ClinVar Genomic variation as it relates to human health
NM_000179.3(MSH6):c.1190_1191del (p.Tyr397fs)
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.1190_1191del (p.Tyr397fs)
Variation ID: 89178 Accession: VCV000089178.40
- Type and length
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Deletion, 2 bp
- Location
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Cytogenetic: 2p16.3 2: 47799172-47799173 (GRCh38) [ NCBI UCSC ] 2: 48026311-48026312 (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 May 1, 2024 Sep 5, 2013 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000179.3:c.1190_1191del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000170.1:p.Tyr397fs frameshift NM_000179.2:c.1190_1191delAT NM_001281492.2:c.800_801del NP_001268421.1:p.Tyr267fs frameshift NM_001281493.2:c.284_285del NP_001268422.1:p.Tyr95fs frameshift NM_001281494.2:c.284_285del NP_001268423.1:p.Tyr95fs frameshift NC_000002.12:g.47799173_47799174del NC_000002.11:g.48026312_48026313del NG_007111.1:g.21027_21028del LRG_219:g.21027_21028del - Protein change
- Y267fs, Y95fs
- Other names
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- Canonical SPDI
- NC_000002.12:47799171:TAT: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 |
9037 | 9343 |
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 (2) |
reviewed by expert panel
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Sep 5, 2013 | RCV000074640.6 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jun 6, 2022 | RCV000160740.8 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jun 9, 2023 | RCV000497288.12 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 24, 2024 | RCV001045033.8 | |
not provided (1) |
no classification provided
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- | RCV001535637.2 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Aug 11, 2023 | RCV002265594.3 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 13, 2022 | RCV003460659.1 | |
Pathogenic (1) |
no assertion criteria provided
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Jul 1, 2021 | RCV003162469.2 |
Submissions - Germline
Classification
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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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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: SCV000107842.3
First in ClinVar: Dec 19, 2013 Last updated: Dec 24, 2022
Comment:
Classified with v1.9 guidelines: https://docs.google.com/file/d/0B3JL6rP6JzhoN2EydHRVMEI1UGs
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Comment:
Coding sequence variation resulting in a stop codon
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Pathogenic
(Nov 15, 2017)
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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: SCV000919727.1
First in ClinVar: Jun 03, 2019 Last updated: Jun 03, 2019 |
Comment:
Variant summary: The MSH6 c.1190_1191delAT (p.Tyr397CysfsX3) variant results in a premature termination codon, predicted to cause a truncated or absent MSH6 protein due to nonsense … (more)
Variant summary: The MSH6 c.1190_1191delAT (p.Tyr397CysfsX3) variant results in a premature termination codon, predicted to cause a truncated or absent MSH6 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.1444C>T (p.Arg482X), c.1572C>A (p.Tyr524X), c.1634_1637delAAGA (p.Lys545fsX25)). The variant has been observed in patients with HNPCC-associated cancers (i.e. CRC and cancer of the endometrium), in one of them a CRC tumor sample showing loss of MSH6 and microsatellite instability (Plaschke 2004, Susswein 2015). This variant was found in 2/245974 control chromosomes at a frequency of 0.0000081, which does not exceed the estimated maximal expected allele frequency of a pathogenic MSH6 variant (0.0001421). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. (less)
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Pathogenic
(May 08, 2021)
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criteria provided, single submitter
Method: curation
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Sema4, Sema4
Accession: SCV002535610.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Comment:
The MSH6 c.1190_1191delAT (p.Y397CfsX3) variant has been reported in heterozygosity in at least three individuals with hereditary non-polyposis colorectal cancer or endometrial cancer (PMID: 14974087, … (more)
The MSH6 c.1190_1191delAT (p.Y397CfsX3) variant has been reported in heterozygosity in at least three individuals with hereditary non-polyposis colorectal cancer or endometrial cancer (PMID: 14974087, 26681312, 18301448, 21081928). This variant causes a frameshift at amino acid 397 that results in premature termination 3 amino acids downstream. At this location, this is predicted to cause nonsense-mediated decay and result in an absent protein (loss of function). Loss of function variants in MSH6 are known to be pathogenic (PMID: 24362816). This variant was observed in 1/34572 chromosomes in the Latino population according to the Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654) and has been reported in ClinVar (Variation ID: 89178). Based on the current evidence available, this variant is interpreted as pathogenic. (less)
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Pathogenic
(Jun 23, 2021)
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criteria provided, single submitter
Method: clinical testing
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Lynch syndrome 5
Affected status: unknown
Allele origin:
inherited
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New York Genome Center
Study: CSER-NYCKidSeq
Accession: SCV002548624.1 First in ClinVar: Jul 18, 2022 Last updated: Jul 18, 2022 |
Comment:
The inherited c.1190_1191del (p.Tyr397CysfsTer3) variant identified in the MSH6 gene is the deletion of two nucleotides resulting in a frameshift of the protein at amino … (more)
The inherited c.1190_1191del (p.Tyr397CysfsTer3) variant identified in the MSH6 gene is the deletion of two nucleotides resulting in a frameshift of the protein at amino acid 397/1361 (exon 4/10), which is predicted to lead to the termination of the protein approximately 3 amino acids downstream. This variant is absent from gnomAD(v3.1.1) suggesting it is not a common benign variant in the populations represented in that database. This variant has been reviewedby an Expert Panel and reported in ClinVar as Pathogenic (VarID:89178) and has been reported in several affected individuals in the literature [PMID:15483016,18301448, 21081928]. The inherited c.1190_1191del (p.Tyr397CysfsTer3) variant identified in the MSH6 gene is reported as Pathogenic. (less)
