ClinVar Genomic variation as it relates to human health
NM_000251.3(MSH2):c.380A>G (p.Asn127Ser)
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.380A>G (p.Asn127Ser)
Variation ID: 36577 Accession: VCV000036577.50
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2p21 2: 47410107 (GRCh38) [ NCBI UCSC ] 2: 47637246 (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 Jun 9, 2014 Feb 28, 2024 Sep 5, 2013 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000251.3:c.380A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000242.1:p.Asn127Ser missense NM_001258281.1:c.182A>G NP_001245210.1:p.Asn61Ser missense NC_000002.12:g.47410107A>G NC_000002.11:g.47637246A>G NG_007110.2:g.11984A>G LRG_218:g.11984A>G LRG_218t1:c.380A>G LRG_218p1:p.Asn127Ser P43246:p.Asn127Ser - Protein change
- N127S, N61S
- Other names
- -
- Canonical SPDI
- NC_000002.12:47410106: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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0.02476 (G)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00575
Exome Aggregation Consortium (ExAC) 0.00699
The Genome Aggregation Database (gnomAD) 0.02317
Trans-Omics for Precision Medicine (TOPMed) 0.02455
1000 Genomes Project 0.02476
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.02637
1000 Genomes Project 30x 0.02670
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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MSH2 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
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Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Benign (2) |
reviewed by expert panel
|
Sep 5, 2013 | RCV000030253.15 | |
Benign (10) |
criteria provided, multiple submitters, no conflicts
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Aug 15, 2023 | RCV000035361.42 | |
Conflicting interpretations of pathogenicity (6) |
criteria provided, conflicting classifications
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Jul 7, 2023 | RCV000144619.18 | |
Benign (4) |
criteria provided, multiple submitters, no conflicts
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Feb 6, 2020 | RCV000162398.13 | |
Benign (1) |
criteria provided, single submitter
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Feb 1, 2024 | RCV000757470.16 | |
Benign (3) |
criteria provided, multiple submitters, no conflicts
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Nov 28, 2023 | RCV001353586.19 | |
Likely benign (1) |
criteria provided, single submitter
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Apr 23, 2022 | RCV002490419.8 | |
Benign (1) |
criteria provided, single submitter
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Jul 2, 2021 | RCV003149584.9 |
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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no known pathogenicity
(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
|
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)
Accession: SCV000107622.3
First in ClinVar: Dec 19, 2013 Last updated: Dec 24, 2022 |
Comments (2):
MAF >1%
Converted during submission to Benign.
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Benign
(-)
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criteria provided, single submitter
Method: clinical testing
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NOT SPECIFIED
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV000303165.1
First in ClinVar: Oct 02, 2016 Last updated: Oct 02, 2016 |
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Benign
(Sep 21, 2015)
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criteria provided, single submitter
Method: clinical testing
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Lynch syndrome 1
Affected status: yes
Allele origin:
germline
|
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Study: VKGL Data-share Consensus
Accession: SCV000744267.1 First in ClinVar: Oct 19, 2014 Last updated: Oct 19, 2014 |
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Benign
(Dec 11, 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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Genome Diagnostics Laboratory, Amsterdam University Medical Center
Study: VKGL Data-share Consensus
Accession: SCV000745632.1 First in ClinVar: Oct 19, 2014 Last updated: Oct 19, 2014 |
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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: SCV000781768.1
First in ClinVar: Oct 19, 2014 Last updated: Oct 19, 2014 |
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Benign
(Apr 10, 2014)
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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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Eurofins Ntd Llc (ga)
Accession: SCV000203031.7
First in ClinVar: Jan 31, 2015 Last updated: May 03, 2018 |
Number of individuals with the variant: 1
Sex: mixed
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Benign
(Dec 14, 2011)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000059009.5
First in ClinVar: May 03, 2013 Last updated: Oct 02, 2016 |
Comment:
The Asn127Ser variant in MSH2 is not expected to have clinical significance beca use it was reported in dbSNP at a frequency ranging from ~1% … (more)
The Asn127Ser variant in MSH2 is not expected to have clinical significance beca use it was reported in dbSNP at a frequency ranging from ~1% to ~14% in various populations, and is most commonly observed in individuals with African ancestry (rs17217772). (less)
Number of individuals with the variant: 1
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Likely benign
(Jan 23, 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: SCV000430913.3
