ClinVar Genomic variation as it relates to human health
NM_000179.3(MSH6):c.3119_3120del (p.Asn1039_Phe1040insTer)
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.3119_3120del (p.Asn1039_Phe1040insTer)
Variation ID: 89339 Accession: VCV000089339.38
- Type and length
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Deletion, 2 bp
- Location
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Cytogenetic: 2p16.3 2: 47801101-47801102 (GRCh38) [ NCBI UCSC ] 2: 48028240-48028241 (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 Apr 15, 2024 Sep 5, 2013 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000179.3:c.3119_3120del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000170.1:p.Asn1039_Phe1040insTer nonsense NM_000179.2:c.3119_3120delTT NM_001281492.2:c.2729_2730del NP_001268421.1:p.Asn909_Phe910insTer nonsense NM_001281493.2:c.2213_2214del NP_001268422.1:p.Asn737_Phe738insTer nonsense NM_001281494.2:c.2213_2214del NP_001268423.1:p.Asn737_Phe738insTer nonsense NC_000002.12:g.47801102_47801103del NC_000002.11:g.48028241_48028242del NG_007111.1:g.22956_22957del LRG_219:g.22956_22957del - Protein change
- Other names
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- Canonical SPDI
- NC_000002.12:47801100:TTT:T
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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.
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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 |
8944 | 9250 |
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
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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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Pathogenic (1) |
reviewed by expert panel
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Sep 5, 2013 | RCV000074804.10 | |
Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Nov 3, 2021 | RCV000486939.26 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Aug 11, 2021 | RCV000491377.14 | |
Pathogenic (1) |
criteria provided, single submitter
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Jun 25, 2023 | RCV000531248.15 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 30, 2020 | RCV001175453.8 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Aug 22, 2023 | RCV003224862.9 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 3, 2021 | RCV003466946.1 |
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
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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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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
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International Society for Gastrointestinal Hereditary Tumours (InSiGHT)
Accession: SCV000108015.3
First in ClinVar: Dec 19, 2013 Last updated: Dec 24, 2022 |
Comment:
Coding sequence variation resulting in a stop codon
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Pathogenic
(Aug 11, 2021)
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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: SCV000580131.5
First in ClinVar: Jun 25, 2017 Last updated: Nov 29, 2022 |
Comment:
The c.3119_3120delTT pathogenic mutation, located in coding exon 4 of the MSH6 gene, results from a deletion of two nucleotides at nucleotide positions 3119 to … (more)
The c.3119_3120delTT pathogenic mutation, located in coding exon 4 of the MSH6 gene, results from a deletion of two nucleotides at nucleotide positions 3119 to 3120, causing a translational frameshift with a predicted alternate stop codon (p.F1040*). This mutation has been reported in an individual diagnosed with duodenal cancer at age 57 and whose tumor showed microsatellite instability and absent MSH6 on IHC (Roncari B et al. Clin Genet. 2007 Sep;72(3):230-7). This mutation has also been subsequently identified in several Hispanic individuals with Lynch syndrome (Cruz-Correa M et al. Fam. Cancer 2015 Sep;14:415-25; Sunga AY et al. Cancer Genet 2017 Apr;212-213:1-7; Rossi BM et al. BMC Cancer 2017 Sep;17:623). Of note, this alteration is also designated as p.Phe1040Ter, c.3119delTT, and p.Phe1040Terfs in published literature. In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. (less)
Number of individuals with the variant: 1
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Pathogenic
(Mar 03, 2023)
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criteria provided, single submitter
Method: clinical testing
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Lynch syndrome 5
Affected status: yes
Allele origin:
unknown
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Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV003921088.1
First in ClinVar: May 06, 2023 Last updated: May 06, 2023 |
Comment:
_x000D_ Criteria applied: PVS1, PS4_MOD, PM2_SUP
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Pathogenic
(Nov 03, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: not provided
Allele origin:
germline
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Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden
Accession: SCV002010098.3
First in ClinVar: Nov 06, 2021 Last updated: Jul 16, 2023 |
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Pathogenic
(Aug 22, 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: SCV004185715.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
Comment:
This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
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Pathogenic
(Sep 03, 2021)
