For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals affected with MSH6-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Glu226*) in the MSH6 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MSH6 are known to be pathogenic (PMID: 18269114, 24362816).
ClinVar Genomic variation as it relates to human health
NM_000179.3(MSH6):c.675dup (p.Glu226Ter)
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.
(2)
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
2
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000179.3(MSH6):c.675dup (p.Glu226Ter)
Variation ID: 2027774 Accession: VCV002027774.3
- Type and length
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Duplication, 1 bp
- Location
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Cytogenetic: 2p16.3 2: 47798656-47798657 (GRCh38) [ NCBI UCSC ] 2: 48025795-48025796 (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 Feb 8, 2023 Feb 20, 2024 Aug 29, 2022 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000179.3:c.675dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000170.1:p.Glu226Ter nonsense NM_001281492.2:c.285dup NP_001268421.1:p.Glu96Ter nonsense NM_001281493.2:c.-232dup 5 prime UTR NM_001281494.2:c.-232dup 5 prime UTR NM_001406795.1:c.771dup NP_001393724.1:p.Glu258Terfs frameshift nonsense NM_001406796.1:c.675dup NP_001393725.1:p.Glu226Terfs frameshift nonsense NM_001406797.1:c.378dup NP_001393726.1:p.Glu127Terfs frameshift nonsense NM_001406798.1:c.675dup NP_001393727.1:p.Glu226Terfs frameshift nonsense NM_001406799.1:c.150dup NP_001393728.1:p.Glu51Terfs frameshift nonsense NM_001406800.1:c.675dup NP_001393729.1:p.Glu226Terfs frameshift nonsense NM_001406801.1:c.378dup NP_001393730.1:p.Glu127Terfs frameshift nonsense NM_001406802.1:c.771dup NP_001393731.1:p.Glu258Terfs frameshift nonsense NM_001406803.1:c.675dup NP_001393732.1:p.Glu226Terfs frameshift nonsense NM_001406804.1:c.597dup NP_001393733.1:p.Glu200Terfs frameshift nonsense NM_001406805.1:c.378dup NP_001393734.1:p.Glu127Terfs frameshift nonsense NM_001406806.1:c.150dup NP_001393735.1:p.Glu51Terfs frameshift nonsense NM_001406807.1:c.150dup NP_001393736.1:p.Glu51Terfs frameshift nonsense NM_001406808.1:c.675dup NP_001393737.1:p.Glu226Terfs frameshift nonsense NM_001406809.1:c.675dup NP_001393738.1:p.Glu226Terfs frameshift nonsense NM_001406811.1:c.-232dup NM_001406812.1:c.-232dup NM_001406813.1:c.681dup NP_001393742.1:p.Glu228Terfs frameshift nonsense NM_001406814.1:c.-232dup NM_001406815.1:c.-232dup NM_001406816.1:c.-232dup NM_001406817.1:c.675dup NP_001393746.1:p.Glu226Terfs frameshift nonsense NM_001406818.1:c.378dup NP_001393747.1:p.Glu127Terfs frameshift nonsense NM_001406819.1:c.378dup NP_001393748.1:p.Glu127Terfs frameshift nonsense NM_001406820.1:c.378dup NP_001393749.1:p.Glu127Terfs frameshift nonsense NM_001406821.1:c.378dup NP_001393750.1:p.Glu127Terfs frameshift nonsense NM_001406822.1:c.378dup NP_001393751.1:p.Glu127Terfs frameshift nonsense NM_001406823.1:c.-232dup NM_001406824.1:c.378dup NP_001393753.1:p.Glu127Terfs frameshift nonsense NM_001406825.1:c.378dup NP_001393754.1:p.Glu127Terfs frameshift nonsense NM_001406826.1:c.507dup NP_001393755.1:p.Glu170Terfs frameshift nonsense NM_001406827.1:c.378dup NP_001393756.1:p.Glu127Terfs frameshift nonsense NM_001406828.1:c.378dup NP_001393757.1:p.Glu127Terfs frameshift nonsense NM_001406829.1:c.-232dup NM_001406830.1:c.378dup NP_001393759.1:p.Glu127Terfs frameshift nonsense NR_176257.1:n.764dup NR_176258.1:n.764dup NR_176259.1:n.764dup NR_176261.1:n.764dup NC_000002.12:g.47798658dup NC_000002.11:g.48025797dup NG_007111.1:g.20512dup LRG_219:g.20512dup LRG_219t1:c.675dup LRG_219p1:p.Glu226Terfs - Protein change
- E226*, E96*
- Other names
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- Canonical SPDI
- NC_000002.12:47798656:TT:TTT
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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
Help
The frequency of the allele represented by this VCV record.
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- 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. |
|||
| MSH6 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
9159 | 9475 | |
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. |
|---|---|---|---|---|
| Likely pathogenic (1) |
criteria provided, single submitter
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Jun 28, 2022 | RCV003464620.1 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Aug 29, 2022 | RCV002866787.3 |
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. |
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|---|---|---|---|---|---|
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Likely pathogenic
(Jun 28, 2022)
|
criteria provided, single submitter
Method: clinical testing
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Endometrial carcinoma
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004198144.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Aug 29, 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
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV003233541.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 20, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals affected with MSH6-related conditions. … (more)
For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals affected with MSH6-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Glu226*) in the MSH6 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MSH6 are known to be pathogenic (PMID: 18269114, 24362816). (less)
|
Comment:
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:
For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals affected with MSH6-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Glu226*) in the MSH6 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MSH6 are known to be pathogenic (PMID: 18269114, 24362816).
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| 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 |
| Germline MSH6 mutations are more prevalent in endometrial cancer patient cohorts than hereditary non polyposis colorectal cancer cohorts. | Devlin LA | The Ulster medical journal | 2008 | PMID: 18269114 |
Text-mined citations for this variant ...
HelpRecord last updated Sep 29, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.