ClinVar Genomic variation as it relates to human health
NM_000251.3(MSH2):c.198C>T (p.Tyr66=)
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(2); Benign(2); Likely benign(11)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000251.3(MSH2):c.198C>T (p.Tyr66=)
Variation ID: 182608 Accession: VCV000182608.35
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2p21 2: 47403389 (GRCh38) [ NCBI UCSC ] 2: 47630528 (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 May 29, 2016 May 1, 2024 Feb 5, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000251.3:c.198C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000242.1:p.Tyr66= synonymous NM_001258281.1:c.-1C>T 5 prime UTR NM_001406631.1:c.198C>T NP_001393560.1:p.Tyr66= synonymous NM_001406632.1:c.198C>T NP_001393561.1:p.Tyr66= synonymous NM_001406633.1:c.198C>T NP_001393562.1:p.Tyr66= synonymous NM_001406634.1:c.198C>T NP_001393563.1:p.Tyr66= synonymous NM_001406635.1:c.198C>T NP_001393564.1:p.Tyr66= synonymous NM_001406636.1:c.198C>T NP_001393565.1:p.Tyr66= synonymous NM_001406637.1:c.198C>T NP_001393566.1:p.Tyr66= synonymous NM_001406638.1:c.198C>T NP_001393567.1:p.Tyr66= synonymous NM_001406639.1:c.198C>T NP_001393568.1:p.Tyr66= synonymous NM_001406640.1:c.198C>T NP_001393569.1:p.Tyr66= synonymous NM_001406641.1:c.198C>T NP_001393570.1:p.Tyr66= synonymous NM_001406642.1:c.198C>T NP_001393571.1:p.Tyr66= synonymous NM_001406643.1:c.198C>T NP_001393572.1:p.Tyr66= synonymous NM_001406644.1:c.198C>T NP_001393573.1:p.Tyr66= synonymous NM_001406645.1:c.198C>T NP_001393574.1:p.Tyr66= synonymous NM_001406646.1:c.198C>T NP_001393575.1:p.Tyr66= synonymous NM_001406647.1:c.198C>T NP_001393576.1:p.Tyr66= synonymous NM_001406648.1:c.198C>T NP_001393577.1:p.Tyr66= synonymous NM_001406649.1:c.198C>T NP_001393578.1:p.Tyr66= synonymous NM_001406650.1:c.198C>T NP_001393579.1:p.Tyr66= synonymous NM_001406651.1:c.198C>T NP_001393580.1:p.Tyr66= synonymous NM_001406652.1:c.198C>T NP_001393581.1:p.Tyr66= synonymous NM_001406653.1:c.198C>T NP_001393582.1:p.Tyr66= synonymous NM_001406654.1:c.-143C>T 5 prime UTR NM_001406655.1:c.198C>T NP_001393584.1:p.Tyr66= synonymous NM_001406656.1:c.-798C>T 5 prime UTR NM_001406657.1:c.198C>T NP_001393586.1:p.Tyr66= synonymous NM_001406658.1:c.-1121C>T 5 prime UTR NM_001406659.1:c.-1271C>T 5 prime UTR NM_001406660.1:c.-1468C>T 5 prime UTR NM_001406661.1:c.-1423C>T 5 prime UTR NM_001406662.1:c.-1340C>T 5 prime UTR NM_001406666.1:c.198C>T NP_001393595.1:p.Tyr66= synonymous NM_001406669.1:c.-1271C>T 5 prime UTR NM_001406672.1:c.198C>T NP_001393601.1:p.Tyr66= synonymous NM_001406674.1:c.198C>T NP_001393603.1:p.Tyr66= synonymous NR_176230.1:n.234C>T non-coding transcript variant NR_176231.1:n.234C>T non-coding transcript variant NR_176232.1:n.234C>T non-coding transcript variant NR_176233.1:n.234C>T non-coding transcript variant NR_176234.1:n.234C>T non-coding transcript variant NR_176235.1:n.234C>T non-coding transcript variant NR_176236.1:n.234C>T non-coding transcript variant NR_176237.1:n.234C>T non-coding transcript variant NR_176238.1:n.234C>T non-coding transcript variant NR_176239.1:n.234C>T non-coding transcript variant NR_176240.1:n.234C>T non-coding transcript variant NR_176241.1:n.234C>T non-coding transcript variant NR_176242.1:n.234C>T non-coding transcript variant NR_176243.1:n.234C>T non-coding transcript variant NR_176244.1:n.234C>T non-coding transcript variant NR_176245.1:n.234C>T non-coding transcript variant NR_176246.1:n.234C>T non-coding transcript variant NR_176247.1:n.234C>T non-coding transcript variant NR_176248.1:n.234C>T non-coding transcript variant NR_176249.1:n.234C>T non-coding transcript variant NR_176250.1:n.234C>T non-coding transcript variant NC_000002.12:g.47403389C>T NC_000002.11:g.47630528C>T NG_007110.2:g.5266C>T NG_095167.1:g.593C>T LRG_218:g.5266C>T LRG_218t1:c.198C>T LRG_218p1:p.Tyr66= - Protein change
- Other names
- p.Y66Y:TAC>TAT
- Canonical SPDI
- NC_000002.12:47403388: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
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00009
The Genome Aggregation Database (gnomAD) 0.00011
Trans-Omics for Precision Medicine (TOPMed) 0.00011
Exome Aggregation Consortium (ExAC) 0.00013
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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MSH2 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
7326 | 7479 |
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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Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Jun 28, 2021 | RCV000160652.11 | |
Likely benign (1) |
criteria provided, single submitter
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Feb 1, 2024 | RCV000206199.14 | |
Benign/Likely benign (4) |
criteria provided, multiple submitters, no conflicts
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Dec 27, 2023 | RCV000212580.13 | |
Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Mar 20, 2023 | RCV000409186.11 | |
Likely benign (1) |
no assertion criteria provided
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- | RCV001354005.4 | |
Likely benign (1) |
criteria provided, single submitter
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Sep 8, 2023 | RCV001284171.4 | |
Likely benign (1) |
criteria provided, single submitter
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Sep 21, 2022 | RCV003492655.1 | |
Likely benign (1) |
criteria provided, single submitter
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Feb 5, 2024 | RCV003998489.2 | |
MSH2-related disorder
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Likely benign (1) |
criteria provided, single submitter
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Apr 26, 2021 | RCV004544470.1 |
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
(Nov 25, 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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Color Diagnostics, LLC DBA Color Health
Accession: SCV000537504.1
First in ClinVar: May 29, 2016 Last updated: May 29, 2016 |
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Likely benign
(Dec 08, 2020)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: no
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV002066720.1
First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022 |
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Likely benign
(Sep 20, 2016)
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criteria provided, single submitter
Method: clinical testing
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Lynch syndrome 1
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000489340.2
First in ClinVar: Jan 06, 2017 Last updated: Dec 24, 2022 |
