DNA sequence analysis of the MSH2 gene demonstrated a sequence change, c.1182T>G, in exon 7 that results in an amino acid change, p.Phe394Leu. This sequence has been described in the gnomAD database in five individuals with an overall population frequency of 0.0018% (dbSNP rs374135434), and has also been reported in one individual with breast cancer (PMID: 28202063). The p.Phe394Leu change affects a highly conserved amino acid residue located in a domain of the MSH2 protein that is known to be functional. The p.Phe394Leu substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Phe394Leu change remains unknown at this time.
ClinVar Genomic variation as it relates to human health
NM_000251.3(MSH2):c.1182T>G (p.Phe394Leu)
Germline
Classification
Help
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.
(11)
Help
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.
Conflicting classifications of pathogenicity
Uncertain significance(8); Benign(1); Likely benign(2)
Uncertain significance(8); Benign(1); Likely benign(2)
11
criteria provided, conflicting classifications
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000251.3(MSH2):c.1182T>G (p.Phe394Leu)
Variation ID: 127627 Accession: VCV000127627.41
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 2p21 2: 47429847 (GRCh38) [ NCBI UCSC ] 2: 47656986 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Dec 19, 2017 May 1, 2024 Jan 8, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000251.3:c.1182T>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000242.1:p.Phe394Leu missense NM_001258281.1:c.984T>G NP_001245210.1:p.Phe328Leu missense NC_000002.12:g.47429847T>G NC_000002.11:g.47656986T>G NG_007110.2:g.31724T>G LRG_218:g.31724T>G LRG_218t1:c.1182T>G LRG_218p1:p.Phe394Leu - Protein change
- F394L, F328L
- Other names
-
p.F394L:TTT>TTG
- Canonical SPDI
- NC_000002.12:47429846:T:G
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
The Genome Aggregation Database (gnomAD), exomes 0.00001
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD) 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00004
- Links
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 | ||
|---|---|---|---|---|---|---|
| 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. |
|||
| MSH2 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
7404 | 7566 | |
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. |
|---|---|---|---|---|
| Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
|
Aug 23, 2023 | RCV000115496.18 | |
| Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
|
Jan 23, 2023 | RCV000212598.18 | |
| Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
|
Oct 3, 2023 | RCV000663103.7 | |
| Benign (1) |
criteria provided, single submitter
|
Dec 12, 2023 | RCV000477595.11 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Dec 2, 2020 | RCV001818271.4 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Jan 8, 2024 | RCV003997267.2 |
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. |
|
|---|---|---|---|---|---|
|
Uncertain significance
(Apr 19, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV001134330.3
First in ClinVar: Jan 05, 2020 Last updated: Jan 01, 2022 |
|
|
|
Uncertain significance
(Dec 02, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: no
Allele origin:
germline
|
Genetic Services Laboratory, University of Chicago
Accession: SCV002066714.1
First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022 |
Comment:
DNA sequence analysis of the MSH2 gene demonstrated a sequence change, c.1182T>G, in exon 7 that results in an amino acid change, p.Phe394Leu. This sequence … (more)
DNA sequence analysis of the MSH2 gene demonstrated a sequence change, c.1182T>G, in exon 7 that results in an amino acid change, p.Phe394Leu. This sequence has been described in the gnomAD database in five individuals with an overall population frequency of 0.0018% (dbSNP rs374135434), and has also been reported in one individual with breast cancer (PMID: 28202063). The p.Phe394Leu change affects a highly conserved amino acid residue located in a domain of the MSH2 protein that is known to be functional. The p.Phe394Leu substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Phe394Leu change remains unknown at this time. (less)
|
|
|
Uncertain significance
(Aug 23, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV000684913.5
First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces phenylalanine with leucine at codon 394 of the MSH2 protein. Computational prediction suggests that this variant may not impact protein structure … (more)
This missense variant replaces phenylalanine with leucine at codon 394 of the MSH2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). This variant does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold <= -1.32, PMID: 33357406). This variant has been reported in an individual affected with breast cancer (PMID: 28202063). This variant has been identified in 5/282800 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
|
|
|
Uncertain significance
(Nov 15, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: unknown
Allele origin:
germline
|
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000884131.1
First in ClinVar: Dec 19, 2017 Last updated: Dec 19, 2017 |
|
|
|
Uncertain significance
(Jan 23, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000149405.16
First in ClinVar: May 17, 2014 Last updated: Nov 11, 2023 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; … (more)
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in an individual with breast cancer (Jalkh et al., 2017); This variant is associated with the following publications: (PMID: 28202063, 18822302, 21120944) (less)
|
|
|
Uncertain significance
(Jul 24, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Lynch syndrome 1
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004194504.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
|
|
|
Uncertain significance
(Mar 23, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Lynch syndrome 1
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000786218.2
First in ClinVar: Jul 15, 2018 Last updated: Jul 15, 2018 |
|
|
|
Likely benign
(Oct 03, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Lynch syndrome 1
Affected status: unknown
Allele origin:
unknown
|
Myriad Genetics, Inc.
