ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.557A>G (p.Asn186Ser) (rs151129360)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130716 SCV000185603 uncertain significance Hereditary cancer-predisposing syndrome 2018-04-13 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Conflicting evidence
Color RCV000130716 SCV000910737 likely benign Hereditary cancer-predisposing syndrome 2016-06-07 criteria provided, single submitter clinical testing
Counsyl RCV000411418 SCV000488523 uncertain significance Lynch syndrome I 2016-04-19 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000587046 SCV000203032 uncertain significance not provided 2014-03-17 criteria provided, single submitter clinical testing
GeneDx RCV000587046 SCV000211213 uncertain significance not provided 2018-08-02 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.557A>G at the cDNA level, p.Asn186Ser (N186S) at the protein level, and results in the change of an Asparagine to a Serine (AAT>AGT). This variant was observed in at least two individuals with suspected Lynch syndrome based on personal and/or family history of cancer and in a pediatric sarcoma patient, but has also been observed in one population-based control subject (Samowitz 2001, Zhang 2015, Lagerstedt-Robinson 2016, Rossi 2017). Additionally, this variant was reported to co-occur with another reportedly pathogenic MSH2 variant, in an individual with multiple synchronous colon cancers (Pearlman 2016). MSH2 Asn186Ser was observed at an allele frequency of 0.02% (7/34,420) in individuals of Latino ancestry in large population cohorts (Lek 2016). This variant is located in the connector domain (Lutzen 2008, Kansikas 2011). In-silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether MSH2 Asn186Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
GeneKor MSA RCV000130716 SCV000822055 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000587046 SCV000696276 uncertain significance not provided 2016-12-12 criteria provided, single submitter clinical testing Variant summary: The MSH2 c.557A>G (p.Asn186Ser) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 11/121558 control chromosomes at a frequency of 0.0000905, which does not exceed the estimated maximal expected allele frequency of a pathogenic MSH2 variant (0.0005683). This variant has been reported in at least two LS patients without clear evidence supporting pathogenicity. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as VUS.
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000076637 SCV000107672 uncertain significance Lynch syndrome 2013-09-05 reviewed by expert panel research Insufficient evidence
Invitae RCV000524414 SCV000254425 uncertain significance Hereditary nonpolyposis colon cancer 2018-01-24 criteria provided, single submitter clinical testing This sequence change replaces asparagine with serine at codon 186 of the MSH2 protein (p.Asn186Ser). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and serine. This variant is present in population databases (rs151129360, ExAC 0.02%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in a family with suspected Lynch syndrome (PMID: 27601186), an individual affected with colorectal cancer (PMID: 27273229), an individual with rhabdomyosarcoma (PMID: 26580448), and an unaffected control individual (PMID: 11606497). ClinVar contains an entry for this variant (Variation ID: 91133). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. However, an algorithm developed specifically for the MSH2 gene suggests that this missense change is likely to be tolerated (PMID: 26333163). These predictions have not been confirmed by published functional 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.
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000202264 SCV000257192 uncertain significance not specified no assertion criteria provided clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000202264 SCV000601484 uncertain significance not specified 2017-04-26 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000587046 SCV000888222 uncertain significance not provided 2018-02-18 criteria provided, single submitter clinical testing

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