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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: SCV002552187.4
First in ClinVar: Jul 27, 2022 Last updated: Aug 18, 2023 |
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Likely benign
(Sep 21, 2022)
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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
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CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Accession: SCV004239277.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
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Likely benign
(Oct 24, 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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Ambry Genetics
Accession: SCV000212860.7
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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Benign
(Jul 28, 2014)
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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: SCV000211255.10
First in ClinVar: Feb 24, 2015 Last updated: Jun 01, 2016 |
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
(Apr 27, 2017)
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criteria provided, single submitter
Method: clinical testing
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Lynch syndrome 1
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV001304221.1
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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
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Uncertain significance
(Jun 28, 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: SCV002534435.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Comment:
The MSH2 c.198C>T (p.Tyr66=) variant has been reported in heterozygosity in at least one individual with ovarian cancer (PMID: 23047549). It was observed in 23/117090 … (more)
The MSH2 c.198C>T (p.Tyr66=) variant has been reported in heterozygosity in at least one individual with ovarian cancer (PMID: 23047549). It was observed in 23/117090 chromosomes, with no homozygotes, in the Non-Finnish European subpopulation in the large and broad cohorts of the Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654). The variant has been reported in ClinVar (Variation ID: 182608). In silico tools suggest the variant may potentially have an impact on splicing, though these predictions have not been confirmed by functional studies. 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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Benign
(Mar 20, 2023)
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criteria provided, single submitter
Method: clinical testing
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Lynch syndrome 1
Affected status: unknown
Allele origin:
unknown
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Myriad Genetics, Inc.
Accession: SCV004018293.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
Comment:
This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing.
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Likely benign
(Sep 08, 2023)
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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: SCV001469806.2
First in ClinVar: Jan 26, 2021 Last updated: Jan 06, 2024 |
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Likely benign
(Dec 27, 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: SCV004241702.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
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Likely 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
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Invitae
Accession: SCV000260791.10
First in ClinVar: Jan 31, 2016 Last updated: Feb 20, 2024 |
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Likely benign
(Apr 26, 2021)
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criteria provided, single submitter
Method: clinical testing
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MSH2-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004776793.1
First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024 |
Comment:
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
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Likely Benign
(Feb 05, 2024)
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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: SCV004832027.1
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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Number of individuals with the variant: 24
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Likely 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: SCV000592454.2 First in ClinVar: Jun 01, 2016 Last updated: Apr 13, 2021 |
Comment:
MSH2, EXON01, c.198C>T, p.= (p.Tyr66Tyr), Heterozygous, Likely benign rnrnThe MSH2 c.198C>T variant was not identified in the literature nor was it identified in the COSMIC, … (more)
MSH2, EXON01, c.198C>T, p.= (p.Tyr66Tyr), Heterozygous, Likely benign rnrnThe MSH2 c.198C>T variant was not identified in the literature nor was it identified in the COSMIC, “Mismatch Repair Genes Variant Database”, “MMR Gene Unclassified Variants Database”, InSiGHT Colon Cancer Gene Variant Database (LOVD), Zhejiang Colon Cancer Database (LOVD) and GeneInsight - COGR database. The variant was identified in dbSNP (ID: rs730881784) as “With Likely benign allele”, ClinVar database (classified as benign by GeneDx and likely benign by Ambry Genetics and Invitae) and UMD (1x with an “unclassified variant” classification). This variant was identified in the Exome Aggregation Consortium database (August 8, 2016) in 11 of 83058 chromosomes (freq. 0.0001) in the following populations: European in 11 of 47956 chromosomes (freq. 0.0002), increasing the likelihood that this may be a low frequency benign variant in certain populations of origin. The p.Tyr66Tyr variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. The variant occurs outside of the splicing consensus sequence and 2 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is 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 although we would lean towards a more benign role for this variant. This variant is classified as likely benign. (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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Frequency of mutations in mismatch repair genes in a population-based study of women with ovarian cancer. | Pal T | British journal of cancer | 2012 | PMID: 23047549 |
Text-mined citations for rs730881784 ...
HelpRecord last updated Jun 30, 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.