ClinVar Genomic variation as it relates to human health
NM_000179.3(MSH6):c.3202C>T (p.Arg1068Ter)
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
-
NM_000179.3(MSH6):c.3202C>T (p.Arg1068Ter)
Variation ID: 89352 Accession: VCV000089352.67
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 2p16.3 2: 47803449 (GRCh38) [ NCBI UCSC ] 2: 48030588 (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 May 1, 2024 Sep 5, 2013 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000179.3:c.3202C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000170.1:p.Arg1068Ter nonsense NM_001281492.2:c.2812C>T NP_001268421.1:p.Arg938Ter nonsense NM_001281493.2:c.2296C>T NP_001268422.1:p.Arg766Ter nonsense NM_001281494.2:c.2296C>T NP_001268423.1:p.Arg766Ter nonsense NC_000002.12:g.47803449C>T NC_000002.11:g.48030588C>T NG_007111.1:g.25303C>T LRG_219:g.25303C>T LRG_219t1:c.3202C>T LRG_219p1:p.Arg1068Ter - Protein change
- R1068*, R766*, R938*
- Other names
- p.R1068*:CGA>TGA
- Canonical SPDI
- NC_000002.12:47803448:C:T
-
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.
The Genome Aggregation Database (gnomAD) 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 |
9037 | 9343 |
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. |
---|---|---|---|---|
Pathogenic (2) |
reviewed by expert panel
|
Sep 5, 2013 | RCV000074817.12 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Dec 21, 2022 | RCV000160692.13 | |
Pathogenic (1) |
criteria provided, single submitter
|
Oct 30, 2014 | RCV000172816.5 | |
Pathogenic (10) |
criteria provided, multiple submitters, no conflicts
|
Jan 1, 2024 | RCV000201960.31 | |
Pathogenic (1) |
criteria provided, single submitter
|
Jan 28, 2024 | RCV000524156.13 | |
Pathogenic (8) |
criteria provided, multiple submitters, no conflicts
|
Aug 22, 2023 | RCV000607176.10 | |
Pathogenic (1) |
criteria provided, single submitter
|
Oct 31, 2018 | RCV000763497.6 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Jul 6, 2023 | RCV001253564.6 | |
Pathogenic (1) |
no assertion criteria provided
|
Jul 1, 2019 | RCV001249973.5 | |
Pathogenic (1) |
no assertion criteria provided
|
- | RCV001353539.5 | |
Pathogenic (1) |
no assertion criteria provided
|
Jul 1, 2021 | RCV003162474.5 | |
Pathogenic (1) |
criteria provided, single submitter
|
Oct 10, 2023 | RCV003389678.1 | |
click to load more click to collapse |
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. |
|
---|---|---|---|---|---|
Pathogenic
(Sep 05, 2013)
|
reviewed by expert panel
Method: research
|
Lynch Syndrome
Affected status: unknown
Allele origin:
germline
|
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)
Accession: SCV000108028.3
First in ClinVar: Dec 19, 2013 Last updated: Dec 24, 2022
Comment:
Classified with v1.9 guidelines: https://docs.google.com/file/d/0B3JL6rP6JzhoN2EydHRVMEI1UGs
|
Comment:
Coding sequence variation resulting in a stop codon
|
|
Pathogenic
(Oct 30, 2014)
|
criteria provided, single submitter
Method: clinical testing
|
Lynch syndrome I
Affected status: no
Allele origin:
germline
|
Pathway Genomics
Accession: SCV000223782.1
First in ClinVar: Jun 04, 2015 Last updated: Jun 04, 2015 |
|
|
Pathogenic
(Oct 28, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Vantari Genetics
Accession: SCV000267056.1
First in ClinVar: Apr 13, 2016 Last updated: Apr 13, 2016 |
|
|
Pathogenic
(Oct 08, 2014)
|
criteria provided, single submitter
Method: clinical testing
|
Lynch syndrome 5
Affected status: yes
Allele origin:
germline
|
Genome Diagnostics Laboratory, University Medical Center Utrecht
Study: VKGL Data-share Consensus
Accession: SCV000743212.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018 |
|
|
Pathogenic
(Jan 30, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Lynch syndrome 5
Affected status: unknown
Allele origin:
germline
|
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine
Accession: SCV000840012.1
First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018 |
Comment:
This c.3202C>T variant in the MSH6 gene has been reported in multiple rectal cancer, HNPCC and Lynch syndrome patients [PMID:18301448, 20028993, 24323032] while not observed … (more)
This c.3202C>T variant in the MSH6 gene has been reported in multiple rectal cancer, HNPCC and Lynch syndrome patients [PMID:18301448, 20028993, 24323032] while not observed in general population according to gnomad database. This variant is predicted to cause loss of function of normal protein through mRNA decay or producing a truncated protein, which is a known disease mechanism for this gene. Based on the current evidence, this c.3202C>T (p.Arg1068*) in the MSH6 gene is classified as pathogenic. (less)
|
|
Pathogenic
(May 05, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: unknown
Allele origin:
germline
|
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000604284.2
