ClinVar Genomic variation as it relates to human health
NM_000251.3(MSH2):c.557A>G (p.Asn186Ser)
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(9); Benign(1); Likely benign(4)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000251.3(MSH2):c.557A>G (p.Asn186Ser)
Variation ID: 91133 Accession: VCV000091133.62
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2p21 2: 47410284 (GRCh38) [ NCBI UCSC ] 2: 47637423 (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 Oct 8, 2024 Jan 29, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000251.3:c.557A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000242.1:p.Asn186Ser missense NM_001258281.1:c.359A>G NP_001245210.1:p.Asn120Ser missense NC_000002.12:g.47410284A>G NC_000002.11:g.47637423A>G NG_007110.2:g.12161A>G LRG_218:g.12161A>G LRG_218t1:c.557A>G LRG_218p1:p.Asn186Ser - Protein change
- N120S
- Other names
- p.N186S:AAT>AGT
- Canonical SPDI
- NC_000002.12:47410283: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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Allele frequency
Help
The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00008
The Genome Aggregation Database (gnomAD), exomes 0.00009
Trans-Omics for Precision Medicine (TOPMed) 0.00010
The Genome Aggregation Database (gnomAD) 0.00011
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00038
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 |
7401 | 7563 |
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 (4) |
criteria provided, conflicting classifications
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Mar 2, 2022 | RCV000130716.25 | |
Likely benign (2) |
criteria provided, single submitter
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Jul 5, 2023 | RCV000202264.21 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Mar 22, 2023 | RCV000411418.12 | |
Uncertain significance (5) |
criteria provided, multiple submitters, no conflicts
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Jan 24, 2024 | RCV000587046.43 | |
Likely benign (1) |
criteria provided, single submitter
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Jan 29, 2024 | RCV001081828.16 | |
Uncertain significance (1) |
criteria provided, single submitter
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Mar 1, 2021 | RCV001798268.10 |
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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Uncertain significance
(Mar 01, 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: SCV002042111.1
First in ClinVar: Jan 03, 2022 Last updated: Jan 03, 2022 |
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Likely benign
(Dec 05, 2019)
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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: SCV000185603.9
First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024 |
Comment:
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more)
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
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Uncertain significance
(Dec 01, 2022)
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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: SCV001152274.24
First in ClinVar: Feb 03, 2020 Last updated: Oct 08, 2024 |
Number of individuals with the variant: 1
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Uncertain significance
(Aug 01, 2018)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: yes
Allele origin:
germline
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GeneKor MSA
Accession: SCV000822055.1
First in ClinVar: Oct 10, 2018 Last updated: Oct 10, 2018 |
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Uncertain significance
(Mar 17, 2014)
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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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Eurofins Ntd Llc (ga)
Accession: SCV000203032.7
First in ClinVar: Feb 02, 2015 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 1
Sex: mixed
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Likely benign
(Jun 07, 2016)
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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: SCV000910737.1
First in ClinVar: May 20, 2019 Last updated: May 20, 2019 |
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Uncertain significance
(Mar 02, 2022)
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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: SCV002534533.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Comment:
The MSH2 c.557A>G (p.N186S) variant has been reported in the literature in individuals affected with colorectal cancer or Lynch Syndrome (PMID: 27273229, 28874130, 27601186, 27978560, … (more)
The MSH2 c.557A>G (p.N186S) variant has been reported in the literature in individuals affected with colorectal cancer or Lynch Syndrome (PMID: 27273229, 28874130, 27601186, 27978560, 11606497), and has also been reported in several women with breast cancer (PMID: 29752822, 33471991). However, it has also been reported in healthy controls (PMID: 11606497, 33471991, 32980694). This variant has co-occurred with other disease-causing variants in MSH2 and MLH1 genes, providing supporting evidence for a benign role (PMID: 27978560, 11606497). It was observed in 27/282864 chromosomes across all populations in the large and broad cohorts of the Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654), and has been reported in ClinVar (Variation ID 91133). In silico tools suggest the impact of the variant on protein function is deleterious, though these predictions have not been confirmed by functional studies. There is no indication that this variant causes disease, but the evidence is insufficient currently to prove that conclusively. Thus, the clinical significance of this variant is currently uncertain. (less)
