice variant demonstrated to result in the creation of novel splice acceptor site which may result in the deletion of 14 amino acids of exon 12 (PMID: 30833417); In silico analysis supports a deleterious effect on splicing.; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 15761860, 17949294, 26269718, 25525159, 21520333, 34758253, 25186627, 34981295, 30833417, 16879101, 20816984) (less)
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Likely pathogenic
(Jun 10, 2024)
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criteria provided, single submitter
Method: clinical testing
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Familial adenomatous polyposis 2
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV005204925.1
First in ClinVar: Sep 16, 2024 Last updated: Sep 16, 2024 |
Comment:
Variant summary: MUTYH c.1038G>A (also reported as S332S, G996A or c.996G>A) alters a non-conserved nucleotide resulting in a synonymous change. Several computational tools predict a … (more)
Variant summary: MUTYH c.1038G>A (also reported as S332S, G996A or c.996G>A) alters a non-conserved nucleotide resulting in a synonymous change. Several computational tools predict a significant impact on normal splicing: Four predict the variant creates a 3' acceptor site. At least one publication reports experimental evidence that this variant affects mRNA splicing, resulting in an in-frame loss of 42 bp (example, Thibodeau_2019). The variant allele was found at a frequency of 4.5e-05 in 242534 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in MUTYH causing MUTYH-Associated Polyposis (4.5e-05 vs 0.0046), allowing no conclusion about variant significance. c.1038G>A has been reported in the literature in the simple heterozygous, presumed compound heterozygous, or compound heterozygous state in multiple individuals affected with MUTYH-Associated Polyposis, pancreatic ductal adenocarcinoma, and/or breast cancer (example, Kairupan_2005, Olschwang_2007, Tung_2015, Thibodeau_2019). These data indicate that the variant is likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 15761860, 17949294, 30833417, 25186627). ClinVar contains an entry for this variant (Variation ID: 186251). Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
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Likely pathogenic
(Jul 01, 2023)
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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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV000692628.29
First in ClinVar: Mar 03, 2018 Last updated: Oct 08, 2024 |
Comment:
MUTYH: PM3:Strong, PM2:Supporting, PP3
Number of individuals with the variant: 2
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Uncertain significance
(Aug 15, 2023)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV004024945.1
First in ClinVar: Aug 19, 2023 Last updated: Aug 19, 2023 |
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Likely pathogenic
(Dec 18, 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:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000545703.10
First in ClinVar: Apr 17, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change affects codon 346 of the MUTYH mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid … (more)
This sequence change affects codon 346 of the MUTYH mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the MUTYH protein. RNA analysis indicates that this variant induces altered splicing and likely results in the loss of 14 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. This variant is present in population databases (rs372673338, gnomAD 0.01%). This variant has been observed in individual(s) with breast and pancreatic cancers and/or colonic adenomas (PMID: 15761860, 17949294, 21520333, 25186627, 30833417; Invitae). 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 c.996G>A and p.S332S. ClinVar contains an entry for this variant (Variation ID: 186251). Studies have shown that this variant results in the activation of a cryptic splice site in exon 12 (PMID: 21520333, 30833417; Invitae). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. (less)
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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Familial adenomatous polyposis 2
Affected status: yes
Allele origin:
germline
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Genomics England Pilot Project, Genomics England
Accession: SCV001760034.1
First in ClinVar: Jul 27, 2021 Last updated: Jul 27, 2021 |
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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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Base excision repair deficiency signatures implicate germline and somatic MUTYH aberrations in pancreatic ductal adenocarcinoma and breast cancer oncogenesis. | Thibodeau ML | Cold Spring Harbor molecular case studies | 2019 | PMID: 30833417 |
RNA splicing. The human splicing code reveals new insights into the genetic determinants of disease. | Xiong HY | Science (New York, N.Y.) | 2015 | PMID: 25525159 |
Frequency of mutations in individuals with breast cancer referred for BRCA1 and BRCA2 testing using next-generation sequencing with a 25-gene panel. | Tung N | Cancer | 2015 | PMID: 25186627 |
LOVD v.2.0: the next generation in gene variant databases. | Fokkema IF | Human mutation | 2011 | PMID: 21520333 |
Similar colorectal cancer risk in patients with monoallelic and biallelic mutations in the MYH gene identified in a population with adenomatous polyposis. | Olschwang S | Genetic testing | 2007 | PMID: 17949294 |
Mutation analysis of the MYH gene in an Australian series of colorectal polyposis patients with or without germline APC mutations. | Kairupan CF | International journal of cancer | 2005 | PMID: 15761860 |
Text-mined citations for rs372673338 ...
HelpRecord last updated Oct 08, 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.