First in ClinVar: Sep 30, 2017 Last updated: Feb 17, 2019 |
|
|
Pathogenic
(Oct 31, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Mismatch repair cancer syndrome 1
Endometrial carcinoma Lynch syndrome 5
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV000894283.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
|
|
Pathogenic
(Oct 23, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Endometrial carcinoma
Affected status: yes
Allele origin:
germline
|
Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV001429346.1
First in ClinVar: Aug 17, 2020 Last updated: Aug 17, 2020 |
Number of individuals with the variant: 1
|
|
Pathogenic
(Mar 27, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics and Genomics, Karolinska University Hospital
Accession: SCV001449723.1
First in ClinVar: Dec 12, 2020 Last updated: Dec 12, 2020 |
Number of individuals with the variant: 4
|
|
Pathogenic
(Jul 03, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
COLORECTAL CANCER, HEREDITARY NONPOLYPOSIS, TYPE 5
Affected status: yes
Allele origin:
germline
|
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego
Accession: SCV001984869.1
First in ClinVar: Oct 30, 2021 Last updated: Oct 30, 2021 |
Comment:
This nonsense variant found in exon 5 of 10 is predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated … (more)
This nonsense variant found in exon 5 of 10 is predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant has been reported in multiple individuals and families with Lynch syndrome-associated cancers such as colorectal cancer, endometrial cancer, pancreatic cancer and renal cancer (PMID: 11807791, 24323032, 20379851, 18301448, 20028993). This variant is absent from the gnomAD population database and thus is presumed to be rare. Based on the available evidence, the c.3202C>T (p.Arg1068Ter) variant is classified as Pathogenic. (less)
|
|
Pathogenic
(Apr 08, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Lynch syndrome 5
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Genetics and Molecular Pathology, SA Pathology
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002761612.1
First in ClinVar: Dec 17, 2022 Last updated: Dec 17, 2022 |
|
|
Pathogenic
(Oct 22, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000211314.16
First in ClinVar: Feb 24, 2015 Last updated: Mar 04, 2023 |
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; Observed … (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; Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Plaschke et al., 2002; Steinke et al., 2008; Baglietto et al., 2010; McIlvried et al., 2010; Talseth-Palmer et al., 2010; Hinrichsen et al., 2013; Goodfellow et al., 2015; Morak et al., 2017; Salvador et al., 2019); 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); This variant is associated with the following publications: (PMID: 23733757, 24323032, 20487569, 11807791, 18301448, 25741868, 25525159, 21247423, 20028993, 28152038, 26552419, 23403630, 15483016, 28002797, 20379851, 28528517, 29360161, 29489754, 30702970, 30324682, 30322717, 31447099, 34426522, 34178123, 31742824, 30787465) (less)
|
|
Pathogenic
(Jun 17, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: not provided
Allele origin:
germline
|
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden
Accession: SCV004026071.1
First in ClinVar: Aug 19, 2023 Last updated: Aug 19, 2023 |
Comment:
PS4_MOD, PVS1
|
|
Pathogenic
(Jul 03, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Lynch syndrome 5
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
unknown
|
Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV001251422.2
First in ClinVar: May 31, 2020 Last updated: Sep 09, 2023 |
Comment:
Criteria applied: PVS1,PS4,PM2_SUP,PP4
Clinical Features:
Thyroid gland carcinoma (present) , Rectal neoplasm (present)
Sex: male
|
|
Pathogenic
(Oct 10, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary nonpolyposis colon cancer
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000917784.2
First in ClinVar: Jun 03, 2019 Last updated: Nov 20, 2023 |
Comment:
Variant summary: MSH6 c.3202C>T (p.Arg1068X) 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.3202C>T (p.Arg1068X) 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. The variant was absent in 251326 control chromosomes. c.3202C>T has been reported in the literature in multiple individuals affected with Lynch Syndrome (Baglietto_2010, Dudley_2018, Plaschke_2002, Steinke_2008, Talseth-Palmer_2010, Thodi_2010). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 20028993, 29360161, 11807791, 18301448, 20487569, 20937110, 24362816, 25525159). 19 submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
Pathogenic
(Aug 22, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Lynch syndrome 5
Affected status: unknown
Allele origin:
unknown
|
Myriad Genetics, Inc.
