ClinVar Miner

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

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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)
Ambry Genetics RCV000216042 SCV000276633 likely pathogenic Hereditary cancer-predisposing syndrome 2019-08-05 criteria provided, single submitter clinical testing The p.E102K variant (also known as c.304G>A), located in coding exon 3 of the MLH1 gene, results from a G to A substitution at nucleotide position 304. The glutamic acid at codon 102 is replaced by lysine, an amino acid with similar properties. This variant has been reported in an HNPCC family which met Amsterdam criteria and in vitro studies have found that the c.304G>A nucleotide substitution results in a 5-bp deletion in the 3' end of exon 3 (Nakagawa H et al. Cancer Res. 2002 Aug 15;62(16):4579-82). Additionally, further functional studies have shown decreased or complete loss of MMR function (Ellison AR. et al. Hum. Mol. Genet. 2001:1889-900; Hinrichsen I et al. Clin. Cancer Res. 2013 May; 19(9):2432-41). However, Takahashi et al. also studied the MMR activity of this variant in vitro and found this variant to result in an MMR function of 44.4% compared to 79.7% in WT which they report as inconclusive (Takahashi M et al. Cancer Research. 2007: 4595-60). Based on protein sequence alignment, this amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000781538 SCV000919653 likely pathogenic Hereditary nonpolyposis colon cancer 2021-02-15 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 (IPR002099) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. 4/4 computational tools predict no significant impact on normal splicing. The presence of a cryptic 5' donor site 5 bp upstream of the canonical splice site was however noted at exon 3. Nakagawa et al (2002) suggest that this cryptic splice site is preferentially/exclusively used when the variant is present, resulting in a deletion of the last 5 bp of exon 3, eventually causing a downstream frameshift. A different study however, was unable to detect such an effect and reported no aberrant splicing in relation to the variant (Auclair_2006). Additional functional studies show defective or partially defective MMR activity (Ellison_2001; Hinrichsen_2013; Takahashi_2007, Reyes_2020). The variant was absent in 251344 control chromosomes (gnomAD) but has been reported in the literature in individuals affected with Lynch Syndrome (e.g. Duraturo_2015, Nakagawa_2002). Six ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=1) and likely pathogenic (n=5, including one expert panel- International Society for Gastrointestinal Hereditary Tumours (InSiGHT)). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Invitae RCV000807476 SCV000947529 likely pathogenic Hereditary nonpolyposis colorectal neoplasms 2019-11-08 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, 18373977). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000493419 SCV001134310 likely pathogenic not provided 2019-02-15 criteria provided, single submitter clinical testing Not found in the total gnomAD dataset, and the data is high quality (0/251334 chr). Statistically enriched in patients compared to ethnically matched controls. Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Located in potentially important domain of the protein. One other pathogenic or likely pathogenic variant affects the same amino acid. Results on protein functions were inconclusive.
Color Health, Inc RCV000216042 SCV001340144 likely pathogenic Hereditary cancer-predisposing syndrome 2019-08-09 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353830 SCV000592348 likely pathogenic Carcinoma of colon no assertion criteria provided clinical testing Note: This variant was identified by this lab in a Teresa Minella. IHC not interpretable and MSI results were high.
Mayo Clinic Laboratories, Mayo Clinic RCV000501856 SCV000691845 uncertain significance not specified no assertion criteria provided clinical testing

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