ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.382C>G (p.Leu128Val) (rs145649774)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212583 SCV000149437 uncertain significance not specified 2017-10-27 criteria provided, single submitter clinical testing The MSH2 c.382C>G variant was observed in at least one individual with possible Lynch syndrome (Grandval 2013). MSH2 Leu128Val was observed at an allele frequency of 0.1817% (30/16512 alleles) in individuals of South Asian ancestry in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Leucine and Valine share similar properties, this is considered a conservative amino acid substitution. MSH2 Leu128Val occurs at a position that is conserved across species and is located in the Connector domain (Lutzen 2008). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether MSH2 Leu128Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000115528 SCV000187641 likely benign Hereditary cancer-predisposing syndrome 2019-03-12 criteria provided, single submitter clinical testing Insufficient or conflicting evidence;Co-occurence with a mutation in another gene that clearly explains a proband's phenotype;Other data supporting benign classification
Invitae RCV000524406 SCV000254420 likely benign not provided 2019-02-27 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000212583 SCV000592463 likely benign not specified 2016-07-21 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000212583 SCV000604261 uncertain significance not specified 2016-11-26 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000212583 SCV000696263 likely benign not specified 2018-06-08 criteria provided, single submitter clinical testing Variant summary: MSH2 c.382C>G (p.Leu128Val) results in a conservative amino acid change located in the DNA mismatch repair protein MutS-like, N-terminal domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00035 in 121402 control chromosomes, predominantly at a frequency of 0.0018 within the South Asian subpopulation in the ExAC database. The observed variant frequency within South Asian control individuals in the ExAC database is approximately 3.17 fold of the estimated maximal expected allele frequency for a pathogenic variant in MSH2 causing Lynch Syndrome phenotype (0.00057), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. c.382C>G has been reported in the literature in individuals affected with Lynch Syndrome. In one HNPCC family with this variant, 1 transmission of the variant allele and 1 transmission of the reference allele to affected individuals was reported (Juhari_2018). These data suggest the variant of interest does not co-segregate with the disease. Co-occurrence with other pathogenic variant has been found in our internal database (BRCA2 c.9097dupA, p.Thr3033fsX11), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (3 VUS, 2 likely benign). Based on the evidence outlined above, the variant was classified as likely benign.
Mendelics RCV000195415 SCV000837818 uncertain significance Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing
Color RCV000115528 SCV000910713 likely benign Hereditary cancer-predisposing syndrome 2017-06-22 criteria provided, single submitter clinical testing
Mendelics RCV000986649 SCV001135700 uncertain significance Lynch syndrome I 2019-05-28 criteria provided, single submitter clinical testing
GenomeConnect, ClinGen RCV000195415 SCV000607332 not provided Lynch syndrome no assertion provided phenotyping only GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
True Health Diagnostics RCV000115528 SCV000788038 uncertain significance Hereditary cancer-predisposing syndrome 2017-08-11 no assertion criteria provided clinical testing

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