ClinVar Genomic variation as it relates to human health
NM_000179.3(MSH6):c.3425C>T (p.Thr1142Met)
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(12); 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.3425C>T (p.Thr1142Met)
Variation ID: 89381 Accession: VCV000089381.39
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2p16.3 2: 47803672 (GRCh38) [ NCBI UCSC ] 2: 48030811 (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 Sep 16, 2024 Jun 25, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000179.3:c.3425C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000170.1:p.Thr1142Met missense NM_001281492.2:c.3035C>T NP_001268421.1:p.Thr1012Met missense NM_001281493.2:c.2519C>T NP_001268422.1:p.Thr840Met missense NM_001281494.2:c.2519C>T NP_001268423.1:p.Thr840Met missense NC_000002.12:g.47803672C>T NC_000002.11:g.48030811C>T NG_007111.1:g.25526C>T LRG_219:g.25526C>T LRG_219t1:c.3425C>T LRG_219p1:p.Thr1142Met - Protein change
- T1142M, T1012M, T840M
- Other names
- p.T1142M:ACG>ATG
- Canonical SPDI
- NC_000002.12:47803671: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.
The Genome Aggregation Database (gnomAD), exomes 0.00002
Exome Aggregation Consortium (ExAC) 0.00003
The Genome Aggregation Database (gnomAD) 0.00005
Trans-Omics for Precision Medicine (TOPMed) 0.00005
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 |
9149 | 9462 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
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Feb 8, 2023 | RCV000115415.25 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Sep 11, 2021 | RCV000212683.17 | |
Likely benign (1) |
criteria provided, single submitter
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Jan 24, 2024 | RCV000524175.18 | |
Uncertain significance (4) |
criteria provided, multiple submitters, no conflicts
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Jun 25, 2024 | RCV000656899.22 | |
Uncertain significance (1) |
no assertion criteria provided
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- | RCV001357449.9 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jun 30, 2022 | RCV002288562.9 | |
Uncertain significance (1) |
criteria provided, single submitter
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Oct 3, 2023 | RCV003460683.1 | |
Uncertain significance (1) |
criteria provided, single submitter
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Dec 18, 2023 | RCV003997089.2 |
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
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. |
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Uncertain significance
(Jun 16, 2016)
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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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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000539707.1
First in ClinVar: Apr 08, 2017 Last updated: Apr 08, 2017 |
Comment:
Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or … (more)
Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: ClinVar: 4 VUS (including expert panel - no new evidence since expert classification) (less)
Method: Genome/Exome Filtration
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Uncertain significance
(Sep 11, 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: SCV001426992.2
First in ClinVar: Aug 09, 2020 Last updated: Oct 30, 2021 |
Comment:
Variant summary: MSH6 c.3425C>T (p.Thr1142Met) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, C-terminal domain of the encoded … (more)
Variant summary: MSH6 c.3425C>T (p.Thr1142Met) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, C-terminal domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 252032 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3425C>T has been reported in the literature in individuals affected with Lynch Syndrome or HBOC (example, Perez-Cabornero_2013, Castera_2014). These reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant on mismatch repair (MMR) activity (Houlleberghs_2017). Six 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 uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
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Uncertain significance
(Jun 23, 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: SCV002528022.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Comment:
The MSH6 c.3425C>T (p.T1142M) variant has been reported in at least one individual with colon polyps (PMID: 23523604). The variant was also reported in one … (more)
The MSH6 c.3425C>T (p.T1142M) variant has been reported in at least one individual with colon polyps (PMID: 23523604). The variant was also reported in one individual with a personal/family history of breast/ovarian cancer (PMID: 24549055). It was also reported in 3/60466 breast cancer cases and 4/53461 healthy controls by a large case-control study (PMID: 33471991). A functional study demonstrated that this variant results in normal MMR function in mouse embryonic stem cells (PMID: 28531214). It was observed in 1/24936 chromosomes of the African/African American subpopulation according to the Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654). The variant has been reported in ClinVar (Variation ID 89381). The evidence is insufficient to meet ACMG/AMP criteria for classifying the variant as benign or pathogenic. Thus, the clinical significance of this variant is currently uncertain. (less)
