ClinVar Genomic variation as it relates to human health
NM_000179.3(MSH6):c.4000C>T (p.Arg1334Trp)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Uncertain significance(9); Likely benign(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000179.3(MSH6):c.4000C>T (p.Arg1334Trp)
Variation ID: 184389 Accession: VCV000184389.29
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2p16.3 2: 47806650 (GRCh38) [ NCBI UCSC ] 2: 48033789 (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 Jan 6, 2017 Sep 29, 2024 Mar 29, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000179.3:c.4000C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000170.1:p.Arg1334Trp missense NM_001281492.2:c.3610C>T NP_001268421.1:p.Arg1204Trp missense NM_001281493.2:c.3094C>T NP_001268422.1:p.Arg1032Trp missense NM_001281494.2:c.3094C>T NP_001268423.1:p.Arg1032Trp missense NC_000002.12:g.47806650C>T NC_000002.11:g.48033789C>T NG_007111.1:g.28504C>T NG_008397.1:g.104026G>A LRG_219:g.28504C>T LRG_219t1:c.4000C>T LRG_219p1:p.Arg1334Trp - Protein change
- R1334W, R1032W, R1204W
- Other names
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- Canonical SPDI
- NC_000002.12:47806649:C: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.
Exome Aggregation Consortium (ExAC) 0.00004
The Genome Aggregation Database (gnomAD), exomes 0.00004
The Genome Aggregation Database (gnomAD) 0.00006
Trans-Omics for Precision Medicine (TOPMed) 0.00006
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 | ||
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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
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. |
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MSH6 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
9153 | 9466 |
Conditions - Germline
Condition
Help
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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Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Oct 12, 2023 | RCV000163638.14 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jan 24, 2024 | RCV000198598.14 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Mar 28, 2023 | RCV000409323.4 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Mar 26, 2024 | RCV000657088.6 | |
Uncertain significance (1) |
criteria provided, single submitter
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Aug 6, 2021 | RCV001706075.1 | |
Uncertain significance (1) |
criteria provided, single submitter
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Mar 29, 2024 | RCV003462121.2 | |
Uncertain significance (1) |
criteria provided, single submitter
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Nov 30, 2023 | RCV003995266.2 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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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
(Aug 06, 2021)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001821390.1
First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021 |
Comment:
Variant summary: MSH6 c.4000C>T (p.Arg1334Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging … (more)
Variant summary: MSH6 c.4000C>T (p.Arg1334Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 3.7e-05 in 244568 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4000C>T has been reported in the literature as somatic occurrence in individuals affected with chronic lymphocytic leukemia, HNSCC, polyposis and endometrial cancer (Landau_2013, Martin_2014, Elsayed_2015) and as germline occurrence in individuals affected with cancer including colorectal, pancreatic and breast cancer (Chubb_2015, Dudley_2018, Li_2020, Dorling_2021), but it was also reported in controls (Dorling_2021). These reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
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Uncertain significance
(Mar 28, 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: SCV004018890.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
Comment:
This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
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Uncertain significance
(Mar 29, 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: SCV004197638.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
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Uncertain significance
(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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000254324.12
First in ClinVar: Oct 11, 2015 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1334 of the MSH6 protein … (more)
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1334 of the MSH6 protein (p.Arg1334Trp). This variant is present in population databases (rs773763465, gnomAD 0.01%). This missense change has been observed in individual(s) with colorectal cancer, breast cancer, and/or pancreatic cancer (PMID: 25559809, 29360161, 35449176). ClinVar contains an entry for this variant (Variation ID: 184389). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Studies have shown that this missense change is associated with inconclusive levels of altered splicing (Invitae). 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
(Nov 01, 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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Color Diagnostics, LLC DBA Color Health
Accession: SCV000685474.6
First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces arginine with tryptophan at codon 1334 of the MSH6 protein. Computational prediction is inconclusive regarding the impact of this variant on … (more)
This missense variant replaces arginine with tryptophan at codon 1334 of the MSH6 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected by early-onset, familial colorectal cancer (PMID: 25559809). This variant has been identified in 11/275890 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, c.4001G>A (p.Arg1334Gln), is considered to be disease-causing (ClinVar variation ID: 89506), 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
(Nov 30, 2023)
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criteria provided, single submitter
Method: clinical testing
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Lynch syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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All of Us Research Program, National Institutes of Health
Accession: SCV004835193.1
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)
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Comment:
This missense variant replaces arginine with tryptophan at codon 1334 of the MSH6 protein. Computational prediction is inconclusive regarding the impact of this variant on … (more)
This missense variant replaces arginine with tryptophan at codon 1334 of the MSH6 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected by early-onset, familial colorectal cancer (PMID: 25559809). This variant has been identified in 11/275890 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, c.4001G>A (p.Arg1334Gln), is considered to be disease-causing (ClinVar variation ID: 89506), 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)
Number of individuals with the variant: 6
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Uncertain significance
(Mar 26, 2024)
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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: SCV000279624.13
First in ClinVar: May 29, 2016 Last updated: Sep 29, 2024 |
Comment:
Observed in an individual with a personal and family history of colon cancer as well as in individuals with a personal history of breast and/or … (more)
Observed in an individual with a personal and family history of colon cancer as well as in individuals with a personal history of breast and/or pancreatic cancer (PMID: 25559809, 29360161, 35449176, 33471991); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25559809, 25275298, 29360161, 31391288, 23415222, 33471991, 25370038, 35449176, 17531815, 21120944, 12019211, 36243179) (less)
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Uncertain significance
(Oct 15, 2019)
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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: SCV000601597.2
First in ClinVar: Sep 28, 2017 Last updated: Jan 26, 2021 |
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Uncertain significance
(Dec 28, 2015)
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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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Counsyl
Accession: SCV000488106.2
First in ClinVar: Jan 06, 2017 Last updated: Dec 24, 2022 |
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Likely benign
(Oct 12, 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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Ambry Genetics
Accession: SCV000214206.8
First in ClinVar: Mar 24, 2015 Last updated: May 01, 2024 |
Comment:
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more)
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (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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Clinical relevance of pathogenic germline variants in mismatch repair genes in Chinese breast cancer patients. | Hu L | NPJ breast cancer | 2022 | PMID: 35449176 |
Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women. | Breast Cancer Association Consortium | The New England journal of medicine | 2021 | PMID: 33471991 |
Tumour characteristics provide evidence for germline mismatch repair missense variant pathogenicity. | Li S | Journal of medical genetics | 2020 | PMID: 31391288 |
Germline mutation prevalence in individuals with pancreatic cancer and a history of previous malignancy. | Dudley B | Cancer | 2018 | PMID: 29360161 |
Genetic diagnosis of high-penetrance susceptibility for colorectal cancer (CRC) is achievable for a high proportion of familial CRC by exome sequencing. | Chubb D | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2015 | PMID: 25559809 |
Germline variants in POLE are associated with early onset mismatch repair deficient colorectal cancer. | Elsayed FA | European journal of human genetics : EJHG | 2015 | PMID: 25370038 |
The head and neck cancer cell oncogenome: a platform for the development of precision molecular therapies. | Martin D | Oncotarget | 2014 | PMID: 25275298 |
Evolution and impact of subclonal mutations in chronic lymphocytic leukemia. | Landau DA | Cell | 2013 | PMID: 23415222 |
Text-mined citations for rs773763465 ...
HelpRecord last updated Oct 08, 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.