ClinVar Genomic variation as it relates to human health
NM_000179.3(MSH6):c.3843_3847dup (p.Ile1283fs)
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.3843_3847dup (p.Ile1283fs)
Variation ID: 2119724 Accession: VCV002119724.3
- Type and length
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Duplication, 5 bp
- Location
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Cytogenetic: 2p16.3 2: 47806491-47806492 (GRCh38) [ NCBI UCSC ] 2: 48033630-48033631 (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 25, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000179.3:c.3843_3847dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000170.1:p.Ile1283fs frameshift NM_001281492.2:c.3453_3457dup NP_001268421.1:p.Ile1153fs frameshift NM_001281493.2:c.2937_2941dup NP_001268422.1:p.Ile981fs frameshift NM_001281494.2:c.2937_2941dup NP_001268423.1:p.Ile981fs frameshift NM_001406795.1:c.3939_3943dup NP_001393724.1:p.Ile1315Argfs frameshift NM_001406796.1:c.3843_3847dup NP_001393725.1:p.Ile1283Argfs frameshift NM_001406797.1:c.3546_3550dup NP_001393726.1:p.Ile1184Argfs frameshift NM_001406798.1:c.3669_3673dup NP_001393727.1:p.Ile1225Argfs frameshift NM_001406799.1:c.3318_3322dup NP_001393728.1:p.Ile1108Argfs frameshift NM_001406800.1:c.3830_3834dup NP_001393729.1:p.Leu1279Aspfs frameshift NM_001406801.1:c.3546_3550dup NP_001393730.1:p.Ile1184Argfs frameshift NM_001406803.1:c.2979_2983dup NP_001393732.1:p.Ile995Argfs frameshift NM_001406804.1:c.3765_3769dup NP_001393733.1:p.Ile1257Argfs frameshift NM_001406805.1:c.3546_3550dup NP_001393734.1:p.Ile1184Argfs frameshift NM_001406806.1:c.3318_3322dup NP_001393735.1:p.Ile1108Argfs frameshift NM_001406807.1:c.3318_3322dup NP_001393736.1:p.Ile1108Argfs frameshift NM_001406808.1:c.3843_3847dup NP_001393737.1:p.Ile1283Argfs frameshift NM_001406809.1:c.3843_3847dup NP_001393738.1:p.Ile1283Argfs frameshift NM_001406811.1:c.2937_2941dup NP_001393740.1:p.Ile981Argfs frameshift NM_001406812.1:c.2937_2941dup NP_001393741.1:p.Ile981Argfs frameshift NM_001406813.1:c.3849_3853dup NP_001393742.1:p.Ile1285Argfs frameshift NM_001406814.1:c.2937_2941dup NP_001393743.1:p.Ile981Argfs frameshift NM_001406815.1:c.2937_2941dup NP_001393744.1:p.Ile981Argfs frameshift NM_001406816.1:c.2937_2941dup NP_001393745.1:p.Ile981Argfs frameshift NM_001406817.1:c.2277_2281dup NP_001393746.1:p.Ile761Argfs frameshift NM_001406818.1:c.3546_3550dup NP_001393747.1:p.Ile1184Argfs frameshift NM_001406819.1:c.3546_3550dup NP_001393748.1:p.Ile1184Argfs frameshift NM_001406820.1:c.3546_3550dup NP_001393749.1:p.Ile1184Argfs frameshift NM_001406821.1:c.3546_3550dup NP_001393750.1:p.Ile1184Argfs frameshift NM_001406822.1:c.3546_3550dup NP_001393751.1:p.Ile1184Argfs frameshift NM_001406823.1:c.2937_2941dup NP_001393752.1:p.Ile981Argfs frameshift NM_001406824.1:c.3546_3550dup NP_001393753.1:p.Ile1184Argfs frameshift NM_001406825.1:c.3546_3550dup NP_001393754.1:p.Ile1184Argfs frameshift NM_001406826.1:c.3675_3679dup NP_001393755.1:p.Ile1227Argfs frameshift NM_001406827.1:c.3546_3550dup NP_001393756.1:p.Ile1184Argfs frameshift NM_001406828.1:c.3546_3550dup NP_001393757.1:p.Ile1184Argfs frameshift NM_001406829.1:c.2937_2941dup NP_001393758.1:p.Ile981Argfs frameshift NM_001406830.1:c.3546_3550dup NP_001393759.1:p.Ile1184Argfs frameshift NM_001406831.1:c.624_628dup NP_001393760.1:p.Ile210Argfs frameshift NM_001406832.1:c.690_694dup NP_001393761.1:p.Ile232Argfs frameshift NM_001407362.1:c.1788_1792dup NP_001394291.1:p.Ile598Argfs frameshift NR_176256.1:n.2773_2777dup NR_176257.1:n.4104_4108dup NR_176258.1:n.4033_4037dup NR_176259.1:n.3932_3936dup NR_176260.1:n.1877_1881dup NR_176261.1:n.3814_3818dup NC_000002.12:g.47806493_47806497dup NC_000002.11:g.48033632_48033636dup NG_007111.1:g.28347_28351dup NG_008397.1:g.104180_104184dup LRG_219:g.28347_28351dup LRG_219t1:c.3843_3847dup LRG_219p1:p.Ile1283Argfs - Protein change