First in ClinVar: Dec 06, 2016 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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Benign
(Mar 03, 2015)
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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: SCV001891611.1
First in ClinVar: Sep 19, 2021 Last updated: Sep 19, 2021 |
Comment:
This variant is associated with the following publications: (PMID: 14574163, 28932927, 24728327, 27629256, 26951660, 27884173, 12624141, 20176959, 16237223, 18470917, 22949387, 18951462, 21120944, 17720936, 11606497, 25107687, … (more)
This variant is associated with the following publications: (PMID: 14574163, 28932927, 24728327, 27629256, 26951660, 27884173, 12624141, 20176959, 16237223, 18470917, 22949387, 18951462, 21120944, 17720936, 11606497, 25107687, 21056691, 18547406) (less)
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Benign
(Nov 18, 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: SCV000212723.7
First in ClinVar: Mar 24, 2015 Last updated: Nov 29, 2022 |
Comment:
This alteration is classified as benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA … (more)
This alteration is classified as 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
(Apr 23, 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: SCV002797244.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Benign
(Jul 07, 2023)
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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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KCCC/NGS Laboratory, Kuwait Cancer Control Center
Accession: SCV004015938.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
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Benign
(Nov 28, 2023)
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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: SCV000885710.7
First in ClinVar: Feb 18, 2019 Last updated: Feb 20, 2024 |
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Benign
(Feb 06, 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: SCV002534515.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 |
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Benign
(Nov 18, 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
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV000685086.2
First in ClinVar: Feb 19, 2018 Last updated: Dec 11, 2022 |
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Benign
(Jul 02, 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: SCV003837615.1
First in ClinVar: Mar 11, 2023 Last updated: Mar 11, 2023 |
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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: SCV002552195.4
First in ClinVar: Jul 30, 2022 Last updated: Aug 18, 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
|
Invitae
Accession: SCV000559220.9
First in ClinVar: Dec 06, 2016 Last updated: Feb 28, 2024 |
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Benign
(Jul 24, 2014)
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no assertion criteria provided
Method: clinical testing
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Lynch syndrome I
Affected status: unknown
Allele origin:
germline
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Pathway Genomics
Accession: SCV000189946.1
First in ClinVar: Oct 19, 2014 Last updated: Oct 19, 2014 |
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Benign
(Dec 21, 2011)
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no assertion criteria provided
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: SCV000052920.2
First in ClinVar: Apr 04, 2013 Last updated: Mar 24, 2015 |
|
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Benign
(-)
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no assertion criteria provided
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
unknown
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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV000257187.2
First in ClinVar: Nov 20, 2015 Last updated: Oct 02, 2016 |
|
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Benign
(-)
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no assertion criteria provided
Method: clinical testing
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not specified
Affected status: yes
Allele origin:
germline
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Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Study: VKGL Data-share Consensus
Accession: SCV001799601.1 First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021 |
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Benign
(-)
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no assertion criteria provided
Method: clinical testing
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not specified
Affected status: yes
Allele origin:
germline
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Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001906115.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021 |
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Benign
(-)
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no assertion criteria provided
Method: clinical testing
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not specified
Affected status: yes
Allele origin:
germline
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Clinical Genetics, Academic Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001923645.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021 |
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Benign
(-)
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no assertion criteria provided
Method: clinical testing
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not specified