Accession: SCV004187404.1
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.
|
|
Pathogenic
(Jul 06, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Endometrial carcinoma
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004195677.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
|
|
Pathogenic
(Apr 22, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV003820256.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
|
|
Pathogenic
(Dec 21, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV000537682.4
First in ClinVar: May 29, 2016 Last updated: Feb 14, 2024 |
Comment:
This variant changes 1 nucleotide in exon 5 of the MSH6 gene, creating a premature translation stop signal. This variant is expected to result in … (more)
This variant changes 1 nucleotide in exon 5 of the MSH6 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with Lynch syndrome or Lynch syndrome associated cancers (PMID: 11807791, 18301448, 20028993, 20379851, 20487569, 20937110, 24323032, 29967336). This variant has not been identified 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)
|
|
Pathogenic
(Jan 01, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV004011166.6
First in ClinVar: Jul 16, 2023 Last updated: Apr 15, 2024 |
Comment:
MSH6: PVS1, PM2, PS4:Moderate
Number of individuals with the variant: 4
|
|
Pathogenic
(May 31, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Lynch syndrome 5
Affected status: yes
Allele origin:
germline
|
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Study: VKGL Data-share Consensus
Accession: SCV000744295.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018 |
|
|
Pathogenic
(Jan 21, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000889487.3
First in ClinVar: Mar 13, 2019 Last updated: Jan 06, 2024 |
Comment:
This nonsense variant causes the premature termination of MSH6 protein synthesis. The frequency of this variant in the general population, 0.00002 (3/152096 chromosomes, http://gnomad.broadinstitute.org), is … (more)
This nonsense variant causes the premature termination of MSH6 protein synthesis. The frequency of this variant in the general population, 0.00002 (3/152096 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in individuals/families with Lynch syndrome- associated cancers (PMIDs: 11807791 (2002), 18301448 (2008), 24323032 (2014), 28528517(2017), 29360161 (2018), 30324682 (2018), 30702970 (2019), 33422027 (2021), and 34178123 (2021)). Based on the available information, this variant is classified as pathogenic. (less)
|
|
Pathogenic
(Jan 28, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary nonpolyposis colorectal neoplasms
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV000253778.12
First in ClinVar: Oct 11, 2015 Last updated: Feb 20, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg1068*) 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.Arg1068*) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with colorectal cancer, endometrial cancer, pancreatic cancer, and renal cancer (PMID: 11807791, 18301448, 20028993, 20379851, 24323032). ClinVar contains an entry for this variant (Variation ID: 89352). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
Pathogenic
(Jan 08, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Lynch syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
All of Us Research Program, National Institutes of Health
Accession: SCV004842817.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024
Comment:
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more)
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)
|
Comment:
The c.3202C>T (p.Arg1068*) variant in the MSH6 gene is located on the exon 5 and introduces a premature translation termination codon (p.Arg1068*), resulting in an … (more)
The c.3202C>T (p.Arg1068*) variant in the MSH6 gene is located on the exon 5 and introduces a premature translation termination codon (p.Arg1068*), resulting in an absent or disrupted protein product. The variant has been reported in multiple individuals with Lynch syndrome-associated cancers (PMID: 30324682, 29360161, 33422027, 28528517, 20487569). Loss-of-function variants of MSH6 are known to be pathogenic, and frameshift/truncating variants located upstream and downstream to this position have been reported in individuals with Lynch syndrome-associated cancers (PMID: 30376427, 18269114, 29345684). The variant is reported in ClinVar as pathogenic (ID: 89352) and reviewed by the expert panel. The variant is absent in the general population database (gnomAD). Therefore, the c.3202C>T (p.Arg1068*) variant of MSH6 has been classified as pathogenic. (less)
Number of individuals with the variant: 3
|
|
Pathogenic
(Aug 12, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000580090.6
