ClinVar Genomic variation as it relates to human health
NM_000179.3(MSH6):c.2315G>A (p.Arg772Gln)
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.2315G>A (p.Arg772Gln)
Variation ID: 237155 Accession: VCV000237155.22
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2p16.3 2: 47800298 (GRCh38) [ NCBI UCSC ] 2: 48027437 (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 8, 2017 Aug 25, 2024 May 6, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000179.3:c.2315G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000170.1:p.Arg772Gln missense NM_001281492.2:c.1925G>A NP_001268421.1:p.Arg642Gln missense NM_001281493.2:c.1409G>A NP_001268422.1:p.Arg470Gln missense NM_001281494.2:c.1409G>A NP_001268423.1:p.Arg470Gln missense NC_000002.12:g.47800298G>A NC_000002.11:g.48027437G>A NG_007111.1:g.22152G>A LRG_219:g.22152G>A LRG_219t1:c.2315G>A LRG_219p1:p.Arg772Gln P52701:p.Arg772Gln - Protein change
- R772Q, R470Q, R642Q
- Other names
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- Canonical SPDI
- NC_000002.12:47800297: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.
Trans-Omics for Precision Medicine (TOPMed) 0.00001
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00002
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 |
9148 | 9458 |
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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Uncertain significance (1) |
criteria provided, single submitter
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Dec 8, 2023 | RCV000234432.10 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Jun 26, 2023 | RCV000418671.3 | |
Uncertain significance (1) |
criteria provided, single submitter
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May 1, 2018 | RCV000758668.3 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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May 6, 2024 | RCV001015160.10 | |
Uncertain significance (1) |
criteria provided, single submitter
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Mar 3, 2024 | RCV004567710.1 |
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
(May 01, 2018)
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criteria provided, single submitter
Method: clinical testing
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Lynch syndrome
Affected status: yes
Allele origin:
somatic
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University of Washington Department of Laboratory Medicine, University of Washington
Accession: SCV000887439.1
First in ClinVar: Mar 11, 2019 Last updated: Mar 11, 2019 |
Comment:
MSH6 NM_000179.2:c.2315G>A has a 63.2% probability of pathogenicity based on combining prior probability from public data with a likelihood ratio of 0.20 to 1, generated … (more)
MSH6 NM_000179.2:c.2315G>A has a 63.2% probability of pathogenicity based on combining prior probability from public data with a likelihood ratio of 0.20 to 1, generated from evidence of seeing this as a somatic mutation in a tumor without loss of heterozygosity at the MSH6 locus. See Shirts et al 2018, PMID 29887214. (less)
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Uncertain significance
(Sep 26, 2019)
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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: SCV000521710.4
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
Comment:
Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious … (more)
Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Observed as a germline variant in an individual with multiple adenomas who also carried an MSH6 nonsense variant (phase not determined), and as a somatic variant in a colon tumor exhibiting microsatellite instability in an individual with a germline MSH6 variant on the opposite allele (Ohmiya 2001, Taylor 2015); This variant is associated with the following publications: (PMID: 14974087, 18176851, 28514183, 11470537, 23621914, 25985138, 25307252, 8176851, 29548617, 24323032, 29887214) (less)
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Uncertain significance
(Dec 08, 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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Invitae
Accession: SCV000283747.10
First in ClinVar: Jul 01, 2016 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 772 of the MSH6 protein (p.Arg772Gln). … (more)
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 772 of the MSH6 protein (p.Arg772Gln). This variant is present in population databases (rs63750725, gnomAD 0.004%). This missense change has been observed in individual(s) with colorectal adenomas who also had a pathogenic MSH6 variant (PMID: 25985138). ClinVar contains an entry for this variant (Variation ID: 237155). 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 with a positive predictive value of 95%. This variant disrupts the p.Arg772 amino acid residue in MSH6. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 14974087, 18176851, 23621914, 24323032, 25307252, 26333163, 28449805, 28514183; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. (less)
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Uncertain significance
(Feb 02, 2023)
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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: SCV001354859.3
First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces arginine with glutamine at codon 772 of the MSH6 protein. A different variant affecting the same position c.2314C>T (p.Arg772Trp) is considered … (more)
This missense variant replaces arginine with glutamine at codon 772 of the MSH6 protein. A different variant affecting the same position c.2314C>T (p.Arg772Trp) is considered to be disease-causing (ClinVar variation ID: 89267). Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual with multiple adenomas who also had a MSH6 nonsense mutation (PMID: 25985138). This variant has been identified in 5/282522 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, c.2314C>T (p.Arg772Trp), is considered to be disease-causing (ClinVar variation ID: 89267), suggesting that this position is important for the protein function. The available evidence is insufficient 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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Uncertain significance
(Mar 03, 2024)
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criteria provided, single submitter
Method: clinical testing
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Endometrial carcinoma
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV005054877.1
First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024 |
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Uncertain significance
(May 06, 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: SCV001175967.6
First in ClinVar: Mar 16, 2020 Last updated: Aug 11, 2024 |
Comment:
The p.R772Q variant (also known as c.2315G>A), located in coding exon 4 of the MSH6 gene, results from a G to A substitution at nucleotide … (more)
The p.R772Q variant (also known as c.2315G>A), located in coding exon 4 of the MSH6 gene, results from a G to A substitution at nucleotide position 2315. The arginine at codon 772 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been detected in conjunction with a pathogenic MSH6 mutation (phase unknown) in an individual with an unspecified number of multiple adenomas (Taylor JC et al. Nat Genet. 2015 Jul;47(7):717-26). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. (less)
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Uncertain significance
(Jun 26, 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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Clinical Genetics Laboratory, Skane University Hospital Lund
Accession: SCV005199204.1
First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024 |
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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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Using Somatic Mutations from Tumors to Classify Variants in Mismatch Repair Genes. | Shirts BH | American journal of human genetics | 2018 | PMID: 29887214 |
Multigene Panel Testing Provides a New Perspective on Lynch Syndrome. | Espenschied CR | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2017 | PMID: 28514183 |
Spectrum of mismatch repair gene mutations and clinical presentation of Hispanic individuals with Lynch syndrome. | Sunga AY | Cancer genetics | 2017 | PMID: 28449805 |
Classification of Amino Acid Substitutions in Mismatch Repair Proteins Using PON-MMR2. | Niroula A | Human mutation | 2015 | PMID: 26333163 |
Factors influencing success of clinical genome sequencing across a broad spectrum of disorders. | Taylor JC | Nature genetics | 2015 | PMID: 25985138 |
The gastrointestinal manifestation of constitutional mismatch repair deficiency syndrome: from a single adenoma to polyposis-like phenotype and early onset cancer. | Levi Z | Clinical genetics | 2015 | PMID: 25307252 |
Tumor mismatch repair immunohistochemistry and DNA MLH1 methylation testing of patients with endometrial cancer diagnosed at age younger than 60 years optimizes triage for population-level germline mismatch repair gene mutation testing. | Buchanan DD | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2014 | PMID: 24323032 |
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 |
Working through a diagnostic challenge: colonic polyposis, Amsterdam criteria, and a mismatch repair mutation. | Jasperson KW | Familial cancer | 2008 | PMID: 18176851 |
Eight novel MSH6 germline mutations in patients with familial and nonfamilial colorectal cancer selected by loss of protein expression in tumor tissue. | Plaschke J | Human mutation | 2004 | PMID: 14974087 |
Text-mined citations for rs63750725 ...
HelpRecord last updated Aug 25, 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.