ClinVar Genomic variation as it relates to human health
NM_000251.3(MSH2):c.484G>A (p.Gly162Arg)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000251.3(MSH2):c.484G>A (p.Gly162Arg)
Variation ID: 91105 Accession: VCV000091105.25
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2p21 2: 47410211 (GRCh38) [ NCBI UCSC ] 2: 47637350 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Mar 24, 2015 Sep 16, 2024 Sep 5, 2013 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000251.3:c.484G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000242.1:p.Gly162Arg missense NM_001258281.1:c.286G>A NP_001245210.1:p.Gly96Arg missense NC_000002.12:g.47410211G>A NC_000002.11:g.47637350G>A NG_007110.2:g.12088G>A LRG_218:g.12088G>A LRG_218t1:c.484G>A LRG_218p1:p.Gly162Arg P43246:p.Gly162Arg - Protein change
- G162R, G96R
- Other names
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- Canonical SPDI
- NC_000002.12:47410210:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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 |
7401 | 7563 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
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The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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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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Pathogenic (1) |
reviewed by expert panel
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Sep 5, 2013 | RCV000076608.5 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jun 13, 2023 | RCV000491163.10 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Mar 22, 2023 | RCV000662882.3 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jul 26, 2023 | RCV000985811.3 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 9, 2023 | RCV000524412.8 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 29, 2019 | RCV001194033.1 | |
Pathogenic (1) |
criteria provided, single submitter
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- | RCV004546430.1 |
Submissions - Germline
Classification
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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
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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
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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
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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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Pathogenic
(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: SCV000107644.3
First in ClinVar: Dec 19, 2013 Last updated: Dec 24, 2022
Comment:
Classified with v1.9 guidelines: https://docs.google.com/file/d/0B3JL6rP6JzhoN2EydHRVMEI1UGs
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Comment:
Multifactorial likelihood analysis posterior probability >0.99
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Pathogenic
(Jan 25, 2019)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV001134365.3
First in ClinVar: Jan 05, 2020 Last updated: Jan 01, 2022 |
Comment:
The best available variant frequency is uninformative. Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Located in … (more)
The best available variant frequency is uninformative. Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Located in potentially important domain of the protein. Assessment of experimental evidence suggests this variant results in abnormal protein function. (less)
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Pathogenic
(Nov 28, 2017)
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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: SCV000785789.2
First in ClinVar: Jul 15, 2018 Last updated: Jul 15, 2018 |
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Pathogenic
(Nov 29, 2020)
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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: SCV002534525.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Comment:
The MSH2 c.484G>A (p.G162R) variant has been reported in heterozygosity in multiple individuals with Lynch syndrome, HNPCC, endometrial, or ovarian cancer (PMID: 17101317, 24362816, 28491141, … (more)
The MSH2 c.484G>A (p.G162R) variant has been reported in heterozygosity in multiple individuals with Lynch syndrome, HNPCC, endometrial, or ovarian cancer (PMID: 17101317, 24362816, 28491141, 29625052, 18781619, among others). Functional studies have shown that this variant alters the MMR activity of the protein and may disrupt the normal heteroduplex formation with MSH6 (PMID: 17101317, 30998989, 26951660, 18781619). This variant was observed in 1/113756 chromosomes in the European (non-Finnish population, with no homozygotes, according to the Genome Aggregation Database (PMID: 27535533). This variant has been classified as pathogenic by a ClinGen-approved expert panel. Based on the current evidence available, this variant is interpreted as pathogenic. (less)
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Pathogenic
(Jun 13, 2023)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Color Diagnostics, LLC DBA Color Health
Accession: SCV000905218.3
First in ClinVar: May 19, 2019 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces glycine with arginine at codon 162 of the MSH2 protein. Computational prediction tool suggests that this variant may have deleterious impact … (more)
This missense variant replaces glycine with arginine at codon 162 of the MSH2 protein. Computational prediction tool suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant has defects in mismatch repair activity, protein expression/stability and sub-cellular localization (PMID: 18781619, 18951462) and tolerance to DNA-damaging agents (PMID: 30998989, 33357406). This variant has been reported in individuals affected with Lynch syndrome and Lynch syndrome-associated cancers (PMID: 12537652, 17101317, 18781619, 34667028, 36356413). Several of these individuals had tumors displaying microsatellite instability and/or mismatch repair protein loss in MSH2 via immunohistochemistry. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. (less)