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Uncertain significance
(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: SCV002010093.3
First in ClinVar: Nov 06, 2021 Last updated: Jul 16, 2023 |
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Uncertain significance
(Oct 03, 2023)
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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: SCV004197677.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Uncertain significance
(Feb 08, 2023)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Color Diagnostics, LLC DBA Color Health
Accession: SCV000685399.5
First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces threonine with methionine at codon 1142 of the MSH6 protein. Computational prediction suggests that this variant may have deleterious impact on … (more)
This missense variant replaces threonine with methionine at codon 1142 of the MSH6 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional assay to detect DNA mismatch repair (MMR) deficiency in MSH6 deficient mouse embryonic stem cells found that the variant protein is likely MMR proficient (PMID: 28531214). This variant has been reported in individuals affected with Lynch syndrome (PMID: 19250818, 23523604), and an individual suspected to be affected with hereditary breast and ovarian cancer (PMID: 24549055). This variant has been identified in 7/282732 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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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Likely benign
(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: SCV000166230.13
First in ClinVar: Jun 15, 2014 Last updated: Feb 20, 2024 |
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Uncertain significance
(Jun 25, 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: SCV000149324.19
First in ClinVar: May 17, 2014 Last updated: Sep 16, 2024 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; … (more)
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate proficient mismatch repair activity (PMID: 28531214); Observed in individuals with polyps or history suggestive of hereditary breast and ovarian cancer syndrome (PMID: 23523604, 24549055); This variant is associated with the following publications: (PMID: 26333163, 27632392, 23621914, 23523604, 19250818, 23588873, 24549055, n/a, 33471991, 32885271, 28531214, 21120944, 12019211, 37937776) (less)
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Uncertain significance
(Jun 30, 2022)
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criteria provided, single submitter
Method: clinical testing
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Lynch syndrome 5
Affected status: yes
Allele origin:
germline
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MGZ Medical Genetics Center
Accession: SCV002579167.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Comment:
ACMG criteria applied: PM2_SUP, PP3
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Number of individuals with the variant: 1
Sex: female
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Uncertain significance
(Dec 05, 2022)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV003808966.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
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Uncertain significance
(Nov 30, 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: SCV000186590.10
First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024 |
Comment:
The p.T1142M variant (also known as c.3425C>T), located in coding exon 5 of the MSH6 gene, results from a C to T substitution at nucleotide … (more)
The p.T1142M variant (also known as c.3425C>T), located in coding exon 5 of the MSH6 gene, results from a C to T substitution at nucleotide position 3425. The threonine at codon 1142 is replaced by methionine, an amino acid with similar properties. This variant was reported in a Spanish family meeting Amsterdam criteria and segregated with disease in 2/2 affected relatives; however, tumor testing in this family demonstrated microsatellite stability and normal staining on IHC (Perez-Cabornero L et al. Eur. J. Cancer. 2009 May;45:1485-93; Perez-Cabornero L et al. J Mol Diagn. 2013 May;15:380-90). This alteration was reported in a cohort of suspected hereditary breast and ovarian cancer patients who underwent multi-gene panel testing (Castéra L et al. Eur. J. Hum. Genet., 2014 Nov;22:1305-13). This variant was also observed in 2/3251 individuals who met eligibility criteria for hereditary breast and ovarian cancer syndrome (Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879), and was reported in 3/60,466 breast cancer cases and in 4/53,461 controls in another study (Dorling et al. N Engl J Med. 2021 02;384:428-439). In a functional study that utilized a genetic screening method to test mismatch repair activity in murine embryonic stem cells, p.T1142M did not demonstrate attenuated mismatch repair (Houlleberghs H et al. PLoS Genet., 2017 May;13:e1006765). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
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Uncertain significance
