ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.304G>A (p.Glu102Lys) (rs63750453)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000216042 SCV000276633 likely pathogenic Hereditary cancer-predisposing syndrome 2016-01-14 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Deficient protein function in appropriate functional assay(s),Rarity in general population databases (dbsnp, esp, 1000 genomes),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Other strong data supporting pathogenic classification
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000501856 SCV000592348 uncertain significance not specified 2016-12-05 criteria provided, single submitter clinical testing
GeneDx RCV000493419 SCV000581719 likely pathogenic not provided 2014-12-29 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.304G>A at the cDNA level, p.Glu102Lys (E102K) at the protein level, and results in the change of a Glutamic Acid to a Lysine (GAG>AAG). This variant was observed in several individuals with personal and/or family histories consistent with Lynch syndrome (Nakagawa 2002, Chao 2008, Bonadona 2011). Some in vitro studies have demonstrated protein expression comparable to wild type, however others have shown reduced repair activity and expression levels associated with this variant, supporting a likely deleterious role (Ellison, 2001, Takahashi 2007, Hinrichsen 2013). MLH1 Glu102Lys was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Glutamic Acid and Lysine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MLH1 Glu102Lys occurs at a position that is moderately conserved across species and is located in ATP binding and hydrolysis domain (Raevaara 2005, Hardt 2011). While some studies have yielded mixed results with respect to how this variant may impact splicing (Nakagawa 2002, Auclair 2006), in silico analyses predict that this variant is probably damaging to protein structure and function. Based on the currently available information, we consider MLH1 Glu102Lys to be a likely pathogenic variant.
Integrated Genetics/Laboratory Corporation of America RCV000781538 SCV000919653 likely pathogenic Lynch syndrome 2018-05-01 criteria provided, single submitter clinical testing Variant summary: MLH1 c.304G>A (p.Glu102Lys) results in a conservative amino acid change located in the N-terminal DNA mismatch repair protein family domain and Histidine kinase/HSP90-like ATPase domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant is the third to last nucleotide at the exon 3/intron 3 junction and may impact splicing. Although 5/5 computational tools predict no significant impact on normal splicing, 4 tools predict the presence of a cryptic 5' donor site 5 bp upstream of the canonical splice site. These predictions are supported by a study that suggested the cryptic splice site is preferentially/exclusively used when the variant is present, causing a downstream frameshift (Nakagawa_2002). Additional functional studies show defective or partially defective MMR activity (Takahashi_2007; Ellison_2001). The variant was absent in 246140 control chromosomes (gnomAD) but has been reported numerous times in reputable disease databases (e.g., reported in 23 entries in the InSiGHT database; reported once in UMD with a classification of likely causal). The variant, c.304G>A, has been reported in the literature in individuals affected with Lynch Syndrome, however mostly without cosegregation data. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely pathogenic and one as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic.
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075627 SCV000106629 likely pathogenic Lynch syndrome I 2018-06-13 reviewed by expert panel curation Multifactorial likelihood analysis posterior probability > 0.99 (0.995)
Invitae RCV000807476 SCV000947529 likely pathogenic Hereditary nonpolyposis colon cancer 2018-10-02 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 102 of the MLH1 protein (p.Glu102Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in the literature and Universal Mutation Database in individuals affected with Lynch syndrome (PMID: 12183410, 23729658, 21642682, 22736432, 28514183). ClinVar contains an entry for this variant (Variation ID: 90141). Experimental studies have shown that this this missense change impairs mismatch repair (MMR) activity and results in reduced expression of the MLH1 protein (PMID: 17510385, 11555625, 23403630). However, experimental studies have reported conflicting results on whether or not this variant impacts splicing (PMID: 12183410, 16395668). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000501856 SCV000691845 uncertain significance not specified no assertion criteria provided clinical testing

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