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.Thr1282Asnfs*7) 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.3844dup (p.Thr1282fs)
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.
(1)
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
1
criteria provided, single submitter
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.3844dup (p.Thr1282fs)
Variation ID: 2732833 Accession: VCV002732833.1
- Type and length
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Duplication, 1 bp
- Location
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Cytogenetic: 2p16.3 2: 47806493-47806494 (GRCh38) [ NCBI UCSC ] 2: 48033632-48033633 (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 14, 2024 Feb 14, 2024 Jun 29, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000179.3:c.3844dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000170.1:p.Thr1282fs frameshift NM_001281492.2:c.3454dup NP_001268421.1:p.Thr1152fs frameshift NM_001281493.2:c.2938dup NP_001268422.1:p.Thr980fs frameshift NM_001281494.2:c.2938dup NP_001268423.1:p.Thr980fs frameshift NM_001406795.1:c.3940dup NP_001393724.1:p.Thr1314fs frameshift NM_001406796.1:c.3844dup NP_001393725.1:p.Thr1282fs frameshift NM_001406797.1:c.3547dup NP_001393726.1:p.Thr1183fs frameshift NM_001406798.1:c.3670dup NP_001393727.1:p.Thr1224fs frameshift NM_001406799.1:c.3319dup NP_001393728.1:p.Thr1107fs frameshift NM_001406800.1:c.3831dup NP_001393729.1:p.Leu1278fs frameshift NM_001406801.1:c.3547dup NP_001393730.1:p.Thr1183fs frameshift NM_001406802.1:c.3897+136dup intron variant NM_001406803.1:c.2980dup NP_001393732.1:p.Thr994fs frameshift NM_001406804.1:c.3766dup NP_001393733.1:p.Thr1256fs frameshift NM_001406805.1:c.3547dup NP_001393734.1:p.Thr1183fs frameshift NM_001406806.1:c.3319dup NP_001393735.1:p.Thr1107fs frameshift NM_001406807.1:c.3319dup NP_001393736.1:p.Thr1107fs frameshift NM_001406808.1:c.3844dup NP_001393737.1:p.Thr1282fs frameshift NM_001406809.1:c.3844dup NP_001393738.1:p.Thr1282fs frameshift NM_001406811.1:c.2938dup NP_001393740.1:p.Thr980fs frameshift NM_001406812.1:c.2938dup NP_001393741.1:p.Thr980fs frameshift NM_001406813.1:c.3850dup NP_001393742.1:p.Thr1284fs frameshift NM_001406814.1:c.2938dup NP_001393743.1:p.Thr980fs frameshift NM_001406815.1:c.2938dup NP_001393744.1:p.Thr980fs frameshift NM_001406816.1:c.2938dup NP_001393745.1:p.Thr980fs frameshift NM_001406817.1:c.2278dup NP_001393746.1:p.Thr760fs frameshift NM_001406818.1:c.3547dup NP_001393747.1:p.Thr1183fs frameshift NM_001406819.1:c.3547dup NP_001393748.1:p.Thr1183fs frameshift NM_001406820.1:c.3547dup NP_001393749.1:p.Thr1183fs frameshift NM_001406821.1:c.3547dup NP_001393750.1:p.Thr1183fs frameshift NM_001406822.1:c.3547dup NP_001393751.1:p.Thr1183fs frameshift NM_001406823.1:c.2938dup NP_001393752.1:p.Thr980fs frameshift NM_001406824.1:c.3547dup NP_001393753.1:p.Thr1183fs frameshift NM_001406825.1:c.3547dup NP_001393754.1:p.Thr1183fs frameshift NM_001406826.1:c.3676dup NP_001393755.1:p.Thr1226fs frameshift NM_001406827.1:c.3547dup NP_001393756.1:p.Thr1183fs frameshift NM_001406828.1:c.3547dup NP_001393757.1:p.Thr1183fs frameshift NM_001406829.1:c.2938dup NP_001393758.1:p.Thr980fs frameshift NM_001406830.1:c.3547dup NP_001393759.1:p.Thr1183fs frameshift NM_001406831.1:c.625dup NP_001393760.1:p.Thr209fs frameshift NM_001406832.1:c.691dup NP_001393761.1:p.Thr231fs frameshift NM_001407362.1:c.1789dup NP_001394291.1:p.Thr597fs frameshift NR_176256.1:n.2774dup non-coding transcript variant NR_176257.1:n.4105dup non-coding transcript variant NR_176258.1:n.4034dup non-coding transcript variant NR_176259.1:n.3933dup non-coding transcript variant NR_176260.1:n.1878dup NR_176261.1:n.3815dup non-coding transcript variant NC_000002.12:g.47806494dup NC_000002.11:g.48033633dup NG_007111.1:g.28348dup NG_008397.1:g.104182dup LRG_219:g.28348dup LRG_219t1:c.3844dup LRG_219p1:p.Thr1282Asnfs - Protein change
- T1107fs, T1224fs, T597fs, T760fs, L1278fs, T1152fs, T1284fs, T209fs, T231fs, T980fs, T994fs, T1183fs, T1226fs, T1256fs, T1282fs, T1314fs
- Other names
- -
- Canonical SPDI
- NC_000002.12:47806493:A:AA
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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.
- -
- 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 |
9161 | 9479 | |
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 (1) |
criteria provided, single submitter
|
Jun 29, 2023 | RCV003595560.2 |
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
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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Pathogenic
(Jun 29, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary nonpolyposis colorectal neoplasms
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV004291380.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 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.Thr1282Asnfs*7) 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.Thr1282Asnfs*7) 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 30, 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.