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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: SCV004196357.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Mar 16, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV001470564.2
First in ClinVar: Jan 26, 2021 Last updated: Jan 06, 2024 |
Comment:
The MSH6 c.3119_3120del (p.Phe1040*) variant alters the translational reading frame of the MSH6 mRNA and causes the premature termination of MSH6 protein synthesis. This variant … (more)
The MSH6 c.3119_3120del (p.Phe1040*) variant alters the translational reading frame of the MSH6 mRNA and causes the premature termination of MSH6 protein synthesis. This variant has been reported in the published literature in individuals and families affected with Lynch syndrome associated cancers (PMIDs: 17718861 (2007), 25782445 (2015), 31297337 (2019)). The frequency of this variant in the general population, 0.000004 (1/248958 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic. (less)
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Pathogenic
(Jun 25, 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: SCV000624817.8
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 89339). This variant has not been … (more)
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 89339). This variant has not been reported in the literature in individuals affected with MSH6-related conditions. This variant is present in population databases (rs267608042, gnomAD 0.006%). This sequence change creates a premature translational stop signal (p.Phe1040*) in the MSH6 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MSH6 are known to be pathogenic (PMID: 18269114, 24362816). (less)
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Pathogenic
(Sep 01, 2020)
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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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001501270.17
First in ClinVar: Mar 14, 2021 Last updated: Apr 15, 2024 |
Number of individuals with the variant: 1
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Pathogenic
(Mar 30, 2020)
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criteria provided, single submitter
Method: clinical testing
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Lynch syndrome
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001339019.1
First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020 |
Comment:
Variant summary: MSH6 c.3119_3120delTT (p.Phe1040X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: MSH6 c.3119_3120delTT (p.Phe1040X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4e-06 in 248958 control chromosomes. c.3119_3120delTT has been reported in the literature in individuals affected with Hereditary Non-Polyposis Colon Cancer and lung cancer (Sun_2019, Cruz-Correa_2015, Roncari_2007). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Jan 08, 2021)
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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: SCV000568724.4
First in ClinVar: Apr 27, 2017 Last updated: Apr 27, 2017 |
Comment:
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not … (more)
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (Lek 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Observed in patients with Lynch-related cancers and tumor studies consistent with pathogenic variants in this gene (Roncari 2007, Cruz-Correa 2015, Rossi 2017, Sunga 2017); This variant is associated with the following publications: (PMID: 28449805, 17718861, 25782445, 31297337, 28874130) (less)
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Pathogenic
(Jan 15, 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: SCV000685354.3
First in ClinVar: Feb 19, 2018 Last updated: Jan 12, 2022 |
Comment:
This variant deletes 2 nucleotides in exon 4 of the MSH6 gene, creating a frameshift and premature translation stop signal. This variant is expected to … (more)
This variant deletes 2 nucleotides in exon 4 of the MSH6 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been identified in 1/248958 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of MSH6 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. (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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Identification of Germline Mismatch Repair Gene Mutations in Lung Cancer Patients With Paired Tumor-Normal Next Generation Sequencing: A Retrospective Study. | Sun S | Frontiers in oncology | 2019 | PMID: 31297337 |
A survey of the clinicopathological and molecular characteristics of patients with suspected Lynch syndrome in Latin America. | Rossi BM | BMC cancer | 2017 | PMID: 28874130 |
Spectrum of mismatch repair gene mutations and clinical presentation of Hispanic individuals with Lynch syndrome. | Sunga AY | Cancer genetics | 2017 | PMID: 28449805 |
Clinical characterization and mutation spectrum in Caribbean Hispanic families with Lynch syndrome. | Cruz-Correa M | Familial cancer | 2015 | PMID: 25782445 |
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 |
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 |
Frequency of constitutional MSH6 mutations in a consecutive series of families with clinical suspicion of HNPCC. | Roncari B | Clinical genetics | 2007 | PMID: 17718861 |
http://www.insight-database.org/classifications/index.html?gene=MSH6&variant=c.3119_3120del | - | - | - | - |
Text-mined citations for rs267608042 ...
HelpRecord last updated Apr 20, 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.