First in ClinVar: May 29, 2016 Last updated: May 01, 2024 |
Comment:
The p.R1068* pathogenic mutation (also known as c.3202C>T), located in coding exon 5 of the MSH6 gene, results from a C to T substitution at … (more)
The p.R1068* pathogenic mutation (also known as c.3202C>T), located in coding exon 5 of the MSH6 gene, results from a C to T substitution at nucleotide position 3202. This changes the amino acid from an arginine to a stop codon within coding exon 5. This mutation has been reported in multiple hereditary non-polyposis colorectal cancer (HNPCC)/Lynch syndrome families, several with tumors showing high microsatellite instability and/or absent MSH6 protein expression on IHC (Plaschke J et al. Int. J. Cancer, 2002 Feb;97:643-8; Steinke V et al. Eur J Hum Genet, 2008 May;16:587-92; Baglietto L et al. J Natl Cancer Inst, 2010 Feb;102:193-201; Talseth-Palmer BA et al. Hered Cancer Clin Pract, 2010 May;8:5; McIlvried DE et al. Fam. Cancer, 2010 Sep;9:377-81; Thodi G et al. BMC Cancer, 2010 Oct;10:544; Ward RL et al. J Clin Oncol, 2013 Jul;31:2554-62; Buchanan DD et al. J Clin Oncol, 2014 Jan;32:90-100; Goodfellow PJ et al. J Clin Oncol, 2015 Dec;33:4301-8; Carter NJ et al. Gynecol Oncol, 2018 12;151:481-488; Iordache PD et al. J Cell Mol Med, 2018 12;22:6068-6076; Dudley B et al. Cancer, 2018 04;124:1691-1700; Salvador MU et al. J Clin Oncol, 2019 03;37:647-657; Xu Y et al. BMC Cancer, 2021 Jan;21:45). 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)
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: research
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV000257241.1
First in ClinVar: Nov 20, 2015 Last updated: Nov 20, 2015 |
Number of individuals with the variant: 1
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
Lynch syndrome 5
Affected status: yes
Allele origin:
germline
|
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV000734217.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018 |
|
|
Pathogenic
(Jul 01, 2019)
|
no assertion criteria provided
Method: clinical testing
|
Lynch-like syndrome
Affected status: yes
Allele origin:
somatic
|
Constitutional Genetics Lab, Leon Berard Cancer Center
Accession: SCV001423987.1
First in ClinVar: Jul 27, 2020 Last updated: Jul 27, 2020 |
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
Carcinoma of colon
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: SCV000592625.2 First in ClinVar: Oct 11, 2015 Last updated: Apr 13, 2021 |
Comment:
The MSH6 p.Arg1068X variant was identified in 8 of 3948 proband chromosomes (frequency: 0.002) from individuals or families with Lynch syndrome and endometrial cancer, and … (more)
The MSH6 p.Arg1068X variant was identified in 8 of 3948 proband chromosomes (frequency: 0.002) from individuals or families with Lynch syndrome and endometrial cancer, and is classified as pathogenic in the literature (Buchanan 2014, Plaschke 2002, Plaschke 2004, Steinke 2008, Talseth Palmer 2010, Ward 2013, Castillejo 2011, Mcllvried 2010). The variant was also identified in the following databases: dbSNP (ID: rs63749843) as “With Pathogenic allele”, ClinVar (10x as pathogenic, reviewed by an expert panel), Clinvitae (4x as pathogenic), COGR, Cosmic (4x in colon cancer), UMD-LSDB (12x as "causal"), Insight Colon Cancer Gene Variant Database (15 x as pathogenic), and Mismatch Repair Genes Variant Database. The variant was not identified in MutDB, Zhejiang Colon Cancer Database, or Insight Hereditary Tumors Database. The variant was also identified by our laboratory in 2 individuals with uterine and endometrial cancer. The variant was not identified in the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project or the Exome Aggregation Consortium (August 8th 2016) control databases. The p.Arg1068X variant leads to a premature stop codon at position 1068, which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the MSH6 gene are an established mechanism of disease in Lynch syndrome and is the type of variant expected to cause the disorder. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic. (less)
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001951712.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV002035556.1 First in ClinVar: Dec 18, 2021 Last updated: Dec 18, 2021 |
|
|
Pathogenic
(Jul 01, 2021)
|
no assertion criteria provided
Method: research
|
Gastric cancer
Affected status: unknown
Allele origin:
germline
|
Laboratory for Genotyping Development, RIKEN
Accession: SCV002758079.1
First in ClinVar: Apr 15, 2023 Last updated: Apr 15, 2023 |
|
|
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 |
---|---|---|---|---|
Helicobacter pylori, Homologous-Recombination Genes, and Gastric Cancer. | Usui Y | The New England journal of medicine | 2023 | PMID: 36988593 |