Accession: SCV004018339.3
First in ClinVar: Jul 29, 2023 Last updated: Oct 28, 2023 |
Comment:
This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic … (more)
This variant is considered likely 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: 27363726]. (less)
|
|
|
Benign
(Dec 12, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary nonpolyposis colorectal neoplasms
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000548230.9
First in ClinVar: Apr 17, 2017 Last updated: Feb 20, 2024 |
|
|
|
Uncertain Significance
(Jan 08, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Lynch syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
All of Us Research Program, National Institutes of Health
Accession: SCV004832535.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024
Comment:
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more)
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)
|
Comment:
This missense variant replaces phenylalanine with leucine at codon 394 of the MSH2 protein. Computational prediction suggests that this variant may not impact protein structure … (more)
This missense variant replaces phenylalanine with leucine at codon 394 of the MSH2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). This variant does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold <= -1.32, PMID: 33357406). This variant has been reported in an individual affected with breast cancer (PMID: 28202063). This variant has been identified in 5/282800 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
Number of individuals with the variant: 3
|
|
|
Likely benign
(May 16, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000184289.10
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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| click to load more click to collapse | |||||
Comment:
Comment:
This missense variant replaces phenylalanine with leucine at codon 394 of the MSH2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). This variant does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold <= -1.32, PMID: 33357406). This variant has been reported in an individual affected with breast cancer (PMID: 28202063). This variant has been identified in 5/282800 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in an individual with breast cancer (Jalkh et al., 2017); This variant is associated with the following publications: (PMID: 28202063, 18822302, 21120944)
Comment:
This variant is considered likely 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: 27363726].
Comment:
This missense variant replaces phenylalanine with leucine at codon 394 of the MSH2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). This variant does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold <= -1.32, PMID: 33357406). This variant has been reported in an individual affected with breast cancer (PMID: 28202063). This variant has been identified in 5/282800 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
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 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.
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. |
Comment:
DNA sequence analysis of the MSH2 gene demonstrated a sequence change, c.1182T>G, in exon 7 that results in an amino acid change, p.Phe394Leu. This sequence has been described in the gnomAD database in five individuals with an overall population frequency of 0.0018% (dbSNP rs374135434), and has also been reported in one individual with breast cancer (PMID: 28202063). The p.Phe394Leu change affects a highly conserved amino acid residue located in a domain of the MSH2 protein that is known to be functional. The p.Phe394Leu substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Phe394Leu change remains unknown at this time.
Comment:
This missense variant replaces phenylalanine with leucine at codon 394 of the MSH2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). This variant does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold <= -1.32, PMID: 33357406). This variant has been reported in an individual affected with breast cancer (PMID: 28202063). This variant has been identified in 5/282800 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in an individual with breast cancer (Jalkh et al., 2017); This variant is associated with the following publications: (PMID: 28202063, 18822302, 21120944)
Comment:
This variant is considered likely 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: 27363726].
Comment:
This missense variant replaces phenylalanine with leucine at codon 394 of the MSH2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). This variant does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold <= -1.32, PMID: 33357406). This variant has been reported in an individual affected with breast cancer (PMID: 28202063). This variant has been identified in 5/282800 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
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 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.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Massively parallel functional testing of MSH2 missense variants conferring Lynch syndrome risk. | Jia X | American journal of human genetics | 2021 | PMID: 33357406 |
| Next-generation sequencing in familial breast cancer patients from Lebanon. | Jalkh N | BMC medical genomics | 2017 | PMID: 28202063 |
| Classification of genetic variants in genes associated with Lynch syndrome using a clinical history weighting algorithm. | Morris B | BMC genetics | 2016 | PMID: 27363726 |
| Accurate classification of MLH1/MSH2 missense variants with multivariate analysis of protein polymorphisms-mismatch repair (MAPP-MMR). | Chao EC | Human mutation | 2008 | PMID: 18383312 |
Text-mined citations for rs374135434 ...
HelpThese 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 Sep 29, 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.