ClinVar Genomic variation as it relates to human health
NM_000179.3(MSH6):c.1186C>G (p.Leu396Val)
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.1186C>G (p.Leu396Val)
Variation ID: 36582 Accession: VCV000036582.59
- Type and length
-
single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2p16.3 2: 47799169 (GRCh38) [ NCBI UCSC ] 2: 48026308 (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 Apr 12, 2013 May 12, 2024 Sep 5, 2013 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000179.3:c.1186C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000170.1:p.Leu396Val missense NM_001281492.2:c.796C>G NP_001268421.1:p.Leu266Val missense NM_001281493.2:c.280C>G NP_001268422.1:p.Leu94Val missense NM_001281494.2:c.280C>G NP_001268423.1:p.Leu94Val missense NC_000002.12:g.47799169C>G NC_000002.11:g.48026308C>G NG_007111.1:g.21023C>G LRG_219:g.21023C>G LRG_219t1:c.1186C>G LRG_219p1:p.Leu396Val P52701:p.Leu396Val - Protein change
- L396V, L94V, L266V
- Other names
- p.L396V:CTC>GTC
- Canonical SPDI
- NC_000002.12:47799168:C:G
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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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0.00200 (G)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
1000 Genomes Project 0.00200
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00461
Exome Aggregation Consortium (ExAC) 0.00518
The Genome Aggregation Database (gnomAD), exomes 0.00540
The Genome Aggregation Database (gnomAD) 0.00565
1000 Genomes Project 30x 0.00234
Trans-Omics for Precision Medicine (TOPMed) 0.00386
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
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. |
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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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Benign (3) |
reviewed by expert panel
|
Sep 5, 2013 | RCV000030259.10 | |
Likely benign (1) |
criteria provided, single submitter
|
Apr 1, 2024 | RCV000034490.20 | |
Benign (1) |
no assertion criteria provided
|
Jul 24, 2014 | RCV000144628.3 | |
Benign (10) |
criteria provided, multiple submitters, no conflicts
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Aug 15, 2023 | RCV000121576.34 | |
Benign (5) |
criteria provided, multiple submitters, no conflicts
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Sep 27, 2022 | RCV000157762.12 | |
Benign/Likely benign (6) |
criteria provided, multiple submitters, no conflicts
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May 28, 2019 | RCV000625241.10 | |
Benign (1) |
no assertion criteria provided
|
- | RCV001353801.3 | |
Benign (1) |
criteria provided, single submitter
|
Feb 1, 2024 | RCV001083342.7 | |
Benign (1) |
criteria provided, single submitter
|
May 6, 2021 | RCV001798021.4 |
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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no known pathogenicity
(Sep 05, 2013)
|
reviewed by expert panel
Method: research
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Lynch Syndrome
Affected status: unknown
Allele origin:
germline
|
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)
Accession: SCV000107841.3
First in ClinVar: Dec 19, 2013 Last updated: Dec 24, 2022
Comment:
Classified with v1.9 guidelines: https://docs.google.com/file/d/0B3JL6rP6JzhoN2EydHRVMEI1UGs
|
Comments (2):
Multifactorial likelihood analysis posterior probability <0.001
Converted during submission to Benign.