(May 26, 2022)
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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: SCV000888273.4
First in ClinVar: Jul 09, 2018 Last updated: Jan 06, 2024 |
Comment:
The frequency of this variant in the general population, 0.000031 (4/129104 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the … (more)
The frequency of this variant in the general population, 0.000031 (4/129104 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in an individual with personal or family history of breast/ovarian cancer, and in two family members affected with colon polyps (PMID: 24549055 (2014), 23523604 (2013)). In vitro functional study evaluating the function of the variant in response to a DNA-damaging agent indicated that this variant may not be pathogenic (PMID: 28531214 (2017)). Based on the available information, we are unable to determine the clinical significance of this variant. (less)
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Uncertain Significance
(Dec 18, 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: SCV004835066.1
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 threonine with methionine at codon 1142 of the MSH6 protein. Computational prediction suggests that this variant may have deleterious impact on … (more)
This missense variant replaces threonine with methionine at codon 1142 of the MSH6 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional assay to detect DNA mismatch repair (MMR) deficiency in MSH6 deficient mouse embryonic stem cells found that the variant protein is likely MMR proficient (PMID: 28531214). This variant has been reported in individuals affected with Lynch syndrome (PMID: 19250818, 23523604, Goverde 2018) and an individual suspected to be affected with hereditary breast and ovarian cancer (PMID: 24549055). This variant has been identified in 7/282732 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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: 11
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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Malignant tumor of breast
Affected status: yes
Allele origin:
unknown
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Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV001552926.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
The MSH6 p.Thr1142Met variant was identified in 3 of 1454 proband chromosomes (frequency: 0.002) from individuals or families with breast cancer/ovarian cancer, Lynch Syndrome, and … (more)
The MSH6 p.Thr1142Met variant was identified in 3 of 1454 proband chromosomes (frequency: 0.002) from individuals or families with breast cancer/ovarian cancer, Lynch Syndrome, and polyps (Castera 2014, Perez-Cabornero 2009, Perez-Cabornero 2013). The variant was also identified in the following databases: dbSNP (ID: rs267608089) as "With Uncertain significance allele", ClinVar (5x, uncertain significance), Clinvitae (3x, uncertain significance), Cosmic (2x, confirmed somatic, in a carcinoma of the liver), Insight Colon Cancer Gene Variant Database (1x, uncertain significance), Mismatch Repair Genes Variant Database, and Insight Hereditary Tumors Database. The variant was not identified in MutDB, UMD-LSDB, or the Zhejiang Colon Cancer Database. The variant was identified in control databases in 7 of 277124 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017). A functional study used an oligonucleotide directed mutagenesis screen in mouse embryonic stem cells to determine pathogenicity for MSH6 variants (Houlleberghs 2017). The c.3425C>T variant was classified as "not pathogenic" by this method. The p.Thr1142 residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is also not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. (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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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 |
Multigene panel testing for hereditary breast and ovarian cancer in the province of Ontario. | Lerner-Ellis J | Journal of cancer research and clinical oncology | 2021 | PMID: 32885271 |
Suspected Lynch syndrome associated MSH6 variants: A functional assay to determine their pathogenicity. | Houlleberghs H | PLoS genetics | 2017 | PMID: 28531214 |
Next-generation sequencing for the diagnosis of hereditary breast and ovarian cancer using genomic capture targeting multiple candidate genes. | Castéra L | European journal of human genetics : EJHG | 2014 | PMID: 24549055 |
CoDP: predicting the impact of unclassified genetic variants in MSH6 by the combination of different properties of the protein. | Terui H | Journal of biomedical science | 2013 | PMID: 23621914 |
Evaluating the effect of unclassified variants identified in MMR genes using phenotypic features, bioinformatics prediction, and RNA assays. | Pérez-Cabornero L | The Journal of molecular diagnostics : JMD | 2013 | PMID: 23523604 |
A new strategy to screen MMR genes in Lynch Syndrome: HA-CAE, MLPA and RT-PCR. | Perez-Cabornero L | European journal of cancer (Oxford, England : 1990) | 2009 | PMID: 19250818 |
Text-mined citations for rs267608089 ...
HelpRecord last updated Sep 29, 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.