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Uncertain significance
(Apr 19, 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: SCV000488523.2
First in ClinVar: Jan 06, 2017 Last updated: Dec 24, 2022 |
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Uncertain significance
(Oct 20, 2022)
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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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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV003800395.2
First in ClinVar: Feb 13, 2023 Last updated: Mar 04, 2023 |
Comment:
The MSH2 c.557A>G; p.Asn186Ser variant (rs151129360) is reported in the literature in individuals with suspected Lynch syndrome, colorectal cancer, breast cancer, or hereditary cancer predisposition … (more)
The MSH2 c.557A>G; p.Asn186Ser variant (rs151129360) is reported in the literature in individuals with suspected Lynch syndrome, colorectal cancer, breast cancer, or hereditary cancer predisposition syndrome (Buchanan 2017, Li 2019, Rossi 2017, Tsaousis 2019). Immunohistochemistry (IHC) staining of tumor sample containing this variant was normal, but showed high microsatellite instability (MSI-H) (Buchanan 2017). This variant is also reported in ClinVar (Variation ID: 91133). It is found in the general population with an overall allele frequency of 0.0095% (27/282864 alleles) in the Genome Aggregation Database. The asparagine at codon 186 is moderately conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.769). However, due to limited information, the clinical significance of this variant is uncertain at this time. References: Buchanan DD et al. Tumor testing to identify lynch syndrome in two Australian colorectal cancer cohorts. J Gastroenterol Hepatol. 2017 Feb;32(2):427-438. PMID: 27273229. Li JY et al. Germline mutations in 40 cancer susceptibility genes among Chinese patients with high hereditary risk breast cancer. Int J Cancer. 2019 Jan 15;144(2):281-289. PMID: 29752822. Rossi BM et al. A survey of the clinicopathological and molecular characteristics of patients with suspected Lynch syndrome in Latin America. BMC Cancer. 2017 Sep 5;17(1):623. PMID: 28874130. Tsaousis GN et al. Analysis of hereditary cancer syndromes by using a panel of genes: novel and multiple pathogenic mutations. BMC Cancer. 2019 Jun 3;19(1):535. PMID: 31159747. (less)
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Benign
(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: SCV004018379.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
Comment:
This variant is considered benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants … (more)
This variant is considered benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. This variant has been observed in conjunction with multiple pathogenic variants, reducing the likelihood this variant itself is pathogenic. (less)
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Likely benign
(Jul 05, 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: SCV000696276.5
First in ClinVar: Mar 17, 2018 Last updated: Aug 26, 2023 |
Comment:
Variant summary: MSH2 c.557A>G (p.Asn186Ser) results in a conservative amino acid change located in the DNA mismatch repair protein MutS, connector domain of the encoded … (more)
Variant summary: MSH2 c.557A>G (p.Asn186Ser) results in a conservative amino acid change located in the DNA mismatch repair protein MutS, connector domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 9.5e-05 in 251626 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in MSH2 causing Hereditary Nonpolyposis Colorectal Cancer (9.5e-05 vs 0.00057), allowing no conclusion about variant significance. c.557A>G has been reported in the literature in individuals affected with Lynch Syndrome (examples: Lagerstedt-Robinson_2016, Buchanan_2016, Perlman_2016, Mu_2016, Rossi_2017) or breast cancer (examples: Li_2018, Hu_2022). These reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. At-least one pathogenic co-occurring evariant has been reported (Pearlman_2016, MSH2 c.2096C>A, p.Ser699X), providing supporting evidence for a benign role. A recent study analyzed MMR pathogenic variant association with MSI/IHC status, and estimated likelihood ratios to compute a tumour characteristic likelihood ratio (TCLR), that was further assessed in combination with in-silico predictors, and a multifactorial variant prediction (Li_2010). This specific variant was predicted to be likely benign based on this model (Li_2020). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eleven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as uncertain significance (n=8) and likely benign (n=3). Based on the evidence outlined above, the variant was classified as likely benign. (less)
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Uncertain significance
(Mar 24, 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: SCV000888222.5
First in ClinVar: Dec 15, 2018 Last updated: Jan 06, 2024 |
Comment:
The frequency of this variant in the general population, 0.0002 (7/35440 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the … (more)
The frequency of this variant in the general population, 0.0002 (7/35440 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with Lynch syndrome or Lynch-related cancer (PMIDs: 31391288 (2020), 28874130 (2017), 27273229 (2017), 27978560 (2016), 27601186 (2016)), breast and/or ovarian cancer (PMIDs: 31159747 (2019), 29752822 (2018)), and rhabdosarcoma (PMID 26580448 (2015)). The variant was also observed in unaffected population controls (PMIDs: 32980694 (2020), 11606497 (2001)). In an individual with colon cancer, this variant co-occurred with a deleterious frameshift variant in the MSH2 gene, suggesting the c.557A>G (p.Asn186Ser) variant may not be the cause of disease (PMID: 27978560 (2016)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant. (less)
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Likely benign
(Jan 29, 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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000254425.12
First in ClinVar: Oct 11, 2015 Last updated: Feb 20, 2024 |
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Uncertain significance
(Jan 24, 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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GeneDx
Accession: SCV000211213.17
First in ClinVar: Feb 24, 2015 Last updated: Sep 16, 2024 |
Comment:
Observed in individuals with suspected Lynch syndrome and/or breast cancer, but also in unaffected controls (PMID: 11606497, 26580448, 27601186, 28874130, 32980694, 33471991, 35449176); In silico … (more)
Observed in individuals with suspected Lynch syndrome and/or breast cancer, but also in unaffected controls (PMID: 11606497, 26580448, 27601186, 28874130, 32980694, 33471991, 35449176); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 11606497, 12419761, 27273229, 26333163, 27601186, 27720647, 26580448, 28874130, 29752822, 31159747, 31391288, 17531815, 32980694, 33471991, 35449176, 18822302, 21120944, 36243179, 27978560, 36845387) (less)
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
unknown
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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV000257192.2
First in ClinVar: Nov 20, 2015 Last updated: Sep 28, 2017 |
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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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Clinical relevance of pathogenic germline variants in mismatch repair genes in Chinese breast cancer patients. | Hu L | NPJ breast cancer | 2022 | PMID: 35449176 |
Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women. | Breast Cancer Association Consortium | The New England journal of medicine | 2021 | PMID: 33471991 |
Genetic characterization of pancreatic cancer patients and prediction of carrier status of germline pathogenic variants in cancer-predisposing genes. | Mizukami K | EBioMedicine | 2020 | PMID: 32980694 |
Tumour characteristics provide evidence for germline mismatch repair missense variant pathogenicity. | Li S | Journal of medical genetics | 2020 | PMID: 31391288 |
Analysis of hereditary cancer syndromes by using a panel of genes: novel and multiple pathogenic mutations. | Tsaousis GN | BMC cancer | 2019 | PMID: 31159747 |
Germline mutations in 40 cancer susceptibility genes among Chinese patients with high hereditary risk breast cancer. | Li JY | International journal of cancer | 2019 | PMID: 29752822 |
A survey of the clinicopathological and molecular characteristics of patients with suspected Lynch syndrome in Latin America. | Rossi BM | BMC cancer | 2017 | PMID: 28874130 |
Prevalence and Spectrum of Germline Cancer Susceptibility Gene Mutations Among Patients With Early-Onset Colorectal Cancer. | Pearlman R | JAMA oncology | 2017 | PMID: 27978560 |
Tumor testing to identify lynch syndrome in two Australian colorectal cancer cohorts. | Buchanan DD | Journal of gastroenterology and hepatology | 2017 | PMID: 27273229 |
Sanger Confirmation Is Required to Achieve Optimal Sensitivity and Specificity in Next-Generation Sequencing Panel Testing. | Mu W | The Journal of molecular diagnostics : JMD | 2016 | PMID: 27720647 |
Mismatch repair gene mutation spectrum in the Swedish Lynch syndrome population. | Lagerstedt-Robinson K | Oncology reports | 2016 | PMID: 27601186 |
Germline Mutations in Predisposition Genes in Pediatric Cancer. | Zhang J | The New England journal of medicine | 2015 | PMID: 26580448 |
Classification of Amino Acid Substitutions in Mismatch Repair Proteins Using PON-MMR2. | Niroula A | Human mutation | 2015 | PMID: 26333163 |
RNA splicing. The human splicing code reveals new insights into the genetic determinants of disease. | Xiong HY | Science (New York, N.Y.) | 2015 | PMID: 25525159 |
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 |
Structure of the human MutSalpha DNA lesion recognition complex. | Warren JJ | Molecular cell | 2007 | PMID: 17531815 |
The colon cancer burden of genetically defined hereditary nonpolyposis colon cancer. | Samowitz WS | Gastroenterology | 2001 | PMID: 11606497 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=MSH2 | - | - | - | - |
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Text-mined citations for rs151129360 ...
HelpRecord last updated Oct 08, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.