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 likely benign Hereditary cancer-predisposing syndrome 2019-12-05 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other strong data supporting benign classification;Structural 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 2021-07-14 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with suspected Lynch syndrome, but also in a population-based control subject (Samowitz 2001, Zhang 2015, Lagerstedt-Robinson 2016, Rossi 2017); This variant is associated with the following publications: (PMID: 18822302, 21120944, 27978560, 31391288, 31159747, 29752822, 28874130, 27273229, 12419761, 26580448, 27720647, 27601186, 26333163, 11606497)
Invitae RCV001081828 SCV000254425 likely benign Hereditary nonpolyposis colorectal neoplasms 2020-12-04 criteria provided, single submitter clinical testing
Counsyl RCV000411418 SCV000488523 uncertain significance Lynch syndrome I 2016-04-19 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000202264 SCV000696276 likely benign not specified 2020-12-18 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 Hereditary Nonpolyposis Colorectal Cancer (9.5e-05 vs 0.00057), allowing no conclusion about variant significance. 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. At-least one co-occurrence with another pathogenic variant has been reported (Pearlman_2016, MSH2 c.2096C>A, p.Ser699X), providing supporting evidence for a benign role. A recent study analyzed MMR pathogenic variant association with MSI/IHC status, and estimated likelihood ratios to compute a tumour characteristic likelihood ratio (TCLR), that was further assessed in combination with in-silico predictors, and a multifactorial variant prediction (Li_2010). This specific variant was predicted to be likely benign based on this model (Li_2020). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely benign, n=3). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above and the emerging consensus towards a neutral outcome, this variant was re-classified as likely 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 Health, Inc 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 Laboratories, Mayo Clinic RCV000202264 SCV000257192 uncertain significance not specified no assertion criteria provided clinical testing

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