Multifactorial likelihood analysis posterior probability >0.99
ClinVar Genomic variation as it relates to human health
NM_000179.3(MSH6):c.3647-1G>A
Germline
Top reviewed classifications are shown here.
Submission summary:
Reviewed by expert panel
Pathogenic
Sep 2013 by
International …
for
Lynch Syndrome
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.3647-1G>A
Variation ID: 89434 Accession: VCV000089434.29
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2p16.3 2: 47806203 (GRCh38) [ NCBI UCSC ] 2: 48033342 (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 Mar 24, 2015 Aug 4, 2024 Sep 5, 2013 - HGVS
- ... more HGVS ... less HGVS
- Protein change
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- Other names
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- Canonical SPDI
- NC_000002.12:47806202:G:A
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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 |
9164 | 9483 | |
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) |
reviewed by expert panel
|
Sep 5, 2013 | RCV000074902.7 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Oct 17, 2019 | RCV000491917.4 | |
| Pathogenic (1) |
criteria provided, single submitter
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Jul 16, 2023 | RCV000791366.10 | |
| Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Jul 31, 2024 | RCV001781398.13 | |
| Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Aug 24, 2023 | RCV002467438.4 |
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
(Sep 05, 2013)
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reviewed by expert panel
Method: research
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Lynch Syndrome
Affected status: unknown
Allele origin:
germline
|
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)
Accession: SCV000108114.3
First in ClinVar: Dec 19, 2013 Last updated: Dec 24, 2022
Comment:
Classified with v1.9 guidelines: https://docs.google.com/file/d/0B3JL6rP6JzhoN2EydHRVMEI1UGs
|
Comment:
Multifactorial likelihood analysis posterior probability >0.99
|
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Pathogenic
(Feb 01, 2019)
|
criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV002017580.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Oct 17, 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: SCV000580144.6
First in ClinVar: Jun 25, 2017 Last updated: May 01, 2024 |
Comment:
The c.3647-1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide upstream from coding exon 8 of the MSH6 gene. This mutation … (more)
The c.3647-1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide upstream from coding exon 8 of the MSH6 gene. This mutation has been reported in multiple individuals having features of or meeting clinical diagnostic criteria for hereditary non-polyposis colorectal cancer (HNPCC)/Lynch syndrome (Ambry internal data; Nilbert M et al Fam. Cancer 2009;8(1):75-83; Therkildsen C et al Eur. J. Neurol. 2015 Apr;22(4):717-24; Klarskov L et al Am. J. Surg. Pathol. 2011 Sep;35(9):1391-9; Okkels H et al Appl. Immunohistochem. Mol. Morphol. 2012;20(5):470-7; Yurgelun MB et al Gastroenterology 2015;149(3):604-613). This mutation has also been detected in a man with prostate cancer whose tumor showed loss of the MSH6 protein on immunohistochemistry (Dominguez-Valentin M et al. BMC Urol, 2016 Mar;16:15). In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and may result in the creation or strengthening of a novel splice acceptor site; however, direct evidence is insufficient at this time (Ambry internal data). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation. (less)
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Pathogenic
(Dec 09, 2022)
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criteria provided, single submitter
Method: research
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Lynch syndrome 5
Affected status: no
Allele origin:
germline
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Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV002762827.2
First in ClinVar: Dec 17, 2022 Last updated: Feb 25, 2023 |
Comment:
PVS1, PS4_MOD, PM2_SUP, PP1
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Likely pathogenic
(Aug 24, 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: SCV004189250.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
Comment:
This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either … (more)
This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function. (less)
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Pathogenic
(Jul 16, 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
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000253780.8
First in ClinVar: Oct 11, 2015 Last updated: Feb 28, 2024 |
Comment:
This sequence change affects an acceptor splice site in intron 7 of the MSH6 gene. It is expected to disrupt RNA splicing. Variants that disrupt … (more)
This sequence change affects an acceptor splice site in intron 7 of the MSH6 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and 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). Disruption of this splice site has been observed in individual(s) with Lynch syndrome (PMID: 18566915, 21836479). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 89434). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Jul 31, 2024)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV002552355.7
First in ClinVar: Jul 28, 2022 Last updated: Aug 04, 2024 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV002034937.1 First in ClinVar: Dec 18, 2021 Last updated: Dec 18, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV002035907.1 First in ClinVar: Dec 18, 2021 Last updated: Dec 18, 2021 |
|
Comment:
Comment:
The c.3647-1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide upstream from coding exon 8 of the MSH6 gene. This mutation has been reported in multiple individuals having features of or meeting clinical diagnostic criteria for hereditary non-polyposis colorectal cancer (HNPCC)/Lynch syndrome (Ambry internal data; Nilbert M et al Fam. Cancer 2009;8(1):75-83; Therkildsen C et al Eur. J. Neurol. 2015 Apr;22(4):717-24; Klarskov L et al Am. J. Surg. Pathol. 2011 Sep;35(9):1391-9; Okkels H et al Appl. Immunohistochem. Mol. Morphol. 2012;20(5):470-7; Yurgelun MB et al Gastroenterology 2015;149(3):604-613). This mutation has also been detected in a man with prostate cancer whose tumor showed loss of the MSH6 protein on immunohistochemistry (Dominguez-Valentin M et al. BMC Urol, 2016 Mar;16:15). In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and may result in the creation or strengthening of a novel splice acceptor site; however, direct evidence is insufficient at this time (Ambry internal data). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation.
