ClinVar Genomic variation as it relates to human health
NM_000251.3(MSH2):c.1168C>T (p.Leu390Phe)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000251.3(MSH2):c.1168C>T (p.Leu390Phe)
Variation ID: 41641 Accession: VCV000041641.37
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2p21 2: 47429833 (GRCh38) [ NCBI UCSC ] 2: 47656972 (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 Apr 12, 2013 May 1, 2024 Sep 5, 2013 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000251.3:c.1168C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000242.1:p.Leu390Phe missense NM_001258281.1:c.970C>T NP_001245210.1:p.Leu324Phe missense NC_000002.12:g.47429833C>T NC_000002.11:g.47656972C>T NG_007110.2:g.31710C>T LRG_218:g.31710C>T LRG_218t1:c.1168C>T LRG_218p1:p.Leu390Phe P43246:p.Leu390Phe - Protein change
- L390F, L324F
- Other names
- p.L390F:CTT>TTT
- Canonical SPDI
- NC_000002.12:47429832:C:T
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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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0.00280 (T)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
1000 Genomes Project 0.00280
The Genome Aggregation Database (gnomAD) 0.00039
Trans-Omics for Precision Medicine (TOPMed) 0.00082
The Genome Aggregation Database (gnomAD), exomes 0.00155
Exome Aggregation Consortium (ExAC) 0.00166
1000 Genomes Project 30x 0.00234
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
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 |
7392 | 7554 |
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) |
criteria provided, single submitter
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Mar 21, 2016 | RCV000034549.13 | |
Benign (1) |
reviewed by expert panel
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Sep 5, 2013 | RCV000076053.15 | |
Benign/Likely benign (7) |
criteria provided, multiple submitters, no conflicts
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Aug 15, 2023 | RCV000078420.38 | |
Benign (3) |
criteria provided, multiple submitters, no conflicts
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Aug 31, 2020 | RCV000115495.19 | |
Benign (1) |
criteria provided, single submitter
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Feb 1, 2024 | RCV001081498.15 | |
Benign (1) |
no assertion criteria provided
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- | RCV001355669.9 | |
Benign (1) |
criteria provided, single submitter
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Jul 29, 2021 | RCV003149606.9 | |
Likely benign (1) |
criteria provided, single submitter
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Mar 6, 2018 | RCV001094729.12 |
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
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International Society for Gastrointestinal Hereditary Tumours (InSiGHT)
Accession: SCV000107066.3
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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Comments (2):
Multifactorial likelihood analysis posterior probability <0.001
Converted during submission to Benign.
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Benign
(Feb 20, 2018)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000149404.12
First in ClinVar: May 17, 2014 Last updated: Apr 09, 2018 |
Comment:
This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at … (more)
This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. (less)
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Benign
(Apr 04, 2017)
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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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PreventionGenetics, part of Exact Sciences
Accession: SCV000805991.1
First in ClinVar: Sep 13, 2018 Last updated: Sep 13, 2018 |
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Likely benign
(Mar 28, 2016)
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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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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000539680.1
First in ClinVar: Apr 08, 2017 Last updated: Apr 08, 2017 |
Comment:
Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or … (more)
Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: 2.1% in East Asian population with 2 homozygotes. (less)
Method: Genome/Exome Filtration
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Benign
(Mar 21, 2016)
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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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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000696199.1
First in ClinVar: Apr 12, 2013 Last updated: Apr 12, 2013 |
Comment:
Variant summary: The c.1168C>T variant affects a non-conserved nucleotide, resulting in amino acid change from Leu to Phe. 2/4 in-silico tools predict this variant to … (more)
Variant summary: The c.1168C>T variant affects a non-conserved nucleotide, resulting in amino acid change from Leu to Phe. 2/4 in-silico tools predict this variant to be benign (SNPs&GO not captured due to low reliability index). This variant is found in 229/123604 control chromosomes (2 homozygotes) at a frequency of 0.0018527. The frequency of this variant in East Asian control population is 0.0217, which is about 38 times of the maximal expected frequency of a pathogenic allele (0.0005683), suggesting this variant is benign. This variant has been reported in a large number of patients with LS or endometrial cancer. Two co-occurrences with a pathogenic variant (MLH1, c.2157dup, p.Val720Cysfs*3 and MSH2 c.196-187dupG, respectively) were reported, along with a reported lack of co-segregation with the disease (Okamura_1998). Multiple functional studies showed that MSH2 p.L390F has similar activity to wild-type MSH2. In addition, multiple clinical laboratories/reputable databases classified this variant as benign. Taken together, this variant was classified as benign. (less)
