ClinVar Genomic variation as it relates to human health
NM_000179.3(MSH6):c.4001+4_4001+8dup
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.4001+4_4001+8dup
Variation ID: 142961 Accession: VCV000142961.27
- Type and length
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Duplication, 5 bp
- Location
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Cytogenetic: 2p16.3 2: 47806653-47806654 (GRCh38) [ NCBI UCSC ] 2: 48033792-48033793 (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 May 27, 2015 Oct 8, 2024 Jan 18, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000179.3:c.4001+4_4001+8dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
intron variant NM_000179.3:c.4001+4_4001+8dupACTAA MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_000179.2:c.4001+4_4001+8dupACTAA NM_001281492.2:c.3611+4_3611+8dup intron variant NM_001281493.2:c.3095+4_3095+8dup intron variant NM_001281494.2:c.3095+4_3095+8dup intron variant NC_000002.12:g.47806655_47806659dup NC_000002.11:g.48033794_48033798dup NG_007111.1:g.28509_28513dup NG_008397.1:g.104018_104022dup LRG_219:g.28509_28513dup LRG_219t1:c.4001+4_4001+8dup - Protein change
- Other names
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- Canonical SPDI
- NC_000002.12:47806653:AACTAA:AACTAAACTAA
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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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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
Help
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
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
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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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Benign/Likely benign (3) |
criteria provided, multiple submitters, no conflicts
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Oct 1, 2019 | RCV000132454.9 | |
Likely benign (2) |
criteria provided, single submitter
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Apr 8, 2020 | RCV000196451.11 | |
Benign/Likely benign (3) |
criteria provided, multiple submitters, no conflicts
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Mar 29, 2023 | RCV000409890.5 | |
Likely benign (1) |
criteria provided, single submitter
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Jan 18, 2024 | RCV001080987.10 | |
Likely benign (1) |
criteria provided, single submitter
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Dec 29, 2023 | RCV003488398.1 | |
MSH6-related disorder
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Likely benign (1) |
no assertion criteria provided
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Mar 19, 2024 | RCV004739463.1 |
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
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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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Likely benign
(Dec 13, 2016)
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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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Color Diagnostics, LLC DBA Color Health
Accession: SCV000902893.1
First in ClinVar: May 20, 2019 Last updated: May 20, 2019 |
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Likely benign
(May 28, 2019)
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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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Mendelics
Accession: SCV001135860.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
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Likely benign
(Apr 08, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000601599.3
First in ClinVar: Sep 30, 2017 Last updated: Jan 26, 2021 |
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Likely benign
(Oct 11, 2016)
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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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Counsyl
Accession: SCV000489495.2
First in ClinVar: Jan 06, 2017 Last updated: Dec 24, 2022 |
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Likely benign
(Dec 29, 2023)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004241761.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
Comment:
Variant summary: MSH6 c.4001+4_4001+8dupACTAA alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly … (more)
Variant summary: MSH6 c.4001+4_4001+8dupACTAA alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 5.1e-05 in 1600866 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in MSH6 causing Lynch Syndrome (5.1e-05 vs 0.00014), allowing no conclusion about variant significance. c.4001+4_4001+8dupACTAA has been reported in the literature at-least one hereditary cancer sample (example: Watson_2013). This report does not provide unequivocal conclusions about association of the variant with Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 24307375). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as likely benign. (less)
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Likely benign
(Jan 18, 2024)
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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: SCV000253115.12
First in ClinVar: Oct 11, 2015 Last updated: Feb 20, 2024 |
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Likely benign
(Oct 01, 2019)
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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: SCV000187548.9
First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024 |
Comment:
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more)
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
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Benign
(Sep 17, 2014)
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criteria provided, single submitter
Method: clinical testing
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Neoplastic Syndromes, Hereditary
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000211367.2
First in ClinVar: Feb 24, 2015 Last updated: May 27, 2015 |
Comment:
The variant is found in BR-OV-HEREDIC panel(s).
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Benign
(Mar 29, 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: SCV004019009.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
Comment:
This variant is considered benign. This variant is intronic and is not expected to impact mRNA splicing. This variant is strongly associated with less severe … (more)
This variant is considered benign. This variant is intronic and is not expected to impact mRNA splicing. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. (less)
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Likely benign
(Mar 19, 2024)
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no assertion criteria provided
Method: clinical testing
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MSH6-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV005358370.1
First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024 |
Comment:
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
unknown
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Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV000592667.2 First in ClinVar: Aug 28, 2017 Last updated: Apr 13, 2021 |
Comment:
The MSH6 c.4001+4_4001+8dup variant was identified in 1 of 256 proband chromosomes (frequency: 0.004) from individuals or families with hereditary cancer (Watson 2013). The variant … (more)
The MSH6 c.4001+4_4001+8dup variant was identified in 1 of 256 proband chromosomes (frequency: 0.004) from individuals or families with hereditary cancer (Watson 2013). The variant was also identified in dbSNP (ID: rs781320845) as “other”, Clinvitae database (conflicting interpretations of pathogenicity), ClinVar database (as uncertain significance by Ambry Genetics, likely benign by Invitae, benign by GeneDx) and UMD (1x with an “unclassified variant” classification). The variant was not identified in GeneInsight - COGR database, InSiGHT Colon Cancer Gene Variant Database (LOVD), Zhejiang Colon Cancer Database (LOVD), “Mismatch Repair Genes Variant Database”, “MMR Gene Unclassified Variants Database” . The variant was identified in the Exome Aggregation Consortium database (August 8, 2016) in 4 of 111884 chromosomes (freq. 3.58x10-5) in the following populations: European (Non-Finnish) in 4 of 61054 but was not seen in African, East Asian, Finnish, Latino, Other or South Asian populations. In addition this variant was identified in case in our laboratory as co-occurring with a pathogenic MLH1 p.Lys751SerfsX3 variant, increasing the likelihood that it does not have clinical significance. The c.4001+4_4001+8dup variant is located in the 5' splice region but does not affect the invariant +1 and +2 positions. However, positions +3 to +6 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. However, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. (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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Development and validation of a new algorithm for the reclassification of genetic variants identified in the BRCA1 and BRCA2 genes. | Pruss D | Breast cancer research and treatment | 2014 | PMID: 25085752 |
Robust diagnostic genetic testing using solution capture enrichment and a novel variant-filtering interface. | Watson CM | Human mutation | 2014 | PMID: 24307375 |
Text-mined citations for rs587782853 ...
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.