ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.274C>G (p.Leu92Val) (rs587779154)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 9
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000221964 SCV000277387 uncertain significance Hereditary cancer-predisposing syndrome 2020-03-31 criteria provided, single submitter clinical testing 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 position 274. The leucine at codon 92 is replaced by valine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Counsyl RCV000412138 SCV000489185 uncertain significance Lynch syndrome I 2016-08-31 criteria provided, single submitter clinical testing
Invitae RCV000552261 SCV000625408 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2020-10-19 criteria provided, single submitter clinical testing 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 small physicochemical difference between leucine and valine. This variant is present in population databases (rs587779154, ExAC 0.02%). This variant has been reported in an individual affected with suspected Lynch syndrome (PMID: 19669161). This variant has also been reported in an individual with constitutional mismatch repair deficiency syndrome (CMMR-D) (PMID: 29302048); however, that individual was homozygous for this variant as well as a different variant of uncertain significance in MSH6. This variant has also been reported in an individual in the Universal Mutation Database (PMID: 23729658); however, in that individual a pathogenic allele was also identified in MSH6, which suggests that this MSH2 c.274C>G variant was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 91041). Experimental studies have shown that MSH2 expression was not lost in the tumor cells of a CMMR-D patient homozygous for this variant, and results of a germline microsatellite instability assay differed between this patient's peripheral blood lymphocytes and a lymphoblastoid cell line derived from this patient's cells (PMID: 29302048). The clinical significance of these findings is uncertain. 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.
Color Health, Inc RCV000221964 SCV000690095 uncertain significance Hereditary cancer-predisposing syndrome 2020-08-26 criteria provided, single submitter clinical testing 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 protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual with personal and/or family history of Lynch syndrome-associated cancers (PMID: 19669161). This variant has also been reported in the homozygous state in an individual affected with constitutional mismatch repair deficiency syndrome (PMID: 28929227, 29302048). However, the individual was found to also have a homozygous variant in the MSH6 gene. The primary cause of the disease is not clear. This variant has been identified in 15/251214 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.
GeneDx RCV001353838 SCV000729490 likely benign not provided 2018-07-31 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 19669161, 26333163, 28135145)
Mendelics RCV000412138 SCV001135696 uncertain significance Lynch syndrome I 2019-05-28 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001196697 SCV001367328 uncertain significance Turcot syndrome 2019-08-28 criteria provided, single submitter clinical testing 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 conclusively support its pathogenic nature. Thus this variant is classified as Uncertain significance - favor pathogenic. The following ACMG criteria were applied in classifying this variant: PM2,PP3,PP5. This variant was detected in homozygous state.
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics RCV000412138 SCV001370542 likely pathogenic Lynch syndrome I 2020-05-29 criteria provided, single submitter clinical testing 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 was detected. The observed variant c.274C>G (p.Leu92Val) has not been reported in the 1000 genomes and has a minor allele frequency of 0.006% in the ExAC database. The observed variation has previously been reported in an individual with family history of Lynch syndrome (Betz B et al. 2010) and it lies in the MutS domain I of the MSH2_HUMAN protein. The in silico prediction of the variant are probably damaging by PolyPhen-2 (HumDiv) and damaging by SIFT, LRT and MutationTaster2 tools. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as likely pathogenic.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353838 SCV000592460 likely benign not provided no assertion criteria provided clinical testing 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 (Betz 2010); "no changes" were predicted for this variant. The variant was also identified in the InSight, Medical center Groningen and Memorial University MMR databases. This residue is conserved in mammals but not in lower organisms and computational analyses (PolyPhen2, SIFT, AlignGVGD, BLOSUM) provide inconsistent predictions regarding the impact to the protein, but this information is not very predictive of pathogenicity. This variant is identified by our laboratory in one individual with a co-occuring pathogenic variant, increasing the likelihood this variant does not have clinical significance. In summary, the clinical significance of this variant cannot be determined with certainty, although we would lean towards a more benign role for this variant. This variant is classified as predicted benign.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.