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Benign
(Feb 19, 2013)
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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: SCV000110269.8
First in ClinVar: Jan 17, 2014 Last updated: Sep 13, 2018 |
Number of individuals with the variant: 1
Sex: mixed
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Likely benign
(Mar 06, 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: SCV000430923.3
First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020 |
Comment:
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more)
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. (less)
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Likely benign
(Jan 19, 2022)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: no
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV002070917.1
First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022 |
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Benign
(Jul 29, 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: SCV003837621.1
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: SCV002552220.4
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
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Invitae
Accession: SCV000261493.11
First in ClinVar: Mar 24, 2015 Last updated: Feb 28, 2024 |
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Benign
(Aug 11, 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: SCV000172768.9
First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024 |
Comment:
This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation … (more)
This alteration is classified as 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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Benign
(Aug 31, 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: SCV002528818.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 |
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Benign
(Apr 09, 2015)
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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: SCV000684912.2
First in ClinVar: Feb 19, 2018 Last updated: Dec 11, 2022 |
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variant of unknown significance
(Jul 13, 2012)
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no assertion criteria provided
Method: research
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not provided
Affected status: no
Allele origin:
germline
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Biesecker Lab/Clinical Genomics Section, National Institutes of Health
Study: ClinSeq
Accession: SCV000043339.1 First in ClinVar: Apr 12, 2013 Last updated: Apr 12, 2013 |
Comment:
Converted during submission to Uncertain significance.
Number of individuals with the variant: 1
Comment on evidence:
The study set was not selected for affection status in relation to any cancer. Pathogenicity categories were based on literature curation. See Pubmed ID:22703879 for … (more)
The study set was not selected for affection status in relation to any cancer. Pathogenicity categories were based on literature curation. See Pubmed ID:22703879 for details. (less)
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Benign
(-)
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no assertion criteria provided
Method: clinical testing
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Carcinoma of colon
Affected status: yes
Allele origin:
unknown
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Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV001550619.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
The MSH2 p.Leu390Phe variant was identified in 12 of 952 proband chromosomes (frequency: 0.013) from individuals or families with colorectal cancer (Jin 2008, Lee 2005, … (more)
The MSH2 p.Leu390Phe variant was identified in 12 of 952 proband chromosomes (frequency: 0.013) from individuals or families with colorectal cancer (Jin 2008, Lee 2005, Wei 2011, Yap 2009, Zhang 2006) and was present in 1 of 220 control chromosomes (frequency: 0.005) from healthy individuals (Zhang 2006). The variant was also identified in dbSNP (ID: rs17224367) as With other allele, ClinVar (classified as benign by InSight, Emory Genetics, Ambry Genetics, Invitae; classified as likely benign by GeneDx, Illumina, LMMPHCPM; classified as uncertain significance by BLDSNIH), Clinvitae (classified as benign by ClinVar, Invitae, EmvClass; classified as uncertain significance by ClinVar), MutDB , UMD-LSDB (2X classified as neutral), Insight Colon Cancer Gene Variant Database (44X classified as class 1), Zhejiang Colon Cancer Database (7X ), Mismatch Repair Genes Variant Database, databases. The variant was not identified in Cosmic, Insight Hereditary Tumors Database, databases. In UMD the variant was identified with a co-occurring pathogenic MLH1 variant (c.304G>A (p.Glu102Lys)), increasing the likelihood that the p.Leu390Phe variant does not have clinical significance. The variant was