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
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.
Invitae RCV000587046 SCV000254425 likely benign not provided 2019-03-04 criteria provided, single submitter clinical testing
Counsyl RCV000411418 SCV000488523 uncertain significance Lynch syndrome I 2016-04-19 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000202264 SCV000601484 uncertain significance not specified 2017-04-26 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.
GeneKor MSA RCV000130716 SCV000822055 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000587046 SCV000888222 uncertain significance not provided 2018-12-24 criteria provided, single submitter clinical testing
Color RCV000130716 SCV000910737 likely benign Hereditary cancer-predisposing syndrome 2016-06-07 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000587046 SCV001152274 uncertain significance not provided 2017-03-01 criteria provided, single submitter clinical testing
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000202264 SCV000257192 uncertain significance not specified no assertion criteria provided clinical testing

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