Clinical Features:
Seizure (present) , Intellectual disability (present)
Secondary finding: yes
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Pathogenic
(Jun 09, 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: SCV000211379.9
First in ClinVar: Feb 24, 2015 Last updated: Jun 24, 2023 |
Comment:
Frameshift 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; Truncating … (more)
Frameshift 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; Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at significant frequency in large population cohorts (gnomAD); Observed in individuals with early-onset colon cancer who had tumors showing microsatellite instability and/or loss of MSH6 on immunohistochemistry staining (Plaschke et al., 2004; Steinke et al., 2008; You et al., 2010; Yang et al., 2021); This variant is associated with the following publications: (PMID: 14974087, 32980694, 29922827, 18301448, 21081928, 26681312, 15483016, 36988593, 34178123) (less)
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Pathogenic
(Aug 11, 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: SCV004188307.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
Comment:
This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
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Pathogenic
(Oct 13, 2022)
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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: SCV004198125.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Jan 24, 2024)
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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: SCV001208862.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Tyr397Cysfs*3) in the MSH6 gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Tyr397Cysfs*3) 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). This variant is present in population databases (rs756896277, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with Lynch syndrome (PMID: 14974087, 15483016, 26681312). ClinVar contains an entry for this variant (Variation ID: 89178). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Jun 06, 2022)
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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: SCV000580232.6
First in ClinVar: Feb 24, 2015 Last updated: May 01, 2024 |
Comment:
The c.1190_1191delAT pathogenic mutation, located in coding exon 4 of the MSH6 gene, results from a deletion of two nucleotides at nucleotide positions 1190 to … (more)
The c.1190_1191delAT pathogenic mutation, located in coding exon 4 of the MSH6 gene, results from a deletion of two nucleotides at nucleotide positions 1190 to 1191, causing a translational frameshift with a predicted alternate stop codon (p.Y397Cfs*3). This mutation was previously reported in an individual with a sigmoid colon tumor at age 33 that was noted to be MSI-H and have absent MSH6 expression by IHC analysis (Plaschke J et al. Hum. Mutat. 2004 Mar;23:285). 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)
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Pathogenic
(Feb 14, 2017)
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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 and Genomics, Karolinska University Hospital
Accession: SCV001449662.1
First in ClinVar: Dec 12, 2020 Last updated: Dec 12, 2020 |
Number of individuals with the variant: 3
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV000691923.1
First in ClinVar: Feb 19, 2018 Last updated: Feb 19, 2018 |
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Pathogenic
(Jul 01, 2021)
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no assertion criteria provided
Method: research
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Gastric cancer
Affected status: unknown
Allele origin:
germline
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Laboratory for Genotyping Development, RIKEN
Accession: SCV002758358.1
First in ClinVar: Apr 15, 2023 Last updated: Apr 15, 2023 |
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not provided
(-)
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no classification provided
Method: phenotyping only
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Lynch syndrome
Hereditary nonpolyposis colon cancer
Affected status: unknown
Allele origin:
unknown
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GenomeConnect - Invitae Patient Insights Network
Accession: SCV001749666.1
First in ClinVar: Jul 18, 2021 Last updated: Jul 18, 2021 |
Comment:
Variant interpreted as Pathogenic and reported on 07-12-2017 by Myriad. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report … (more)
Variant interpreted as Pathogenic and reported on 07-12-2017 by Myriad. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. (less)
Clinical Features:
Breast carcinoma (present) , Family history of cancer (present)
Age: 50-59 years
Sex: female
Testing laboratory: Myriad Genetic Laboratories, Inc.,Myriad Genetic Laboratories, Inc.
Date variant was reported to submitter: 2017-07-12
Testing laboratory interpretation: Pathogenic
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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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Helicobacter pylori, Homologous-Recombination Genes, and Gastric Cancer. | Usui Y | The New England journal of medicine | 2023 | PMID: 36988593 |
Pathogenic and likely pathogenic variant prevalence among the first 10,000 patients referred for next-generation cancer panel testing. | Susswein LR | Genetics in medicine : official journal of the American College of Medical Genetics | 2016 | PMID: 26681312 |
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 |
Tumours with loss of MSH6 expression are MSI-H when screened with a pentaplex of five mononucleotide repeats. | You JF | British journal of cancer | 2010 | PMID: 21081928 |
No association between MUTYH and MSH6 germline mutations in 64 HNPCC patients. | Steinke V | European journal of human genetics : EJHG | 2008 | PMID: 18301448 |
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 |
Lower incidence of colorectal cancer and later age of disease onset in 27 families with pathogenic MSH6 germline mutations compared with families with MLH1 or MSH2 mutations: the German Hereditary Nonpolyposis Colorectal Cancer Consortium. | Plaschke J | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2004 | PMID: 15483016 |
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 |
http://www.insight-database.org/classifications/index.html?gene=MSH6&variant=c.1190_1191del | - | - | - | - |
Text-mined citations for rs63750439 ...
HelpRecord last updated May 12, 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.