ClinVar Genomic variation as it relates to human health
NM_000179.3(MSH6):c.2092C>G (p.Gln698Glu)
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(10); Likely benign(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000179.3(MSH6):c.2092C>G (p.Gln698Glu)
Variation ID: 89251 Accession: VCV000089251.40
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 2p16.3 2: 47800075 (GRCh38) [ NCBI UCSC ] 2: 48027214 (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 Mar 24, 2015 Aug 4, 2024 Mar 13, 2024 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000179.3:c.2092C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000170.1:p.Gln698Glu missense NM_001281492.2:c.1702C>G NP_001268421.1:p.Gln568Glu missense NM_001281493.2:c.1186C>G NP_001268422.1:p.Gln396Glu missense NM_001281494.2:c.1186C>G NP_001268423.1:p.Gln396Glu missense NC_000002.12:g.47800075C>G NC_000002.11:g.48027214C>G NG_007111.1:g.21929C>G LRG_219:g.21929C>G LRG_219t1:c.2092C>G LRG_219p1:p.Gln698Glu P52701:p.Gln698Glu - Protein change
- Q698E, Q568E, Q396E
- Other names
- -
- Canonical SPDI
- NC_000002.12:47800074:C:G
-
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.
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00001
The Genome Aggregation Database (gnomAD) 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00002
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 |
9148 | 9458 |
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. |
---|---|---|---|---|
Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
|
Aug 5, 2023 | RCV000130187.17 | |
Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
|
Mar 1, 2024 | RCV000480300.21 | |
Likely benign (1) |
criteria provided, single submitter
|
Feb 1, 2024 | RCV000524131.10 | |
Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
|
Jul 7, 2023 | RCV000662368.3 | |
Uncertain significance (1) |
criteria provided, single submitter
|
Aug 15, 2023 | RCV003320553.2 | |
Uncertain significance (1) |
criteria provided, single submitter
|
Mar 13, 2024 | RCV003466939.2 |
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
(Jul 07, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Lynch syndrome 5
Affected status: yes
Allele origin:
unknown
|
KCCC/NGS Laboratory, Kuwait Cancer Control Center
Accession: SCV004015201.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
Comment:
This sequence change replaces glutamine, which is neutral and polar, with glutamic acid, which is acidic and polar, at codon 698 of the MSH6 protein … (more)
This sequence change replaces glutamine, which is neutral and polar, with glutamic acid, which is acidic and polar, at codon 698 of the MSH6 protein (p.Gln698Glu). This variant is present in population databases (rs63750832, gnomAD 0.003%). This missense change has been observed in individual(s) with colorectal cancer and/or suspected Lynch syndrome PMID: 25133505, 10480359, 22290698, 23621914, 26333163, 18566915, 32635641, 31391288). ClinVar contains an entry for this variant (Variation ID: 89251) with 6 submissions, all of which describe it as of uncertain significance. (less)
|
|
Likely benign
(Feb 01, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary nonpolyposis colorectal neoplasms
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV000254291.12
First in ClinVar: Oct 11, 2015 Last updated: Feb 14, 2024 |
|
|
Uncertain significance
(Jun 01, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV000685254.6
First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces glutamine with glutamic acid at codon 698 of the MSH6 protein. Computational prediction suggests that this variant may not impact protein … (more)
This missense variant replaces glutamine with glutamic acid at codon 698 of the MSH6 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with or suspected of having Lynch syndrome (PMID: 10480359, 25133505, 31391288, 32635641). This variant has been identified in 2/250646 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 functional and clinical 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)
|
|
Uncertain significance
(Mar 13, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Endometrial carcinoma
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004197559.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
|
|
Uncertain significance
(Mar 01, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV002585790.13
First in ClinVar: Oct 22, 2022 Last updated: Aug 04, 2024 |
Comment:
MSH6: PP2, BP4
Number of individuals with the variant: 2
|
|
Uncertain significance
(May 02, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Lynch syndrome 5
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000784759.2
First in ClinVar: Jul 15, 2018 Last updated: Jul 15, 2018 |
|
|
Uncertain significance
(Oct 27, 2021)
|
criteria provided, single submitter
Method: curation
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Sema4, Sema4
Accession: SCV002535696.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Comment:
The MSH6 c.2092C>G (p.Q698E) variant has been reported in heterozygosity in at least five individuals with Lynch syndrome-related tumors (PMID: 25133505, 10480359, 18566915, 32635641, 31391288). … (more)
The MSH6 c.2092C>G (p.Q698E) variant has been reported in heterozygosity in at least five individuals with Lynch syndrome-related tumors (PMID: 25133505, 10480359, 18566915, 32635641, 31391288). It has also been reported in 10/60466 breast cancer cases and 4/53461 healthy controls by a large case-control study (PMID: 33471991). This variant was observed in 2/113040 chromosomes in the Non-Finnish European population according to the Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654), and has been reported in ClinVar (Variation ID: 89251). Functional studies have not been performed, and in silico predictions of the variant's effect on protein function are inconclusive. Based on the current evidence available, this variant is interpreted as a variant of uncertain significance. (less)
|
|
|
Uncertain significance
(Mar 29, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Lynch syndrome 5
Affected status: unknown
Allele origin:
unknown
|
Myriad Genetics, Inc.
