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NM_000251.2(MSH2):c.274C>G (p.Leu92Val)

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Interpretation:
Conflicting interpretations of pathogenicity​

Likely benign(1);Likely pathogenic(1);Uncertain significance(6)

Review status:
criteria provided, conflicting interpretations
Submissions:
9 (Most recent: Sep 24, 2021)
Last evaluated:
Oct 19, 2020
Accession:
VCV000091041.13
Variation ID:
91041
Description:
single nucleotide variant
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NM_000251.2(MSH2):c.274C>G (p.Leu92Val)

Allele ID
96516
Variant type
single nucleotide variant
Variant length
1 bp
Cytogenetic location
2p21
Genomic location
2: 47408463 (GRCh38) GRCh38 UCSC
2: 47635602 (GRCh37) GRCh37 UCSC
HGVS
Nucleotide Protein Molecular
consequence
LRG_218t1:c.274C>G LRG_218p1:p.Leu92Val
LRG_218:g.10340C>G
NC_000002.11:g.47635602C>G
... more HGVS
Protein change
L92V, L26V
Other names
-
Canonical SPDI
NC_000002.12:47408462:C:G
Functional consequence
Unknown function
Global minor allele frequency (GMAF)
-

Allele frequency
Exome Aggregation Consortium (ExAC) 0.00007
Trans-Omics for Precision Medicine (TOPMed) 0.00004
The Genome Aggregation Database (gnomAD), exomes 0.00006
Links
ClinGen: CA020916
dbSNP: rs587779154
VarSome
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Aggregate interpretations per condition

Interpreted condition Interpretation Number of submissions Review status Last evaluated Variation/condition record
Uncertain significance 2 criteria provided, multiple submitters, no conflicts Aug 26, 2020 RCV000221964.7
Uncertain significance 1 criteria provided, single submitter Oct 19, 2020 RCV000552261.6
Uncertain significance 1 criteria provided, single submitter Aug 28, 2019 RCV001196697.1
Likely benign 2 criteria provided, single submitter Jul 31, 2018 RCV001353838.2
Conflicting interpretations of pathogenicity 3 criteria provided, conflicting interpretations May 29, 2020 RCV000412138.3
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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
4518 4603

Submitted interpretations and evidence

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Interpretation
(Last evaluated)
Review status
(Assertion criteria)
Condition
(Inheritance)
Submitter Supporting information
Uncertain significance
(Aug 31, 2016)
criteria provided, single submitter
Method: clinical testing
Lynch syndrome I
Allele origin: unknown
Counsyl
Accession: SCV000489185.1
Submitted: (Nov 23, 2016)
Evidence details
Publications
PubMed (1)
Uncertain significance
(May 28, 2019)
criteria provided, single submitter
Method: clinical testing
Lynch syndrome I
Allele origin: unknown
Mendelics
Accession: SCV001135696.1
Submitted: (Oct 22, 2019)
Evidence details
Likely pathogenic
(May 29, 2020)
criteria provided, single submitter
Method: clinical testing
Lynch syndrome I
(Autosomal dominant inheritance)
Allele origin: germline
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics
Accession: SCV001370542.1
Submitted: (Jul 04, 2020)
Evidence details
Comment:
A heterozygous missense variation in exon 2 of the MSH2 gene that results in the amino acid substitution of Valine for Leucine at codon 92 … (more)
Uncertain significance
(Mar 31, 2020)
criteria provided, single submitter
Method: clinical testing
Hereditary cancer-predisposing syndrome
Allele origin: germline
Ambry Genetics
Accession: SCV000277387.5
Submitted: (Nov 30, 2020)
Evidence details
Publications
PubMed (2)
Comment:
The p.L92V variant (also known as c.274C>G), located in coding exon 2 of the MSH2 gene, results from a C to G substitution at nucleotide … (more)
Uncertain significance
(Aug 28, 2019)
criteria provided, single submitter
Method: clinical testing
Turcot syndrome
Allele origin: unknown
Centre for Mendelian Genomics,University Medical Centre Ljubljana
Accession: SCV001367328.2
Submitted: (Nov 24, 2020)
Evidence details
Comment:
This variant was classified as: Uncertain significance. The available evidence favors the pathogenic nature of this variant, however the currently available data is insufficient to … (more)
Uncertain significance
(Oct 19, 2020)
criteria provided, single submitter
Method: clinical testing
Hereditary nonpolyposis colorectal neoplasms
Allele origin: germline
Invitae
Accession: SCV000625408.6
Submitted: (Jan 07, 2021)
Evidence details
Publications
PubMed (4)
Comment:
This sequence change replaces leucine with valine at codon 92 of the MSH2 protein (p.Leu92Val). The leucine residue is highly conserved and there is a … (more)
Uncertain significance
(Aug 26, 2020)
criteria provided, single submitter
Method: clinical testing
Hereditary cancer-predisposing syndrome
Allele origin: germline
Color Health, Inc
Accession: SCV000690095.4
Submitted: (Jun 11, 2021)
Evidence details
Comment:
This missense variant replaces leucine with valine at codon 92 of the MSH2 protein. Computational prediction suggests that this variant may have deleterious impact on … (more)
Likely benign
(Jul 31, 2018)
criteria provided, single submitter
Method: clinical testing
Not Provided
Allele origin: germline
GeneDx
Accession: SCV000729490.1
Submitted: (Sep 24, 2021)
Evidence details
Comment:
This variant is associated with the following publications: (PMID: 19669161, 26333163, 28135145)
Likely benign
(-)
no assertion criteria provided
Method: clinical testing
not provided
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: SCV000592460.2
Submitted: (Mar 31, 2021)
Evidence details
Comment:
The p.Leu92Val variant has been reported in the literature from an individual in the German HNPCC consortium in a study that examined several in-silico programs … (more)

Functional evidence

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Functional consequence Method Result Submitter Supporting information
Unknown function
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics
Accession: SCV001370542.1
Submitted: (Jul 04, 2020)
Evidence details

Citations for this variant

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Title Author Journal Year Link
Diagnostic challenges in a child with early onset desmoplastic medulloblastoma and homozygous variants in MSH2 and MSH6. Taeubner J European journal of human genetics : EJHG 2018 PMID: 29302048
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
UMD-MLH1/MSH2/MSH6 databases: description and analysis of genetic variations in French Lynch syndrome families. Grandval P Database : the journal of biological databases and curation 2013 PMID: 23729658
Comparative in silico analyses and experimental validation of novel splice site and missense mutations in the genes MLH1 and MSH2. Betz B Journal of cancer research and clinical oncology 2010 PMID: 19669161

Text-mined citations for rs587779154...

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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 20, 2021