ClinVar Genomic variation as it relates to human health
NM_000251.3(MSH2):c.518T>C (p.Leu173Pro)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000251.3(MSH2):c.518T>C (p.Leu173Pro)
Variation ID: 91121 Accession: VCV000091121.15
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2p21 2: 47410245 (GRCh38) [ NCBI UCSC ] 2: 47637384 (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 Mar 24, 2015 May 1, 2024 Feb 5, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000251.3:c.518T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000242.1:p.Leu173Pro missense NM_001258281.1:c.320T>C NP_001245210.1:p.Leu107Pro missense NC_000002.12:g.47410245T>C NC_000002.11:g.47637384T>C NG_007110.2:g.12122T>C LRG_218:g.12122T>C LRG_218t1:c.518T>C LRG_218p1:p.Leu173Pro P43246:p.Leu173Pro - Protein change
- L173P, L107P
- Other names
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- Canonical SPDI
- NC_000002.12:47410244:T:C
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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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Allele frequency
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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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
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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 |
7394 | 7556 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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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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Likely pathogenic (1) |
no assertion criteria provided
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- | RCV001353990.8 | |
Pathogenic (1) |
criteria provided, single submitter
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Jul 7, 2023 | RCV001854331.12 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Oct 1, 2022 | RCV002290960.9 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jun 22, 2020 | RCV002336228.9 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Feb 5, 2024 | RCV003997177.2 |
Submissions - Germline
Classification
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The submitted germline classification for each SCV record. (Last evaluated) |
Review status
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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
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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
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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
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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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Likely pathogenic
(Oct 01, 2022)
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criteria provided, single submitter
Method: clinical testing
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Hereditary nonpolyposis colon cancer
Affected status: yes
Allele origin:
somatic
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University of Washington Department of Laboratory Medicine, University of Washington
Accession: SCV000887336.2
First in ClinVar: Aug 27, 2017 Last updated: Oct 15, 2022 |
Comment:
MSH2 NM_000251.2:c.518T>C has over 95% probability of pathogenicity based evidence of seeing this as a somatic mutation in a tumor with loss of heterozygosity at … (more)
MSH2 NM_000251.2:c.518T>C has over 95% probability of pathogenicity based evidence of seeing this as a somatic mutation in a tumor with loss of heterozygosity at the MSH2 locus and again as a germline variant paired with a single heterozygous somatic MSH2 mutation in a separate tumor. See Shirts et al 2018, PMID 29887214. (less)
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Pathogenic
(Jul 07, 2023)
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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: SCV002309538.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Leu173 amino acid residue in MSH2. Other variant(s) that disrupt this … (more)
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Leu173 amino acid residue in MSH2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17011982, 22290698, 28577310, 28874130). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects MSH2 function (PMID: 17101317, 18951462, 26951660). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 33357406) indicates that this missense variant is expected to disrupt MSH2 function. ClinVar contains an entry for this variant (Variation ID: 91121). This missense change has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 15849733, 16395668, 17101317, 18383312, 23741719; Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 173 of the MSH2 protein (p.Leu173Pro). (less)
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Likely pathogenic
(Jun 22, 2020)
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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: SCV002643760.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.L173P variant (also known as c.518T>C), located in coding exon 3 of the MSH2 gene, results from a T to C substitution at nucleotide … (more)
The p.L173P variant (also known as c.518T>C), located in coding exon 3 of the MSH2 gene, results from a T to C substitution at nucleotide position 518. The leucine at codon 173 is replaced by proline, an amino acid with similar properties. This alteration was reported in an individual whose colorectal tumor demonstrated high microsatellite instabilty (MSI-H) with loss of MSH2 protein expression on immunohistochemistry (IHC) and had a family history that met Amsterdam criteria for Lynch syndrome (Mangold E et al. Int. J. Cancer, 2005 Sep;116:692-702; Ollila S et al. Gastroenterology, 2006 Nov;131:1408-17). This alteration was also identified as a somatic variant in conjunction with loss of heterozygosity of MSH2 in a Lynch syndrome-related tumor demonstrating MMR deficiency by IHC (Shirts BH et al. Am. J. Hum. Genet., 2018 07;103:19-29). In an in vitro complementation assay using human nuclear extracts from a colorectal cell line, this alteration demonstrated reduced (less than 10%) mismatch repair (MMR) activity compared to wild type MSH2 (Ollila S et al. Gastroenterology, 2006 Nov;131:1408-17). In another functional study, this alteration showed resistance to a DNA damaging agent known to cause cell death in MMR-proficient cells, had reduced protein expression compared to wild type MSH2, and demonstrated microsatellite instability in a cellular assay using a slippage reporter (Houlleberghs H et al. Proc. Natl. Acad. Sci. U.S.A., 2016 Apr;113:4128-33). Furthermore, this alteration demonstrated no aberrant splicing in a functional assay using RT-PCR (Auclair J et al. Hum. Mutat., 2006 Feb;27:145-54). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. In addition, this alteration is predicted to be deleterious by MAPP-MMR in silico analysis (Chao EC et al. Hum. Mutat. 2008 Jun;29:852-60). Based on the majority of available evidence to date, this variant is likely to be pathogenic. (less)
