ClinVar Genomic variation as it relates to human health
NM_000179.3(MSH6):c.1990dup (p.Ser664fs)
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_000179.3(MSH6):c.1990dup (p.Ser664fs)
Variation ID: 2674009 Accession: VCV002674009.3
- Type and length
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Duplication, 1 bp
- Location
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Cytogenetic: 2p16.3 2: 47799971-47799972 (GRCh38) [ NCBI UCSC ] 2: 48027110-48027111 (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 May 1, 2024 Nov 14, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000179.3:c.1990dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000170.1:p.Ser664fs frameshift NM_000179.2:c.1990dupT NM_001281492.2:c.1600dup NP_001268421.1:p.Ser534fs frameshift NM_001281493.2:c.1084dup NP_001268422.1:p.Ser362fs frameshift NM_001281494.2:c.1084dup NP_001268423.1:p.Ser362fs frameshift NM_001406795.1:c.2086dup NP_001393724.1:p.Ser696fs frameshift NM_001406796.1:c.1990dup NP_001393725.1:p.Ser664fs frameshift NM_001406797.1:c.1693dup NP_001393726.1:p.Ser565fs frameshift NM_001406798.1:c.1990dup NP_001393727.1:p.Ser664fs frameshift NM_001406799.1:c.1465dup NP_001393728.1:p.Ser489fs frameshift NM_001406800.1:c.1990dup NP_001393729.1:p.Ser664fs frameshift NM_001406801.1:c.1693dup NP_001393730.1:p.Ser565fs frameshift NM_001406802.1:c.2086dup NP_001393731.1:p.Ser696fs frameshift NM_001406803.1:c.1990dup NP_001393732.1:p.Ser664fs frameshift NM_001406804.1:c.1912dup NP_001393733.1:p.Ser638fs frameshift NM_001406805.1:c.1693dup NP_001393734.1:p.Ser565fs frameshift NM_001406806.1:c.1465dup NP_001393735.1:p.Ser489fs frameshift NM_001406807.1:c.1465dup NP_001393736.1:p.Ser489fs frameshift NM_001406808.1:c.1990dup NP_001393737.1:p.Ser664fs frameshift NM_001406809.1:c.1990dup NP_001393738.1:p.Ser664fs frameshift NM_001406811.1:c.1084dup NP_001393740.1:p.Ser362fs frameshift NM_001406812.1:c.1084dup NP_001393741.1:p.Ser362fs frameshift NM_001406813.1:c.1996dup NP_001393742.1:p.Ser666fs frameshift NM_001406814.1:c.1084dup NP_001393743.1:p.Ser362fs frameshift NM_001406815.1:c.1084dup NP_001393744.1:p.Ser362fs frameshift NM_001406816.1:c.1084dup NP_001393745.1:p.Ser362fs frameshift NM_001406817.1:c.1606+384dup intron variant NM_001406818.1:c.1693dup NP_001393747.1:p.Ser565fs frameshift NM_001406819.1:c.1693dup NP_001393748.1:p.Ser565fs frameshift NM_001406820.1:c.1693dup NP_001393749.1:p.Ser565fs frameshift NM_001406821.1:c.1693dup NP_001393750.1:p.Ser565fs frameshift NM_001406822.1:c.1693dup NP_001393751.1:p.Ser565fs frameshift NM_001406823.1:c.1084dup NP_001393752.1:p.Ser362fs frameshift NM_001406824.1:c.1693dup NP_001393753.1:p.Ser565fs frameshift NM_001406825.1:c.1693dup NP_001393754.1:p.Ser565fs frameshift NM_001406826.1:c.1822dup NP_001393755.1:p.Ser608fs frameshift NM_001406827.1:c.1693dup NP_001393756.1:p.Ser565fs frameshift NM_001406828.1:c.1693dup NP_001393757.1:p.Ser565fs frameshift NM_001406829.1:c.1084dup NP_001393758.1:p.Ser362fs frameshift NM_001406830.1:c.1693dup NP_001393759.1:p.Ser565fs frameshift NM_001407362.1:c.628-693dup intron variant NR_176256.1:n.852dup non-coding transcript variant NR_176257.1:n.2079dup non-coding transcript variant NR_176258.1:n.2079dup non-coding transcript variant NR_176259.1:n.2079dup non-coding transcript variant NR_176261.1:n.2079dup non-coding transcript variant NC_000002.12:g.47799973dup NC_000002.11:g.48027112dup NG_007111.1:g.21827dup LRG_219:g.21827dup LRG_219t1:c.1990dup LRG_219p1:p.Ser664Phefs - Protein change
- S362fs, S489fs, S534fs, S565fs, S608fs, S638fs, S664fs, S666fs, S696fs
- Other names
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- Canonical SPDI
- NC_000002.12:47799971: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
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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
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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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MSH6 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
9153 | 9466 |
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
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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) |
criteria provided, single submitter
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Nov 14, 2023 | RCV003450610.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 30, 2023 | RCV003759862.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 24, 2023 | RCV004364756.1 |
Submissions - Germline
Classification
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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
(Nov 14, 2023)
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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: SCV004186018.1
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
(Mar 30, 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: SCV004451359.1
First in ClinVar: Feb 20, 2024 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.Ser664Phefs*4) 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)
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Pathogenic
(Sep 24, 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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Ambry Genetics
Accession: SCV005032822.1
First in ClinVar: May 01, 2024 Last updated: May 01, 2024 |
Comment:
The c.1990dupT pathogenic mutation, located in coding exon 4 of the MSH6 gene, results from a duplication of T at nucleotide position 1990, causing a … (more)
The c.1990dupT pathogenic mutation, located in coding exon 4 of the MSH6 gene, results from a duplication of T at nucleotide position 1990, causing a translational frameshift with a predicted alternate stop codon (p.S664Ffs*4). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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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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 |
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.