identified in control databases in 402(4 homozygous) of 277162 chromosomes at a frequency of 0.00145 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). The p.Leu390 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out 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 a difference in splicing. The variant is located with the DNA mismatch repair protein MutS, core DNA mismatch repair protein, MSH2 functional domains, increasing the likelihood that it may have clinical significance. Functional study of MSH2 on the corresponding yeast allele L402 demonstrated no reduction in steady-state levels of MSH2 and positive interaction with all MSH2 partners (Gammie 2007). The variant was also found co-occurring with pathogenic mutation MLH1 variant c.2157dupT (Wei 2011). However, study by Fan (2005) provides strong molecular epidemiologic, structural, bioinformatic, and functional evidence that MSH2 c.1168C>T (p.Leu390Phe) underlies a newly identified phenotype relevant to young sporadic CRC or GC. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign. (less)
Number of individuals with the variant: 1
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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: SCV000085763.1
First in ClinVar: Jun 09, 2014 Last updated: Jun 09, 2014
Comment:
Please see associated publication for description of ethnicities
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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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Mutation analysis of 13 driver genes of colorectal cancer-related pathways in Taiwanese patients. | Chang YC | World journal of gastroenterology | 2016 | PMID: 26900293 |
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 |
Missense mutations of MLH1 and MSH2 genes detected in patients with gastrointestinal cancer are associated with exonic splicing enhancers and silencers. | Zhu M | Oncology letters | 2013 | PMID: 23760103 |
Calibration of multiple in silico tools for predicting pathogenicity of mismatch repair gene missense substitutions. | Thompson BA | Human mutation | 2013 | PMID: 22949387 |
Secondary variants in individuals undergoing exome sequencing: screening of 572 individuals identifies high-penetrance mutations in cancer-susceptibility genes. | Johnston JJ | American journal of human genetics | 2012 | PMID: 22703879 |
Classification of mismatch repair gene missense variants with PON-MMR. | Ali H | Human mutation | 2012 | PMID: 22290698 |
A rapid and cell-free assay to test the activity of lynch syndrome-associated MSH2 and MSH6 missense variants. | Drost M | Human mutation | 2012 | PMID: 22102614 |
Distinct mutations in MLH1 and MSH2 genes in hereditary non-polyposis colorectal cancer (HNPCC) families from China. | Wei W | BMB reports | 2011 | PMID: 21615986 |
Determination of splice-site mutations in Lynch syndrome (hereditary non-polyposis colorectal cancer) patients using functional splicing assay. | Naruse H | Familial cancer | 2009 | PMID: 19685281 |
Investigation on the role of nsSNPs in HNPCC genes--a bioinformatics approach. | Doss CG | Journal of biomedical science | 2009 | PMID: 19389263 |
Functional characterization of pathogenic human MSH2 missense mutations in Saccharomyces cerevisiae. | Gammie AE | Genetics | 2007 | PMID: 17720936 |
Prognosis in patients with hepatocellular carcinoma correlates to mutations of p53 and/or hMSH2 genes. | Yano M | European journal of cancer (Oxford, England : 1990) | 2007 | PMID: 17350822 |
Variations in exon 7 of the MSH2 gene and susceptibility to gastrointestinal cancer in a Chinese population. | Fan Y | Cancer genetics and cytogenetics | 2006 | PMID: 17011982 |
Systematic mRNA analysis for the effect of MLH1 and MSH2 missense and silent mutations on aberrant splicing. | Auclair J | Human mutation | 2006 | PMID: 16395668 |
Met688Ile and Leu390Phe of the MSH2 gene are not functional mutations, but polymorphisms in Japanese individuals. | Banno K | Cancer genetics and cytogenetics | 2004 | PMID: 15527911 |
Multiple epithelial and nonepithelial tumors in hereditary nonpolyposis colorectal cancer: characterization of germline and somatic mutations of the MSH2 gene and heterogeneity of replication error phenotypes. | Huang RL | Cancer genetics and cytogenetics | 2004 | PMID: 15350299 |
Genotyping possible polymorphic variants of human mismatch repair genes in healthy Korean individuals and sporadic colorectal cancer patients. | Kim JC | Familial cancer | 2004 | PMID: 15340264 |
Identification of germline MSH2 gene mutations in endometrial cancer not fulfilling the new clinical criteria for hereditary nonpolyposis colorectal cancer. | Banno K | Cancer genetics and cytogenetics | 2003 | PMID: 14499697 |
Mutator phenotypes of yeast strains heterozygous for mutations in the MSH2 gene. | Drotschmann K | Proceedings of the National Academy of Sciences of the United States of America | 1999 | PMID: 10077621 |
Novel germline mutations of hMSH2 in a patient with hereditary nonpolyposis colorectal cancer (HNPCC) and in a patient with six primary cancers. | Okamura S | Journal of human genetics | 1998 | PMID: 9621522 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=MSH2 | - | - | - | - |
http://www.insight-database.org/classifications/index.html?gene=MSH2&variant=c.1168C%3ET | - | - | - | - |
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Text-mined citations for rs17224367 ...
HelpRecord last updated Aug 18, 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.