ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.306G>T (p.Glu102Asp) (rs63751665)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075637 SCV000106639 uncertain significance Lynch syndrome 2018-06-13 reviewed by expert panel curation G>non-G at last base of exon with first 6 bases of the intron not GTRRGT; Insufficient evidence
GeneDx RCV000115480 SCV000149389 pathogenic not provided 2018-07-13 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.306G>T at the cDNA level. Located at the last nucleotide of exon 3, it is predicted to damage or destroy the natural splice donor site and cause abnormal splicing. RNA analysis of an alternate nucleotide change at the same location, MLH1 c.306G>C, demonstrated skipping of exon 3 (Borras 2012, Buchanan 2014). MLH1 c.306G>T has been observed in an individual with synchronous colorectal cancers showing microsatellite instability (MSI-H) and loss of MLH1 protein expression and in at least four other individuals with suspected Lynch syndrome whose tumors demonstrated microsatellite instability (Whitworth 2016, Borras 2017). In vitro studies found this variant to exhibit mildly deficient mismatch repair (MMR) activity (Takahashi 2007). Although the nucleotide substitution results in the change of a Glutamic Acid to an Aspartic Acid at codon 102, and is called Glu102Asp in the literature, we are using only the nucleotide nomenclature to refer to the variant since the defect is determined to be one of splicing rather than a resulting missense variant. MLH1 c.306G>T was not observed at a significant allele frequency in large population cohorts (Lek 2016). Based on currently available evidence, we consider MLH1 c.306G>T to be pathogenic.
Ambry Genetics RCV000216647 SCV000275253 pathogenic Hereditary cancer-predisposing syndrome 2018-12-06 criteria provided, single submitter clinical testing Last nucleotide of exon;Deficient protein function in appropriate functional assay(s);Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation
Invitae RCV000524291 SCV000543564 likely pathogenic Hereditary nonpolyposis colorectal neoplasms 2019-11-14 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with aspartic acid at codon 102 of the MLH1 protein (p.Glu102Asp). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and aspartic acid. This variant also falls at the last nucleotide of exon 3 of the MLH1 coding sequence, which is part of the consensus splice site for this exon. This variant is present in population databases (rs63751665, ExAC 0.01%). This variant has been reported in individuals affected with colon cancer and/or colon polyps (PMID: 26681312), and an individual with cecal and sigmoid colon cancers (PMID: 26659639). Additionally, this variant has been reported in individuals with MLH1-related disease in the Leiden Open-source Variant Database (PMID: 21520333) and the Universal Mutation Database (PMID: 23729658). ClinVar contains an entry for this variant (Variation ID: 90151). Experimental in vitro studies have shown that this missense change results in a small reduction of mismatch repair activity of the MLH1 protein (PMID: 17510385). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. A different variant affecting this nucleotide (c.306G>C) has been determined to be pathogenic (PMID: 22736432). This suggests that this nucleotide is important for normal RNA splicing, and that other variants at this position may also be pathogenic. 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.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000075637 SCV000592349 pathogenic Lynch syndrome 2012-07-23 criteria provided, single submitter clinical testing
Color RCV000216647 SCV000689874 likely pathogenic Hereditary cancer-predisposing syndrome 2020-01-15 criteria provided, single submitter clinical testing
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000851292 SCV000993564 pathogenic Lynch syndrome II 2018-09-21 criteria provided, single submitter research
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics RCV000851292 SCV001161675 likely pathogenic Lynch syndrome II 2020-01-09 criteria provided, single submitter clinical testing The heterozygous missense substitution c.306G>T (p.Glu102Asp) lies in exon 3 of the MLH1 gene and alters a conserved residue in the protein. The variant is predicted to be damaging by SIFT, LRT, Mutation Taster, Mutation Assessor and FATHMM. The variant lies in the ATPase domain (residues 25-207) of the protein, which is crucial for the MMR activity of the MLH1 protein (PMID: 26249686). In silico splice prediction tools (ASSP, NNSPLICE and MaxEntScan) suggests that this variant might affect splicing or create alternate cryptic splice site. The variant has been reported as Likely pathogenic in the ClinVar database. In summary, the variant meets our criteria to be classified as likely pathogenic.

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