ClinVar Genomic variation as it relates to human health
NM_000179.3(MSH6):c.59C>T (p.Ala20Val)
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.59C>T (p.Ala20Val)
Variation ID: 89540 Accession: VCV000089540.46
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2p16.3 2: 47783292 (GRCh38) [ NCBI UCSC ] 2: 48010431 (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 Dec 6, 2014 May 1, 2024 Jun 13, 2018 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000179.3:c.59C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000170.1:p.Ala20Val missense NM_001281492.2:c.59C>T NP_001268421.1:p.Ala20Val missense NM_001281493.2:c.-678C>T 5 prime UTR NC_000002.12:g.47783292C>T NC_000002.11:g.48010431C>T NG_007111.1:g.5146C>T LRG_219:g.5146C>T LRG_219t1:c.59C>T LRG_219p1:p.Ala20Val P52701:p.Ala20Val - Protein change
- A20V
- Other names
- p.A20V:GCC>GTC
- Canonical SPDI
- NC_000002.12:47783291: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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0.00020 (A)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00013
Trans-Omics for Precision Medicine (TOPMed) 0.00019
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00023
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
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. |
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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. |
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Likely benign (1) |
reviewed by expert panel
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Jun 13, 2018 | RCV000075009.7 | |
Likely benign (3) |
criteria provided, multiple submitters, no conflicts
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Mar 25, 2021 | RCV000115435.14 | |
Uncertain significance (1) |
no assertion criteria provided
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Jun 1, 2014 | RCV000148647.4 | |
Conflicting interpretations of pathogenicity (5) |
criteria provided, conflicting classifications
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Aug 15, 2023 | RCV000254665.23 | |
Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Mar 29, 2023 | RCV000412384.9 | |
Likely benign (1) |
criteria provided, single submitter
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Jan 25, 2024 | RCV000524208.11 | |
Benign (1) |
no assertion criteria provided
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- | RCV001353783.2 | |
Likely benign (3) |
no assertion criteria provided
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- | RCV001529757.5 |
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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Likely benign
(Jun 13, 2018)
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reviewed by expert panel
Method: curation
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Lynch syndrome 1
Affected status: yes
Allele origin:
germline
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International Society for Gastrointestinal Hereditary Tumours (InSiGHT)
Accession: SCV000108229.4
First in ClinVar: Dec 19, 2013 Last updated: Dec 11, 2022 |
Comment:
Multifactorial likelihood analysis posterior probability < 0.05 (0.028)
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Likely benign
(Nov 29, 2017)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000149344.11
First in ClinVar: May 17, 2014 Last updated: Apr 09, 2018 |
Comment:
This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at … (more)
This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. (less)
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Uncertain significance
(Nov 24, 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: SCV000487828.2
First in ClinVar: Jan 06, 2017 Last updated: Dec 24, 2022 |
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Likely benign
(Jan 25, 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: SCV000254329.12
First in ClinVar: Oct 11, 2015 Last updated: Feb 28, 2024 |
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Likely benign
(Dec 06, 2018)
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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: SCV000184016.9
First in ClinVar: Aug 06, 2014 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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Uncertain significance
(Feb 20, 2017)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000712602.1
First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018 |
Comment:
The p.Ala20Val variant in MSH6 has been reported in 3 individuals with Lynch syn drome-associated cancers (Charames 2000, Nilbert 2009) and has also been reporte … (more)
The p.Ala20Val variant in MSH6 has been reported in 3 individuals with Lynch syn drome-associated cancers (Charames 2000, Nilbert 2009) and has also been reporte d in ClinVar (Variation ID 89540). In vitro functional studies provide some evid ence that the p.Ala20Val variant may not impact protein function (Drost 2012). H owever, these types of assays may not accurately represent biological function. This variant has also been identified in 7/62168 of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs6375 0664). Computational prediction tools and conservation analysis suggest that the p.Ala20Val variant may not impact the protein, though this information is not p redictive enough to rule out pathogenicity. In summary, the clinical significanc e of the p.Ala20Val variant is uncertain. (less)
Number of individuals with the variant: 1