The genetic structure of the Turkish population reveals high levels of variation and admixture. | Kars ME | Proceedings of the National Academy of Sciences of the United States of America | 2021 | PMID: 34426522 |
Development and external validation of a novel nomogram for screening Chinese Lynch syndrome: based on a multicenter, population study. | Yang M | Therapeutic advances in medical oncology | 2021 | PMID: 34178123 |
Comparison of long-term outcomes between Lynch sydrome and sporadic colorectal cancer: a propensity score matching analysis. | Xu Y | BMC cancer | 2021 | PMID: 33422027 |
Prevalence of hereditary breast and ovarian cancer (HBOC) predisposition gene mutations among 882 HBOC high-risk Chinese individuals. | Shao D | Cancer science | 2020 | PMID: 31742824 |
Harmonizing Clinical Sequencing and Interpretation for the eMERGE III Network. | eMERGE Consortium. Electronic address: agibbs@bcm.edu | American journal of human genetics | 2019 | PMID: 31447099 |
Toward automation of germline variant curation in clinical cancer genetics. | Ravichandran V | Genetics in medicine : official journal of the American College of Medical Genetics | 2019 | PMID: 30787465 |
Comprehensive Paired Tumor/Germline Testing for Lynch Syndrome: Bringing Resolution to the Diagnostic Process. | Salvador MU | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2019 | PMID: 30702970 |
Microsatellite Instability Is Associated With the Presence of Lynch Syndrome Pan-Cancer. | Latham A | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2019 | PMID: 30376427 |
Identification of Lynch syndrome risk variants in the Romanian population. | Iordache PD | Journal of cellular and molecular medicine | 2018 | PMID: 30324682 |
Germline pathogenic variants identified in women with ovarian tumors. | Carter NJ | Gynecologic oncology | 2018 | PMID: 30322717 |
Optimization of the diagnosis of inherited colorectal cancer using NGS and capture of exonic and intronic sequences of panel genes. | Baert-Desurmont S | European journal of human genetics : EJHG | 2018 | PMID: 29967336 |
The landscape of genomic alterations across childhood cancers. | Gröbner SN | Nature | 2018 | PMID: 29489754 |
Germline mutation prevalence in individuals with pancreatic cancer and a history of previous malignancy. | Dudley B | Cancer | 2018 | PMID: 29360161 |
MSH6 and PMS2 germ-line pathogenic variants implicated in Lynch syndrome are associated with breast cancer. | Roberts ME | Genetics in medicine : official journal of the American College of Medical Genetics | 2018 | PMID: 29345684 |
Loss of MSH2 and MSH6 due to heterozygous germline defects in MSH3 and MSH6. | Morak M | Familial cancer | 2017 | PMID: 28528517 |
Combined Microsatellite Instability, MLH1 Methylation Analysis, and Immunohistochemistry for Lynch Syndrome Screening in Endometrial Cancers From GOG210: An NRG Oncology and Gynecologic Oncology Group Study. | Goodfellow PJ | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2015 | PMID: 26552419 |
RNA splicing. The human splicing code reveals new insights into the genetic determinants of disease. | Xiong HY | Science (New York, N.Y.) | 2015 | PMID: 25525159 |
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 |
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 |
Population-based molecular screening for Lynch syndrome: implications for personalized medicine. | Ward RL | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2013 | PMID: 23733757 |
Screening of the DNA mismatch repair genes MLH1, MSH2 and MSH6 in a Greek cohort of Lynch syndrome suspected families. | Thodi G | BMC cancer | 2010 | PMID: 20937110 |
MSH6 and PMS2 mutation positive Australian Lynch syndrome families: novel mutations, cancer risk and age of diagnosis of colorectal cancer. | Talseth-Palmer BA | Hereditary cancer in clinical practice | 2010 | PMID: 20487569 |
Atypical identification of Lynch syndrome by immunohistochemistry and microsatellite instability analysis on jejunal adenocarcinoma. | McIlvried DE | Familial cancer | 2010 | PMID: 20379851 |
Risks of Lynch syndrome cancers for MSH6 mutation carriers. | Baglietto L | Journal of the National Cancer Institute | 2010 | PMID: 20028993 |
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 |
Involvement of hMSH6 in the development of hereditary and sporadic colorectal cancer revealed by immunostaining is based on germline mutations, but rarely on somatic inactivation. | Plaschke J | International journal of cancer | 2002 | PMID: 11807791 |
http://www.insight-database.org/classifications/index.html?gene=MSH6&variant=c.3202C%3ET | - | - | - | - |
click to load more click to collapse |
Text-mined citations for rs63749843 ...
HelpRecord last updated May 01, 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.