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Likely Pathogenic
(Feb 05, 2024)
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criteria provided, single submitter
Method: clinical testing
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Lynch syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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All of Us Research Program, National Institutes of Health
Accession: SCV004822610.1
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)
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Comment:
This missense variant replaces leucine with proline at codon 173 of the MSH2 protein. Computational prediction suggests that this variant may have deleterious impact on … (more)
This missense variant replaces leucine with proline at codon 173 of the MSH2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant causes significantly decreased mismatch repair activity compared to wild type protein (PMID: 17101317, 17594722, 18951462), and that the variant impacts MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold >= 0.88, PMID: 33357406). This variant has been reported in individuals affected with Lynch syndrome (PMID: 15849733, 17101317, 17594722, 18951462, 33422027). A different variant affecting the same codon, c.518T>G (p.Leu173Arg), is considered to be disease-causing (ClinVar variation ID: 91122), suggesting that this position is important for the protein function. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. (less)
Number of individuals with the variant: 1
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Likely pathogenic
(-)
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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: SCV000592467.2 First in ClinVar: Aug 27, 2017 Last updated: Apr 13, 2021 |
Comment:
The p.Leu173Pro variant has been reported in the literature in 16/3584 proband chromosomes (Auclair 2006, Chao 2008, Kansikas 2011, Mangold 2005, Ollila 2006, Ollila 2006b, … (more)
The p.Leu173Pro variant has been reported in the literature in 16/3584 proband chromosomes (Auclair 2006, Chao 2008, Kansikas 2011, Mangold 2005, Ollila 2006, Ollila 2006b, Ollila 2008, Ou 2007) from patients who met either the Bethesda criteria or Amsterdam criteria II. However, no control chromosomes were tested to establish the frequency of the variant in the general population. It is listed in dbSNP database as coming from a "clinical source" (ID#: rs63750070), but no frequency information was provided, and so the prevalence of this variant in the population is not known. The p.Leu173 residue is conserved across mammals and computational analyses (PolyPhen, SIFT, AlignGVGD) suggest that the p.Leu173Pro variant may impact the protein. However, this information is not predictive enough to assume pathogenicity. Functional assays evaluating the stability and/or MMR activity of the variant reveal that compared to the wildtype allele, the variant exhibits reduced repair efficiency and is also less stable (Ollila 2006b, Kansikas 2011, Ollila 2008). In addition, HNPCC-associated tumors from carriers were MSI-H and MSH2 deficient by immunohistochemistry (Kansikas 2011, Mangold 2005, Ollila 2006b). In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time, although we would lean towards a more pathogenic role for this variant. This variant is classified as Predicted Pathogenic. (less)
Number of individuals with the variant: 1
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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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Comparison of long-term outcomes between Lynch sydrome and sporadic colorectal cancer: a propensity score matching analysis. | Xu Y | BMC cancer | 2021 | PMID: 33422027 |
Massively parallel functional testing of MSH2 missense variants conferring Lynch syndrome risk. | Jia X | American journal of human genetics | 2021 | PMID: 33357406 |
Using Somatic Mutations from Tumors to Classify Variants in Mismatch Repair Genes. | Shirts BH | American journal of human genetics | 2018 | PMID: 29887214 |
A survey of the clinicopathological and molecular characteristics of patients with suspected Lynch syndrome in Latin America. | Rossi BM | BMC cancer | 2017 | PMID: 28874130 |
Elucidating the molecular basis of MSH2-deficient tumors by combined germline and somatic analysis. | Vargas-Parra GM | International journal of cancer | 2017 | PMID: 28577310 |
Oligonucleotide-directed mutagenesis screen to identify pathogenic Lynch syndrome-associated MSH2 DNA mismatch repair gene variants. | Houlleberghs H | Proceedings of the National Academy of Sciences of the United States of America | 2016 | PMID: 26951660 |
Development of a new, simple and cost-effective diagnostic tool for genetic screening of hereditary colorectal cancer--the DNA microarray assay. | Stojcev Z | Acta biochimica Polonica | 2013 | PMID: 23741719 |
Calibration of multiple in silico tools for predicting pathogenicity of mismatch repair gene missense substitutions. | Thompson BA | Human mutation | 2013 | PMID: 22949387 |
Classification of mismatch repair gene missense variants with PON-MMR. | Ali H | Human mutation | 2012 | PMID: 22290698 |
Verification of the three-step model in assessing the pathogenicity of mismatch repair gene variants. | Kansikas M | Human mutation | 2011 | PMID: 21120944 |
Mechanisms of pathogenicity in human MSH2 missense mutants. | Ollila S | Human mutation | 2008 | PMID: 18951462 |
Accurate classification of MLH1/MSH2 missense variants with multivariate analysis of protein polymorphisms-mismatch repair (MAPP-MMR). | Chao EC | Human mutation | 2008 | PMID: 18383312 |
Functional analysis helps to clarify the clinical importance of unclassified variants in DNA mismatch repair genes. | Ou J | Human mutation | 2007 | PMID: 17594722 |
Pathogenicity of MSH2 missense mutations is typically associated with impaired repair capability of the mutated protein. | Ollila S | Gastroenterology | 2006 | PMID: 17101317 |
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 |
Spectrum and frequencies of mutations in MSH2 and MLH1 identified in 1,721 German families suspected of hereditary nonpolyposis colorectal cancer. | Mangold E | International journal of cancer | 2005 | PMID: 15849733 |
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Text-mined citations for rs63750070 ...
HelpRecord last updated Sep 08, 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.