ClinVar Genomic variation as it relates to human health
NM_000179.3(MSH6):c.-2G>T
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.
Uncertain significance(6); Likely benign(4)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000179.3(MSH6):c.-2G>T
Variation ID: 142219 Accession: VCV000142219.25
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 2p16.3 2: 47783232 (GRCh38) [ NCBI UCSC ] 2: 48010371 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Oct 11, 2015 Aug 4, 2024 Jul 31, 2024 - HGVS
- ... more HGVS ... less HGVS
- Protein change
- Other names
- -
- Canonical SPDI
- NC_000002.12:47783231:G:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
-
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.
-
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD) 0.00003
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. |
|||
MSH6 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
9149 | 9462 |
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. |
---|---|---|---|---|
Likely benign (2) |
criteria provided, multiple submitters, no conflicts
|
Jul 17, 2018 | RCV000131214.21 | |
Uncertain significance (2) |
criteria provided, single submitter
|
Jun 13, 2015 | RCV000199508.12 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
|
Jun 30, 2023 | RCV000588323.17 | |
Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
|
Jul 31, 2024 | RCV001818322.17 | |
Uncertain significance (1) |
criteria provided, single submitter
|
Jan 5, 2023 | RCV003492616.1 | |
MSH6-related disorder
|
Likely benign (1) |
criteria provided, single submitter
|
May 23, 2019 | RCV004532569.1 |
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. |
|
---|---|---|---|---|---|
Uncertain significance
(Jun 13, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
Lynch syndrome
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000254236.2
First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015 |
Comment:
This sequence change falls in the 5' UTR promoter region of the MSH6 gene. It does not change the encoded amino acid sequence of the … (more)
This sequence change falls in the 5' UTR promoter region of the MSH6 gene. It does not change the encoded amino acid sequence of the MSH6 protein. This variant has not been published in the literature and is present in population databases (rs374748889, 0.02%). ClinVar contains an entry for this variant (RCV000131214). In summary, this is a rare 5' non-coding change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. (less)
|
|
Uncertain significance
(Aug 27, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: no
Allele origin:
germline
|
Genetic Services Laboratory, University of Chicago
Accession: SCV002070924.1
First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022 |
Comment:
DNA sequence analysis of the MSH6 gene demonstrated a homozygous sequence change in the 5√¢‚Ǩ‚Ñ¢ UTR, c.-2G>T. This sequence change has been described in the … (more)
DNA sequence analysis of the MSH6 gene demonstrated a homozygous sequence change in the 5’ UTR, c.-2G>T. This sequence change has been described in the gnomAD database with a frequency of 0.01% in the East Asian subpopulation (dbSNP rs374748889). This sequence change is not clearly predicted to have a deleterious effect on splicing based on in silico splice prediction programs. This change does not appear to have been previously described in individuals with MSH6-related disorders. The functional significance of this sequence change is not known at present and its contribution to this individual's disease phenotype cannot definitively be determined. (less)
|
|
Uncertain significance
(Jan 05, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Breast and/or ovarian cancer
Affected status: unknown
Allele origin:
germline
|
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Accession: SCV004239311.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
|
|
Uncertain significance
(Jul 31, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV005090462.1
First in ClinVar: Aug 04, 2024 Last updated: Aug 04, 2024 |
|
|
Likely benign
(Apr 25, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV000910735.1
First in ClinVar: May 20, 2019 Last updated: May 20, 2019 |
|
|
Likely benign
(Sep 27, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000211375.11
First in ClinVar: Feb 24, 2015 Last updated: Mar 04, 2023 |
Comment:
This variant is associated with the following publications: (PMID: 26888055)
|
|
Uncertain significance
(Jun 30, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000601552.4
First in ClinVar: Mar 08, 2017 Last updated: Jan 06, 2024 |
Comment:
In the published literature, the variant has been reported in a tumor sample from an individual with colorectal cancer (PMID: 34197922 (2021)). The frequency of … (more)
In the published literature, the variant has been reported in a tumor sample from an individual with colorectal cancer (PMID: 34197922 (2021)). The frequency of this variant in the general population, 0.000015 (4/275398 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Based on the available information, we are unable to determine the clinical significance of this variant. (less)
|
|
Likely benign
(May 23, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
MSH6-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004735006.1
First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 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).
|
|
Likely benign
(Jul 17, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000186165.9
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)
|
|
Uncertain significance
(Nov 15, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000695836.4
First in ClinVar: Mar 17, 2018 Last updated: Jun 09, 2024 |
Comment:
Variant summary: MSH6 c.-2G>T alters a non-conserved nucleotide located in the untranslated mRNA region upstream of the initiation codon. The variant allele was found at … (more)
Variant summary: MSH6 c.-2G>T alters a non-conserved nucleotide located in the untranslated mRNA region upstream of the initiation codon. The variant allele was found at a frequency of 1.2e-05 in 244064 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.-2G>T has been reported in the literature (example, Liu_2016), however, this report does not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer/Lynch syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments (likely benign, n=3;VUS, n=3). Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
|
|
Uncertain significance
(-)
|
no assertion criteria provided
Method: clinical testing
|
Lynch syndrome
Affected status: yes
Allele origin:
unknown
|
Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV000592560.2 First in ClinVar: Mar 08, 2017 Last updated: Apr 13, 2021 |
Comment:
MSH6, EXON1, c.-2G>T, r.(spl)?, Heterozygous, Uncertain Significance The MSH6 c.-2G>T variant was not identified in the literature in an affected population. The variant was identified … (more)
MSH6, EXON1, c.-2G>T, r.(spl)?, Heterozygous, Uncertain Significance The MSH6 c.-2G>T variant was not identified in the literature in an affected population. The variant was identified in dbSNP (ID: rs374748889 as “With other allele”) and ClinVar (classified as likely benign by GeneDx and classified as uncertain significance by Ambry Genetics, Invitae, COGR, Quest Diagnostics, and Integrated Genetics). The variant was not identified in Cosmic, MutDB, UMD-LSDB, Zhejiang University Database, Mismatch Repair Genes Variant Database or Insight Hereditary Tumors database. The variant was identified in control databases in 5 of 270534 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 1 of 6350 chromosomes (freq: 0.0002), East Asian in 3 of 18528 chromosomes (freq: 0.0002), and South Asian in 1 of 30416 chromosomes (freq: 0.00003); it was not observed in the African, Latino, European Non-Finnish, Ashkenazi Jewish or Finnish populations. The variant was previously identified by our laboratory in 1 individual with endometrial and ovarian cancer as co-occurring with a pathogenic PMS2 variant (c.2500_2501delinsG, p.Met834Glyfs*17), increasing the likelihood that the MSH6 c.-2G>T variant does not have clinical significance. The variant is located in the MSH6 promoter region (Liu 2016), which could result in reduced gene expression but further study would be needed to confirm this. 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)
|
|
click to load more click to collapse |
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 |
---|---|---|---|---|
Use of Treatment-Focused Tumor Sequencing to Screen for Germline Cancer Predisposition. | Lau TTY | The Journal of molecular diagnostics : JMD | 2021 | PMID: 34197922 |
Clinical laboratories collaborate to resolve differences in variant interpretations submitted to ClinVar. | Harrison SM | Genetics in medicine : official journal of the American College of Medical Genetics | 2017 | PMID: 28301460 |
Understanding the Pathogenicity of Noncoding Mismatch Repair Gene Promoter Variants in Lynch Syndrome. | Liu Q | Human mutation | 2016 | PMID: 26888055 |
Text-mined citations for rs374748889 ...
HelpRecord last updated Sep 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.