Affected status: yes
Allele origin:
germline
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001958444.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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Benign
(Oct 10, 2017)
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no assertion criteria provided
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
True Health Diagnostics
Accession: SCV000788037.1
First in ClinVar: Feb 19, 2018 Last updated: Feb 19, 2018 |
|
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Likely benign
(-)
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no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
unknown
|
Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV000592462.2 First in ClinVar: Oct 02, 2016 Last updated: Apr 13, 2021 |
Comment:
The MSH2 p.Asn127Ser variant was identified in the literature in black, white and Hispanic populations with functional studies suggesting that the p.Asn127Ser variant, in isolation, … (more)
The MSH2 p.Asn127Ser variant was identified in the literature in black, white and Hispanic populations with functional studies suggesting that the p.Asn127Ser variant, in isolation, does not compromise MMR. However in 2 studies, this variant was identified together with other missense substitutions (especially p.Ala328Pro), and demonstrated significantly decreased repair deficiency (Kantelinen 2012, Ollila 2008, Samowitz 2001). The variant was also identified in dbSNP (ID: rs17217772) “With benign, uncertain significance allele” and is listed in the 1000 Genomes Project in 124 of 5000 chromosomes (frequency: 0.0248). The variant is also identified in the NHLBI Exome Sequencing Project (ESP) in 4 of 8600 European American (frequency: 00005) and in 339 of 4406 African American alleles (frequency: 0.077). The variant is listed in the Exome Aggregation Consortium (ExAC) database (released Mar 14, 2016) and identified in 848 of 121398 chromosomes of which 27 were homozygous (frequency: 0.007) or 791 of 10402 Africans (frequency: 0.076), 20 of 11578 Latino (frequency: 0.002), 29 of 66732 European (Non-Finish) (frequency: 0.0004), 4 of 16510 South Asian (frequency: 0.0002) and 4 in 908 (frequency: 0.004) in other, increasing the likelihood this could be a low frequency benign variant. The variant is listed in GeneInsight - COGR (1x as benign by LMM and 2x as benign by ARUP); ClinVar (listed as benign by InSIGHT, Laboratory for Molecular Medicine, Emory Genetics, Ambry Genetics, Mayo Clinic, Pathway Genomics LabCorp and by TMI with no clinical significance given); in Clinvitae (by EmyClass 1x as benign) and InSiGHT Colon Cancer Gene Variant Databases (LOVD) 34x as Class 1 - not pathogenic. In UMD, the variant was identified 23x as neutral with a co-occurring pathogenic MLH1 p.Pro649LeufsX12, increasing the likelihood that the p.Asn127Ser variant does not have clinical significance. The p.Asn127 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the p.Asn127Ser variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict the abolishment of the consensus splice site; however, HumanSpliceFinder and MaxEntScan predict an altered 3' splice site in this region and we cannot eliminate the possibility of a novel cryptic splice site. 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)
Number of individuals with the variant: 17
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not provided
(Sep 19, 2013)
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no classification provided
Method: reference population
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AllHighlyPenetrant
Affected status: unknown
Allele origin:
germline
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ITMI
Accession: SCV000085761.1
First in ClinVar: Jun 09, 2014 Last updated: Jun 09, 2014 |
Observation 1:
Ethnicity/Population group: Whole_cohort
Observation 2:
Ethnicity/Population group: African
Observation 3:
Ethnicity/Population group: African_European
Observation 4:
Ethnicity/Population group: Central_Asian
Observation 5:
Ethnicity/Population group: East_Asian
Observation 6:
Ethnicity/Population group: European
Observation 7:
Ethnicity/Population group: Hispanic
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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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 |
MLH1 and MSH2 mutation screening in HNPCC families of Hungary - Two new MMR gene mutations. | Tanyi M | European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology | 2014 | PMID: 25107687 |
Prevalence of alterations in DNA mismatch repair genes in patients with young-onset colorectal cancer. | Limburg PJ | Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association | 2011 | PMID: 21056691 |
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 |
Pedigree and genetic analysis of a novel mutation carrier patient suffering from hereditary nonpolyposis colorectal cancer. | Tanyi M | World journal of gastroenterology | 2006 | PMID: 16534870 |
Systematic mRNA analysis for the effect of MLH1 and MSH2 missense and silent mutations on aberrant splicing. | Auclair J | Human mutation | 2006 | PMID: 16395668 |
Assay validation for identification of hereditary nonpolyposis colon cancer-causing mutations in mismatch repair genes MLH1, MSH2, and MSH6. | Hegde M | The Journal of molecular diagnostics : JMD | 2005 | PMID: 16237223 |
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 | - | - | - | - |
http://www.insight-database.org/classifications/index.html?gene=MSH2&variant=c.380A%3EG | - | - | - | - |
Text-mined citations for rs17217772 ...
HelpRecord last updated Apr 15, 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.