ClinVar Miner

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

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000221964 SCV000277387 uncertain significance Hereditary cancer-predisposing syndrome 2016-11-29 criteria provided, single submitter clinical testing Insufficient evidence
Counsyl RCV000412138 SCV000489185 uncertain significance Lynch syndrome I 2016-08-31 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000502373 SCV000592460 likely benign not specified 2013-08-21 criteria provided, single submitter clinical testing
Invitae RCV000552261 SCV000625408 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-12-22 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 RCV000221964 SCV000690095 uncertain significance Hereditary cancer-predisposing syndrome 2019-05-08 criteria provided, single submitter clinical testing
GeneDx RCV000502373 SCV000729490 likely benign not specified 2017-09-12 criteria provided, single submitter clinical testing 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.
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 Astrocytoma; Hypermelanotic macule; Colorectal polyposis 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,PM4,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.

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