This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 702 of the MSH2 protein (p.Val702Leu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MSH2-related conditions. ClinVar contains an entry for this variant (Variation ID: 1785968). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 33357406) indicates that this missense variant is not expected to disrupt MSH2 function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
ClinVar Genomic variation as it relates to human health
NM_000251.3(MSH2):c.2104G>T (p.Val702Leu)
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.
(3)
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(1); Likely benign(1)
Uncertain significance(1); Likely benign(1)
3
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.2104G>T (p.Val702Leu)
Variation ID: 1785968 Accession: VCV001785968.8
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 2p21 2: 47476465 (GRCh38) [ NCBI UCSC ] 2: 47703604 (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 Nov 29, 2022 May 1, 2024 Feb 1, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000251.3:c.2104G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000242.1:p.Val702Leu missense NM_001258281.1:c.1906G>T NP_001245210.1:p.Val636Leu missense NM_001406631.1:c.2104G>T NP_001393560.1:p.Val702Leu missense NM_001406632.1:c.2104G>T NP_001393561.1:p.Val702Leu missense NM_001406633.1:c.2104G>T NP_001393562.1:p.Val702Leu missense NM_001406634.1:c.2104G>T NP_001393563.1:p.Val702Leu missense NM_001406635.1:c.2104G>T NP_001393564.1:p.Val702Leu missense NM_001406636.1:c.2071G>T NP_001393565.1:p.Val691Leu missense NM_001406637.1:c.2104G>T NP_001393566.1:p.Val702Leu missense NM_001406638.1:c.2143G>T NP_001393567.1:p.Val715Leu missense NM_001406639.1:c.2104G>T NP_001393568.1:p.Val702Leu missense NM_001406640.1:c.2104G>T NP_001393569.1:p.Val702Leu missense NM_001406641.1:c.2104G>T NP_001393570.1:p.Val702Leu missense NM_001406642.1:c.2104G>T NP_001393571.1:p.Val702Leu missense NM_001406643.1:c.2104G>T NP_001393572.1:p.Val702Leu missense NM_001406644.1:c.2104G>T NP_001393573.1:p.Val702Leu missense NM_001406645.1:c.2104G>T NP_001393574.1:p.Val702Leu missense NM_001406646.1:c.2104G>T NP_001393575.1:p.Val702Leu missense NM_001406647.1:c.1954G>T NP_001393576.1:p.Val652Leu missense NM_001406648.1:c.2104G>T NP_001393577.1:p.Val702Leu missense NM_001406649.1:c.1954G>T NP_001393578.1:p.Val652Leu missense NM_001406650.1:c.1954G>T NP_001393579.1:p.Val652Leu missense NM_001406651.1:c.1954G>T NP_001393580.1:p.Val652Leu missense NM_001406652.1:c.1954G>T NP_001393581.1:p.Val652Leu missense NM_001406653.1:c.2044G>T NP_001393582.1:p.Val682Leu missense NM_001406654.1:c.1684G>T NP_001393583.1:p.Val562Leu missense NM_001406656.1:c.1207G>T NP_001393585.1:p.Val403Leu missense NM_001406658.1:c.748G>T NP_001393587.1:p.Val250Leu missense NM_001406659.1:c.748G>T NP_001393588.1:p.Val250Leu missense NM_001406660.1:c.748G>T NP_001393589.1:p.Val250Leu missense NM_001406661.1:c.748G>T NP_001393590.1:p.Val250Leu missense NM_001406662.1:c.748G>T NP_001393591.1:p.Val250Leu missense NM_001406669.1:c.748G>T NP_001393598.1:p.Val250Leu missense NM_001406674.1:c.2104G>T NP_001393603.1:p.Val702Leu missense NR_176230.1:n.2140G>T NR_176231.1:n.2140G>T NR_176232.1:n.2140G>T NR_176233.1:n.1982G>T NR_176234.1:n.2140G>T NR_176235.1:n.2140G>T NR_176236.1:n.2140G>T NR_176237.1:n.2140G>T NR_176238.1:n.2273G>T NR_176239.1:n.2140G>T NR_176241.1:n.2140G>T NR_176242.1:n.2140G>T NR_176243.1:n.1990G>T NR_176244.1:n.2140G>T NR_176245.1:n.2140G>T NR_176246.1:n.2140G>T NR_176247.1:n.2140G>T NR_176248.1:n.2140G>T NR_176249.1:n.2370G>T NR_176250.1:n.1880G>T NC_000002.12:g.47476465G>T NC_000002.11:g.47703604G>T NG_007110.2:g.78342G>T LRG_218:g.78342G>T LRG_218t1:c.2104G>T LRG_218p1:p.Val702Leu - Protein change
- V636L, V682L, V691L, V250L, V403L, V562L, V715L, V652L, V702L
- Other names
- -
- Canonical SPDI
- NC_000002.12:47476464:G:T
-
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.