Accession: SCV004018997.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
Comment:
This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
|
|
Uncertain significance
(Aug 15, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV004024792.1
First in ClinVar: Aug 19, 2023 Last updated: Aug 19, 2023 |
|
|
Uncertain significance
(Aug 11, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000567405.7
First in ClinVar: Apr 29, 2017 Last updated: Aug 18, 2023 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in … (more)
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with a personal and/or family history of colorectal cancer (Wang et al., 1999; Nilbert et al., 2009; Loizidou et al., 2014; Damaso et al., 2020); This variant is associated with the following publications: (PMID: 25133505, 10480359, 22290698, 23621914, 26333163, 18566915, 32635641, 31391288, 34426522, 17531815, 21120944, 33471991) (less)
|
|
Uncertain significance
(Aug 05, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000185024.9
First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024 |
Comment:
The p.Q698E variant (also known as c.2092C>G), located in coding exon 4 of the MSH6 gene, results from a C to G substitution at nucleotide … (more)
The p.Q698E variant (also known as c.2092C>G), located in coding exon 4 of the MSH6 gene, results from a C to G substitution at nucleotide position 2092. The glutamine at codon 698 is replaced by glutamic acid, an amino acid with highly similar properties. In one study, this alteration was detected in 1/115 Caucasian Lynch-like syndrome patients harboring MMR deficient tumors and/or microsatellite instability (MSI) and called a variant of uncertain significance (Dámaso E et al. Cancers (Basel), 2020 Jul;12:). In another study, this alteration was reported as a variant of uncertain significance in one individual from a Danish hereditary colorectal cancer registry and was reported in an individual with colorectal cancer at age 65 from a Cypriot cohort of 77 patients fulfilling revised Bethesda guidelines (Nilbert M et al. Fam. Cancer. 2009 Jun;8:75-83; Loizidou MA et al. PLoS ONE. 2014 Aug;9:e105501). This alteration has also been reported in a familial colorectal cancer kindred (Wang Q et al. Hum. Genet. 1999;105:79-85). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
|
|
Uncertain significance
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
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: SCV001550863.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
The MSH6 p.Gln698Glu variant was identified in 3 of 2420 proband chromosomes (frequency: 0.001) from French, Danish and Cypriot individuals or families with Lynch Syndrome … (more)
The MSH6 p.Gln698Glu variant was identified in 3 of 2420 proband chromosomes (frequency: 0.001) from French, Danish and Cypriot individuals or families with Lynch Syndrome and was not identified in 100 control chromosomes from healthy individuals (Wang 1999, Nilbert 2009, Loizidou 2014). Using 2 different bioinformatics tools predicting the impact of missense variants in the MSH6 gene, it was found that variant is neutral (Terui 2013, Ali 2012). The variant was also identified in dbSNP (ID: rs63750832) as “With Uncertain significance allele”, in ClinVar (classified as uncertain significance, reviewed by an expert panel (2013); submitters: INSIGHT, Ambry Genetics, Invitae, GeneDx, and Color Genomics Inc.), Clinvitae (4x), Cosmic (1x in a breast carcinoma), UMD-LSDB (1x classified UV), Mismatch Repair Genes Variant Database (1x), and Insight Hereditary Tumors Database (1x). The variant was not identified in the COGR, MutDB, or Zhejiang Colon Cancer Databases. The variant was identified in control databases in 3 of 245362 chromosomes at a frequency of 0.00001 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: Latino in 1 of 33568 chromosomes (freq: 0.00003), European Non-Finnish in 2 of 110928 chromosomes (freq: 0.00002), it was not observed in the African, Other, Ashkenazi Jewish, East Asian, European Finnish, and South Asian populations. The p.Gln698Glu residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 2 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. 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 |
---|---|---|---|---|
Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women. | Breast Cancer Association Consortium | The New England journal of medicine | 2021 | PMID: 33471991 |
Comprehensive Constitutional Genetic and Epigenetic Characterization of Lynch-Like Individuals. | Dámaso E | Cancers | 2020 | PMID: 32635641 |
Tumour characteristics provide evidence for germline mismatch repair missense variant pathogenicity. | Li S | Journal of medical genetics | 2020 | PMID: 31391288 |
The mutational spectrum of Lynch syndrome in cyprus. | Loizidou MA | PloS one | 2014 | PMID: 25133505 |
CoDP: predicting the impact of unclassified genetic variants in MSH6 by the combination of different properties of the protein. | Terui H | Journal of biomedical science | 2013 | PMID: 23621914 |
Classification of mismatch repair gene missense variants with PON-MMR. | Ali H | Human mutation | 2012 | PMID: 22290698 |
Major contribution from recurrent alterations and MSH6 mutations in the Danish Lynch syndrome population. | Nilbert M | Familial cancer | 2009 | PMID: 18566915 |
Prevalence of germline mutations of hMLH1, hMSH2, hPMS1, hPMS2, and hMSH6 genes in 75 French kindreds with nonpolyposis colorectal cancer. | Wang Q | Human genetics | 1999 | PMID: 10480359 |
Text-mined citations for rs63750832 ...
HelpRecord last updated Aug 04, 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.