Comment:
PVS1, PS4_MOD, PM2_SUP, PP1
Comment:
This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function.
Comment:
This sequence change affects an acceptor splice site in intron 7 of the MSH6 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and 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). Disruption of this splice site has been observed in individual(s) with Lynch syndrome (PMID: 18566915, 21836479). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 89434). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus 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:
Multifactorial likelihood analysis posterior probability >0.99
Comment:
The c.3647-1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide upstream from coding exon 8 of the MSH6 gene. This mutation has been reported in multiple individuals having features of or meeting clinical diagnostic criteria for hereditary non-polyposis colorectal cancer (HNPCC)/Lynch syndrome (Ambry internal data; Nilbert M et al Fam. Cancer 2009;8(1):75-83; Therkildsen C et al Eur. J. Neurol. 2015 Apr;22(4):717-24; Klarskov L et al Am. J. Surg. Pathol. 2011 Sep;35(9):1391-9; Okkels H et al Appl. Immunohistochem. Mol. Morphol. 2012;20(5):470-7; Yurgelun MB et al Gastroenterology 2015;149(3):604-613). This mutation has also been detected in a man with prostate cancer whose tumor showed loss of the MSH6 protein on immunohistochemistry (Dominguez-Valentin M et al. BMC Urol, 2016 Mar;16:15). In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and may result in the creation or strengthening of a novel splice acceptor site; however, direct evidence is insufficient at this time (Ambry internal data). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation.
Comment:
PVS1, PS4_MOD, PM2_SUP, PP1
Comment:
This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function.
Comment:
This sequence change affects an acceptor splice site in intron 7 of the MSH6 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and 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). Disruption of this splice site has been observed in individual(s) with Lynch syndrome (PMID: 18566915, 21836479). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 89434). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus 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 |
|---|---|---|---|---|
| Frequent mismatch-repair defects link prostate cancer to Lynch syndrome. | Dominguez-Valentin M | BMC urology | 2016 | PMID: 27013479 |
| Identification of a Variety of Mutations in Cancer Predisposition Genes in Patients With Suspected Lynch Syndrome. | Yurgelun MB | Gastroenterology | 2015 | PMID: 25980754 |
| Glioblastomas, astrocytomas and oligodendrogliomas linked to Lynch syndrome. | Therkildsen C | European journal of neurology | 2015 | PMID: 25648859 |
| 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 |
| MSH6 mutations are frequent in hereditary nonpolyposis colorectal cancer families with normal pMSH6 expression as detected by immunohistochemistry. | Okkels H | Applied immunohistochemistry & molecular morphology : AIMM | 2012 | PMID: 22495361 |
| Challenges in the identification of MSH6-associated colorectal cancer: rectal location, less typical histology, and a subset with retained mismatch repair function. | Klarskov L | The American journal of surgical pathology | 2011 | PMID: 21836479 |
| Mismatch repair defective breast cancer in the hereditary nonpolyposis colorectal cancer syndrome. | Jensen UB | Breast cancer research and treatment | 2010 | PMID: 19575290 |
| Major contribution from recurrent alterations and MSH6 mutations in the Danish Lynch syndrome population. | Nilbert M | Familial cancer | 2009 | PMID: 18566915 |
| 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 |
| Splicing in action: assessing disease causing sequence changes. | Baralle D | Journal of medical genetics | 2005 | PMID: 16199547 |
| http://www.insight-database.org/classifications/index.html?gene=MSH6&variant=c.3647-1G%3EA | - | - | - | - |
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Text-mined citations for rs587779279 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record 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.