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Uncertain significance
(Apr 27, 2017)
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criteria provided, single submitter
Method: clinical testing
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Lynch syndrome 5
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV001299751.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
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Likely benign
(Mar 25, 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: SCV002536331.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 |
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Likely benign
(Dec 15, 2014)
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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: SCV000690451.2
First in ClinVar: Feb 19, 2018 Last updated: Dec 11, 2022 |
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Likely benign
(Apr 20, 2023)
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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: SCV000695918.5
First in ClinVar: Mar 17, 2018 Last updated: Jun 03, 2023 |
Comment:
Variant summary: MSH6 c.59C>T (p.Ala20Val) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign … (more)
Variant summary: MSH6 c.59C>T (p.Ala20Val) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 9.8e-05 in 244188 control chromosomes, predominantly at a frequency of 0.00019 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1.34 fold of the estimated maximal expected allele frequency for a pathogenic variant in MSH6 causing Hereditary Nonpolyposis Colorectal Cancer phenotype (0.00014), suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.59C>T has been reported in the literature in individuals affected with tumors belonging to the Lynch syndrome spectrum (e.g. Charames_2000, Nilbert_2009, Hinrichsen_2013, Grant_2015, Frolova_2015, Gordon_2019, Li_2020, Svensson_2022). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. In vitro studies reported experimental evidence evaluating an impact on protein function, in which MMR activity of the variant protein was 50%-90% of wild-type activity (Drost_2011, Drost_2020). Ten other submitters, including an expert panel (InSiGHT), have provided clinical-significance assessments for this variant in ClinVar after 2014, mostly without evidence for independent evaluation, and classified the variant as VUS (n=3), likely benign (n=6, including the expert panel) or benign (n=1). Based on the evidence outlined above, the variant was classified as likely benign. (less)
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Benign
(Mar 29, 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: SCV004018951.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
Comment:
This variant is considered benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants … (more)
This variant is considered benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. This variant has been observed in trans with a known pathogenic variant in one or more individuals lacking clinical features consistent with gene-specific recessive disease. (less)
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Likely benign
(Aug 15, 2023)
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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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Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV002552265.4
First in ClinVar: Jul 27, 2022 Last updated: Aug 18, 2023 |
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Uncertain significance
(Jun 01, 2014)
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no assertion criteria provided
Method: research
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Colorectal / endometrial cancer
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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CSER _CC_NCGL, University of Washington
Study: ESP 6500 variant annotation
Accession: SCV000190362.1 First in ClinVar: Dec 06, 2014 Last updated: Dec 06, 2014
Comment:
Variants classified for the Actionable exomic incidental findings in 6503 participants: challenges of variant classification manuscript
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Benign
(-)
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no assertion criteria provided
Method: clinical testing
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Carcinoma of colon
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: SCV000592562.2 First in ClinVar: Dec 06, 2016 Last updated: Apr 13, 2021 |
Comment:
The p.Ala20Val variant was identified in 3 of 2290 proband chromosomes (frequency: 0.001) from individuals or families with colorectal cancer (Charames 2000, Nilbert 2009, Wasielewski … (more)
