ClinVar Miner

Submissions for variant NM_000251.3(MSH2):c.382C>G (p.Leu128Val) (rs145649774)

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Total submissions: 12
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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 Co-occurence with a mutation in another gene that clearly explains a proband's phenotype;Insufficient or conflicting evidence;Other data supporting benign classification
Invitae RCV000524406 SCV000254420 likely benign Hereditary nonpolyposis colorectal neoplasms 2020-12-01 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
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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 Health, Inc 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
Illumina Clinical Services Laboratory,Illumina RCV000986649 SCV001304223 uncertain significance Lynch syndrome I 2018-09-12 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353804 SCV000592463 likely benign Endometrial carcinoma no assertion criteria provided clinical testing The MSH2, p.Leu128Val variant was not identified in the literature. The p.Leu128Val variant was identified in dbSNP (ID: rs145649774) as “With Uncertain significance allele”, Clinvitae database (classified as VUS), MUTDB, ClinVar database (classified as uncertain significance, submitters: GeneDx, Ambry Genetics, Invitae), and UMD (1x with an “unclassified variant” classification).The p.Leu128Val variant was also identified in the NHLBI GO Exome Sequencing Project in 3 of 8600 European American alleles and 1 of 4406 African American alleles, and in the Exome Aggregation Consortium database (March 14, 2016) in 30 of 16512 chromosomes (frequency: 0.002) of South Asian individuals, 9 of 66732 (frequency: 0.00013) of European (Non-Finnish) individuals, 1 of 10404 (frequency: 9.61E-05) of African individuals, 1 of 11578 (frequency: 8.64E-05) of Latino individuals and 2 of 908 (frequency: 0.002) in other individuals, increasing the likelihood that this may be a low frequency benign variant in certain populations of origin. The p.Leu128 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The p.Leu128Val variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. The observation of this variant with a co-occurring pathogenic variant (MLH1, EXON05-8, c.381-?_677del+?) by our laboratory increases the likelihood this variant does not have clinical significance. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time but we would lean towards a more benign role for this variant. This variant is classified as likely benign.
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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