- -
- 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. |
|---|---|---|---|---|
| Likely benign (1) |
criteria provided, single submitter
|
May 1, 2023 | RCV002424280.3 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Feb 1, 2024 | RCV003098617.3 | |
| Uncertain significance (1) |
no assertion criteria provided
|
Dec 19, 2022 | RCV003151407.2 |
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
(Feb 01, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary nonpolyposis colorectal neoplasms
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV003334680.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 702 of the MSH2 protein (p.Val702Leu). … (more)
This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 702 of the MSH2 protein (p.Val702Leu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MSH2-related conditions. ClinVar contains an entry for this variant (Variation ID: 1785968). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 33357406) indicates that this missense variant is not expected to disrupt MSH2 function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
|
|
|
Likely benign
(May 01, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002728387.3
First in ClinVar: Nov 29, 2022 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)
|
|
|
Uncertain significance
(Dec 19, 2022)
|
no assertion criteria provided
Method: clinical testing
|
not specified
Affected status: no
Allele origin:
germline
|
Genetic Services Laboratory, University of Chicago
Accession: SCV003839739.1
First in ClinVar: Mar 18, 2023 Last updated: Mar 18, 2023 |
Comment:
DNA sequence analysis of the MSH2 gene demonstrated a sequence change, c.2104G>T, in exon 13 that results in an amino acid change, p.Val702Leu. This sequence … (more)
DNA sequence analysis of the MSH2 gene demonstrated a sequence change, c.2104G>T, in exon 13 that results in an amino acid change, p.Val702Leu. This sequence change does not appear to have been previously described in individuals with MSH2-related disorders and has also not been described in population databases such as ExAC and gnomAD. The p.Val702Leu change affects a poorly conserved amino acid residue located in a domain of the MSH2 protein that is known to be functional. The p.Val702Leu substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Val702Leu change remains unknown at this time. Heterozygous pathogenic variants in MSH2 cause Lynch syndrome and Muir-Torre syndrome [OMIM #120435, 158320]. Biallelic pathogenic variants in MSH2 are associated with mismatch repair cancer syndrome [OMIM #276300]. (less)
|
Comment:
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.
Comment:
DNA sequence analysis of the MSH2 gene demonstrated a sequence change, c.2104G>T, in exon 13 that results in an amino acid change, p.Val702Leu. This sequence change does not appear to have been previously described in individuals with MSH2-related disorders and has also not been described in population databases such as ExAC and gnomAD. The p.Val702Leu change affects a poorly conserved amino acid residue located in a domain of the MSH2 protein that is known to be functional. The p.Val702Leu substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Val702Leu change remains unknown at this time. Heterozygous pathogenic variants in MSH2 cause Lynch syndrome and Muir-Torre syndrome [OMIM #120435, 158320]. Biallelic pathogenic variants in MSH2 are associated with mismatch repair cancer syndrome [OMIM #276300].
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:
This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 702 of the MSH2 protein (p.Val702Leu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MSH2-related conditions. ClinVar contains an entry for this variant (Variation ID: 1785968). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 33357406) indicates that this missense variant is not expected to disrupt MSH2 function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been 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.
Comment:
DNA sequence analysis of the MSH2 gene demonstrated a sequence change, c.2104G>T, in exon 13 that results in an amino acid change, p.Val702Leu. This sequence change does not appear to have been previously described in individuals with MSH2-related disorders and has also not been described in population databases such as ExAC and gnomAD. The p.Val702Leu change affects a poorly conserved amino acid residue located in a domain of the MSH2 protein that is known to be functional. The p.Val702Leu substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Val702Leu change remains unknown at this time. Heterozygous pathogenic variants in MSH2 cause Lynch syndrome and Muir-Torre syndrome [OMIM #120435, 158320]. Biallelic pathogenic variants in MSH2 are associated with mismatch repair cancer syndrome [OMIM #276300].
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 |
| Pathogenic Variants in Cancer Predisposition Genes and Prostate Cancer Risk in Men of African Ancestry. | Matejcic M | JCO precision oncology | 2020 | PMID: 32832836 |
Text-mined citations for this variant ...
HelpRecord 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.