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NM_000251.3(MSH2):c.118G>A (p.Gly40Ser)

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Interpretation:
Conflicting interpretations of pathogenicity​

Likely benign(2);Uncertain significance(4)

Review status:
criteria provided, conflicting interpretations
Submissions:
6 (Most recent: Sep 30, 2021)
Last evaluated:
May 24, 2021
Accession:
VCV000090560.15
Variation ID:
90560
Description:
single nucleotide variant
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NM_000251.3(MSH2):c.118G>A (p.Gly40Ser)

Allele ID
96035
Variant type
single nucleotide variant
Variant length
1 bp
Cytogenetic location
2p21
Genomic location
2: 47403309 (GRCh38) GRCh38 UCSC
2: 47630448 (GRCh37) GRCh37 UCSC
HGVS
Nucleotide Protein Molecular
consequence
P43246:p.Gly40Ser
NC_000002.11:g.47630448G>A
NM_000251.2:c.118G>A NP_000242.1:p.Gly40Ser missense
... more HGVS
Protein change
G40S
Other names
-
Canonical SPDI
NC_000002.12:47403308:G:A
Functional consequence
-
Global minor allele frequency (GMAF)
-

Allele frequency
Exome Aggregation Consortium (ExAC) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00000
The Genome Aggregation Database (gnomAD), exomes 0.00001
Links
ClinGen: CA017443
UniProtKB: P43246#VAR_043739
dbSNP: rs63751260
VarSome
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Aggregate interpretations per condition

Interpreted condition Interpretation Number of submissions Review status Last evaluated Variation/condition record
Uncertain significance 1 criteria provided, single submitter Aug 14, 2019 RCV000236371.2
Uncertain significance 1 criteria provided, single submitter Oct 27, 2020 RCV000627704.5
Likely benign 1 criteria provided, single submitter May 24, 2021 RCV000781559.4
Uncertain significance 1 criteria provided, single submitter May 1, 2019 RCV001030704.1
Conflicting interpretations of pathogenicity 2 criteria provided, conflicting interpretations Jun 12, 2019 RCV000491838.4
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Gene OMIM ClinGen Gene Dosage Sensitivity Curation Variation viewer Related variants
HI score Help TS score Help Within gene All
MSH2 Sufficient evidence for dosage pathogenicity No evidence available GRCh38
GRCh37
4521 4606

Submitted interpretations and evidence

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Interpretation
(Last evaluated)
Review status
(Assertion criteria)
Condition
(Inheritance)
Submitter Supporting information
Uncertain significance
(Jun 12, 2019)
criteria provided, single submitter
Method: clinical testing
Hereditary cancer-predisposing syndrome
Allele origin: germline
Color Health, Inc
Accession: SCV000684914.3
Submitted: (May 19, 2020)
Evidence details
Likely benign
(Oct 03, 2018)
criteria provided, single submitter
Method: clinical testing
Hereditary cancer-predisposing syndrome
Allele origin: germline
Ambry Genetics
Accession: SCV000580530.4
Submitted: (Nov 30, 2020)
Evidence details
Publications
PubMed (2)
Comment:
In silico models in agreement (benign);Other data supporting benign classification
Uncertain significance
(Oct 27, 2020)
criteria provided, single submitter
Method: clinical testing
Hereditary nonpolyposis colorectal neoplasms
Allele origin: germline
Invitae
Accession: SCV000284097.7
Submitted: (Jan 07, 2021)
Evidence details
Publications
PubMed (5)
Comment:
This sequence change replaces glycine with serine at codon 40 of the MSH2 protein (p.Gly40Ser). The glycine residue is weakly conserved and there is a … (more)
Uncertain significance
(Aug 14, 2019)
criteria provided, single submitter
Method: clinical testing
Not Provided
Allele origin: germline
GeneDx
Accession: SCV000293503.10
Submitted: (Sep 30, 2021)
Evidence details
Comment:
Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports … (more)
Uncertain significance
(May 01, 2019)
criteria provided, single submitter
Method: research
Hereditary breast and ovarian cancer syndrome
Allele origin: germline
Cancer Genomics Group,Japanese Foundation For Cancer Research
Accession: SCV001193626.2
Submitted: (Jun 25, 2020)
Evidence details
Likely benign
(May 24, 2021)
criteria provided, single submitter
Method: clinical testing
not specified
Allele origin: germline
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000919699.4
Submitted: (Jun 17, 2021)
Evidence details
Publications
PubMed (5)
Comment:
Variant summary: MSH2 c.118G>A (p.Gly40Ser) results in a non-conservative amino acid change located in the N-terminal domain (IPR007695) of the encoded protein sequence. Three of … (more)

Functional evidence

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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 this variant

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Title Author Journal Year Link
Prevalence of disease-causing genes in Japanese patients with <i>BRCA1/2</i>-wildtype hereditary breast and ovarian cancer syndrome. Kaneyasu T NPJ breast cancer 2020 PMID: 32566746
Germline mutations in cancer-predisposition genes in patients with biliary tract cancer. Terashima T Oncotarget 2019 PMID: 31666926
Germline mismatch repair gene variants analyzed by universal sequencing in Japanese cancer patients. Kiyozumi Y Cancer medicine 2019 PMID: 31386297
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. Nykamp K Genetics in medicine : official journal of the American College of Medical Genetics 2017 PMID: 28492532
Total colectomy for multiple metachronous colon cancers in a patient with Lynch syndrome. Kochi M Surgical case reports 2015 PMID: 26380806
Microsatellite instability at tetranucleotide repeats in sporadic colorectal cancer in Japan. Yamada K Oncology reports 2010 PMID: 20043121
Accurate classification of MLH1/MSH2 missense variants with multivariate analysis of protein polymorphisms-mismatch repair (MAPP-MMR). Chao EC Human mutation 2008 PMID: 18383312
Oncogenic pathway of sporadic colorectal cancer with novel germline missense mutations in the hMSH2 gene. Yamada K Oncology reports 2003 PMID: 12792735

Text-mined citations for rs63751260...

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These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 27, 2021