ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.302G>A (p.Gly101Asp) (rs267607727)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000568721 SCV000676037 likely pathogenic Hereditary cancer-predisposing syndrome 2016-02-26 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Deficient protein function in appropriate functional assay(s),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Other strong data supporting pathogenic classification
GeneDx RCV000481030 SCV000565141 likely pathogenic not provided 2015-02-10 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.302G>A at the cDNA level, p.Gly101Asp (G101D) at the protein level, and results in the change of a Glycine to an Aspartic Acid (GGT>GAT). This variant has been observed in multiple individuals with personal and/or family histories consistent with Lynch syndrome (Taylor 2003, Tournier 2008). Functional studies in vitro and in a yeast model report statistically significant reduced protein expression and reduced MMR repair activity compared to wild type (Ellison 2004, Hinrichsen 2013). MLH1 Gly101Asp 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 Glycine and Aspartic Acid differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MLH1 Gly101Asp occurs at a position that is highly conserved across species and is located in the ATPase domain, also published as the MLH domain (Pang 1997, Raevaara 2005, Hardt 2011). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on the current evidence, we consider MLH1 Gly101Asp to be a likely pathogenic variant.
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075624 SCV000106626 likely pathogenic Lynch syndrome I 2018-03-09 reviewed by expert panel curation Class 4 - Likely Pathogenic Classification using multifactorial probability: 0.968

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