- I1283fs, I981fs, I1153fs
- Other names
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- Canonical SPDI
- NC_000002.12:47806491:AGACTA:AGACTAGACTA
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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
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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
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 |
9149 | 9460 |
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
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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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Oct 27, 2022 | RCV003033238.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 25, 2023 | RCV003455665.1 |
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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Pathogenic
(Aug 25, 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: SCV004187354.1
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
(Oct 27, 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: SCV003337144.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 20, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Ile1283Argfs*46) in the MSH6 gene. While this is not anticipated to result in nonsense mediated decay, … (more)
This sequence change creates a premature translational stop signal (p.Ile1283Argfs*46) in the MSH6 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 78 amino acid(s) of the MSH6 protein. For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the MSH6 protein in which other variant(s) (p.Arg1331*) have been determined to be pathogenic (PMID: 16034045, 16418736, 18301448, 19851887, 20587412, 21056691, 21155762, 21642682, 27601186). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. 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). (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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Mismatch repair gene mutation spectrum in the Swedish Lynch syndrome population. | Lagerstedt-Robinson K | Oncology reports | 2016 | PMID: 27601186 |
Cancer risks associated with germline mutations in MLH1, MSH2, and MSH6 genes in Lynch syndrome. | Bonadona V | JAMA | 2011 | PMID: 21642682 |
Characterization of two Ashkenazi Jewish founder mutations in MSH6 gene causing Lynch syndrome. | Raskin L | Clinical genetics | 2011 | PMID: 21155762 |
Prevalence of alterations in DNA mismatch repair genes in patients with young-onset colorectal cancer. | Limburg PJ | Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association | 2011 | PMID: 21056691 |
Current clinical criteria for Lynch syndrome are not sensitive enough to identify MSH6 mutation carriers. | Sjursen W | Journal of medical genetics | 2010 | PMID: 20587412 |
An Ashkenazi founder mutation in the MSH6 gene leading to HNPCC. | Goldberg Y | Familial cancer | 2010 | PMID: 19851887 |
No association between MUTYH and MSH6 germline mutations in 64 HNPCC patients. | Steinke V | European journal of human genetics : EJHG | 2008 | PMID: 18301448 |
Compound heterozygosity for two MSH6 mutations in a patient with early onset of HNPCC-associated cancers, but without hematological malignancy and brain tumor. | Plaschke J | European journal of human genetics : EJHG | 2006 | PMID: 16418736 |
Immunohistochemistry identifies carriers of mismatch repair gene defects causing hereditary nonpolyposis colorectal cancer. | Stormorken AT | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2005 | PMID: 16034045 |
Text-mined citations for this variant ...
HelpRecord last updated Feb 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.