ClinVar Miner

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

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Total submissions: 11
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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 2018-11-21 criteria provided, single submitter clinical testing 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 RCV001081828 SCV000254425 likely benign Hereditary nonpolyposis colorectal neoplasms 2019-12-31 criteria provided, single submitter clinical testing
Counsyl RCV000411418 SCV000488523 uncertain significance Lynch syndrome I 2016-04-19 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000202264 SCV000696276 uncertain significance not specified 2019-12-27 criteria provided, single submitter clinical testing Variant summary: MSH2 c.557A>G (p.Asn186Ser) results in a conservative amino acid change located in the DNA mismatch repair protein MutS, connector 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 9.5e-05 in 251626 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in MSH2 causing Lynch Syndrome (9.5e-05 vs 0.00057), allowing no conclusion about variant significance. The variant, c.557A>G, has been reported in the literature in individuals affected with Lynch Syndrome (Lagerstedt-Robinson_2016, Buchanan_2016, Perlman_2016, Mu_2016, Rossi_2017) or breast cancer (Li_2018). These reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. Co-occurrence with a pathogenic variant has been reported (MSH2 c.2096C>A, p.Ser699X), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven ClinVar submissions from other clinical diagnostic laboratories (evaluation after 2014) cite the variant as uncertain significance (5x) or likely benign (2x). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
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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