ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.649C>T (p.Arg217Cys) (rs4986984)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212524 SCV000149392 likely benign not specified 2018-02-20 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.
Invitae RCV000590255 SCV000166256 likely benign not provided 2019-03-02 criteria provided, single submitter clinical testing
Ambry Genetics RCV000115483 SCV000184755 likely benign Hereditary cancer-predisposing syndrome 2018-09-24 criteria provided, single submitter clinical testing Other data supporting benign classification
Color RCV000115483 SCV000689902 benign Hereditary cancer-predisposing syndrome 2015-12-08 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000212524 SCV000696175 likely benign not specified 2019-04-23 criteria provided, single submitter clinical testing Variant summary: MLH1 c.649C>T (p.Arg217Cys) results in a non-conservative amino acid change located in the N-terminal domain that functions in promoting dimerization (IPR002099). Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00039 in 251981 control chromosomes, predominantly at a frequency of 0.0047 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 6.5 fold of the estimated maximal expected allele frequency for a pathogenic variant in MLH1 causing Lynch Syndrome phenotype (0.00071), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.649C>T has also been reported in the literature in several individuals affected with Lynch Syndrome, who were predominantly of Asian descent and the majority of these publications only performed evaluation of MLH1 and could not rule out variants in other Lynch syndrome associated genes. These reports therefore do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. In addition, in one publication (Sapari 2014), the variant was found in co-occurrence with another pathogenic MLH1 variant, c.790+1G>A (although it was only identified through NGS and not confirmed by Sanger sequencing). Several publications reported experimental evidence evaluating an impact on protein function (Ellison 2001, Trojan 2002, Kondo 2003, Takahashi 2007, Zhao 2008, Peng 2016), showing no or only a mild effect on function. A recent study suggested based on in vitro evidence that the variant might affect splicing by affecting splicesome assembly (Rhine 2018), however earlier reports that identified the variant in patients through RNA-based direct sequencing, did not indicate any specific splicing effect (Furukawa 2002, Wang 2005); therefore the significance of this finding is uncertain. Six other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (1 calling it benign, 4 as likely benign, and 1 as VUS). Based on the evidence outlined above, the variant was classified as likely benign.
Mendelics RCV000075793 SCV000838001 uncertain significance Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000590255 SCV000889402 likely benign not provided 2017-11-22 criteria provided, single submitter clinical testing
Mendelics RCV000987154 SCV001136381 uncertain significance Lynch syndrome II 2019-05-28 criteria provided, single submitter clinical testing

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