ClinVar Genomic variation as it relates to human health
NM_000179.3(MSH6):c.3416G>A (p.Gly1139Asp)
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.
Likely pathogenic(3); Uncertain significance(3)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000179.3(MSH6):c.3416G>A (p.Gly1139Asp)
Variation ID: 581014 Accession: VCV000581014.17
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2p16.3 2: 47803663 (GRCh38) [ NCBI UCSC ] 2: 48030802 (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 Oct 10, 2018 Oct 8, 2024 May 27, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000179.3:c.3416G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000170.1:p.Gly1139Asp missense NM_001281492.2:c.3026G>A NP_001268421.1:p.Gly1009Asp missense NM_001281493.2:c.2510G>A NP_001268422.1:p.Gly837Asp missense NM_001281494.2:c.2510G>A NP_001268423.1:p.Gly837Asp missense NC_000002.12:g.47803663G>A NC_000002.11:g.48030802G>A NG_007111.1:g.25517G>A LRG_219:g.25517G>A LRG_219t1:c.3416G>A LRG_219p1:p.Gly1139Asp - Protein change
- G1139D, G1009D, G837D
- Other names
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- Canonical SPDI
- NC_000002.12:47803662: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
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00000
- 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 |
9157 | 9471 |
Conditions - Germline
Condition
Help
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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Uncertain significance (1) |
criteria provided, single submitter
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Aug 28, 2023 | RCV000704717.8 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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May 27, 2024 | RCV001524596.6 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Mar 26, 2024 | RCV003453499.3 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Sep 14, 2023 | RCV004721570.1 |
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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Uncertain significance
(Nov 03, 2020)
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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: SCV001734517.1
First in ClinVar: Jun 19, 2021 Last updated: Jun 19, 2021 |
Comment:
This missense variant replaces a conserved glycine with aspartic acid at codon 1139 in the ATPase domain (the Walker A motif) of the MSH6 protein. … (more)
This missense variant replaces a conserved glycine with aspartic acid at codon 1139 in the ATPase domain (the Walker A motif) of the MSH6 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant protein and its equivalent in the mouse and budding yeast MSH6 homologs are defective in DNA mismatch repair and associated activities (PMID: 9819445, 31965077). To our knowledge, this variant has not been reported in individuals affected with hereditary cancer in the literature. However, a different missense variant p.Gly1139Ser has been observed in at least two individuals affected with Lynch syndrome (PMID: 16203774, 18301448) and found to be defective in DNA mismatch repair and related functional assays (PMID: 22102614, 24040339, 28531214, 31965077). This variant has been identified in 1/251346 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Although there is a suspicion that this variant may be associated with disease, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
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Likely pathogenic
(Aug 23, 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: SCV004185559.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
Comment:
This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 31965077]. This variant is expected to disrupt protein structure [Myriad … (more)
This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 31965077]. This variant is expected to disrupt protein structure [Myriad internal data]. (less)
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Uncertain significance
(Aug 28, 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: SCV000833676.6
First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024 |
Comment:
In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant … (more)
In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (PMID: 32123317). Experimental studies have shown that this missense change affects MSH6 function (PMID: 31965077). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MSH6 protein function. ClinVar contains an entry for this variant (Variation ID: 581014). This variant has not been reported in the literature in individuals affected with MSH6-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.003%). This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 1139 of the MSH6 protein (p.Gly1139Asp). (less)
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Uncertain significance
(Mar 26, 2024)
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criteria provided, single submitter
Method: clinical testing
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Lynch syndrome 5
Affected status: unknown
Allele origin:
germline
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Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004807259.1
First in ClinVar: Apr 06, 2024 Last updated: Apr 06, 2024 |
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Likely pathogenic
(May 27, 2024)
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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: SCV002618551.3
First in ClinVar: Nov 29, 2022 Last updated: Aug 11, 2024 |
Comment:
The p.G1139D variant (also known as c.3416G>A), located in coding exon 5 of the MSH6 gene, results from a G to A substitution at nucleotide … (more)
The p.G1139D variant (also known as c.3416G>A), located in coding exon 5 of the MSH6 gene, results from a G to A substitution at nucleotide position 3416. The glycine at codon 1139 is replaced by aspartic acid, an amino acid with similar properties. This variant has been identified in a proband whose Lynch syndrome-associated tumor demonstrated loss of MSH6 expression by immunohistochemistry (Ambry internal data). Another variant at the same codon, p.G1139S (c.3415G>A), demonstrated deficient mismatch repair activity in functional studies and was detected in individuals with MSI-H colorectal tumors that showed loss of MSH2 and/or MSH6 expression by immunohistochemistry (Drost M et al. Hum Mutat, 2012 Mar;33:488-94; Wielders EA et al. PLoS One, 2013 Sep;8:e74766; Houlleberghs H et al. PLoS Genet, 2017 May;13:e1006765; Drost M et al. Genet Med, 2020 05;22:847-856; Woods MO et al. Clin Cancer Res, 2005 Oct;11:6853-61; Steinke V et al. Eur J Hum Genet, 2008 May;16:587-92). Based on internal structural analysis, G1139D disrupts a key position in the MSH6 phosphate-binding motif (Walker JE et al. EMBO J, 1982;1:945-51; Antony E et al. DNA Repair (Amst), 2006 Feb;5:153-62; Warren JJ et al. Mol Cell, 2007 May;26:579-92; Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. (less)
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Likely pathogenic
(Sep 14, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV005326749.1
First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024 |
Comment:
Published functional studies demonstrate reduced mismatch repair (MMR) activity (Drost et al., 2020); Not observed at significant frequency in large population cohorts (gnomAD); In silico … (more)
Published functional studies demonstrate reduced mismatch repair (MMR) activity (Drost et al., 2020); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 37076482, 32123317, 31965077, 21120944, 12019211, 17531815) (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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Blood RNA analysis can increase clinical diagnostic rate and resolve variants of uncertain significance. | Wai HA | Genetics in medicine : official journal of the American College of Medical Genetics | 2020 | PMID: 32123317 |
Two integrated and highly predictive functional analysis-based procedures for the classification of MSH6 variants in Lynch syndrome. | Drost M | Genetics in medicine : official journal of the American College of Medical Genetics | 2020 | PMID: 31965077 |
Structure of the human MutSalpha DNA lesion recognition complex. | Warren JJ | Molecular cell | 2007 | PMID: 17531815 |
Contribution of Msh2 and Msh6 subunits to the asymmetric ATPase and DNA mismatch binding activities of Saccharomyces cerevisiae Msh2-Msh6 mismatch repair protein. | Antony E | DNA repair | 2006 | PMID: 16214425 |
Distantly related sequences in the alpha- and beta-subunits of ATP synthase, myosin, kinases and other ATP-requiring enzymes and a common nucleotide binding fold. | Walker JE | The EMBO journal | 1982 | PMID: 6329717 |
Text-mined citations for rs1316409501 ...
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.