ClinVar Genomic variation as it relates to human health
NM_000251.3(MSH2):c.505A>G (p.Ile169Val)
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_000251.3(MSH2):c.505A>G (p.Ile169Val)
Variation ID: 91115 Accession: VCV000091115.41
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2p21 2: 47410232 (GRCh38) [ NCBI UCSC ] 2: 47637371 (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 Feb 14, 2024 Sep 5, 2013 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000251.3:c.505A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000242.1:p.Ile169Val missense NM_001258281.1:c.307A>G NP_001245210.1:p.Ile103Val missense NC_000002.12:g.47410232A>G NC_000002.11:g.47637371A>G NG_007110.2:g.12109A>G LRG_218:g.12109A>G LRG_218t1:c.505A>G LRG_218p1:p.Ile169Val P43246:p.Ile169Val - Protein change
- I169V, I103V
- Other names
- p.I169V:ATA>GTA
- Canonical SPDI
- NC_000002.12:47410231:A: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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0.00060 (G)
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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) 0.00013
Exome Aggregation Consortium (ExAC) 0.00053
1000 Genomes Project 30x 0.00062
Trans-Omics for Precision Medicine (TOPMed) 0.00024
The Genome Aggregation Database (gnomAD), exomes 0.00047
1000 Genomes Project 0.00060
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 |
7262 | 7411 |
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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Sep 5, 2013 | RCV000076619.14 | |
Benign/Likely benign (3) |
criteria provided, multiple submitters, no conflicts
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Jan 2, 2022 | RCV000115535.20 | |
Benign/Likely benign (5) |
criteria provided, multiple submitters, no conflicts
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Aug 15, 2023 | RCV000212588.22 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Feb 27, 2018 | RCV000659879.15 | |
Likely benign (1) |
criteria provided, single submitter
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May 1, 2019 | RCV001030707.9 | |
Benign (1) |
criteria provided, single submitter
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Feb 1, 2024 | RCV001086693.15 | |
Likely benign (1) |
no assertion criteria provided
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- | RCV001355673.9 | |
Likely benign (1) |
criteria provided, single submitter
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Apr 18, 2022 | RCV002498370.8 | |
Likely benign (1) |
criteria provided, single submitter
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Sep 20, 2021 | RCV003149754.9 |
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
(Sep 05, 2013)
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reviewed by expert panel
Method: research
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Lynch Syndrome
Affected status: unknown
Allele origin:
germline
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International Society for Gastrointestinal Hereditary Tumours (InSiGHT)
Accession: SCV000107654.3
First in ClinVar: Dec 19, 2013 Last updated: Dec 24, 2022 |
Comment:
Multifactorial likelihood analysis posterior probability 0.001-0.049
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Likely benign
(Sep 05, 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: SCV000149444.12
First in ClinVar: May 17, 2014 Last updated: Dec 19, 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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Uncertain significance
(Nov 01, 2016)
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criteria provided, single submitter
Method: clinical testing
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Lynch syndrome 1
Affected status: yes
Allele origin:
germline
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Center for Human Genetics, Inc, Center for Human Genetics, Inc
Accession: SCV000781770.1
First in ClinVar: Jul 09, 2018 Last updated: Jul 09, 2018 |
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Likely benign
(Feb 27, 2018)
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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: SCV001297031.1
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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
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Likely benign
(May 01, 2019)
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criteria provided, single submitter
Method: research
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Hereditary breast and ovarian cancer syndrome
Affected status: yes
Allele origin:
germline
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Cancer Genomics Group, Japanese Foundation For Cancer Research
Accession: SCV001193629.2
First in ClinVar: Apr 06, 2020 Last updated: Apr 06, 2020 |
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Likely benign
(Jun 28, 2021)
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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: SCV002066141.1
First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022 |
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Benign
(Dec 05, 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: SCV002534528.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 |
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Benign
(May 05, 2022)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
unknown
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000889441.3
First in ClinVar: Mar 14, 2019 Last updated: Dec 31, 2022 |
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Likely benign
(Apr 18, 2022)
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criteria provided, single submitter
Method: clinical testing
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Lynch syndrome 1
Muir-Torré syndrome Mismatch repair cancer syndrome 2
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002804884.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Likely benign
(Sep 20, 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
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CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Accession: SCV003837616.1
First in ClinVar: Mar 11, 2023 Last updated: Mar 11, 2023 |
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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
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Invitae
Accession: SCV000166283.13
First in ClinVar: Jun 15, 2014 Last updated: Feb 14, 2024 |
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Benign
(Nov 26, 2019)
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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: SCV001360857.1
First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020 |
Comment:
Variant summary: MSH2 c.505A>G (p.Ile169Val) results in a conservative amino acid change located in the DNA mismatch repair protein MutS, connector domain (IPR007860) of the … (more)
