ClinVar Genomic variation as it relates to human health
NM_000251.3(MSH2):c.1566C>G (p.Tyr522Ter)
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_000251.3(MSH2):c.1566C>G (p.Tyr522Ter)
Variation ID: 90699 Accession: VCV000090699.15
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2p21 2: 47466713 (GRCh38) [ NCBI UCSC ] 2: 47693852 (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 Mar 24, 2015 May 1, 2024 Sep 5, 2013 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000251.3:c.1566C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000242.1:p.Tyr522Ter nonsense NM_001258281.1:c.1368C>G NP_001245210.1:p.Tyr456Ter nonsense NC_000002.12:g.47466713C>G NC_000002.11:g.47693852C>G NG_007110.2:g.68590C>G LRG_218:g.68590C>G LRG_218t1:c.[1566C>G] - Protein change
- Y522*, Y456*
- Other names
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- Canonical SPDI
- NC_000002.12:47466712:C:G
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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.
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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
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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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MSH2 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
7313 | 7466 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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 (1) |
reviewed by expert panel
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Sep 5, 2013 | RCV000076195.4 | |
Pathogenic (1) |
no assertion criteria provided
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- | RCV001357508.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 4, 2022 | RCV001388417.6 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Aug 2, 2023 | RCV001823110.4 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 13, 2020 | RCV002399452.2 |
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
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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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Pathogenic
(Sep 05, 2013)
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reviewed by expert panel
Method: research
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Lynch Syndrome
Affected status: unknown
Allele origin:
germline
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International Society for Gastrointestinal Hereditary Tumours (InSiGHT)
Accession: SCV000107212.3
First in ClinVar: Dec 19, 2013 Last updated: Dec 24, 2022
Comment:
Classified with v1.9 guidelines: https://docs.google.com/file/d/0B3JL6rP6JzhoN2EydHRVMEI1UGs
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Comment:
Coding sequence variation introducing premature termination codon
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Lynch syndrome 1
Affected status: yes
Allele origin:
germline
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Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV002073154.1
First in ClinVar: Feb 04, 2022 Last updated: Feb 04, 2022 |
Comment:
The stop gained p.Y522* in MSH2 (NM_000251.3) has been previously reported in affected patients (Mangold E et al, Thompson BA et al). The variant has … (more)
The stop gained p.Y522* in MSH2 (NM_000251.3) has been previously reported in affected patients (Mangold E et al, Thompson BA et al). The variant has been submitted to ClinVar as Pathogenic. The p.Y522* variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been reported to be disease causing. For these reasons, this variant has been classified as Pathogenic. (less)
Clinical Features:
Vulvar adenocarcinoma (present) , Neuroendocrine neoplasm (present) , Colonic neoplasm (present)
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Pathogenic
(Aug 02, 2023)
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criteria provided, single submitter
Method: clinical testing
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Lynch syndrome 1
Affected status: unknown
Allele origin:
unknown
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Myriad Genetics, Inc.
Accession: SCV004188139.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
Comment:
This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
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Pathogenic
(Aug 04, 2022)
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criteria provided, single submitter
Method: clinical testing
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Hereditary nonpolyposis colorectal neoplasms
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001589396.4
First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Tyr522*) in the MSH2 gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Tyr522*) in the MSH2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MSH2 are known to be pathogenic (PMID: 15849733, 24362816). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Lynch syndrome (PMID: 15713769). ClinVar contains an entry for this variant (Variation ID: 90699). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Oct 13, 2020)
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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: SCV002709937.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.Y522* pathogenic mutation (also known as c.1566C>G), located in coding exon 10 of the MSH2 gene, results from a C to G substitution at … (more)
The p.Y522* pathogenic mutation (also known as c.1566C>G), located in coding exon 10 of the MSH2 gene, results from a C to G substitution at nucleotide position 1566. This changes the amino acid from a tyrosine to a stop codon within coding exon 10. This alteration was identified in multiple individuals diagnosed with colorectal cancer (Casey G et al. JAMA, 2005 Feb;293:799-809; Walker M et al. Br J Surg, 2007 Dec;94:1567-71). 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)
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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Endometrial carcinoma
Affected status: yes
Allele origin:
unknown
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Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV001552996.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
The MSH2 p.Tyr522* variant was identified in 2 of 488 proband chromosomes (frequency: 0.004) from individuals or families with colorectal cancer (Thompson 2013, Walker 2007). … (more)
The MSH2 p.Tyr522* variant was identified in 2 of 488 proband chromosomes (frequency: 0.004) from individuals or families with colorectal cancer (Thompson 2013, Walker 2007). The variant was also identified in dbSNP (ID: rs63750224) as "With Pathogenic allele", ClinVar (classified as pathogenic by an expert panel), Cosmic (1x in Lung tissue), and Insight Hereditary Tumors Database (8x as class 5). The variant was not identified in GeneInsight-COGR, UMD-LSDB, Zhejiang University Database, or Mismatch Repair Genes Variant Database. The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016) or the Genome Aggregation Database (Feb 27, 2017). The p.Tyr522* variant leads to a premature stop codon at position 522, which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the MSH2 gene are an established mechanism of disease in Lynch syndrome and this is the type of variant expected to cause the disorder. A functional study of the MSH2 c.1566C>G variant showed reduced expression of this allele (<90% of wild type) and the consequential loss of MSH2 and MSH6 protein expression (Casey 2005). Further, this variant was identified by our laboratory in a patient with an MSH2- and MSH6-deficient tumour. 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: 3
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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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Application of a 5-tiered scheme for standardized classification of 2,360 unique mismatch repair gene variants in the InSiGHT locus-specific database. | Thompson BA | Nature genetics | 2014 | PMID: 24362816 |
Selecting patients with young-onset colorectal cancer for mismatch repair gene analysis. | Walker M | The British journal of surgery | 2007 | PMID: 17665423 |
Spectrum and frequencies of mutations in MSH2 and MLH1 identified in 1,721 German families suspected of hereditary nonpolyposis colorectal cancer. | Mangold E | International journal of cancer | 2005 | PMID: 15849733 |
Conversion analysis for mutation detection in MLH1 and MSH2 in patients with colorectal cancer. | Casey G | JAMA | 2005 | PMID: 15713769 |
http://www.insight-database.org/classifications/index.html?gene=MSH2&variant=c.1566C%3EG | - | - | - | - |
Text-mined citations for rs63750224 ...
HelpRecord last updated May 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.