ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.362A>G (p.Tyr121Cys) (rs587779971)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000115527 SCV000149436 uncertain significance not provided 2018-06-29 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.362A>G at the cDNA level, p.Tyr121Cys (Y121C) at the protein level, and results in the change of a Tyrosine to a Cysteine (TAT>TGT). This variant has been reported in the literature in an individual referred for multi-gene hereditary cancer testing (Mu 2016). MSH2 Tyr121Cys was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the mismatch binding domain (L?tzen 2008, Kansikas 2011). Protein-based in silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. In addition, multiple splicing models predict that this variant may create a cryptic splice donor site upstream of the nearby natural splice donor site. However, in the absence of RNA or functional studies, the actual effect of this variant is unknown. Based on currently available evidence, it is unclear whether MSH2 Tyr121Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000220764 SCV000277258 uncertain significance Hereditary cancer-predisposing syndrome 2019-06-12 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000226077 SCV000284168 uncertain significance Hereditary nonpolyposis colon cancer 2019-12-12 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with cysteine at codon 121 of the MSH2 protein (p.Tyr121Cys). The tyrosine residue is weakly conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is present in population databases (rs587779971, ExAC 0.009%). This variant has not been reported in the literature in individuals with MSH2-related disease. ClinVar contains an entry for this variant (Variation ID: 127643). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C15"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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 RCV000220764 SCV000685082 uncertain significance Hereditary cancer-predisposing syndrome 2019-08-02 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000115527 SCV000885711 uncertain significance not provided 2017-07-27 criteria provided, single submitter clinical testing The MSH2 c.362A>G;p.Tyr121Cys variant has been published in the medical literature in at least one individual suspected of having hereditary cancer (Mu 2016). The variant is listed in the ClinVar database (Variation ID: 127643) and the dbSNP variant database (rs587779971) with an allele frequency of 0.003253 percent (9/276636 alleles) in the Genome Aggregation Database. The amino acid at this position is located in the mismatch binding domain (Lutzen 2008), but the amino acid is weakly conserved and computational algorithms do not reach a consensus as to the effect of this variant (AlignGVGD: C15, SIFT: Tolerated, MutationTaster: disease causing). However, this variant occurs near an exon/intron boundary and splicing prediction programs (SpliceSiteFinder-like, MaxEntScan, NNSplice, GeneSplicer, Human Splicing Finder) predict this variant may alter splicing. Considering available information, there is insufficient evidence to classify the variant at this time. Pathogenic MSH2 variants are causative for Lynch syndrome (MIM#120435). References Lutzen A et al. Functional analysis of HNPCC-related missense mutations in MSH2. Mutat Res. 2008 Oct 14;645(1-2):44-55. Mu W et al. Sanger Confirmation Is Required to Achieve Optimal Sensitivity and Specificity in Next-Generation Sequencing Panel Testing. J Mol Diagn. 2016 Nov;18(6):923-932.

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