Variant summary: MSH2 c.505A>G (p.Ile169Val) results in a conservative amino acid change located in the DNA mismatch repair protein MutS, connector domain (IPR007860) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00047 in 251484 control chromosomes, predominantly at a frequency of 0.0064 within the East Asian subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 11 fold of the estimated maximal expected allele frequency for a pathogenic variant in MSH2 causing Lynch Syndrome phenotype (0.00057), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.505A>G has been reported in the literature in individuals affected with colon cancer and gastric cancer (Tomita_2003, Park_2008, Kim_2017). These reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. Additionally, Park_2008 reports that this variant did not co-segregate with disease in one family. Co-occurrence with a pathogenic variant has been reported (MSH2 c.905T>A, p.Leu302Ter) (Tomita_2003), providing supporting evidence for a benign role. At least one publication reports this variant showed no damaging effect of this variant (Zhu_2013). Six ClinVar submitters including one expert panel (InSiGHT, classified as likely benign in 2013) (evaluation after 2014) cite the variant as uncertain significance (1x), likely benign (3x) and benign (2x). Based on the evidence outlined above, the variant was classified as benign. (less)
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Likely benign
(Nov 30, 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: SCV000183948.8
First in ClinVar: Aug 06, 2014 Last updated: Nov 29, 2022 |
Comment:
This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, … (more)
This alteration is classified as likely benign based on a combination of the following: 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)
Number of individuals with the variant: 1
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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: SCV002760633.3
First in ClinVar: Dec 17, 2022 Last updated: Aug 18, 2023 |
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Benign
(Jan 02, 2022)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Color Diagnostics, LLC DBA Color Health
Accession: SCV000537440.2
First in ClinVar: Mar 24, 2017 Last updated: Feb 14, 2024 |
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Likely benign
(-)
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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: SCV001550624.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
The MSH2 p.Ile169Val variant was identified in 5 of 4626 proband chromosomes (frequency: 0.001) from individuals or families with colorectal cancer, Lynch syndrome, ovarian cancer … (more)
The MSH2 p.Ile169Val variant was identified in 5 of 4626 proband chromosomes (frequency: 0.001) from individuals or families with colorectal cancer, Lynch syndrome, ovarian cancer or diffuse large B cell lymphoma (Fan 2005, Liu 2014, Miranda 2013, Pal 2012, Ward 2013). The variant was also identified in dbSNP (ID: rs63750716) as "With other allele", ClinVar (classified as benign by Invitae and Quest Diagnostics Nichols Institute San Juan Capistrano; as likely benign by four submitters; and as uncertain significance by Center for Human Genetics). The variant was not identified in UMD-LSDB. The variant was identified in control databases in 124 of 277218 chromosomes (1 homozygous) at a frequency of 0.0005, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 2 of 6468 chromosomes (freq: 0.0003) and East Asian in 122 of 18862 chromosomes (freq: 0.007), while the variant was not observed in the African, Latino, European, Ashkenazi Jewish, Finnish, or South Asian populations. The p.Ile169 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 variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. 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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Analysis of human MutS homolog 2 missense mutations in patients with colorectal cancer. | Zhang X | Oncology letters | 2018 | PMID: 29731845 |
Profiling cancer-associated genetic alterations and molecular classification of cancer in Korean gastric cancer patients. | Kim Y | Oncotarget | 2017 | PMID: 29050249 |
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. | Richards S | Genetics in medicine : official journal of the American College of Medical Genetics | 2015 | PMID: 25741868 |
Challenges in assessing pathogenicity based on frequency of variants in mismatch repair genes: an extreme case of a MSH2 variant and a meta-analysis. | Woo HI | Gene | 2014 | PMID: 24933000 |
[Establishment of a hMSH2/hMSH6 protein interaction system and functional evaluation of hMSH2 gene missense mutations]. | Zhu M | Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics | 2013 | PMID: 24078570 |
DNA repair genes are selectively mutated in diffuse large B cell lymphomas. | de Miranda NF | The Journal of experimental medicine | 2013 | PMID: 23960188 |
Missense mutations of MLH1 and MSH2 genes detected in patients with gastrointestinal cancer are associated with exonic splicing enhancers and silencers. | Zhu M | Oncology letters | 2013 | PMID: 23760103 |
Population-based molecular screening for Lynch syndrome: implications for personalized medicine. | Ward RL | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2013 | PMID: 23733757 |
Novel DNA variants and mutation frequencies of hMLH1 and hMSH2 genes in colorectal cancer in the Northeast China population. | Hu F | PloS one | 2013 | PMID: 23573243 |
Prevalence of pathological germline mutations of hMLH1 and hMSH2 genes in colorectal cancer. | Li D | PloS one | 2013 | PMID: 23526924 |
Racial differences in MLH1 and MSH2 mutation: an analysis of yellow race and white race based on the InSiGHT database. | Wei W | Journal of bioinformatics and computational biology | 2010 | PMID: 21155023 |
Recurring MLH1 deleterious mutations in unrelated Chinese Lynch syndrome families in Singapore. | Yap HL | Familial cancer | 2009 | PMID: 18726168 |
A novel missense MSH2 gene mutation in a patient of a Korean family with hereditary nonpolyposis colorectal cancer. | Park SJ | Cancer genetics and cytogenetics | 2008 | PMID: 18406877 |
Variations in exon 7 of the MSH2 gene and susceptibility to gastrointestinal cancer in a Chinese population. | Fan Y | Cancer genetics and cytogenetics | 2006 | PMID: 17011982 |
Clinical and molecular characteristics of hereditary non-polyposis colorectal cancer families in Southeast Asia. | Lee SC | Clinical genetics | 2005 | PMID: 15996210 |
The novel germline mutation of hMSH2 gene in a case of a hereditary non-polyposis colorectal cancer (HNPCC) patient who meets the revised Amsterdam criteria. | Tomita N | Japanese journal of clinical oncology | 2003 | PMID: 14594944 |
http://www.insight-database.org/classifications/index.html?gene=MSH2&variant=c.505A%3EG | - | - | - | - |
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Text-mined citations for rs63750716 ...
HelpRecord last updated Apr 20, 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.