ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1255C>A (p.Gln419Lys) (rs63750006)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000076079 SCV000107094 likely benign Lynch syndrome 2013-09-05 reviewed by expert panel research Multifactorial likelihood analysis posterior probability 0.001-0.049
GeneDx RCV000121568 SCV000211245 likely benign not specified 2017-09-27 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics RCV000160643 SCV000213572 likely benign Hereditary cancer-predisposing syndrome 2018-11-16 criteria provided, single submitter clinical testing In silico models in agreement (benign);Subpopulation frequency in support of benign classification
Invitae RCV000759096 SCV000260558 benign not provided 2019-03-01 criteria provided, single submitter clinical testing
Color RCV000160643 SCV000537420 likely benign Hereditary cancer-predisposing syndrome 2015-04-14 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000121568 SCV000601426 likely benign not specified 2016-10-06 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000759096 SCV000888201 benign not provided 2017-12-20 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000121568 SCV000917686 likely benign not specified 2019-05-06 criteria provided, single submitter clinical testing Variant summary: MSH2 c.1255C>A (p.Gln419Lys) results in a conservative amino acid change located in the core domain (IPR007696) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00057 in 252292 control chromosomes, predominantly at a frequency of 0.0075 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 13 fold of the estimated maximal expected allele frequency for a pathogenic variant in MSH2 causing Lynch Syndrome phenotype (0.00057), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. The variant, c.1255C>A has been reported in the literature in individuals affected with Lynch Syndrome (e.g. Tang_2009, Yap_2009) without strong evidence of causality. These reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. In our internal database, co-occurrence with another pathogenic variant has been reported (BRCA2 c.6952C>T, p.R2318*) for this variant, providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect. Five submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as benign (2x) /likely benign (3x). Based on the evidence outlined above, the variant was classified as likely benign.
Mendelics RCV000986666 SCV001135724 benign Lynch syndrome I 2019-05-28 criteria provided, single submitter clinical testing
ITMI RCV000121568 SCV000085764 not provided not specified 2013-09-19 no assertion provided reference population

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