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Benign
(-)
|
criteria provided, single submitter
Method: clinical testing
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NOT SPECIFIED
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV000302868.1
First in ClinVar: Oct 02, 2016 Last updated: Oct 02, 2016 |
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Benign
(Oct 21, 2013)
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criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000170351.11
First in ClinVar: Jun 23, 2014 Last updated: Sep 28, 2017 |
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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Benign
(Sep 21, 2015)
|
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: SCV000744290.1 First in ClinVar: Apr 20, 2018 Last updated: Apr 20, 2018 |
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Likely benign
(Nov 01, 2016)
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criteria provided, single submitter
Method: clinical testing
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Lynch syndrome 5
Affected status: yes
Allele origin:
germline
|
Center for Human Genetics, Inc, Center for Human Genetics, Inc
Accession: SCV000781786.1
First in ClinVar: Apr 20, 2018 Last updated: Apr 20, 2018 |
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Likely benign
(May 28, 2019)
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criteria provided, single submitter
Method: clinical testing
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Lynch syndrome 5
Affected status: unknown
Allele origin:
unknown
|
Mendelics
Accession: SCV001135803.1
First in ClinVar: Jan 13, 2020 Last updated: Jan 13, 2020 |
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Benign
(Jul 23, 2018)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
|
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000604277.2
First in ClinVar: Sep 28, 2017 Last updated: Feb 10, 2020 |
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Likely benign
(Mar 06, 2018)
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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: SCV000430960.3
First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020 |
Comment:
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more)
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. (less)
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Benign
(May 06, 2021)
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criteria provided, single submitter
Method: clinical testing
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Breast and/or ovarian cancer
Affected status: unknown
Allele origin:
germline
|
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Accession: SCV002042031.1
First in ClinVar: Jan 01, 2022 Last updated: Jan 01, 2022 |
|
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Likely benign
(Apr 01, 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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV002544034.11
First in ClinVar: Jul 09, 2022 Last updated: May 12, 2024 |
Comment:
MSH6: BP4, BS2
Number of individuals with the variant: 31
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Benign
(Dec 03, 2015)
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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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Vantari Genetics
Accession: SCV000267054.1
First in ClinVar: Apr 13, 2016 Last updated: Apr 13, 2016 |
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Benign
(Jun 15, 2017)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: no
Allele origin:
germline
|
Genetic Services Laboratory, University of Chicago
Accession: SCV000595841.1
First in ClinVar: Oct 02, 2016 Last updated: Oct 02, 2016 |
|
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Benign
(Jul 11, 2016)
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criteria provided, single submitter
Method: clinical testing
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Lynch syndrome 5
Affected status: yes
Allele origin:
germline
|
Genome Diagnostics Laboratory, Amsterdam University Medical Center
Study: VKGL Data-share Consensus
Accession: SCV000745648.1 First in ClinVar: Apr 20, 2018 Last updated: Apr 20, 2018 |
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Benign
(Sep 17, 2015)
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criteria provided, single submitter
Method: clinical testing
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Lynch syndrome
Affected status: unknown
Allele origin:
unknown
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Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia
Accession: SCV000296878.3
First in ClinVar: Mar 24, 2015 Last updated: Dec 24, 2022 |
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Benign
(Sep 27, 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
|
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.
Accession: SCV002819191.1
First in ClinVar: Jan 15, 2023 Last updated: Jan 15, 2023 |
|
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Benign
(Aug 15, 2023)
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criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV002552291.4
First in ClinVar: Jul 27, 2022 Last updated: Aug 18, 2023 |
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Benign
(Jan 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
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV000537391.2
First in ClinVar: Mar 24, 2017 Last updated: Feb 14, 2024 |
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Benign
(Feb 01, 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
|
Invitae
Accession: SCV000262452.11
First in ClinVar: Mar 24, 2015 Last updated: Feb 20, 2024 |
|
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Benign
(Aug 20, 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
|
Ambry Genetics
Accession: SCV000212712.7
First in ClinVar: Mar 24, 2015 Last updated: May 01, 2024 |
Comment:
This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation … (more)
This alteration is classified as 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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Benign
(Jul 24, 2014)
