This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
ClinVar Genomic variation as it relates to human health
NM_000179.3(MSH6):c.2332_2335dup (p.Cys779fs)
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
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.2332_2335dup (p.Cys779fs)
Variation ID: 2673762 Accession: VCV002673762.2
- Type and length
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Duplication, 4 bp
- Location
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Cytogenetic: 2p16.3 2: 47800314-47800315 (GRCh38) [ NCBI UCSC ] 2: 48027453-48027454 (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 Dec 25, 2023 Feb 14, 2024 Dec 15, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000179.3:c.2332_2335dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000170.1:p.Cys779fs frameshift NM_001281492.2:c.1942_1945dup NP_001268421.1:p.Cys649fs frameshift NM_001281493.2:c.1426_1429dup NP_001268422.1:p.Cys477fs frameshift NM_001281494.2:c.1426_1429dup NP_001268423.1:p.Cys477fs frameshift NM_001406795.1:c.2428_2431dup NP_001393724.1:p.Cys811fs frameshift NM_001406796.1:c.2332_2335dup NP_001393725.1:p.Cys779fs frameshift NM_001406797.1:c.2035_2038dup NP_001393726.1:p.Cys680fs frameshift NM_001406798.1:c.2332_2335dup NP_001393727.1:p.Cys779fs frameshift NM_001406799.1:c.1807_1810dup NP_001393728.1:p.Cys604fs frameshift NM_001406800.1:c.2332_2335dup NP_001393729.1:p.Cys779fs frameshift NM_001406801.1:c.2035_2038dup NP_001393730.1:p.Cys680fs frameshift NM_001406802.1:c.2428_2431dup NP_001393731.1:p.Cys811fs frameshift NM_001406803.1:c.2308+24_2308+27dup intron variant NM_001406804.1:c.2254_2257dup NP_001393733.1:p.Cys753fs frameshift NM_001406805.1:c.2035_2038dup NP_001393734.1:p.Cys680fs frameshift NM_001406806.1:c.1807_1810dup NP_001393735.1:p.Cys604fs frameshift NM_001406807.1:c.1807_1810dup NP_001393736.1:p.Cys604fs frameshift NM_001406808.1:c.2332_2335dup NP_001393737.1:p.Cys779fs frameshift NM_001406809.1:c.2332_2335dup NP_001393738.1:p.Cys779fs frameshift NM_001406811.1:c.1426_1429dup NP_001393740.1:p.Cys477fs frameshift NM_001406812.1:c.1426_1429dup NP_001393741.1:p.Cys477fs frameshift NM_001406813.1:c.2338_2341dup NP_001393742.1:p.Cys781fs frameshift NM_001406814.1:c.1426_1429dup NP_001393743.1:p.Cys477fs frameshift NM_001406815.1:c.1426_1429dup NP_001393744.1:p.Cys477fs frameshift NM_001406816.1:c.1426_1429dup NP_001393745.1:p.Cys477fs frameshift NM_001406817.1:c.1606+726_1606+729dup intron variant NM_001406818.1:c.2035_2038dup NP_001393747.1:p.Cys680fs frameshift NM_001406819.1:c.2035_2038dup NP_001393748.1:p.Cys680fs frameshift NM_001406820.1:c.2035_2038dup NP_001393749.1:p.Cys680fs frameshift NM_001406821.1:c.2035_2038dup NP_001393750.1:p.Cys680fs frameshift NM_001406822.1:c.2035_2038dup NP_001393751.1:p.Cys680fs frameshift NM_001406823.1:c.1426_1429dup NP_001393752.1:p.Cys477fs frameshift NM_001406824.1:c.2035_2038dup NP_001393753.1:p.Cys680fs frameshift NM_001406825.1:c.2035_2038dup NP_001393754.1:p.Cys680fs frameshift NM_001406826.1:c.2164_2167dup NP_001393755.1:p.Cys723fs frameshift NM_001406827.1:c.2035_2038dup NP_001393756.1:p.Cys680fs frameshift NM_001406828.1:c.2035_2038dup NP_001393757.1:p.Cys680fs frameshift NM_001406829.1:c.1426_1429dup NP_001393758.1:p.Cys477fs frameshift NM_001406830.1:c.2035_2038dup NP_001393759.1:p.Cys680fs frameshift NM_001407362.1:c.628-351_628-348dup intron variant NR_176256.1:n.1194_1197dup non-coding transcript variant NR_176257.1:n.2421_2424dup non-coding transcript variant NR_176258.1:n.2421_2424dup non-coding transcript variant NR_176259.1:n.2421_2424dup non-coding transcript variant NR_176261.1:n.2421_2424dup non-coding transcript variant NC_000002.12:g.47800315_47800318dup NC_000002.11:g.48027454_48027457dup NG_007111.1:g.22169_22172dup LRG_219:g.22169_22172dup LRG_219t1:c.2332_2335dup LRG_219p1:p.Cys779Serfs - Protein change
- C477fs, C604fs, C649fs, C680fs, C723fs, C753fs, C779fs, C781fs, C811fs
- Other names
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- Canonical SPDI
- NC_000002.12:47800314:CTTT:CTTTCTTT
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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. |
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| 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. |
|---|---|---|---|---|
| Pathogenic (1) |
criteria provided, single submitter
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Aug 16, 2023 | RCV003450399.1 | |
| Pathogenic (1) |
criteria provided, single submitter
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Dec 15, 2023 | RCV003594678.2 |
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
(Aug 16, 2023)
|
criteria provided, single submitter
Method: clinical testing
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Lynch syndrome 5
Affected status: unknown
Allele origin:
unknown
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Myriad Genetics, Inc.
Accession: SCV004187339.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
Comment:
This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
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Pathogenic
(Dec 15, 2023)
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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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV004293911.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Cys779Serfs*7) in the MSH6 gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Cys779Serfs*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). 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: 28874130). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. (less)
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Comment:
Comment:
This sequence change creates a premature translational stop signal (p.Cys779Serfs*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). 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: 28874130). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been 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:
This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Comment:
This sequence change creates a premature translational stop signal (p.Cys779Serfs*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). 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: 28874130). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| A survey of the clinicopathological and molecular characteristics of patients with suspected Lynch syndrome in Latin America. | Rossi BM | BMC cancer | 2017 | PMID: 28874130 |
| 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 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.