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Pathogenic
(Dec 09, 2023)
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criteria provided, single submitter
Method: clinical testing
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Hereditary nonpolyposis colorectal neoplasms
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000548190.7
First in ClinVar: Mar 24, 2015 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 162 of the MSH2 protein (p.Gly162Arg). … (more)
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 162 of the MSH2 protein (p.Gly162Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with breast and prostate cancer, as well as individuals with clinicial features of Lynch syndrome (PMID: 12537652, 17101317, 18781619, 27606285, 28491141, 28874130, 29025352; Invitae). ClinVar contains an entry for this variant (Variation ID: 91105). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 33357406) indicates that this missense variant is expected to disrupt MSH2 function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects MSH2 function (PMID: 17101317, 18781619, 18951462, 22949387, 24362816, 30998989). RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Muir-Torré syndrome
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV005042633.1
First in ClinVar: May 12, 2024 Last updated: May 12, 2024 |
Comment:
The missense variant c.484G>Ap.Gly162Arg in MSH2 gene has been observed in heterozygous state in individuals with MSH2 related disorders Ponz et. al., 2018; Rossi et. … (more)
The missense variant c.484G>Ap.Gly162Arg in MSH2 gene has been observed in heterozygous state in individuals with MSH2 related disorders Ponz et. al., 2018; Rossi et. al., 2017. Experimental studies have shown that this missense change affects MSH2 function Ollila et. al., 2008. The p.Gly162Arg variant is novel not in any individuals in 1000 Genomes and has allele frequency of 0.0004% in gnomAD exomes database. This variant has been reported to the ClinVar database as Pathogenic by mutiple submitters. The amino acid change p.Gly162Arg in MSH2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Gly at position 162 is changed to a Arg changing protein sequence and it might alter its composition and physicochemical properties. For these reasons, this variant has been classified as Pathogenic. (less)
Clinical Features:
Neoplasm (present)
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Pathogenic
(Oct 29, 2019)
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criteria provided, single submitter
Method: clinical testing
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Lynch syndrome
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001363269.1
First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020 |
Comment:
Variant summary: MSH2 c.484G>A (p.Gly162Arg) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, connector domain (IPR007860) of the … (more)
Variant summary: MSH2 c.484G>A (p.Gly162Arg) results in a non-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 damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251482 control chromosomes (gnomAD). c.484G>A has been reported in the literature in multiple individuals affected with colon cancer and HNPCC (Loader_2002, Ollila_2006, Belvederesi_2008, Thompson_2013, Brennan_2017, Rossi_2017). These data indicate that the variant is very likely to be associated with disease. At least one publication, Ollila_2006, reports this variant had effects on protein stability, localization and DNA repair activity. Four ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic (less)
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Pathogenic
(Mar 22, 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: SCV004018373.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
Comment:
This variant is considered pathogenic. Functional studies indicate this variant impacts protein function [PMID: 18951462, 17101317, 18781619]. This variant is strongly associated with more severe … (more)
This variant is considered pathogenic. Functional studies indicate this variant impacts protein function [PMID: 18951462, 17101317, 18781619]. This variant is strongly associated with more severe personal and family histories of cancer, typical for individuals with pathogenic variants in this gene [PMID: 25085752]. (less)
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Pathogenic
(Sep 17, 2020)
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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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Genetics and Molecular Pathology, SA Pathology
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV004175554.1
First in ClinVar: Dec 17, 2023 Last updated: Dec 17, 2023 |
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Pathogenic
(Jun 14, 2021)
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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: SCV000580414.6
First in ClinVar: Jun 25, 2017 Last updated: May 01, 2024 |
Comment:
The p.G162R pathogenic mutation (also known as c.484G>A), located in coding exon 3 of the MSH2 gene, results from a G to A substitution at … (more)
The p.G162R pathogenic mutation (also known as c.484G>A), located in coding exon 3 of the MSH2 gene, results from a G to A substitution at nucleotide position 484. The glycine at codon 162 is replaced by arginine, an amino acid with dissimilar properties. This mutation has been seen in several individuals who met Amsterdam I/II or Bethesda criteria for HNPCC (Ollila S et al. Gastroenterology. 2006 Nov;131:1408-17; Belvederesi L et al. Hum. Mutat. 2008 Nov;29:E296-309; Rossi BM et al. BMC Cancer, 2017 Sep;17:623). Several studies have shown this mutation to result in abnormal subcellular localization patterns, reduced MMR efficiency compared to the wild type, or was partially deleterious (Ollila S et al. Gastroenterology. 2006 Nov;131:1408-17; Kansikas M et al Hum. Mutat. 2011 Jan;32:107-15; Belvederesi L et al. Hum. Mutat. 2008 Nov;29:E296-309; Houlleberghs H et al. Proc. Natl. Acad. Sci. U.S.A., 2016 Apr;113:4128-33). This alteration has been classified as pathogenic using the following lines of evidence: in silico prediction models, segregation with disease, clinical phenotype including tumor characteristics, mutation co-occurrence, and functional studies (Thompson BA et al. Hum. Mutat. 2013 Jan;34:200-9; Thompson BA et al. Nat. Genet. 2014 Feb;46:107-15; available at [www.insight-group.org/variants/classifications/]). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