The p.Ala20Val variant was identified in 3 of 2290 proband chromosomes (frequency: 0.001) from individuals or families with colorectal cancer (Charames 2000, Nilbert 2009, Wasielewski 2009) and was present in 1 of 332 control chromosomes (frequency: 0.003) from healthy individuals (Wasielewski 2009). The variant was also identified in dbSNP (ID: rs63750664), with a minor allele frequency of 0.0002 (1000 Genomes Project), NHLBI Exome Sequencing Project (Exome Variant Server), HGMD, MutDB, “Mismatch Repair Genes Variant Database”, “InSiGHT Colon Cancer Database”, the ClinVar database (classified with uncertain significance by InSiGHT and Ambry Genetics; classified as likely benign by GeneDx), and UMD (1X as a likely neutral variant). The variant was identified by the Exome Variant Server project in 3 of 8566 European American alleles (frequency: 0.0003), although this low number of observations and low frequency is not substantive enough to determine the prevalence of the variant in the general population and its relationship to disease.The p.Ala20 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein. However, this information is not predictive enough to rule out pathogenicity. The p.Ala20Val 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, although this is not very predictive of pathogenicity. A study by Charames (2000) suggested this alteration result in a significant change in amino acid polarity occurring outside of the MSH6 domains known to interact with MSH2.However, three functional studies have suggested the variant has no impact on MSH6 gene and has neutral functional effect (Ali 2012, Drost 2012, Terui 2013). In addition, this variant was identified in one individual by our laboratory as co-occuring with a pathogenic variant in MSH6 (c.3932_3935dup, p.Ile1313SerfsX7), increasing the likelihood this variant does not have clinical significance. In summary, based on the above information, this variant is classified as benign. (less)
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
unknown
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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV000691915.1
First in ClinVar: Feb 19, 2018 Last updated: Feb 19, 2018 |
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Likely benign
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, Amsterdam University Medical Center
Study: VKGL Data-share Consensus
Accession: SCV001807447.1 First in ClinVar: Aug 25, 2021 Last updated: Aug 25, 2021 |
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Likely benign
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001743775.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021 |
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Likely benign
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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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: SCV002037018.1 First in ClinVar: Dec 18, 2021 Last updated: Dec 18, 2021 |
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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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Merged testing for colorectal cancer syndromes and re-evaluation of genetic variants improve diagnostic yield: Results from a nationwide prospective cohort. | Svensson S | Genes, chromosomes & cancer | 2022 | PMID: 35430768 |
Two integrated and highly predictive functional analysis-based procedures for the classification of MSH6 variants in Lynch syndrome. | Drost M | Genetics in medicine : official journal of the American College of Medical Genetics | 2020 | PMID: 31965077 |
Tumour characteristics provide evidence for germline mismatch repair missense variant pathogenicity. | Li S | Journal of medical genetics | 2020 | PMID: 31391288 |
Rates of Actionable Genetic Findings in Individuals with Colorectal Cancer or Polyps Ascertained from a Community Medical Setting. | Gordon AS | American journal of human genetics | 2019 | PMID: 31422818 |
Prioritizing Variants in Complete Hereditary Breast and Ovarian Cancer Genes in Patients Lacking Known BRCA Mutations. | Caminsky NG | Human mutation | 2016 | PMID: 26898890 |
Actionable exomic incidental findings in 6503 participants: challenges of variant classification. | Amendola LM | Genome research | 2015 | PMID: 25637381 |
Impact of an immunohistochemistry-based universal screening protocol for Lynch syndrome in endometrial cancer on genetic counseling and testing. | Frolova AI | Gynecologic oncology | 2015 | PMID: 25617771 |
Prevalence of germline mutations in cancer predisposition genes in patients with pancreatic cancer. | Grant RC | Gastroenterology | 2015 | PMID: 25479140 |
Development and validation of a new algorithm for the reclassification of genetic variants identified in the BRCA1 and BRCA2 genes. | Pruss D | Breast cancer research and treatment | 2014 | PMID: 25085752 |
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 |
Expression defect size among unclassified MLH1 variants determines pathogenicity in Lynch syndrome diagnosis. | Hinrichsen I | Clinical cancer research : an official journal of the American Association for Cancer Research | 2013 | PMID: 23403630 |
Classification of mismatch repair gene missense variants with PON-MMR. | Ali H | Human mutation | 2012 | PMID: 22290698 |
A rapid and cell-free assay to test the activity of lynch syndrome-associated MSH2 and MSH6 missense variants. | Drost M | Human mutation | 2012 | PMID: 22102614 |
Association of rare MSH6 variants with familial breast cancer. | Wasielewski M | Breast cancer research and treatment | 2010 | PMID: 19924528 |
Major contribution from recurrent alterations and MSH6 mutations in the Danish Lynch syndrome population. | Nilbert M | Familial cancer | 2009 | PMID: 18566915 |
Do MSH6 mutations contribute to double primary cancers of the colorectum and endometrium? | Charames GS | Human genetics | 2000 | PMID: 11153917 |
http://www.insight-database.org/classifications/?gene=MSH6&variant=c.59C%3ET | - | - | - | - |
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Text-mined citations for rs63750664 ...
HelpRecord last updated May 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.