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no assertion criteria provided
Method: clinical testing
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Lynch syndrome I
Affected status: unknown
Allele origin:
germline
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Pathway Genomics
Accession: SCV000189955.1
First in ClinVar: Oct 19, 2014 Last updated: Oct 19, 2014 |
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Benign
(Oct 16, 2013)
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no assertion criteria provided
Method: clinical testing
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Lynch syndrome
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000052926.2
First in ClinVar: Apr 04, 2013 Last updated: Mar 24, 2015 |
|
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Benign
(-)
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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: SCV000592581.2 First in ClinVar: Oct 02, 2016 Last updated: Apr 13, 2021 |
Comment:
The p.Leu396Val variant has been previously reported in about 9/5154 proband chromosomes in individuals with Lynch syndrome, sporadic colorectal cancer and endometrial cancer. It has … (more)
The p.Leu396Val variant has been previously reported in about 9/5154 proband chromosomes in individuals with Lynch syndrome, sporadic colorectal cancer and endometrial cancer. It has also been observed in 3/5148 control chromosomes (Kim_2004_15340264, Kolodner_1999_10537275, Martinez_2010_20176959, Niessen_2006_16408224, Nilbert_2009_18566915, Perez-Cabornero_2009_19250818, Schafmayer_2007_17417778, Steinke_2008_18301448, Vahteristo_2005_15805151). It is listed in the dbSNP database as coming from a "clinical source" (ID#: rs2020908) with an average heterozygosity score and standard error of 0.008+/-0.064, and a global minor allele frequency (MAF) of 0.004 (1000 Genomes), increasing the likelihood that this is a benign variant. The variant was also identified as a low frequency variant from HapMap samples of different populations of origin as well as in the EPS project as a low frequency variant increasing the liklihood this variant is benign. This residue is conserved in mammals, and computational analyses (PolyPhen2, SIFT, AlignGVGD) suggest this variant may impact protein function. However, this information is not very predictive of pathogenicity. Two functional Saccharomyces cerevisiae-based studies have shown that the MMR activity of the variant is comparable to the wild type protein (Kolodner_1999_10537275, Martinez_2010_20176959), increasing the likelihood that the p.Leu396Val variant is not clinically significant. In summary, based on the above information, this variant is classified as Benign. (less)
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Benign
(-)
|
no assertion criteria provided
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
unknown
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV000257209.2
First in ClinVar: Nov 20, 2015 Last updated: Sep 28, 2017 |
|
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Benign
(Feb 20, 2018)
|
no assertion criteria provided
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
True Health Diagnostics
Accession: SCV000788042.1
First in ClinVar: Mar 24, 2017 Last updated: Mar 24, 2017 |
|
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Benign
(-)
|
no assertion criteria provided
Method: clinical testing
|
not specified
Affected status: yes
Allele origin:
germline
|
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Study: VKGL Data-share Consensus
Accession: SCV001798739.1 First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021 |
|
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Benign
(-)
|
no assertion criteria provided
Method: clinical testing
|
not specified
Affected status: yes
Allele origin:
germline
|
Clinical Genetics, Academic Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001920906.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021 |
|
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Benign
(-)
|
no assertion criteria provided
Method: clinical testing
|
not specified
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: SCV001958614.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
|
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Benign
(Oct 06, 2023)
|
no assertion criteria provided
Method: research
|
Lynch syndrome 5
(Autosomal dominant inheritance)
Affected status: no
Allele origin:
germline
|
Biesecker Lab/Clinical Genomics Section, National Institutes of Health
Study: ClinSeq
Accession: SCV000043352.2 First in ClinVar: Apr 12, 2013 Last updated: Oct 14, 2023 |
Comment:
BA1 based on allele frequency in NFE of 0.007213.
Number of individuals with the variant: 5
Comment on evidence:
The study set was not selected for affection status in relation to any cancer. Pathogenicity categories were based on literature curation. See Pubmed ID:22703879 for … (more)
The study set was not selected for affection status in relation to any cancer. Pathogenicity categories were based on literature curation. See Pubmed ID:22703879 for details. (less)
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not provided
(Sep 19, 2013)
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no classification provided
Method: reference population
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AllHighlyPenetrant
Affected status: unknown
Allele origin:
germline
|
ITMI
Accession: SCV000085772.1
First in ClinVar: Jun 09, 2014 Last updated: Jun 09, 2014
Comment:
Please see associated publication for description of ethnicities
|
Observation 1:
Ethnicity/Population group: Whole_cohort
Observation 2:
Ethnicity/Population group: African
Observation 3:
Ethnicity/Population group: African_European
Observation 4:
Ethnicity/Population group: Central_Asian
Observation 5:
Ethnicity/Population group: East_Asian
Observation 6:
Ethnicity/Population group: European
Observation 7:
Ethnicity/Population group: Hispanic
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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
HelpText-mined citations for rs2020908 ...
HelpRecord last updated May 12, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.