ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.128A>G (p.Tyr43Cys) (rs17217723)

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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 RCV000131211 SCV000186161 likely benign Hereditary cancer-predisposing syndrome 2018-01-29 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Conflicting evidence,Co-occurence with a mutation in another gene that clearly explains a proband's phenotype,Other data supporting benign classification
Color RCV000131211 SCV000537603 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-13 criteria provided, single submitter clinical testing
Counsyl RCV000409784 SCV000488599 uncertain significance Lynch syndrome I 2016-05-04 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000764419 SCV000895476 uncertain significance Lynch syndrome I; Turcot syndrome; Muir-Torré syndrome 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000656872 SCV000211203 uncertain significance not provided 2018-11-23 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.128A>G at the cDNA level, p.Tyr43Cys (Y43C) at the protein level, and results in the change of a Tyrosine to a Cysteine (TAT>TGT). This variant has been observed in individuals with suspected Lynch syndrome, breast cancer, or leukemia (Auclair 2006, Aloraifi 2015, Zhang 2015, Dominguez-Valentin 2018). It has also been reported as a suspected germline variant in an individual with early-onset, microsatellite unstable colorectal cancer who also carried a canonical splice variant in MLH1 (Hampel 2018). The International Society for Gastrointestinal Hereditary Tumours Incorporated (InSiGHT) classifies this variant to be of uncertain significance due to insufficient evidence for classification (Thompson 2014). MSH2 Tyr43Cys was observed at an allele frequency of 0.015% (18/116,308) in individuals of European ancestry in large population cohorts (Lek 2016). This variant is located in the mismatch binding domain (Lutzen 2008, Kansikas 2011). In silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Based on currently available evidence, it is unclear whether MSH2 Tyr43Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000212578 SCV000919683 uncertain significance not specified 2018-11-19 criteria provided, single submitter clinical testing Variant summary: MSH2 c.128A>G (p.Tyr43Cys) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS-like, N-terminal domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7e-05 in 256278 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in MSH2 causing Lynch Syndrome (7e-05 vs 0.00057), allowing no conclusion about variant significance. c.128A>G has been reported in the literature in individuals affected with Lynch Syndrome, breast cancer, acute lymphoblastic leukemia and metastatic pancreatic ductal adenocarcinoma (Chan_2018, Sehdev_2018, Aloraif_2015, Zhang_2015, Auclair_2006). These report(s) do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. Co-occurrences with other pathogenic variant(s) have been reported (MSH6 c.2405del, p.802LeufsX7), providing supporting evidence for a benign role. A functional study, Auclair_2006, evaluated the splicing effect of the variant and found no impact on splicing. Seven ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as uncertain significance (6x) and once as likely benign. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Invitae RCV000524339 SCV000254380 uncertain significance Hereditary nonpolyposis colon cancer 2018-12-21 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with cysteine at codon 43 of the MSH2 protein (p.Tyr43Cys). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is present in population databases (rs17217723, ExAC 0.005%). This variant has been reported in individuals with Lynch syndrome (PMID: 16395668), acute lymphocytic leukemia (PMID: 26580448), and breast cancer (PMID: 26094658). It has also been reported in individuals in the Universal Mutation Database (PMID: 22144684). However, a pathogenic allele was identified in the MSH6 gene in an individual with colon cancer, which suggests that this c.128A>G substitution in MSH2 was not the primary cause of disease in that individual. ClinVar contains an entry for this variant (Variation ID: 90619). Algorithms developed specifically for the MSH2 gene suggest that this missense change is likely to be deleterious (PMID: 22290698, 18383312). However, this prediction has not been confirmed by published functional studies and their clinical significance 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000212578 SCV000539687 uncertain significance not specified 2016-03-31 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: 2 papers in HGMD; ExAC: 2/41748 European; ClinVar: 3 VUS (1 expert panel)
Mendelics RCV000076115 SCV000837814 uncertain significance Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing

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