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Pathogenic
(Jul 26, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV005202067.1
First in ClinVar: Sep 16, 2024 Last updated: Sep 16, 2024 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; … (more)
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate a damaging effect: decreased expression, increased MSI slippage, reduced mismatch repair capability, and partial failure of protein localization to the nucleus (PMID: 17101317, 18781619, 26951660); Identified in patients with a personal and/or family history of Lynch syndrome-related cancers, many meeting clinical criteria and/or with concordant tumor studies (PMID: 12537652, 18781619, 28874130, 29025352); This variant is associated with the following publications: (PMID: 21120944, 22949387, 31609810, 15991316, 22949379, 28874130, 30998989, 27606285, 17250665, 18383312, 18781619, 12537652, 24362816, 17101317, 17594722, 18951462, 26951660, 29625052, 28491141, 29025352, 18822302) (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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Canonical and uncanonical pathogenic germline variants in colorectal cancer patients by next-generation sequencing in a European referral center. | Poliani L | ESMO open | 2022 | PMID: 36356413 |
Morphologic and Genomic Characteristics of Breast Cancers Occurring in Individuals with Lynch Syndrome. | Schwartz CJ | Clinical cancer research : an official journal of the American Association for Cancer Research | 2022 | PMID: 34667028 |
Massively parallel functional testing of MSH2 missense variants conferring Lynch syndrome risk. | Jia X | American journal of human genetics | 2021 | PMID: 33357406 |
Methylation Tolerance-Based Functional Assay to Assess Variants of Unknown Significance in the MLH1 and MSH2 Genes and Identify Patients With Lynch Syndrome. | Bouvet D | Gastroenterology | 2019 | PMID: 30998989 |
Pathogenic Germline Variants in 10,389 Adult Cancers. | Huang KL | Cell | 2018 | PMID: 29625052 |
Risk of colorectal polyps and of malignancies in asymptomatic carriers of mutations in the main DNA mismatch repair genes. | Ponz de Leon M | Scandinavian journal of gastroenterology | 2018 | PMID: 29025352 |
A germline missense mutation in exon 3 of the MSH2 gene in a Lynch syndrome family: correlation with phenotype and localization assay. | Bianchi F | Familial cancer | 2018 | PMID: 28785832 |
A survey of the clinicopathological and molecular characteristics of patients with suspected Lynch syndrome in Latin America. | Rossi BM | BMC cancer | 2017 | PMID: 28874130 |
Universal molecular screening does not effectively detect Lynch syndrome in clinical practice. | Brennan B | Therapeutic advances in gastroenterology | 2017 | PMID: 28491141 |
MLH1 Ile219Val Polymorphism in Argentinean Families with Suspected Lynch Syndrome. | Dominguez-Valentin M | Frontiers in oncology | 2016 | PMID: 27606285 |
Oligonucleotide-directed mutagenesis screen to identify pathogenic Lynch syndrome-associated MSH2 DNA mismatch repair gene variants. | Houlleberghs H | Proceedings of the National Academy of Sciences of the United States of America | 2016 | PMID: 26951660 |
MSH2 role in BRCA1-driven tumorigenesis: A preliminary study in yeast and in human tumors from BRCA1-VUS carriers. | Maresca L | European journal of medical genetics | 2015 | PMID: 26381082 |
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 |
Application of a 5-tiered scheme for standardized classification of 2,360 unique mismatch repair gene variants in the InSiGHT locus-specific database. | Thompson BA | Nature genetics | 2014 | PMID: 24362816 |
Calibration of multiple in silico tools for predicting pathogenicity of mismatch repair gene missense substitutions. | Thompson BA | Human mutation | 2013 | PMID: 22949387 |
A multifactorial likelihood model for MMR gene variant classification incorporating probabilities based on sequence bioinformatics and tumor characteristics: a report from the Colon Cancer Family Registry. | Thompson BA | Human mutation | 2013 | PMID: 22949379 |
Verification of the three-step model in assessing the pathogenicity of mismatch repair gene variants. | Kansikas M | Human mutation | 2011 | PMID: 21120944 |
Mechanisms of pathogenicity in human MSH2 missense mutants. | Ollila S | Human mutation | 2008 | PMID: 18951462 |
MSH2 missense mutations and HNPCC syndrome: pathogenicity assessment in a human expression system. | Belvederesi L | Human mutation | 2008 | PMID: 18781619 |
Accurate classification of MLH1/MSH2 missense variants with multivariate analysis of protein polymorphisms-mismatch repair (MAPP-MMR). | Chao EC | Human mutation | 2008 | PMID: 18383312 |
Effectiveness of the CRCAPRO program in identifying patients suspected for HNPCC. | Bianchi F | Clinical genetics | 2007 | PMID: 17250665 |
Pathogenicity of MSH2 missense mutations is typically associated with impaired repair capability of the mutated protein. | Ollila S | Gastroenterology | 2006 | PMID: 17101317 |
Gene symbol: MSH2. Disease: Hereditary nonpolyposis colorectal cancer. | Otway R | Human genetics | 2005 | PMID: 15991314 |
Patient vs. physician as the target of educational outreach about screening for an inherited susceptibility to colorectal cancer. | Loader S | Genetic testing | 2002 | PMID: 12537652 |
http://www.insight-database.org/classifications/index.html?gene=MSH2&variant=c.484G%3EA | - | - | - | - |
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Text-mined citations for rs63750624 ...
HelpRecord last updated Sep 29, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.